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  • CLASSES

    Opioid Agonists

    BOXED WARNING

    Alcoholism, depression, substance abuse

    Morphine is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Use with caution in patients with a history of substance abuse or alcoholism; the use of morphine rectal suppositories is specifically contraindicated in patients with acute alcoholism or delirium tremens. Injectable morphine products have been associated with abuse and dependence among health care providers. Special measures to control the products within the hospital or clinic are recommended because of the limited indications, the overdosage risk, and the diversion/abuse risk. Specifically, rigid accounting, rigorous wastage control, and restricted access are recommended. Addiction may occur in patients who obtain morphine illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. The misuse of extended-release morphine products by crushing, chewing, snorting, or injecting the dissolved product will result in uncontrolled drug delivery which may produce fatal respiratory depression. To discourage abuse, the smallest appropriate quantity of morphine should be dispensed and proper disposal instructions for unused drug should be given to patients.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, coma, cor pulmonale, emphysema, hypoxemia, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    Morphine is contraindicated for use in patients with significant respiratory depression in unmonitored settings or in the absence of resuscitative equipment. Patients with significant respiratory depression in unmonitored settings should generally not receive injectable solution products due to the risk of fatal respiratory depression. Additionally, avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Monitor patients closely for signs or symptoms of respiratory depression or sedation. All formulations of morphine, with the exception of opium tincture oral solutions, are contraindicated in acute or severe bronchial asthma (i.e., status asthmaticus) in unmonitored settings or in the absence of resuscitative equipment. Receipt of moderate doses in these patients may significantly decrease pulmonary ventilation. Although opium tincture solutions are not specifically contraindicated in patients with pre-existing respiratory depression or hypoxia, therapeutic doses may decrease respiratory drive to the point of apnea. Use of morphine immediate-release tablets and oral solution is contraindicated in patients with hypercarbia, while use of injectable suspension (DepoDur) and solution (Duramorph) is contraindicated in patients with upper airway obstruction. Rapid IV administration may result in chest wall rigidity. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Only healthcare professionals who are knowledgeable of the use of opioids for the management of chronic pain should prescribe morphine extended-release capsules and tablets. These extended-release products should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use extended-release formulations for as-needed analgesics, for acute pain, or if the pain is mild or not expected to persist for an extended period of time. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly after therapy initiation or after a dose increase. Caution should be exercised when converting from a different opioid to morphine, as initial dose overestimation may lead to fatal overdose. In patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, emphysema, hypoxia, hypercapnia, respiratory insufficiency, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to morphine, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Significant decreases in respiratory drive may lead to adverse intracranial effects from carbon dioxide retention; therefore, it is recommended to avoid the use of morphine extended-release tablets and capsules during a coma or impaired consciousness. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with advanced age, debilitation, or sleep apnea are at an increased risk for the development of respiratory depression associated with morphine. Use morphine with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Respiratory depression or other adverse reactions may persist for a significant period of time after discontinuation of or overdosage of long-acting morphine preparations; patients require close monitoring until their respiratory rate has stabilized. Patients who receive the extended-release liposome injection (DepoDur) may need monitoring beyond 48 hours after a dose. An increased risk of respiratory depression may be present if the surgical procedure is canceled after DepoDur administration. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. A high level of vigilant monitoring is recommended.

    Ethanol ingestion, ethanol intoxication

    Improper use of various morphine dosage forms is associated with increased risks; advise patients accordingly. Also, instruct patients who will take extended-release capsules (e.g., Avinza or Kadian) to avoid ethanol ingestion and to not use any medication that contains alcohol; concurrent alcohol receipt may lead to rapid release and absorption of a potentially fatal morphine dose. Kadian and Avinza capsules are to be swallowed whole. Alternatively, the capsule contents may be sprinkled on applesauce and swallowed without chewing. The capsule or the pellets/beads in the capsule must not be chewed, crushed, or dissolved because of the risk of rapid release and absorption of a potentially fatal morphine dose. Similarly, instruct patients to swallow extended-release tablets whole. The tablets must not be chewed, crushed, or broken in half because of the risk of rapid release and absorption. Use of an opioid agonist while under the influence of other CNS depressants or ethanol intoxication will increase risk of CNS and respiratory depressant effects.

    Anticoagulant therapy, coagulopathy, infection, intramuscular administration, intrathecal administration, intravenous administration, requires a specialized care setting, requires an experienced clinician, subcutaneous administration

    Morphine sulfate extended-release liposome injection (DepoDur) is only for epidural infusion at the lumbar level. DepoDur is not intended for intravenous administration, intrathecal administration, intramuscular administration, or subcutaneous administration. If DepoDur is accidentally injected into the intrathecal space, profound and prolonged hypoventilation is expected. Prolonged and serious respiratory depression or apnea has occurred when administration of DepoDur was associated with subarachnoid puncture; respiratory depression occurred within 12 hours of DepoDur administration after apparent recovery from anesthesia. As intrathecal leakage from the epidural space may occur through a breached dural membrane, especially when the epidural drug is administered as a bolus, do NOT administer DepoDur to a patient after a recent dural puncture without vigilant monitoring of respiratory function for at least 48 hours. Observe all patients in a fully equipped and staffed environment for a minimum of 48 hours after administration. Immediate availability of emergency mechanical ventilation and opioid antagonists are also needed. Duramorph may be given epidurally, intrathecally, or intravenously; it is not for use in continuous microinfusion devices. Infumorph is only indicated for intrathecal or epidural administration; it is not for single-dose IV, IM, or subcutaneous administration due to the risk of overdose. Infumorph must also not be used for single-dose neuraxial injection because it is too concentrated for accurate delivery of the smaller doses used in this setting. Administration of morphine via neuraxial routes requires an experienced clinician familiar with administration techniques, proper dosing, and potential patient management problems that may occur with epidural or intrathecal administration. Since single-dose neuraxial administration may result in serious adverse reactions, including acute or delayed respiratory depression, administration requires a specialized care setting where patients can be observed for up to 24 hours following the initial dose, including the initial test dose of Infumorph. The facility must be in fully equipped to monitor patients and resuscitate any patient with severe opioid overdosage. Personnel must be familiar with the use of opioid antagonists. Continue to monitor patients receiving Infumorph during the first several days following catheter implantation. Epidural administration has been associated with less potential for immediate or late adverse reactions (e.g., respiratory depression) than intrathecal administration, and is preferable to the intrathecal route whenever possible. For safety concerns, limit Duramorph administration by the intrathecal or epidural routes to the lumbar area; thoracic administration has been shown to greatly increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg. Similarly, limit Infumorph administration by the intrathecal route to the lumbar area. Improper substitution of Infumorph (10 or 25 mg/mL) for Duramorph (0.5 or 1 mg/mL) is likely to result in serious overdosage. Parenteral administration of other opioids in patients receiving epidural or intrathecal morphine may result in overdosage. Use caution when morphine is also given intravenously; because of a delay in maximum CNS effects (30 minutes) with intravenous morphine, rapid administration may result in overdose. Several factors contraindicate the administration of morphine by the epidural or intrathecal routes. These factors include infection at the injection site, concomitant anticoagulant therapy, uncontrolled coagulopathy, or the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous.

    Accidental exposure, opioid-naive patients, potential for overdose or poisoning

    Although all forms of morphine have potential for overdose or poisoning, certain formulations are associated with specific risks. This includes morphine oral solutions due to possible concentration and/or dosing errors, long-acting and high-potency morphine products for the increased risk of life-threatening respiratory depression, and Avinza brand morphine for possible renal toxicity if the maximum dose is exceeded. Knowledge and care in product selection is advised. Serious adverse events and deaths have been reported in conjunction with accidental overdose of morphine 100 mg/5 mL oral solutions and other concentrations. Excessive doses may be a result of morphine oral solutions prescribed in milligrams and erroneously interchanged for milliliters of the product. Improper substitution of Infumorph injectable solution (10 mg/mL or 25 mg/mL) for Duramorph or Astramorph injectable solutions (0.5 mg/mL or 1 mg/mL) may cause serious overdosage. To reduce the risk of life-threatening adverse effects, several formulations of morphine are intended for opioid-tolerant patients only. Do not use the following in opioid-naive patients: 90 or 120 mg morphine biphasic-release capsules (Avinza); 100 or 200 mg morphine extended-release capsules (Kadian); 100 or 200 mg morphine extended-release tablets (MS Contin); 100 mg extended-release tablets (Morphabond); or 100 mg/5 mL morphine oral solution. Only use extended-release morphine (e.g., Arymo, Avinza, Kadian, MS Contin, and Morphabond) for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate; these formulations are not intended for as-needed analgesia. Limit the total daily dose of Avinza to a maximum of 1,600 mg/day; Avinza doses more than 1,600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe and may result in serious renal toxicity. Morphine should be kept out of the reach of pediatric patients and others for whom it was not prescribed, as accidental exposure may cause a fatal overdose.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects. Results for a population-based prospective cohort, including 448 women exposed to morphine at any time during pregnancy and 70 women exposed during the first trimester of pregnancy, indicate no increased risk for congenital malformations; however, risk cannot be excluded due to study methodological limitations. Neural tube defects (i.e., exencephaly and cranioschisis) have been noted when morphine was given subcutaneously to hamsters and mice at 5 and 16 times a human daily dose of 60 mg based on body surface area. Lower fetal body weight and increased abortion incidence were observed at 0.4 times the human daily dose in rabbits, growth retardation at 6 times the human daily dose in rats, and axial skeletal fusion and cryptorchidism at 16 times the human daily dose in mice. Doses of 3 to 4 times the human daily dose given during organogenesis and throughout lactation have produced cyanosis, hypothermia, decreased brain weight or body weight, adverse effects on reproductive tissues, and death in rats. Some long-term neurochemical changes in the brains of rat offspring which correlate with altered behavioral responses that persist through adulthood have been observed with exposures comparable to and less than the human daily dose. Some experts suggest increased risk if morphine is used for prolonged periods during pregnancy or at high doses near term. While certain formulations of morphine have been used in the obstetric setting, caution is advised under various circumstances during labor and obstetric delivery. Morphine sulfate extended-release liposome injection (DepoDur) should not be administered to women for vaginal labor and delivery; this formulation is only for pain associated with Caesarian section after delivery and clamping of the umbilical cord. Morphine sulfate extended-release tablets or capsules are not recommended for use during or immediately prior to labor. Morphine readily crosses the placenta and all other formulations should be used cautiously during pregnancy or obstetric delivery. An opioid antagonist and resuscitative equipment should be readily available. If used during the second stage of labor, the duration of labor can be prolonged by temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of long-acting opioids, such as morphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    DEA CLASS

    Rx, schedule II, schedule III

    DESCRIPTION

    Opiate agonist; alkaloid obtained from the unripened seed capsules of the opium poppy
    Used for the relief of moderate to severe acute and chronic pain, preoperative sedation and as a supplement to anesthesia
    Available in multiple formulations

