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    Compounding Kits Miscellaneous
    Opioid Agonists

    BOXED WARNING

    Asthma, coadministration with other CNS depressants, respiratory depression

    As with other opioid agonists, tramadol should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. As tramadol use is contraindicated in any situation where opioid agonist are contraindicated, do not use in patients with severe respiratory depression. Further, the manufacturers of dual-matrix extended-release tablets (e.g., Ryzolt) and extended-release capsules (e.g., ConZip) specifically contraindicate use in patients with acute or severe asthma or hypercapnia in unmonitored care settings or in the absence of resuscitate equipment. Consider alternative non-opioid analgesics instead of tramadol. Respiratory depression is possible with large doses of tramadol, especially when given concurrently with ethanol and anesthetic agents. Concurrent administration with other respiratory depressants exacerbates this risk. If respiratory depression occurs, treat as an overdose; however, administer naloxone cautiously in these situations due to an increased risk of seizures.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Data are insufficient to inform a drug-associated risk for major birth defects or miscarriage with tramadol use in human pregnancy. Tramadol crosses the placenta. Based on animal data, tramadol may cause fetal harm; advise pregnant women of the potential risk to the fetus. In animal studies of tramadol, decreased fetal weights and reduced ossification were observed in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Decreased body weight and increased mortality were observed in pups at tramadol doses of 1.2 and 1.9 times the MRHD. Tramadol is not recommended for use in women during and immediately prior to labor and obstetric delivery because oral opioid agonists may cause respiratory depression in the newborn. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol during labor. Opioid analgesics can prolong labor by reducing the strength and frequency of uterine contractions; however, this effect may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of tramadol during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including 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. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported during postmarketing experience with tramadol.

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Centrally-active oral analgesic, acts as mu-opioid receptor agonist and weak norepinephrine/serotonin reuptake inhibitor.
    Used to treat acute and chronic moderate to moderately severe pain.
    Compared to typical opioids has lower abuse and respiratory depression potential and higher risk potential for serotonin syndrome.

    COMMON BRAND NAMES

    Active-Tramadol Kit for Compounding, ConZip, EnovaRX, Ryzolt, Ultram, Ultram ER

    HOW SUPPLIED

    Active-Tramadol Kit for Compounding Topical Pwd: 8%
    ConZip/Tramadol/Tramadol Hydrochloride Oral Cap ER: 100mg, 150mg, 200mg, 300mg
    EnovaRX Topical Pwd F/Recon: 3g, 6g
    Ryzolt/Tramadol/Tramadol Hydrochloride/Ultram ER Oral Tab ER: 100mg, 200mg, 300mg
    Tramadol/Tramadol Hydrochloride/Ultram Oral Tab: 50mg

    DOSAGE & INDICATIONS

    For the treatment of moderate pain or moderately severe pain.
    For moderate chronic pain or moderately severe chronic pain in patients requiring continuous, around-the-clock treatment for an extended period of time.
    Oral dosage (coated extended-release tablets; i.e., Ultram ER ONLY, or generic equivalents)
    Adults

    NOT CURRENTLY RECEIVING TRAMADOL: Initially, 100 mg PO once daily; titrate in 100 mg increments every 5 days, if needed. Dose no more frequently than every 24 hours. Maximum: 300 mg PO once daily. Dose no more frequently than every 24 hours. CONVERSION FROM IMMEDIATE-RELEASE: Calculate the 24-hour tramadol dose, and initiate a total daily dose of the extended-release tablets rounded down to the next lowest 100 mg increment. Individualize dose titration as needed. Maximum: 300 mg PO once daily; the clinical benefit higher doses has not been demonstrated. Consider lower doses in geriatric patients over 65 years of age, particularly in those greater than 75 years of age. The concomitant use of the extended-release tablets with other tramadol products is not recommended. Different formulations of extended-release tramadol are not interchangable; pharmacokinetics and dosage titration schedules differ.