    COMMON BRAND NAMES

    ARYMO ER, Astramorph PF, Avinza, DepoDur, Duramorph, Duramorph PF, Infumorph, Kadian, MORPHABOND, MS Contin, MSIR, Oramorph SR, RMS, Roxanol, Roxanol-T

    HOW SUPPLIED

    ARYMO ER/MORPHABOND/Morphine/Morphine Sulfate/MS Contin/Oramorph SR Oral Tab ER: 15mg, 30mg, 60mg, 100mg, 200mg
    Astramorph PF/Duramorph/Duramorph PF/Infumorph/Morphine/Morphine Sulfate Intramuscular Inj Sol: 0.5mg, 1mg, 1mL, 2mg, 4mg, 5mg, 8mg, 10mg, 15mg
    Astramorph PF/Duramorph/Duramorph PF/Infumorph/Morphine/Morphine Sulfate/Morphine Sulfate, Dextrose/Morphine, Dextrose Intravenous Inj Sol: 0.5mg, 1mg, 1mL, 2mg, 4mg, 5mg, 8mg, 10mg, 15mg, 25mg, 50mg, 1-5%
    Astramorph PF/Duramorph/Duramorph PF/Morphine/Morphine Sulfate Epidural Inj Sol: 0.5mg, 1mg, 1mL
    Astramorph PF/Duramorph/Duramorph PF/Morphine/Morphine Sulfate Intrathecal Inj Sol: 0.5mg, 1mg, 1mL
    Astramorph PF/Duramorph/Duramorph PF/Morphine/Morphine Sulfate Subcutaneous Inj Sol: 0.5mg, 1mg, 1mL, 2mg, 4mg, 8mg, 15mg
    Avinza/Kadian/Morphine/Morphine Sulfate Oral Cap ER: 10mg, 20mg, 30mg, 40mg, 45mg, 50mg, 60mg, 75mg, 80mg, 90mg, 100mg, 120mg, 200mg
    DepoDur Epidural Inj Lipos: 1mL, 1.5mL, 10mg, 15mg
    Infumorph Intraspinal Inj Sol: 1mL, 10mg, 25mg
    Morphine, Anhydrous Oral Liq: 2mg, 5mL
    Morphine, Anhydrous Oral Tincture: 1mL, 10mg
    Morphine/Morphine Sulfate/MSIR Oral Tab: 15mg, 30mg
    Morphine/Morphine Sulfate/MSIR/Roxanol/Roxanol-T Oral Sol: 1mL, 5mL, 10mg, 20mg, 100mg
    Morphine/Morphine Sulfate/RMS Rectal Supp: 5mg, 10mg, 20mg, 30mg

    DOSAGE & INDICATIONS

    For the relief of acute and chronic moderate pain or severe pain.
    NOTE: There is substantial interpatient variability in the relative potency of different opioid drugs and products. FDA-approved labeling defines adult opioid-tolerant patients as those who take the following per day for a minimum of 1 week: oral morphine 60 mg or more; oral oxycodone 30 mg or more; oral hydromorphone 8 mg or more; oral oxymorphone 25 mg or more; 60 mg oral hydrocodone or more; transdermal fentanyl 25 mcg or more per hour; or another opioid at an equivalent dose.
    For acute moderate to severe pain related to major orthopedic surgery of the lower extremity.
    Epidural dosage (morphine sulfate extended-release liposome injection (DepoDur) ONLY)
    Adults

    15 mg epidurally as a single-dose. Some patients may benefit from 20 mg, but the risk for serious respiratory depression appears to be dose-related. In clinical trials, the drug was given 30 minutes before surgery.

    For acute moderate to severe pain related to lower abdominal or pelvic surgery.
    Epidural dosage (morphine sulfate extended-release liposome injection (DepoDur) ONLY)
    Adults

    10 to 15 mg epidurally as a single-dose. Some patients may benefit from 20 mg, but the risk for serious respiratory depression appears to be dose-related. In clinical trials, the drug was given 30 minutes before surgery.

    For acute moderate to severe pain related to cesarean section after delivery and clamping of the umbilical cord.
    Epidural dosage (morphine sulfate extended-release liposome injection (DepoDur) ONLY)
    Adults

    10 mg epidurally as a single-dose. As compared with morphine sulfate injection, receipt of either 10 mg or 15 mg of morphine sulfate extended-release liposome injection (DepoDur) after Cesarean delivery resulted in less rescue analgesic use and reported pain over 48 hours as compared with 5 mg of morphine sulfate injection given epidurally.

    For the management of chronic severe pain in patients who require daily, around-the-clock, long-term opioid treatment.
    NOTE: Reserve extended-release morphine for when alternative options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would otherwise provide inadequate pain management. Discontinue all other around-the-clock opioids upon initiation.
    NOTE: Do not use the following morphine products in opioid-naive patients: 60 mg, 90 mg, or 120 mg biphasic-release capsules (Avinza); 100 mg, 130 mg, 150 mg, or 200 mg extended-release capsules (Kadian); 100 mg or 200 mg controlled-release tablets (MS Contin); 100 mg extended-release tablets (Morphabond). In this population, use could result in fatal respiratory depression. Use of a single dose of more than 60 mg, or a total daily dose more than 120 mg, should be limited to opioid-tolerant patients.
    NOTE: There is substantial interpatient variability in the relative potency of different opioid drugs and products. FDA-approved labeling defines adult opioid-tolerant patients as those who take the following per day for a minimum of 1 week: oral morphine 60 mg or more; oral oxycodone 30 mg or more; oral hydromorphone 8 mg or more; oral oxymorphone 25 mg or more; oral hydrocodone 60 mg or more; transdermal fentanyl 25 mcg or more per hour; or another opioid at an equivalent dose.
    Oral dosage [extended-release tablets (Arymo ER, Morphabond, MS Contin) or capsules (Kadian, Avinza)] in opioid non-tolerant adult patients
    Adults

    For use as the first opioid analgesic, 15 mg PO every 8 or 12 hours (MS Contin or Arymo ER), 15 mg PO every 12 hours (Morphabond), or 30 mg PO every 24 hours (Avinza). Do not use Kadian capsules as a first opioid analgesic; initiate with an immediate-release formulation and then convert patients to Kadian. For opioid non-tolerant patients, initiate with 15 mg PO every 12 hours (MS Contin or Morphabond), 15 mg PO every 8 or 12 hours (Arymo ER), or 30 mg PO every 24 hours (Avinza or Kadian). With the exception of Avinza, adjust the dose every 1 to 2 days based upon the total daily morphine requirements (extended-release dose plus breakthrough doses). Adjust the dose of Avinza every 3 to 4 days in increments of 30 mg or less. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. To discontinue, gradually decrease the dose by 25% to 50% every 2 to 4 days to prevent withdrawal.  

    Oral dosage [extended-release tablets (Arymo ER, Morphabond, MS Contin) or capsules (Kadian, Avinza)] in adult patients receiving other opioid agonist therapy
    Adults

    Discontinue all other around-the-clock opioids. To convert from other morphine formulations, calculate the morphine 24-hour oral requirement; in general, the 24-hour oral requirement is 3 times the 24-hour parenteral requirement. Initiate dosing, using the 24-hour oral requirement (round down to the closest available tablet/capsule strength), for: MS Contin or Arymo ER at one-half of the requirement every 12 hours or one-third every 8 hours; Morphabond at one-half every 12 hours; Avinza at the total requirement once every 24 hours; and Kadian at one-half every 12 hours or the total once every 24 hours. When initiating extended-release morphine, anticipate and treat breakthrough pain with adequate doses of immediate-release morphine as needed. When converting from other opioids, established conversion ratios to extended-release formulations have not been defined by clinical trials. Initiate dosing for: MS Contin or Arymo ER at 15 mg PO every 8 or 12 hours; Morphabond at 15 mg PO every 12 hours; and Avinza or Kadian at 30 mg PO every 24 hours. Alternatively, initiate with one-half of the calculated morphine 24-hour oral requirement estimate, anticipating breakthrough pain and providing adequate doses of immediate-release morphine as needed. When converting from methadone, potency ratios to convert to other opioids can vary widely, warranting extreme caution during conversion to extended-release morphine to avoid overdosage. With the exception of Avinza, adjust dosage every 1 to 2 days based on total daily morphine requirements (extended-release dose plus breakthrough doses). Adjust Avinza dose every 3 to 4 days. Monitor frequently for respiratory depression, especially 24 to 72 hours after initiation or dose escalation. To discontinue, taper the dose by 25% to 50% every 2 to 4 days.

    Oral dosage [extended-release tablets (MS Contin)] in pediatric patients
    Children† and Adolescents†

    Although FDA-approved product labeling provides adult dosing for both opioid-naive and opioid-tolerant patients, it would be prudent to limit pediatric use to opioid-tolerant patients. Limited data are available, and there is wide variability in dosage needs. Doses of 0.2 to 2.3 mg/kg/dose PO every 12 hours have been used in patients with various types of cancer and sickle cell disease. Begin at the lower end of the dosage range, and titrate to pain relief. Do not exceed recommended adult doses; the initial adult dosage recommendation is 15 mg PO every 8 to 12 hours, with the longer interval used in opioid-naive patients. Many experts recommend beginning with an immediate-release product to titrate to an appropriate daily dose and then switch to an extended-release formulation and divide the patient's total daily dose into 2 or 3 equal doses. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. Extended-release morphine should not be used for as needed analgesia and is only appropriate for a select group of children; only clinicians highly experienced in pediatric pain management should prescribe extended-release formulations.

    Oral dosage (regular-release formulations)
    Adults

    Initially, 10 to 30 mg PO every 4 hours as needed in opioid-naive patients. Geriatric or debilitated patients may require a lower dose and/or extended dosing interval. Titrate to pain relief. Only use the concentrated oral morphine solution (20 mg/mL) in opioid-tolerant patients. When converting parenteral to oral morphine, an oral dose that is 3 times the parenteral dose is generally sufficient. When converting from extended-release morphine, give the same 24-hour total as a divided regimen given at appropriate intervals. When converting from other oral or parenteral opioids, calculate the 24-hour total dose of the current opioid and consult published relative potency information for conversion. Monitor for sedation and respiratory depression, particularly when therapy is initiated or dosage changes occur. To discontinue, gradually taper the dose to prevent signs and symptoms of withdrawal.

    Infants†, Children†, and Adolescents† ages 6 months to 17 years

    Initially, 0.2 to 0.3 mg/kg/dose PO every 3 to 6 hours as needed. Do not exceed an initial dose of 5 mg/dose PO for children or the adult initial dose of 10 mg/dose PO for larger adolescents. Titrate to pain relief.

    Intermittent Intravenous, Intramuscular, or Subcutaneous dosage
    Adults

    Initially, 2 to 10 mg/70 kg IV, IM, or subcutaneously every 3 to 4 hours as needed, titrated to pain relief. Higher doses (10 mg) are recommended for IM or subcutaneous administration; dosage may range from 5 to 20 mg IM or subcutaneously every 4 hours depending on patient requirements and response. Geriatric or debilitated patients may require lower dosages and/or extended dosing intervals.

    Infants 6 months and older, Children, and Adolescents

    0.05 to 0.2 mg/kg/dose IV, IM, or subcutaneously every 2 to 4 hours as needed; begin at the lower end of dosage range and titrate to effect (usual Max dose: 4 mg for children or 8 mg for adolescents; however, dose must be individualized).

    Neonates† and Infants younger than 6 months

    Initially, 0.03 to 0.1 mg/kg/dose IV, IM, or subcutaneously every 3 to 4 hours as needed. Titrate dosage upward as needed for adequate pain relief.

    Continuous Intravenous Infusion dosage†

    NOTE: Continuous infusions should only be used in acute care settings (e.g., intensive care units) where trained personnel are continuously monitoring the patient and emergency medications and equipment are readily available.

    Adults

    Administer a loading dose by slow IV infusion at a rate of 2 mg/minute. Loading doses of 15 to 20 mg may be required for adequate analgesia; higher doses may be needed in opioid-tolerant patients. Initial infusion rates of 2 to 5 mg/hour have been used, with usual rates of 2 to 30 mg/hour used in critically ill patients. Higher infusion rates may be required in opioid-tolerant patients. Titrate dose to pain relief.

    Infants, Children, and Adolescents

    A bolus of 0.05 to 0.2 mg/kg IV (or 5 to 10 mg IV for patients weighing more than 60 kg) followed by a continuous infusion. Initial infusion rates of 0.01 to 0.03 mg/kg/hour are common, though up to 0.06 mg/kg/hour may be appropriate for some patients. Patients weighing more than 60 kg can alternatively receive rates of 0.8 to 3 mg/hour. Higher maintenance infusion rates up to 0.2 mg/kg/hour have been used in patients with sickle cell disease. Titrate to pain relief.

    Neonates

    0.01 to 0.02 mg/kg/hour IV and titrate to effect. May increase up to 0.03 mg/kg/hour if needed.

    Continuous Subcutaneous Infusion dosage†
    Adults

    Initial infusion rates of 2 to 5 mg/hour subcutaneously may be used, with usual rates of 2 to 30 mg/hour subcutaneously used in critically ill patients. Morphine's dose conversion ratio is 1 mg subcutaneous = 1 mg IV. Higher infusion rates may be required in opioid-tolerant patients. Titrate dose to pain relief. Subcutaneous tissue can absorb up to 3 mL/hour.

    Infants, Children, and Adolescents

    An initial infusion rate of 0.03 mg/kg/hour subcutaneously has been recommended, though an initial dose of 0.01 mg/kg/hour is also reasonable. The mean infusion rate was 0.0175 mg/kg/hour over the first 24 hours after surgery, and decreased to 0.011 to 0.0133 mg/kg/hour over the next 48 hours in 60 patients (7 months to 20 years of age). Higher infusion rates, ranging from 0.025 to 1.79 mg/kg/hour (median: 0.06 mg/kg/hour), were used in 17 patients (22 months thru 22 years) with terminal cancer. Titrate dose to pain relief.

    Intravenous dosage (Patient Controlled Analgesia (PCA))
    Adults

    The starting dose should be based on the patient's recent exposure to opioids. Titrate the regimen to patient response. Larger doses may be needed in opioid-tolerant patients. For OPIOID NAIVE patients, start with a demand dose of 1 mg (range: 0.5 to 2.5 mg) IV and lockout interval of 6 minutes (range: 5 to 10 minutes), with a maximal dosing rate of 10 mg/hour. For OPIOID TOLERANT patients, start with a demand dose of 2 to 5 mg IV and lockout interval of 6 minutes (range: 5 to 10 minutes), with a maximal dosing rate of 30 mg/hour.

    Children 7 years and older and Adolescents

    Various regimens have been reported. Titrate regimen to patient response. Initiate with a demand dose of 0.01 to 0.025 mg/kg (Max: 1 mg/dose) IV, a lockout interval of 5 to 10 minutes, 5 total doses per hour, an optional basal rate of 0.004 to 0.015 mg/kg/hour IV, and an optional 4-hour limit of 0.24 to 0.375 mg/kg.

    Epidural dosage (morphine sulfate injection, but NOT DepoDur)
    Adults

    Initially, inject 5 mg epidurally in the lumbar region and assess the patient in 1 hour; if pain relief is not adequate at that time, administer incremental doses of 1 to 2 mg, with sufficient time between injections to appropriately assess for efficacy. The manufacturer recommends a maximum of 10 mg per 24 hours. For continuous epidural infusion, initiate at 2 to 4 mg per 24 hours, with additional doses of 1 to 2 mg given if pain relief is not initially achieved. The incidence of early and late respiratory depression is dramatically increased with thoracic administration. Use preservative-free formulations only.

    Infants†, Children†, and Adolescents†

    Various regimens have been reported including single preoperative and postoperative doses of 0.03 to 0.1 mg/kg epidurally, postoperative doses of 0.02 to 0.03 mg/kg/dose epidurally every 8 hours, and postoperative continuous infusions of 0.004 to 0.01 mg/kg/hour. Use preservative-free formulations only.

    Intrathecal dosage (morphine sulfate injection, but NOT DepoDur)
    Adults

    0.2 to 1 mg in the lumbar area as a single dose or to establish dosage for continuous intrathecal infusion; repeated injections are not recommended. Intrathecal doses more than 20 mg/day increase the development of tolerance and serious toxicity including myoclonic spasms. Intrathecal dosage is usually one-tenth the epidural dosage. Use preservative-free formulations only.

    Infants†, Children†, and Adolescents†

    Single preoperative doses of 0.002 to 0.02 mg/kg intrathecally have been reported. Use preservative free formulations only.

    Rectal dosage
    Adults

    10 to 20 mg rectally every 4 hours, as needed.

    Infants†, Children†, and Adolescents†

    0.2 mg/kg/dose rectally every 4 hours or 0.3 mg/kg/dose rectally every 6 hours as needed have been recommended. Do not exceed the usual adult dose of 10 to 20 mg/dose.

    For the treatment of diarrhea.
    For the treatment of noninfectious diarrhea.
    WARNING: Proper product selection is critical. Deodorized opium tincture 10 mg/mL solution is 25 times more concentrated than camphorated opium tincture 0.4 mg/mL solution. Serious patient harm may occur with incorrect product selection.
    Oral dosage (Deodorized Opium Tincture Solution 10 mg/mL concentration ONLY)
    Adults

    6 mg PO 4 times daily. When using deodorized opium tincture 10 mg/mL, 6 mg = 0.6 mL. Use caution in geriatric patients due to the potential for adverse CNS effects; and consider alternative drugs for treatment.

    Oral dosage (Camphorated Opium Tincture Solution [Paregoric, USP; contains 0.4 mg/mL anhydrous morphine])
    Adults

    2 to 4 mg PO 1 to 4 times daily. NOTE: Dosage is expressed in mg/kg dosing units of morphine. When using opium tincture 2 mg/5 mL concentration (Paregoric, USP), 2 to 4 mg = 5 to 10 mL. Use caution in geriatric patients due to the potential for adverse CNS effects; consider alternative drugs for treatment.

    Adolescents and Children

    0.1 to 0.2 mg/kg/dose PO 1 to 4 times daily (Maximum: 4 mg/dose). NOTE: Dosage is expressed in mg/kg dosing units of morphine. When using opium tincture 2 mg/5 mL concentration (Paregoric, USP), 0.1 to 0.2 mg/kg = 0.25 to 0.5 mL/kg.

    For control of diarrhea† secondary to AIDS-associated enteropathy.
    Oral dosage
    Adults

    Although no published studies exist on the effectiveness of nonspecific antimotility agents in treating AIDS-associated diarrhea, opioid agonists may be effective. Morphine doses of 10 to 30 mg/day PO have been recommended.

    For the management of dyspnea†.
    In patients with end-stage cancer or pulmonary disease†.
    Intravenous dosage
    Adults

    1 to 5 mg IV at frequent intervals (as often as every 5 minutes) until the desired response is achieved. Doses are given in addition to other opiate pain medications. In terminal patients with persistent dyspnea, 25% of the equivalent 4-hour dose of morphine may be sufficient to reduce both dyspnea and tachypnea for 4 hours.

    Oral inhalation dosage (nebulized intravenous solution for injection)†
    Adults

    Reported doses include 20 mg in 5 mL saline via nebulizer every 4 hours.

    For the adjuvant treatment of acute pulmonary edema†.
    Intravenous dosage
    Adults

    1 to 3 mg IV at frequent intervals (as often as every 5 minutes) until the desired response is achieved, or, a dose sufficient to provide relief without producing respiratory depression.

    For acute myocardial infarction† or unstable angina† and to provide potentially beneficial cardiovascular effects.
    Intravenous dosage
    Adults

    Initially, 2 to 5 mg IV every 5 to 30 minutes as needed for pain; some patients may require maintenance doses of 4 to 8 mg IV every 4 to 6 hours.

    For procedural sedation† before short diagnostic procedures or endoscopy.
    NOTE: Morphine should be administered as an inducing agent only by those trained in anesthesia.
    Intravenous dosage
    Adults

    2 mg IV. Premedication with a benzodiazepine may potentiate the response to morphine; a reduced morphine dose may be needed.

    For sedation during rapid-sequence intubation†.
    Intravenous dosage
    Adolescents, Children, and Infants

    0.1 to 0.2 mg/kg IV has been recommended. Onset of action is typically 2 to 5 minutes.

    Neonates

    0.05 to 0.2 mg/kg IV has been recommended. Use the lower end of the range for opioid-naive neonates. Onset is typically 5 minutes. Use a preservative-free formulation.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage (extended-release formulations)
    Adults

    30 mg PO twice daily initially using extended-release tablets (e.g., MS Contin). Use an initial dosage of 15 mg PO twice daily in those who are not opioid tolerant, and consider this lower dose in geriatric patients or those weighing less than 60 kg. For Kadian, Avinza, and equivalent generic dose forms that may be given once daily, the highest starting dose for patients who are not opioid tolerant is 30 mg PO every 24 hours [Kadian is administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours); Avinza is administered at a frequency of once daily (every 24 hours)]. Titrate as tolerated to a maximum dosage of 120 mg/day PO. In one clinical trial, the maximum dosage in patients less than 60 years of age or weighing less than 60 kg was 60 mg/day PO. Clinical practice guidelines classify morphine as probably effective for the treatment of painful diabetic neuropathy.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Immediate-release formulations, extended-release tablets, extended-release capsules (Kadian ONLY), injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release capsules (Avinza ONLY): 1600 mg/day PO due to the high concentrations of fumaric acid in the formulation.
    DepoDur liposome injection: 15 mg/dose epidurally.
    Deodorized opium tincture (10 mg/mL concentration ONLY): 6 mg/dose PO and 24 mg/day PO total.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): 4 mg/dose PO and 16 mg/day PO total.