    Oral dosage (dual-matrix extended-release tablets; i.e., Ryzolt ONLY)
    Adults and Adolescents 16 years and older

    NOT CURRENTLY RECEIVING TRAMADOL: Initially, 100 mg PO once daily; titrate in 100 mg increments every 2 to 3 days. Dose no more frequently than every 24 hours. Maximum: 300 mg PO once daily. CONVERSION FROM IMMEDIATE-RELEASE: Calculate the 24-hour tramadol dose, and initiate a total daily dose of the extended-release tablets rounded down to the next lowest 100 mg increment. Individualize dose titration as needed. Maximum: 300 mg PO once daily; clinical benefit of higher doses has not been demonstrated. Consider lower doses in geriatric adults above 65 years of age, particularly those older than 75 years of age. The concomitant use of the dual-matrix extended-release tablets with other tramadol products is not recommended. Different formulations of extended-release tramadol are not interchangable; pharmacokinetics and dosage titration schedules differ.

    Oral dosage (extended biphasic-release capsules; i.e., ConZip ONLY, or generic equivalents)
    Adults

    NOT CURRENTLY RECEIVING TRAMADOL: Initially, 100 mg PO once daily; titrate upwards to 150 mg, 200 mg, and 300 mg every 5 days. Dose no more frequently than every 24 hours. Maximum: 300 mg PO once daily. CONVERSION FROM IMMEDIATE-RELEASE: Calculate the 24-hour tramadol dose, and initiate a total daily dose rounded down to the next lowest 100 mg increment. Individualize dose titration as needed. Maximum: 300 mg PO once daily; clinical benefit of higher doses has not been demonstrated. Consider lower doses in geriatric adults above 65 years of age, particularly those older than 75 years of age. The concomitant use of the biphasic extended-release capsules with other tramadol products is not recommended. Different formulations of extended-release tramadol are not interchangable; pharmacokinetics and dosage titration schedules differ. When the patient no longer requires tramadol, taper the dose gradually to prevent withdrawal.

    Oral dosage (immediate-release tablets; i.e., Ultram, or generic equivalents)
    Adults and Adolescents 17 years and older

    If rapid onset of analgesia is not required, initiate with 25 mg PO once daily and titrate in 25 mg increments every 3 days to reach a dose of 100 mg/day PO (i.e., 25 mg PO 4 times daily) to improve tolerability. Thereafter, the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day PO (i.e., 50 mg PO 4 times daily). After titration, a dose of 50 to 100 mg PO every 4 to 6 hours may be administered as needed. For rapid relief of moderate to moderately severe pain in patients where more rapid titration is necessary, give 50 to 100 mg PO every 4 to 6 hours as needed. In general, geriatric patients require care in dose selection and titration. Maximum (age up to 75 years): 400 mg/day PO. Maximum (75 years and older): 300 mg/day PO.

    Oral dosage (immediate-release orally disintegrating tablets; i.e., Rybix ODT ONLY)
    Adults and Adolescents 17 years and older

    If rapid onset of analgesia not required, initiate with 50 mg PO once daily and titrate in 50 mg increments every 3 days to reach a dose of 200 mg/day PO (i.e., 50 mg PO 4 times daily) to improve tolerability. After titration, may administer 50 to 100 mg every 4 to 6 hours as needed. For rapid relief of moderate to moderately severe pain in patients where more rapid titration is necessary, give 50 to 100 mg PO every 4 to 6 hours as needed. In general, geriatric patients require care in dose selection and titration. Maximum (age up to 75 years): 400 mg/day PO. Maximum (75 years and older): 300 mg/day PO.

    For the adjuvant treatment of arthralgia† associated with osteoarthritis†.
    Oral dosage (immediate-release tablets)
    Adults and Geriatrics 74 years and younger

    50 mg to 100 mg PO every 4 to 6 hours as needed. Maximum: 400 mg/day. Dosage titration may improve tolerability. Tramadol has been shown to be effective in controlling breakthrough pain in patients receiving NSAIDs. A trial of tramadol versus diclofenac in patients with osteoarthritis of the hip and/or knee showed that the drugs were comparable. Tramadol may be an alternative to NSAIDs in patients who do not tolerate or have preexisting conditions that limit NSAID use or in patients with a limited inflammatory component to their osteoarthritis.

    Geriatrics 75 years and older

    50 mg to 100 mg PO every 4 to 6 hours as needed. Maximum: 300 mg/day PO. Dosage titration may improve tolerability. Tramadol has been shown to be effective in controlling breakthrough pain in patients receiving NSAIDs. A trial of tramadol versus diclofenac in patients with osteoarthritis of the hip and/or knee showed that the drugs were comparable. Tramadol may be an alternative to NSAIDs in patients who do not tolerate or have preexisting conditions that limit NSAID use or in patients with a limited inflammatory component to their osteoarthritis.

    For the treatment of diabetic neuropathy†.
    Oral dosage (immediate-release tablets)
    Adults

    In one study, treatment was initiated at 50 mg/day PO and increased in 50 mg increments every 3 days up to 200 mg/day by Day 10 (i.e., 50 mg PO four times daily). During Days 14 through 28, patients could increase their dose of study medication by 50 mg/day to obtain optimal pain relief, not to exceed 400 mg/day in divided doses. A more rapid titration was permitted if patients were experiencing inadequate pain relief at any time. The mean effective dose in clinical trials was 210 mg/day, in divided doses. The American Academy of Neurology considers tramadol probably effective in lessening the pain of diabetic neuropathy.

    For postherpetic neuralgia†.
    Oral dosage (immediate-release tablets)
    Adults

    Usual doses range from 50 mg/day PO during initial titration, up to 200 mg/day, in divided doses (i.e., 50 mg PO four times daily). Further titration by 50 mg/day to obtain optimal pain relief has been used. Maximum: 400 mg/day PO, in divided doses. Tramadol is not considered a first-line therapy for postherpetic neuralgia and is often recommended only for short-term pain relief. Tricyclic antidepressants, gabapentin, pregabalin, and lidocaine patches are effective in reducing the pain of postherpetic neuralgia and are usually first line treatments.

    For the treatment of postoperative shivering†.
    Intravenous dosage (not commercially available in US)†
    Adults

    1 mg/kg to 2 mg/kg IV stopped shivering within 5 minutes in post-anesthetic patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO for immediate-release and orally disintegrating tablets; 300 mg/day PO for extended-release formulations.

    Geriatric

    65 to 75 years: 400 mg/day PO for immediate-release and orally disintegrating tablets; 300 mg/day PO for extended-release formulations.
    Older than 75 years: 300 mg/day PO.

    Adolescents

    17 years: 400 mg/day PO for immediate-release and orally disintegrating tablets; 300 mg/day PO for dual-matrix extended-release tablets (Ryzolt). Safety and efficacy of other formulations have not been established.
    16 years: 300 mg/day PO for dual-matrix extended-release tablets (Ryzolt). Safety and efficacy of other formulations have not been established.
    13 to 16 years: Safety and efficacy have not been established.

    Children

    12 years: Safety and efficacy have not been established.
    1 to 11 years: Use is contraindicated.

    Infants

    Use is contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Do not use the extended-release tramadol formulations in patients with severe hepatic impairment (Child-Pugh Class C); specific guidelines for dosage adjustments in mild to moderate hepatic impairment are not available. For the immediate-release and orally disintegrating tablets, a dose of 50 mg PO every 12 hours is recommended in patients with cirrhosis.

    Renal Impairment

    CrCl 30—80 ml/min: Specific guidelines for dosage adjustments are not available; decreased rate and extent of drug and metabolite excretion is expected.
    CrCl < 30 ml/min: Do not use the extended-release tramadol formulations. For the immediate-release and orally disintegrating tablets, increase dosage interval to 12 hours; maximum daily dose not to exceed 200 mg/day PO.
     