    Geriatric

    Immediate-release formulations, extended-release tablets, extended-release capsules (Kadian ONLY), injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release capsules (Avinza ONLY): 1600 mg/day PO due to the high concentrations of fumaric acid in the formulation.
    DepoDur liposome injection: 15 mg/dose epidurally.
    Deodorized opium tincture (10 mg/mL concentration ONLY): 6 mg/dose PO and 24 mg/day PO total.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): 4 mg/dose PO and 16 mg/day PO total.

    Adolescents

    Immediate-release formulations, extended-release tablets (MS Contin ONLY), injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release capsules, extended-release tablets (Arymo ER or Morphabond), DepoDur liposome injection: Safety and efficacy have not been established.
    Deodorized opium tincture (10 mg/mL concentration ONLY): Safety and efficacy have not been established.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): 0.2 mg/kg/dose PO (Max: 4 mg/dose) and 0.8 mg/kg/day PO (Max: 16 mg/day).

    Children

    Immediate-release formulations, extended-release tablets (MS Contin ONLY), injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release capsules, extended-release tablets (Arymo ER or Morphabond), DepoDur liposome injection: Safety and efficacy have not been established.
    Deodorized opium tincture (10 mg/mL concentration ONLY): Safety and efficacy have not been established.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): 0.2 mg/kg/dose PO (Max: 4 mg/dose) and 0.8 mg/kg/day PO (Max: 16 mg/day).

    Infants

    Immediate-release formulations, injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release formulations, DepoDur liposome injection: Safety and efficacy have not been established.
    Deodorized opium tincture (10 mg/mL concentration ONLY): Safety and efficacy have not been established.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): Safety and efficacy have not been established.

    Neonates

    Immediate-release formulations, injectable solution (NOT DepoDur): With appropriate dosage titration, there is no maximum dose.
    Extended-release formulations, DepoDur liposome injection: Safety and efficacy have not been established.
    Deodorized opium tincture (10 mg/mL concentration ONLY): Safety and efficacy have not been established.
    Camphorated opium tincture (0.4 mg/mL concentration ONLY): Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    With the exception of morphine sulfate extended-release liposome injection, which is only used as a single epidural dose, morphine dosage should be modified depending on clinical response and degree of hepatic impairment. Begin treatment with a lower than usual initial dosage, and titrate slowly while monitoring for sedation, respiratory depression, and hypotension.

    Renal Impairment

    The 6-glucuronide and 3-glucuronide metabolites are renally eliminated. With the exception of morphine sulfate extended-release liposome injection, which is only used as a single epidural dose, morphine dosage should be modified to prevent accumulation of the metabolite and excessive side effects. Begin treatment with a lower than usual initial dosage, and titrate slowly while monitoring for sedation, respiratory depression, and hypotension.

    ADMINISTRATION

     
    NOTE: If Duramorph or Infumorph gets on the skin, remove any contaminated clothing and rinse the affected area with water.

    Oral Administration

    When initiating therapy, begin with an immediate-release preparation and titrate to the appropriate analgesic dose and then convert the patient to an extended-release product if appropriate.

    Oral Solid Formulations

    Immediate-release tablets
    Administer without regard to meals; may be given with food or milk to minimize gastrointestinal irritation.
     
    Immediate-release capsules
    May be swallowed whole, or opened and the contents sprinkled on cool food such as pudding or applesauce.
    Capsule contents may be added to juice and administered immediately or delivered via gastric or nasogastric tube by either adding to or following with liquid.
     
    Extended-release tablets (e.g., Arymo ER, MS Contin, or Morphabond)
    Swallow whole; do not cut, crush, break, dissolve, or chew due to the risk of rapid release of a potentially fatal dose of morphine. Swallow Arymo tablets one at a time immediately after placing in the mouth. Do not pre-soak, lick, or otherwise wet Arymo tablets prior to placing in the mouth; the tablet may become sticky leading to difficulty in swallowing, choking, gagging, or regurgitation.
    The use of MS Contin 100 mg or 200 mg tablets or Morphabond 100 mg tablets should be limited to opioid tolerant patients. Use of a single dose of extended-release tablets more than 60 mg, or a total daily dose more than 120 mg, should be limited to opioid-tolerant patients.
     
    Extended-release capsules (e.g., Avinza or Kadian)
    Capsules should be swallowed; do not chew, crush, or dissolve.
    Capsules may be opened and the contents sprinkled on applesauce (at room temperature or cooler) immediately prior to ingestion; no other food has been tested. Do not chew, crush, or dissolve the pellets/beads inside the capsule. The applesauce needs to be swallowed without chewing. If the pellets/beads are chewed, an immediate release of a potentially fatal morphine dose may be delivered. Rinse mouth to ensure all the pellets/beads have been swallowed. Do not separate applesauce into separate doses; the entire portion should be taken. Discard any unused portion of the capsules after the contents have been sprinkled on the applesauce.
    Kadian capsules may be administered through a 16 French gastrostomy tube. Flush the tube with water, and sprinkle the capsule contents into 10 mL of water. Using a funnel and a swirling motion, pour the pellets and water into the tube. Rinse the beaker with 10 mL of water, and pour the water into the funnel. Repeat until no pellets remain in the beaker. Do not administer Avinza tablets through a gastrostomy tube. Do not administer Avinza or Kadian through a nasogastric tube.
    Avoid concurrent administration of Avinza or Kadian with prescription or non-prescription medications that contain alcohol. Consumption of alcohol while taking the extended-release capsules may result in the rapid release and absorption of a potentially fatal dose of morphine.
    The use of Avinza 90 mg or 120 mg capsules or Kadian 100 mg or 200 mg capsules should be limited to opioid tolerant patients. Use of a single dose of extended-release capsules more than 60 mg, or a total daily dose more than 120 mg, should be limited to opioid-tolerant patients.

    Oral Liquid Formulations

    Oral solution
    Carefully check dose prior to dispensing medication as many concentrations of morphine oral solution are available.
    May be diluted in fruit juice prior to administration.
    Protect from light.
     
    Opium tincture (10 mg/mL or 0.4 mg/mL formulations)
    Dispense in unit dose packaging.
    Serious overdosage may result if product selection is improper. Place poison labels on all containers of opium tincture as well as label the strength of morphine per mL. Include a warning regarding improper substitution of the 2 products.
    Shake well before using.
    Camphorated opium tincture (0.4 mg/mL) should be protected from light and excessive heat. The product may deposit a sediment if exposed to low temperatures. Filter if necessary.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Unopened solutions should be discarded if a precipitate is present that does not disappear with shaking. Do not use the Duramorph solution if a precipitate is present or if the color is darker than pale yellow.

    Intravenous Administration

    Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available.
    Do not use the highly concentrated morphine injections (i.e., 10 to 25 mg/mL) for IV, IM, or subcutaneous administration of single doses. These injection solutions are intended for use via continuous, controlled-microinfusion devices.
     
    Direct IV injection
    Dilute appropriate dose with at least 5 mL of Sterile Water for Injection or 0.9% Sodium Chloride Injection.
    Inject 2.5 to 15 mg directly into a vein or into the tubing of a freely flowing IV solution over 4 to 5 minutes. Rapid IV injection of morphine may result in an increased frequency of adverse effects. For example, the maximum CNS effects occur 30 minutes after administration. Rapid intravenous administration could result in an overdose.
     
    Continuous IV infusion
    Dilute in 5% Dextrose Injection.
    Administer using a controlled-infusion device.
    Adjust dose and rate based on patient response.
     
    Patient-controlled analgesia (PCA)
    A compatible patient-controlled infusion device must be used.
    Dilute solutions to obtain morphine concentration of 1 or 10 mg/mL for ease in calculations and programming of PCA pumps.
    Adjust dose and rate based on patient response. Consult the patient-controlled infusion device operator's manual for directions on administering the drug at the desired rate of infusion.

    Subcutaneous Administration

    Inject subcutaneously taking care not to inject intradermally.
     
    Continuous subcutaneous infusion
    Morphine is not approved by the FDA for subcutaneous administration.
    Dilute to an appropriate concentration in 5% Dextrose Injection and administer using a portable, controlled, subcutaneous infusion device. Adjust rate based on patient response and tolerance.
    Maximum subcutaneous rate of infusion is 2 mL/hour/site.

    Intrathecal Administration

    NOTE: Intrathecal dose is approximately one-tenth the epidural dose.
    NOTE: Morphine sulfate injection is not interchangeable with morphine sulfate extended-release liposome injection (DepoDur). DepoDur is only for epidural administration.
    NOTE: Do not use Infumorph (10 mg/mL or 25 mg/mL) for single-dose neuraxial injection because lower doses can be more reliably administered with Duramorph (0.5 mg/mL or 1 mg/mL).
    Epidural or intrathecal administration should only be used by specially trained healthcare professionals.
    May be given as intermittent bolus, continuous infusion, or as patient controlled epidural analgesia. Infumorph is only indicated for intrathecal or epidural infusion; Infumorph is not recommended for single-dose intravenous, intramuscular, or subcutaneous administration because of the very large amount of morphine in the ampul and the associated overdosage risk.
    Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible. Immediate availability of naloxone injection and resuscitative equipment is also needed during Infumorph reservoir refilling or reservoir manipulation.
    Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. For example, for thoracic surgery placement at T2 to T8, upper abdominal surgery, T4 to L1, lower abdominal surgery, T10 to L3, upper extremity surgery, C2 to C8 and lower extremity surgery, T12 to L3.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Unopened Infumorph solution should be discarded if a precipitate is present that does not disappear with shaking or if it is not colorless or pale yellow. Do not use the Duramorph solution if a precipitate is present or if the color is darker than pale yellow. 
     
    Intrathecal injection (morphine sulfate injection)
    No more than 2 or 1 mL of the injection containing 0.5 or 1 mg/mL, respectively, should be injected intrathecally.
    After ensuring proper placement of the needle or catheter, inject appropriate dose intrathecally. Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose, as severe respiratory depression may occur up to 24 hours after drug administration. Repeated intrathecal injections are not recommended other than for establishing initial intrathecal dosage for continuous intrathecal infusion.
     
    Continuous intrathecal infusion (morphine sulfate injection)
    NOTE: Intrathecal dose is approximately one-tenth the epidural dose. Epidural dose is usually considered to be one-tenth the IV dose.
    A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored in a fully equipped and staffed environment for several days after implantation of the device.
    If dilution of the injection is necessary, 0.9% Sodium Chloride Injection is recommended.
    Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5 micron (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdosage.
    To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.