    Intermittent hemodialysis
    Approximately 7% of a tramadol dose is removed during a standard hemodialysis session. Therefore, no additional dosing adjustments of immediate-release and orally disintegrating tablets are needed on the day of dialysis. Do not use extended-release tramadol formulations in patients with CrCl < 30 ml/min.

    ADMINISTRATION

    Oral Administration

    Slow titration of tramadol to the effective analgesic dose may improve tolerability (see Dosage).

    Oral Solid Formulations

    Immediate-release tablets (e.g., Ultram)
    Administer tramadol immediate-release tablets with or without food.
     
    Orally disintegrating tablets (Rybix ODT)
    Administer with or without food.
    Remove tablet from the blister pack by peeling back foil from the blister; do not attempt to push the tablet through the foil.
    Do not break, chew, split, or crush the tablets.
    Place tablet in the mouth on the tongue; it will dissolve within one minute.
    May be taken with or without water.
     
    Extended-release tablets and capsules (e.g., Ryzolt, ConZip, Ultram ER)
    NOTE: Different formulations of extended-release tramadol are NOT interchangable; pharmacokinetics and dosage titration schedules differ.
    Administer tramadol dual-matrix extended-release tablets (Ryzolt) and extended-release capsules (ConZip) without regard for meals.
    Administer the coated extended-release tablets (Ultram ER) in a consistent manner, taken regularly either with food or without food.
    Swallow whole; do not break, chew, dissolve, or crush. Taking broken, chewed, dissolved, or crushed extended-release products leads to rapid release and absorption of a potentially fatal dose of tramadol.

    STORAGE

    Generic:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Active-Tramadol Kit for Compounding:
    - Prior to compounding, store at room temperature (between 59 to 86 degrees F)
    ConZip:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    EnovaRX:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a cool, dry place
    Rybix:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Ryzolt:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ultram:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ultram ER:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Lactase deficiency

    Tramadol immediate-release tablets contain lactose; patients with lactase deficiency should take appropriate precautions with use.

    Opiate agonist hypersensitivity, polysorbate 80 hypersensitivity

    Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol, including reports of anaphylactoid reactions after the initial tramadol dose, particularly in patients with a history of codeine hypersensitivity. Tramadol is contraindicated in patients with known tramadol hypersensitivity, opiate agonist hypersensitivity, or hypersensitivity to any other ingredient of the specific product formulation. Some tramadol immediate-release tablets contain polysorbate 80; do not use in patients with polysorbate 80 hypersensitivity.

    Acute intoxication of CNS depressants, alcoholism, depression, ethanol ingestion, ethanol intoxication, potential for overdose or poisoning, suicidal ideation

    Do not prescribe tramadol for patients who have depression, suicidal ideation, or addiction problems such as patients with alcoholism. Consider use of non-narcotic analgesics in these patients. Use of tramadol is associated with a significant potential for overdose or poisoning. Tramadol in excessive doses, either alone or in combination with other CNS depressants such as alcohol, is a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts, as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. The use of immediate-release tramadol, tramadol orally disintegrating tablets (Rybix), and extended-release tablets (specifically Ultram ER and generic equivalents) is contraindicated in cases of acute intoxication of CNS depressants including ethanol intoxication and/or intoxication with opiate agonists, hypnotics, centrally-acting analgesics, or psychotropic drugs. Note that while Ryzolt extended-release tablets (and generic equivalents) and extended-release capsules are not specifically contraindicated, use during acute intoxication is not recommended. Tramadol may worsen central nervous system depression and decrease the respiratory rate in these patients. Tell patients not to exceed the recommended tramadol dose and to avoid ethanol ingestion during tramadol therapy. Advise patients of the additive depressant effects of tramadol and alcohol.