    Other Injectable Administration

    Epidural Administration
    NOTE: Intrathecal dose is approximately one-tenth the epidural dose. Epidural dose is usually considered to be one-tenth the IV dose.
    NOTE: Morphine sulfate injection is not interchangeable with morphine sulfate extended-release liposome injection (DepoDur). DepoDur is only for epidural administration.
    NOTE: Do not use Infumorph (10 mg/mL or 25 mg/mL) for single-dose neuraxial injection because lower doses can be more reliably administered with Duramorph (0.5 mg/mL or 1 mg/mL).
    Epidural administration should only be used by specially trained healthcare professionals.
    May be given as intermittent bolus, continuous infusion, or as patient controlled epidural analgesia. Infumorph is only indicated for intrathecal or epidural infusion; Infumorph is not recommended for single-dose intravenous, intramuscular, or subcutaneous administration because of the very large amount of morphine in the ampul and the associated overdosage risk.
    Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible. Immediate availability of naloxone injection and resuscitative equipment is also needed during Infumorph reservoir refilling or reservoir manipulation.
    Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. For example, for thoracic surgery placement at T2 to T8, upper abdominal surgery, T4 to L1, lower abdominal surgery, T10 to L3, upper extremity surgery, C2 to C8 and lower extremity surgery, T12 to L3.
     
    Epidural injection (morphine sulfate injection)
    After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space. Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose, as severe respiratory depression may occur up to 24 hours after drug administration. 
     
    Continuous epidural infusion (morphine sulfate injection)
    NOTE: Intrathecal dose is approximately one-tenth the epidural dose. Epidural dose is usually considered to be one-tenth the IV dose.
    A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored in a fully equipped and staffed environment for several days after implantation of the device.
    If dilution of the injection is necessary, 0.9% Sodium Chloride Injection is recommended.
    Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5 micron (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdosage.
    To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.
     
    Epidural Administration (morphine sulfate extended-release liposome injection (DepoDur) ONLY)
    NOTE: Morphine sulfate extended-release liposome injection (DepoDur) is not interchangeable with other morphine sulfate injections.
    DepoDur is only for epidural administration. Do not administer by any other parenteral route.
    Epidural administration should only be used by specially trained healthcare professionals.
    Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible. Monitor patient in a fully equipped and staffed environment for at least 48 hours after each dose, as severe respiratory depression may occur.
    Invert the vial to resuspend particles immediately before withdrawal.
    Storage: Administer DepoDur within 4 hours after withdrawal from the vial when kept at controlled room temperature 59 to 86 degrees F (15 to 30 degrees C). The product does not contain any bacteriostatic agents or preservatives. Do not heat- or gas- sterilize.
     
    Epidural injection (morphine sulfate extended-release liposome injection (DepoDur)
    Placement of epidural needle or catheter and administration should be at the lumbar level. Due to lack of study data, administration of DepoDur at the thoracic level or higher is not recommended.
    Determine proper needle or catheter placement by aspiration to check for blood or cerebrospinal fluid and/or by administration of a test dose of 3 mL of 1.5% preservative-free lidocaine and epinephrine 1:200,000 (0.005 mg/mL). If tachycardia or sudden onset of segmental anesthesia occurs, the needle or catheter is in the intrathecal space and thus, needs to be repositioned. If a test dose is given, flush the catheter with 1 mL of preservative-free 0.9% Sodium Chloride Injection and wait at least 15 minutes after test dose administration before administration of DepoDur.
    Inject DepoDur at the lumbar level undiluted or diluted up to 5 mL total volume with preservative-free 0.9% Sodium Chloride Injection. During administration, do not use an in-line filter or mix DepoDur with any medication. Additionally, do not administer any medication into the epidural space within 48 hours of DepoDur receipt.

    Rectal Administration

    Instruct patient on proper use of suppository.
    Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ARYMO ER:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Astramorph PF:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Avinza:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    DepoDur:
    - Discard product that has been stored at room temperature for over 30 days
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Duramorph:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Duramorph PF:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Infumorph:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Kadian:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    MORPHABOND:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    MS Contin:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    MSIR:
    - Store at room temperature (between 59 to 86 degrees F)
    Oramorph SR:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    RMS:
    - Store below 77 degrees F
    Roxanol:
    - Store at room temperature (between 59 to 86 degrees F)
    Roxanol-T:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, use is contraindicated in patients with a history of hypersensitivity reactions to morphine. Further, do not use other opioid agonists of the phenanthrene subclass including oxycodone, codeine, and hydromorphone in such patients. It may be possible to treat these patients with an opioid agonist from the phenylpiperidine subclass (meperidine or fentanyl) or the diphenylheptane subclass (methadone).

    Alcoholism, depression, substance abuse

    Morphine is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Use with caution in patients with a history of substance abuse or alcoholism; the use of morphine rectal suppositories is specifically contraindicated in patients with acute alcoholism or delirium tremens. Injectable morphine products have been associated with abuse and dependence among health care providers. Special measures to control the products within the hospital or clinic are recommended because of the limited indications, the overdosage risk, and the diversion/abuse risk. Specifically, rigid accounting, rigorous wastage control, and restricted access are recommended. Addiction may occur in patients who obtain morphine illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. The misuse of extended-release morphine products by crushing, chewing, snorting, or injecting the dissolved product will result in uncontrolled drug delivery which may produce fatal respiratory depression. To discourage abuse, the smallest appropriate quantity of morphine should be dispensed and proper disposal instructions for unused drug should be given to patients.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, coma, cor pulmonale, emphysema, hypoxemia, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    Morphine is contraindicated for use in patients with significant respiratory depression in unmonitored settings or in the absence of resuscitative equipment. Patients with significant respiratory depression in unmonitored settings should generally not receive injectable solution products due to the risk of fatal respiratory depression. Additionally, avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Monitor patients closely for signs or symptoms of respiratory depression or sedation. All formulations of morphine, with the exception of opium tincture oral solutions, are contraindicated in acute or severe bronchial asthma (i.e., status asthmaticus) in unmonitored settings or in the absence of resuscitative equipment. Receipt of moderate doses in these patients may significantly decrease pulmonary ventilation. Although opium tincture solutions are not specifically contraindicated in patients with pre-existing respiratory depression or hypoxia, therapeutic doses may decrease respiratory drive to the point of apnea. Use of morphine immediate-release tablets and oral solution is contraindicated in patients with hypercarbia, while use of injectable suspension (DepoDur) and solution (Duramorph) is contraindicated in patients with upper airway obstruction. Rapid IV administration may result in chest wall rigidity. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Only healthcare professionals who are knowledgeable of the use of opioids for the management of chronic pain should prescribe morphine extended-release capsules and tablets. These extended-release products should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use extended-release formulations for as-needed analgesics, for acute pain, or if the pain is mild or not expected to persist for an extended period of time. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly after therapy initiation or after a dose increase. Caution should be exercised when converting from a different opioid to morphine, as initial dose overestimation may lead to fatal overdose. In patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, emphysema, hypoxia, hypercapnia, respiratory insufficiency, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to morphine, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Significant decreases in respiratory drive may lead to adverse intracranial effects from carbon dioxide retention; therefore, it is recommended to avoid the use of morphine extended-release tablets and capsules during a coma or impaired consciousness. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with advanced age, debilitation, or sleep apnea are at an increased risk for the development of respiratory depression associated with morphine. Use morphine with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Respiratory depression or other adverse reactions may persist for a significant period of time after discontinuation of or overdosage of long-acting morphine preparations; patients require close monitoring until their respiratory rate has stabilized. Patients who receive the extended-release liposome injection (DepoDur) may need monitoring beyond 48 hours after a dose. An increased risk of respiratory depression may be present if the surgical procedure is canceled after DepoDur administration. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. A high level of vigilant monitoring is recommended.

    Ethanol ingestion, ethanol intoxication

    Improper use of various morphine dosage forms is associated with increased risks; advise patients accordingly. Also, instruct patients who will take extended-release capsules (e.g., Avinza or Kadian) to avoid ethanol ingestion and to not use any medication that contains alcohol; concurrent alcohol receipt may lead to rapid release and absorption of a potentially fatal morphine dose. Kadian and Avinza capsules are to be swallowed whole. Alternatively, the capsule contents may be sprinkled on applesauce and swallowed without chewing. The capsule or the pellets/beads in the capsule must not be chewed, crushed, or dissolved because of the risk of rapid release and absorption of a potentially fatal morphine dose. Similarly, instruct patients to swallow extended-release tablets whole. The tablets must not be chewed, crushed, or broken in half because of the risk of rapid release and absorption. Use of an opioid agonist while under the influence of other CNS depressants or ethanol intoxication will increase risk of CNS and respiratory depressant effects.

    Anticoagulant therapy, coagulopathy, infection, intramuscular administration, intrathecal administration, intravenous administration, requires a specialized care setting, requires an experienced clinician, subcutaneous administration

    Morphine sulfate extended-release liposome injection (DepoDur) is only for epidural infusion at the lumbar level. DepoDur is not intended for intravenous administration, intrathecal administration, intramuscular administration, or subcutaneous administration. If DepoDur is accidentally injected into the intrathecal space, profound and prolonged hypoventilation is expected. Prolonged and serious respiratory depression or apnea has occurred when administration of DepoDur was associated with subarachnoid puncture; respiratory depression occurred within 12 hours of DepoDur administration after apparent recovery from anesthesia. As intrathecal leakage from the epidural space may occur through a breached dural membrane, especially when the epidural drug is administered as a bolus, do NOT administer DepoDur to a patient after a recent dural puncture without vigilant monitoring of respiratory function for at least 48 hours. Observe all patients in a fully equipped and staffed environment for a minimum of 48 hours after administration. Immediate availability of emergency mechanical ventilation and opioid antagonists are also needed. Duramorph may be given epidurally, intrathecally, or intravenously; it is not for use in continuous microinfusion devices. Infumorph is only indicated for intrathecal or epidural administration; it is not for single-dose IV, IM, or subcutaneous administration due to the risk of overdose. Infumorph must also not be used for single-dose neuraxial injection because it is too concentrated for accurate delivery of the smaller doses used in this setting. Administration of morphine via neuraxial routes requires an experienced clinician familiar with administration techniques, proper dosing, and potential patient management problems that may occur with epidural or intrathecal administration. Since single-dose neuraxial administration may result in serious adverse reactions, including acute or delayed respiratory depression, administration requires a specialized care setting where patients can be observed for up to 24 hours following the initial dose, including the initial test dose of Infumorph. The facility must be in fully equipped to monitor patients and resuscitate any patient with severe opioid overdosage. Personnel must be familiar with the use of opioid antagonists. Continue to monitor patients receiving Infumorph during the first several days following catheter implantation. Epidural administration has been associated with less potential for immediate or late adverse reactions (e.g., respiratory depression) than intrathecal administration, and is preferable to the intrathecal route whenever possible. For safety concerns, limit Duramorph administration by the intrathecal or epidural routes to the lumbar area; thoracic administration has been shown to greatly increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg. Similarly, limit Infumorph administration by the intrathecal route to the lumbar area. Improper substitution of Infumorph (10 or 25 mg/mL) for Duramorph (0.5 or 1 mg/mL) is likely to result in serious overdosage. Parenteral administration of other opioids in patients receiving epidural or intrathecal morphine may result in overdosage. Use caution when morphine is also given intravenously; because of a delay in maximum CNS effects (30 minutes) with intravenous morphine, rapid administration may result in overdose. Several factors contraindicate the administration of morphine by the epidural or intrathecal routes. These factors include infection at the injection site, concomitant anticoagulant therapy, uncontrolled coagulopathy, or the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous.

    Accidental exposure, opioid-naive patients, potential for overdose or poisoning

    Although all forms of morphine have potential for overdose or poisoning, certain formulations are associated with specific risks. This includes morphine oral solutions due to possible concentration and/or dosing errors, long-acting and high-potency morphine products for the increased risk of life-threatening respiratory depression, and Avinza brand morphine for possible renal toxicity if the maximum dose is exceeded. Knowledge and care in product selection is advised. Serious adverse events and deaths have been reported in conjunction with accidental overdose of morphine 100 mg/5 mL oral solutions and other concentrations. Excessive doses may be a result of morphine oral solutions prescribed in milligrams and erroneously interchanged for milliliters of the product. Improper substitution of Infumorph injectable solution (10 mg/mL or 25 mg/mL) for Duramorph or Astramorph injectable solutions (0.5 mg/mL or 1 mg/mL) may cause serious overdosage. To reduce the risk of life-threatening adverse effects, several formulations of morphine are intended for opioid-tolerant patients only. Do not use the following in opioid-naive patients: 90 or 120 mg morphine biphasic-release capsules (Avinza); 100 or 200 mg morphine extended-release capsules (Kadian); 100 or 200 mg morphine extended-release tablets (MS Contin); 100 mg extended-release tablets (Morphabond); or 100 mg/5 mL morphine oral solution. Only use extended-release morphine (e.g., Arymo, Avinza, Kadian, MS Contin, and Morphabond) for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate; these formulations are not intended for as-needed analgesia. Limit the total daily dose of Avinza to a maximum of 1,600 mg/day; Avinza doses more than 1,600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe and may result in serious renal toxicity. Morphine should be kept out of the reach of pediatric patients and others for whom it was not prescribed, as accidental exposure may cause a fatal overdose.

    Abrupt discontinuation

    Abrupt discontinuation of prolonged morphine therapy can result in withdrawal symptoms. Gradually taper patients off of prolonged morphine therapy to avoid a withdrawal reaction. Avoid use of partial opioid agonists (e.g., buprenorphine), mixed opioid agonist/antagonists (e.g., nalbuphine), or pure opioid antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the concomitant drug. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial opioid agonists or mixed opioid agonist/antagonists in patients who have received or are receiving morphine should be avoided as these medications may reduce the analgesic effect of morphine.

    Acute abdomen, constipation, diarrhea, GI bleeding, GI disease, GI obstruction, ileus, inflammatory bowel disease, ulcerative colitis

    Morphine tablets, capsules, oral solution, and solution for injection are contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Morphine suspension for injection is contraindicated in patients with paralytic ileus. Due to the effects of opioid agonists on the gastrointestinal tract, all forms of morphine should be used cautiously in patients with GI disease including GI obstruction, ulcerative colitis, GI bleeding, or pre-existing constipation. Instruct patients not to pre-soak, lick, or otherwise wet Arymo extended-release tablets prior to placing in the mouth; tablets may become sticky leading to difficulty in swallowing, choking, gagging, regurgitation, and tablets stuck in the throat. Patients should take 1 tablet at a time with enough water to ensure complete swallowing. Tablet stickiness and swelling may predispose patients to intestinal obstruction and diverticulitis exacerbation. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at a greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in small gastrointestinal lumen. Patients with ulcerative colitis (UC) or other inflammatory bowel disease may be more sensitive to the constipating effects of morphine. Opioid agonists may obscure the diagnosis or clinical course in patients with an acute abdomen; morphine rectal suppositories are contraindicated for use in patients with known or suspected acute abdomen or surgical anastomosis. Although opioid agonists are not desirable for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opioid agonists should not be given until the toxic substance has been eliminated. Deodorized opium tincture (10 mg/mL) and camphorated opium tincture (0.4 mg/mL) are contraindicated for use in diarrhea caused by poisoning until the toxic material is eliminated from the GI tract.

    Biliary tract disease

    Morphine and other opioid agonists increase the tone and pressure in the biliary tract causing spasms (especially in the sphincter of Oddi). Morphine should be used cautiously in patients with biliary tract disease or in patients undergoing biliary tract surgery; morphine suppositories are contraindicated for use after biliary tract surgery. The biliary effects of morphine may result in increased plasma amylase and lipase concentrations of 2 to 15 times the normal values.

    Arteriosclerosis, brain tumor, CNS depression, head trauma, increased intracranial pressure, seizure disorder, seizures, status epilepticus, strychnine toxicity

    Morphine should be used with extreme caution in patients with head trauma, a brain tumor, increased intracranial pressure (ICP), convulsive disorders (such as seizure disorders), or severe CNS depression; the use of morphine suppositories is specifically contraindicated in each of these conditions. Additionally, morphine suspension for injection (DepoDur) is contraindicated in patients with head trauma or increased intracranial pressure (ICP). Camphorated opium tincture (0.4 mg/mL) is specifically contraindicated in convulsive states, such as those occurring in status epilepticus, tetanus, and strychnine toxicity. Opioid agonists can compromise the evaluation of neurologic parameters. Rapid administration of high-dose opioid agonists may transiently elevate ICP and reduce cerebral perfusion pressures. These events are associated with opioid-induced lowering of mean arterial pressure, which stimulates a regulatory response to increase cerebral blood flow leading to increased ICP. Opioid agonist-induced respiratory depression can produce cerebral hypoxia and raise cerebrospinal fluid (CSF) pressure. Monitor patients for signs of sedation and depressed respirations. Use caution in patients with a pre-existing seizure disorder or cerebral arteriosclerosis. Morphine can precipitate seizures, especially at high doses; monitor patients with a history of seizure disorders for worsened seizure control during therapy.

    Angina, atrial fibrillation, atrial flutter, cardiac arrhythmias, cardiac disease, heart failure, hypotension, hypovolemia, orthostatic hypotension, shock

    Morphine and other opioid agonists produce cholinergic side effects by stimulating medullary vagal nuclei. Bradycardia and induction of histamine release causing peripheral vasodilation may result. As such, the use of morphine injectable solution (Astramorph) is contraindicated in patients whose ability to maintain blood pressure has already been compromised by hypovolemia. Extreme caution should be exercised when using other dosage forms in patients with hypovolemia or in those taking phenothiazines or general anesthetics, which may alter the capacity to sustain adequate pressures. Morphine suspension injection (DepoDur) is contraindicated in patients with circulatory shock; use of other morphine formulations should also be avoided. Morphine suppositories are contraindicated in patients with cardiac arrhythmias or heart failure secondary to chronic lung disease, as bradycardia and vasodilation may aggravate these conditions. Use morphine with caution in patients with atrial flutter, atrial fibrillation, or other supraventricular tachycardias, as vagolytic action may produce significant increases in ventricular response rate. Morphine should also be used cautiously in patients with cardiac disease, angina, or hypotension. Opioid agonists can induce vasovagal syncope or orthostatic hypotension; use caution in patients with pre-existing orthostatic hypotension.

    Bladder obstruction, hepatic disease, oliguria, prostatic hypertrophy, renal disease, renal impairment, urethral stricture, urinary retention

    Morphine and other opioid agonists can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, prostatic hypertrophy, urethral stricture, pelvic malignancy, or renal disease. Drug accumulation or prolonged duration of action can occur in patients with renal impairment or hepatic disease. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver or renal disease may require less frequent dosing intervals. Urinary retention may occur with single epidural or intrathecal morphine administration, or during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Urinary retention may persist for 10 to 20 hours and occurs more frequently in male patients than females. Monitor patients closely for difficulty in urination and treat as clinically indicated; cases have responded to cholinomimetic treatment and/or judicious use of catheters.

    Children, infants, neonates

    Opioid agonists may be used in children with moderate to severe pain. However, certain morphine dosage formulations or administration methods may not be appropriate for children; children also require close monitoring during opioid use. The use of deodorized opium tincture (10 mg/mL) is contraindicated for use in neonates, infants, children, and adolescents; safety and efficacy have not been established. Neonates and infants younger than 6 months of age have highly variable clearance of opioid agonists. Therefore, infants younger than 6 months of age may be given morphine but must be closely monitored for apnea until 24 hours after their last dose. Clinical practice guidelines suggest close monitoring of children up to 1 year of age. The safety and efficacy of epidural or intrathecal use of morphine in children, including the DepoDur product, have not been established. The safety and efficacy of extended-release morphine formulations have not been established in pediatric patients younger than 18 years.

    Geriatric

    Use morphine with caution in geriatric or debilitated patients. Geriatric or debilitated patients are more susceptible to adverse reactions, especially sedation and respiratory depression, probably as a result of altered distribution of the drug or decreased elimination. Initial doses may need to be reduced, and doses should be carefully titrated taking into account analgesic effects, adverse reactions, and concomitant drugs that may depress respiration. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Individuals receiving palliative care or those in hospice settings are excluded from the Beers Criteria; the balance of benefits and harms of medication management for these patients may differ from those of the general population of older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The Guidelines caution that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. In addition, the initiation of longer-acting opioids (e.g., sustained-release morphine) is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.

    Driving or operating machinery

    Any patient receiving an opioid agonist should be warned about the possibility of sedation and to use caution when driving or operating machinery.

    MAOI therapy

    Use of morphine oral dosage forms, suppositories, and solution for injection is contraindicated in patients who are receiving or have received MAOI therapy within the past 14 days. Manufacturers of other morphine dosage forms do not recommend the concurrent use of MAOIs or morphine use within 14 days of stopping such treatment. Additive CNS depression, drowsiness, dizziness, or hypotension may occur.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use morphine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects. Results for a population-based prospective cohort, including 448 women exposed to morphine at any time during pregnancy and 70 women exposed during the first trimester of pregnancy, indicate no increased risk for congenital malformations; however, risk cannot be excluded due to study methodological limitations. Neural tube defects (i.e., exencephaly and cranioschisis) have been noted when morphine was given subcutaneously to hamsters and mice at 5 and 16 times a human daily dose of 60 mg based on body surface area. Lower fetal body weight and increased abortion incidence were observed at 0.4 times the human daily dose in rabbits, growth retardation at 6 times the human daily dose in rats, and axial skeletal fusion and cryptorchidism at 16 times the human daily dose in mice. Doses of 3 to 4 times the human daily dose given during organogenesis and throughout lactation have produced cyanosis, hypothermia, decreased brain weight or body weight, adverse effects on reproductive tissues, and death in rats. Some long-term neurochemical changes in the brains of rat offspring which correlate with altered behavioral responses that persist through adulthood have been observed with exposures comparable to and less than the human daily dose. Some experts suggest increased risk if morphine is used for prolonged periods during pregnancy or at high doses near term. While certain formulations of morphine have been used in the obstetric setting, caution is advised under various circumstances during labor and obstetric delivery. Morphine sulfate extended-release liposome injection (DepoDur) should not be administered to women for vaginal labor and delivery; this formulation is only for pain associated with Caesarian section after delivery and clamping of the umbilical cord. Morphine sulfate extended-release tablets or capsules are not recommended for use during or immediately prior to labor. Morphine readily crosses the placenta and all other formulations should be used cautiously during pregnancy or obstetric delivery. An opioid antagonist and resuscitative equipment should be readily available. If used during the second stage of labor, the duration of labor can be prolonged by temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of long-acting opioids, such as morphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    Breast-feeding

    Use morphine with caution in breast-feeding mothers because it can pass into breast milk. The milk to plasma AUC ratio of morphine is approximately 2.5:1. In studies of epidural morphine given postcesarean section, morphine passage into colostrum and breast milk is minimal, while higher concentrations are found with intravenous or oral administration. In a study of 5 breast-feeding women given epidural, IV, or IM morphine postoperatively, the highest morphine concentrations in milk were 82 mcg/L (measured 30 minutes after two, 4 mg epidural doses) vs. 500 mcg/L (measured 45 minutes after 15 mg parenteral dose). Morphine passage into breast milk was assessed in a study of 5 women who were given a 7.5 mg loading dose of IV morphine following umbilical cord clamping, then 1 to 1.5 mg every 6 minutes via IV patient-controlled analgesia (PCA), then 5 to 30 mg PO every 2 to 3 hours as needed for pain. Average IV morphine consumption in the first 48 hours was approximately 150 mg. Average morphine consumption across the entire study period (96 hours) was approximately 250 mg (IV and oral). Average milk concentrations among all patients were 50 to 65 mcg/L during the first 48 hours; concentrations dropped to approximately 20 mcg/L at 72 to 96 hours postpartum. Using the maximum reported concentration of 65 mcg/L and assuming 30% oral absorption by the infant, an exclusively breast-fed infant would absorb a maximum of approximately 3 mcg/kg/day equal to 0.3% of the IV maternal weight-adjusted daily dose. Previous American Academy of Pediatrics recommendations considered morphine usually compatible with breast-feeding, particularly in short-term post-partum use, due to a lack of data regarding symptoms in exposed infants. However, opioids may cause serious adverse effects in the infant, including drowsiness, CNS depression, and death. If morphine is used during breast-feeding, short durations and low doses are recommended with close infant monitoring. If morphine is used long-term, the importance of continuing breast-feeding should be judged against the potential risk of adverse drug effects in the infant. Withdrawal symptoms may occur in infants whose mothers discontinue chronic opioid therapy. Advise the mother to report any excessive sleepiness, breathing difficulties, or difficulties breast-feeding to their health care provider immediately. Other alternative analgesics considered to be usually compatible with breast-feeding include ibuprofen, acetaminophen, and fentanyl.

    Infertility, reproductive risk

    Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Monitor patients for symptoms of opioid-induced endocrinopathy. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    ADVERSE REACTIONS

    Severe

    coma / Early / 0-5.0
    seizures / Delayed / 0-5.0
    ileus / Delayed / 0-5.0
    bradycardia / Rapid / 0-5.0
    oliguria / Early / 2.0-5.0
    pulmonary edema / Early / 0-3.0
    atrial fibrillation / Early / 0-3.0
    anaphylactoid reactions / Rapid / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    GI obstruction / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    biliary obstruction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    SIADH / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    depression / Delayed / 0-10.0
    confusion / Early / 0-10.0
    hypoxia / Early / 5.0-10.0
    dyspnea / Early / 2.0-10.0
    peripheral edema / Delayed / 0-10.0
    sinus tachycardia / Rapid / 0-10.0
    edema / Delayed / 0-5.0
    amnesia / Delayed / 0-5.0
    delirium / Early / 0-5.0
    euphoria / Early / 0-5.0
    ataxia / Delayed / 0-5.0
    hypoventilation / Rapid / 0-5.0
    respiratory depression / Rapid / 2.0-5.0
    dysphagia / Delayed / 0-5.0
    withdrawal / Early / 0-5.0
    palpitations / Early / 0-5.0
    peripheral vasodilation / Rapid / 0-5.0
    hypertension / Early / 0-5.0
    dysuria / Early / 0-5.0
    bladder spasm / Early / 2.0-5.0
    impotence (erectile dysfunction) / Delayed / 0-5.0
    hypokalemia / Delayed / 2.0-5.0
    hallucinations / Early / 0-3.0
    chest pain (unspecified) / Early / 0-3.0
    blurred vision / Early / 0-3.0
    amblyopia / Delayed / 0-3.0
    conjunctivitis / Delayed / 0-3.0
    nystagmus / Delayed / 0-3.0
    hyponatremia / Delayed / 0-3.0
    constipation / Delayed / 10.0
    psychological dependence / Delayed / 10.0
    hypotension / Rapid / 10.0
    urinary retention / Early / 10.0
    tolerance / Delayed / Incidence not known
    dysphoria / Early / Incidence not known
    psychosis / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    hyperalgesia / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 2.0-19.0
    rash (unspecified) / Early / 0-10.0
    insomnia / Early / 0-10.0
    abdominal pain / Early / 0-10.0
    diarrhea / Early / 0-10.0
    flatulence / Early / 5.0-10.0
    anorexia / Delayed / 0-10.0
    asthenia / Delayed / 0-10.0
    pruritus / Rapid / 1.0-10.0
    xerostomia / Early / 0-10.0
    paresthesias / Delayed / 0-10.0
    infection / Delayed / 5.0-10.0
    lethargy / Early / 1.0-9.9
    anxiety / Delayed / 2.0-6.0
    urticaria / Rapid / 0-5.0
    xerosis / Delayed / 0-5.0
    tremor / Early / 0-5.0
    agitation / Early / 0-5.0
    hypoesthesia / Delayed / 0-5.0
    hiccups / Early / 0-5.0
    dyspepsia / Early / 0-5.0
    weight loss / Delayed / 0-5.0
    dysgeusia / Early / 0-5.0
    syncope / Early / 0-5.0
    ocular pain / Early / 0-5.0
    malaise / Early / 0-3.0
    vertigo / Early / 0-3.0
    rhinitis / Early / 0-3.0
    gastroesophageal reflux / Delayed / 0-3.0
    chills / Rapid / 0-3.0
    pallor / Early / 0-3.0
    diaphoresis / Early / 0-3.0
    diplopia / Early / 0-3.0
    gynecomastia / Delayed / 0-3.0
    libido decrease / Delayed / 0-3.0
    amenorrhea / Delayed / 0-3.0
    dizziness / Early / 5.0
    headache / Early / 4.0
    nausea / Early / 7.0
    fever / Early / 10.0
    miosis / Early / 10.0
    weakness / Early / Incidence not known
    restlessness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    vomiting / Early / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of morphine with dihydrocodeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or dihydrocodeine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with morphine may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of oxycodone and/or morphine is recommended; use an initial dose of oxycodone at one-third to one-half the usual dosage. For extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as morphine. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of morphine. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and tramadol. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. Lastly, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    Acrivastine; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as morphine, may decrease adefovir elimination by competing for common renal tubular transport systems, therefore increasing serum concentrations of either adefovir and/or these coadministered drugs.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
    Alfentanil: (Major) Concomitant use of morphine with alfentanil can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. If alfentanil is used concurrently with morphine, monitor patients for sedation and respiratory depression.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Almotriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiloride: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Amitriptyline: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Amoxapine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include amoxapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Amyl Nitrite: (Moderate) Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as opiate agonists, can cause additive hypotensive or orthostatic effects.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including opiate agonists.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of morphine with dihydrocodeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or dihydrocodeine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with morphine may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of oxycodone and/or morphine is recommended; use an initial dose of oxycodone at one-third to one-half the usual dosage. For extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor for sedation and respiratory depression.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
    Atenolol; Chlorthalidone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Atracurium: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Difenoxin: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Diphenoxylate: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Edrophonium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azilsartan; Chlorthalidone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Azithromycin: (Moderate) Monitor patients for increased side effects if morphine and azithromycin are coadministered. Morphine concentrations could be increased with coadministration. Morphine is a substrate of P-glycoprotein (P-gp) and azithromycin is a P-gp inhibitor.
    Baclofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Belladonna; Opium: (Major) Concomitant use of morphine with opium can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or opium is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Bendroflumethiazide; Nadolol: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering morphine with boceprevir due to an increased potential for morphine-related adverse events. If morphine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of morphine. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); boceprevir is an inhibitor of this efflux protein. Coadministration may result in elevated morphine plasma concentrations.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brompheniramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Bumetanide: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as morphine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as morphine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Major) Naloxone can antagonize the therapeutic efficacy of morphine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including morphine. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.
    Bupropion: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7 to 10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur. (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Buspirone: (Moderate) Concomitant use of CNS depressants, such as buspirone, can potentiate the effects of morphine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If concurrent use of morphine and buspirone is imperative, reduce the dose of one or both drugs.
    Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as morphine. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Butorphanol may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of butorphanol with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Cabozantinib: (Moderate) Monitor for an increase in morphine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of morphine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and morphine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Capsaicin; Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine may induce the hepatic metabolism of opiate agonists, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after opiate therapy has begun in patients who are opiate tolerant. Clinicians should be alert to changes in the effect of the opioid agonist. Opiate doses may need to be increased if carbamazepine is added. Conversely, doses may need to be decreased if carbamazepine is discontinued.
    Carbetapentane; Chlorpheniramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Carbinoxamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carvedilol: (Moderate) Increased concentrations of morphine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and morphine is a P-gp substrate.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorcyclizine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Chloroprocaine: (Minor) Due to the central nervous system depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Chlorothiazide: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorpheniramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of morphine with dihydrocodeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or dihydrocodeine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of morphine with dihydrocodeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or dihydrocodeine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Chlorpromazine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Severe hypotension may occur if morphine is administered to a patient taking phenothiazines. Profound sedation and coma may also occur. Prior to use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules).
    Chlorthalidone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorzoxazone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cimetidine: (Moderate) Concurrent use of morphine and cimetidine may increase the adverse effects of morphine, especially if a large cimetidine dose is used or if the patient is not young and healthy. One patient undergoing hemodialysis experienced confusion and severe respiratory depression when given morphine and cimetidine concurrently. As determined by data obtained from healthy patients, the mean systemic exposure, half-life, volume of distribution, and plasma clearance of morphine were similar after 4 days of pretreatment with either placebo or cimetidine 300 mg every 6 hours by mouth. In another crossover study, the concurrent receipt of cimetidine 600 mg orally and 10 mg morphine intramuscularly by 8 healthy adults led to a more profound depression of the CO2 response and delay in its recovery as compared with only morphine receipt; cimetidine alone had negligible respiratory effects. Also, concomitant administration of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. Monitor patients for increased respiratory and CNS depression when receiving both cimetidine and morphine.
    Cisatracurium: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as citalopram, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and citalopram should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Clemastine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clomipramine: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Clopidogrel: (Minor) Preliminary data suggest that coadministration of morphine may delay clopidogrel absorption and active metabolite formation, as well as diminish the inhibition of platelet aggregation. The clinical significance of this potential interaction has yet to be defined and may vary depending on drug regimen, patient population, and comorbid conditions. In a randomized, double-blind, placebo-controlled, crossover trial, healthy adults (n = 24) were given 600 mg of clopidogrel followed by a 5 mg IV bolus of morphine or matching placebo. Morphine delayed the time to maximal concentration of clopidogrel and lowered both the Cmax and AUC of the clopidogrel active metabolite. Platelet function tests revealed that concurrent use of morphine delayed the time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours, p < 0.001); times up to 5 hours were reported. Inhibition of platelet plug formation was delayed, and residual platelet aggregation was greater 1 to 4 hours (p < 0.005) after morphine administration.
    Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clozapine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include clozapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Cobicistat: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
    Codeine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Codeine; Guaifenesin: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Codeine; Promethazine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Conivaptan: (Moderate) Use caution when administering conivaptan and morphine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
    Cyclizine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Cyclobenzaprine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cyproheptadine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Daclatasvir: (Moderate) Systemic exposure of morphine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of morphine; monitor patients for potential adverse effects.
    Dantrolene: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure.
    Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desipramine: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking deutetrabenazine, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg every 24 hours. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dexchlorpheniramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dextromethorphan; Quinidine: (Moderate) Morphine is a substrate for P-glycoprotein (P-gp), and quinidine is a P-gp substrate and inhibitor. Coadministration may lead to increased systemic exposure of morphine and morphine-related side effects.
    Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Dienogest; Estradiol valerate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of morphine with dihydrocodeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or dihydrocodeine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dimenhydrinate: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Diphenhydramine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Diphenhydramine; Ibuprofen: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Diphenhydramine; Naproxen: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor antagonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Donepezil; Memantine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    Doxacurium: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Doxepin: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Doxylamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Doxylamine; Pyridoxine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Dronabinol, THC: (Moderate) Concomitant use of opiate agonists and other CNS depressants such as dronabinol, THC may result in respiratory depression, CNS depression, and/or hypotension. Prior to concurrent use of opiate agonists in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. When levorphanol is used with dronabinol, reduce the initial levorphanol dose by approximately 50% or more.
    Droperidol: (Major) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include droperidol. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Ethanol abuse and the use of benzodiazepines and intravenous opiates are risk factors for the development of prolonged QT syndrome in patients receiving droperidol. If droperidol is used concurrently with morphine, a reduced dosage of morphine is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Drospirenone; Estradiol: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Drospirenone; Ethinyl Estradiol: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Eletriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Eliglustat: (Minor) Coadministration of morphine and eliglustat may result in increased plasma concentrations of morphine. Monitor patients closely for morphine-related adverse effects including respiratory depression, and consider reducing the morphine dosage and titrating to clinical effect. Morphine is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the opiate agonist is possible. Monitor patients for adverse reactions if eltrombopage is administered with an opiate agonist.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as opiate agonists. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. In addition, the CYP3A4 metabolism of some opiate agonists may be inhibited by eluxadoline. Although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as fentanyl and alfentanil. Closely monitor for increased side effects if these drugs are administered together. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Enflurane: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Entecavir: (Moderate) Both entecavir and morphine are secreted by active tubular secretion. In theory, coadministration of entecavir with morphine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and escitalopram should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Esmolol: (Moderate) Morphine increases the steady-state blood concentrations of esmolol by 50%, although morphine blood concentrations are not affected by esmolol. Careful titration of esmolol is prudent when given with morphine.
    Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ester local anesthetics: (Minor) Due to the central nervous system depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Estradiol; Levonorgestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Estradiol; Norethindrone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Estradiol; Norgestimate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Eszopiclone: (Moderate) Concomitant use of morphine with eszopiclone can potentiate the effects of morphine on respiration, blood pressure, and alertness. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If eszopiclone is used concurrently with morphine, a reduced dosage of morphine and/or eszopiclone is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Ethacrynic Acid: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethinyl Estradiol: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Desogestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norethindrone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norgestimate: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethinyl Estradiol; Norgestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Ethotoin: (Moderate) Additive CNS depression could be seen with the combined use of the ethotoin and morphine.
    Etomidate: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Etravirine: (Moderate) Increased concentrations of morphine may occur if it is coadministered with etravirine; exercise caution. Etravirine is an inhibitor of the efflux transporter P-glycoprotein (P-gp). Morphine is a P-gp substrate.
    Fentanyl: (Major) Concomitant use of morphine with fentanyl can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or fentanyl is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as opiate agonists, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and fluoxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and fluoxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include olanzapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Fluphenazine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Severe hypotension may occur if morphine is administered to a patient taking phenothiazines. Profound sedation and coma may also occur. Prior to use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules).
    Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and fluvoxamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Fosamprenavir: (Moderate) Caution is advised when administering morphine with fosamprenavir, as concurrent use may result in reduced morphine plasma concentrations. Morphine is a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Fosphenytoin: (Major) Clinically significant interactions, including withdrawal reactions, may occur with the combined use of opiate agonists and fosphenytoin, which induces CYP450 isoenzymes. Concomitant use of fosphenytoin with opiate agonists may necessitate dose adjustment of the opiate to achieve analgesia or to prevent withdrawal in patients on chronic opiate therapy. In addition, it is possible that additive CNS depression could be seen with the combined use of the hydantoin and opiate agonist.
    Fospropofol: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Frovatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Furosemide: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Gabapentin: (Moderate) Patients who require concomitant treatment with morphine may experience increases in gabapentin serum concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin and/or morphine should be reduced appropriately.
    General anesthetics: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and morphine as coadministration may increase serum concentrations of morphine and increase the risk of adverse effects. Morphine is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and morphine as coadministration may increase serum concentrations of morphine and increase the risk of adverse effects. Morphine is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor antagonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: (Moderate) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Haloperidol: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include haloperidol. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Halothane: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly. (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrocodone: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with morphine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage. Also, consider a using a lower dose of morphine. Monitor patients for sedation and respiratory depression.
    Hydromorphone: (Major) Concomitant use of hydromorphone with morphine can potentiate the effects of both drugs and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of hydromorphone and/or morphine is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. For morphine extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Hydroxyzine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with morphine may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of oxycodone and/or morphine is recommended; use an initial dose of oxycodone at one-third to one-half the usual dosage. For extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor for sedation and respiratory depression.
    Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications, such as morphine, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
    Imipramine: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Isocarboxazid: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Isoflurane: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin may induce the metabolism of morphine and lead to loss of analgesia if coadministered.
    Isoniazid, INH; Rifampin: (Moderate) Rifampin may induce the metabolism of morphine and lead to loss of analgesia if coadministered.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and morphine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Coadministration of ivacaftor with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (P-gp). Morphine is a P-gp substrate, and concomitant use may cause an increase in morphine concentrations. Use caution if ixabepilone is coadministered with morphine and monitor for an increase in side effects.
    Ketamine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended. Monitor patients for sedation and respiratory depression.
    Lactobacillus: (Moderate) Concurrent use of antidiarrheals and opiate agonists, can lead to severe constipation and possibly additive CNS depression. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of morphine-associated adverse reactions is advised with concomitant administration of ledipasvir. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase morphine plasma concentrations.
    Leuprolide; Norethindrone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Levobupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Levonorgestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lincosamides: (Moderate) Lincosamides, which have been shown to exhibit neuromuscular blocking action, can enhance the effects of opiate agonists if used concomitantly, enhancing respiratory depressant effects. They should be used together with caution and the patient carefully monitored.
    Linezolid: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Linezolid is a reversible, non-selective inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Loop diuretics: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction.
    Loperamide: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Loperamide; Simethicone: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Lopinavir; Ritonavir: (Moderate) Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as opiate agonists. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of morphine and lumacaftor; ivacaftor may alter morphine exposure; caution and close monitoring are advised if these drugs are used together. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and morphine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Coadministration of ivacaftor with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as opiate agonists.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include maprotiline. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Meclizine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include sedating H1-blockers. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression.
    Memantine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine; Levonordefrin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meprobamate: (Moderate) Concomitant use of morphine with meprobamate can potentiate the effects of morphine on respiration, blood pressure, and alertness. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If meprobamate is used concurrently with morphine, a reduced dosage of morphine and/or meprobamate is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Mesoridazine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness. Severe hypotension may occur if morphine is administered to a patient taking phenothiazines. Profound sedation and coma may also occur. Prior to use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules).
    Mestranol; Norethindrone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methadone: (Major) Concomitant use of morphine with methadone can potentiate the effects of both drugs on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or methadone is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methocarbamol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methscopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methyclothiazide: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Methylene Blue: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Metoclopramide: (Moderate) Opiate agonists antagonize GI motility and can decrease the gastroprokinetic effects of metoclopramide.
    Metolazone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as opiate agonists, should be used with caution. Additive drowsiness and/or dizziness is possible. Also, hydrocodone is metabolized by CYP3A4. Metyrapone, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with metyrapone.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Major) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include mirtazapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs with serotonergic properties such as morphine and mirtazapine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and mirtazapine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Mivacurium: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Molindone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as molindone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or molindone is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Monoamine oxidase inhibitors: (Severe) Morphine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of morphine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as morphine.
    Nabilone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as nabilone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as morphine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of morphine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Naloxone: (Major) Naloxone can antagonize the therapeutic efficacy of morphine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including morphine. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.
    Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7 to 10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Naproxen; Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Naratriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Nefazodone: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include nefazodone. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Neratinib: (Moderate) Monitor for an increase in morphine-related adverse reactions including hypotension, sedation, and respiratory depression if coadministration with neratinib is necessary. Morphine is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates. Concomitant use of P-gp inhibitors can increase morphine exposure by approximately 2-fold.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Neuromuscular blockers: (Moderate) Concomitant use of morphine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of morphine on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Nilotinib: (Major) Nilotinib is a competitive inhibitor of UGT1A1, and cautious coadministration with UGT1A1 substrates (e.g., morphine), especially substrates with a narrow therapeutic index, is recommended. Morphine is also a substrate for P-glycoprotein (P-gp) and nilotinib is an inhibitor of the efflux transporter P-gp. Increased concentrations of morphine are likely, and caution should be exercised.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
    Norethindrone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Norgestrel: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine.
    Nortriptyline: (Major) Concomitant use of morphine with other CNS depressants, such as tricyclic antidepressants (TCAs), can potentiate the effects of morphine on respiration, blood pressure, and alertness. Use may cause profound sedation, hypotension, hypoventilation, or coma. Orthostasis may occur in ambulatory patients. Additive effects such as constipation may also occur. Prior to concurrent use of morphine in patients taking a TCA, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a TCA is used concurrently with morphine, usually, a reduced initial dosage of morphine is to be considered. For example, for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). A reduced dosage of the TCA may also be necessary. Monitor patients for sedation, hypotension, reduced GI motility, and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering TCAs with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Octreotide: (Moderate) Octreotide can cause additive constipation with opiate agonists such as morphine. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Octreotide may also decrease the analgesic effect of morphine. If a loss or decrease in pain control occurs with concomitant therapy, consider discontinuing the octreotide.
    Olanzapine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include olanzapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release p