    Asthma, coadministration with other CNS depressants, respiratory depression

    As with other opioid agonists, tramadol should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. As tramadol use is contraindicated in any situation where opioid agonist are contraindicated, do not use in patients with severe respiratory depression. Further, the manufacturers of dual-matrix extended-release tablets (e.g., Ryzolt) and extended-release capsules (e.g., ConZip) specifically contraindicate use in patients with acute or severe asthma or hypercapnia in unmonitored care settings or in the absence of resuscitate equipment. Consider alternative non-opioid analgesics instead of tramadol. Respiratory depression is possible with large doses of tramadol, especially when given concurrently with ethanol and anesthetic agents. Concurrent administration with other respiratory depressants exacerbates this risk. If respiratory depression occurs, treat as an overdose; however, administer naloxone cautiously in these situations due to an increased risk of seizures.

    Head trauma, increased intracranial pressure, seizure disorder, seizures

    Seizures have been reported in patients receiving tramadol within the recommended dosage range (see Adverse Reactions). Tramadol should be used with caution in patients who are at risk of seizures including those who have a pre-existing seizure disorder or a history of seizures, are receiving medications that reduce the seizure threshold (see Drug Interactions), who have certain medical conditions (i.e., metabolic disorders, increased intracranial pressure, CNS infection, head trauma), or who are experiencing ethanol or illicit drug withdrawal. The risk of seizures may increase in these patients. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. In tramadol overdose, naloxone administration may increase the risk of seizure. In addition, administration of tramadol to patients with increased intracranial pressure or head trauma may obscure the existence, extent, or course of intracranial pathology because tramadol induces pupillary changes (miosis). Further, the respiratory depressant effects of opioids such as carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in these patients. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol.

    Acute abdomen, biliary tract disease, constipation, diarrhea, GI disease, GI obstruction, ileus, pancreatitis, ulcerative colitis

    Tramadol use is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Due to the effects of opioid agonists on the gastrointestinal tract, tramadol should be used cautiously in patients with pre-existing biliary tract or GI disease, ulcerative colitis (UC), or pre-existing constipation. Patients with UC or other inflammatory bowel disease may be more sensitive to the constipating effects of opioid agonists. Also, use with caution in patients with pancreatic or biliary tract disease, including acute pancreatitis, as mu-opioid agonists are known to cause spasm of the sphincter of Oddi. Opioid agonists may obscure the diagnosis or clinical course in patients with an acute abdomen. 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.

    Substance abuse

    Tramadol is an opioid agonist of the morphine-type and is not recommended in patients with a substance abuse problem associated with opiate agonists. Tramadol has been shown to reinitiate physical dependence in some patients who have been physically dependent on other opiate agonists. Patients who have recently taken substantial amounts of opiate agonists may experience withdrawal symptoms after treatment with tramadol. Tramadol is not recommended in patients with a tendency towards opiate agonist substance abuse, in patients who have been physically dependent on opiate agonists, or in patients chronically taking opiate agonists. Psychologic dependence similar to that of codeine or dextropropoxyphene is possible with tramadol. However, because some of tramadol's activity comes from the active metabolite, µ-opioid activity may be delayed, thus possibly reducing the potential for abuse. The extended-release tablets could be abused by crushing, chewing, snorting, or injecting the dissolved product, which would result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death. The proper usage of tramadol in individuals with active or past drug or alcohol dependence is for the management of pain requiring opioid analgesia. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

    Abrupt discontinuation

    To prevent withdrawal symptoms, avoid abrupt discontinuation of tramadol. Withdrawal symptoms may include anxiety, sweating, nausea, tremors, diarrhea, upper respiratory symptoms, insomnia, rigors, pain, piloerection, panic attacks, paresthesias, and hallucinations (rarely). Clinical experience suggests that withdrawal symptoms may be relieved by tapering the dosage of tramadol.

    Renal impairment

    Tramadol should be administered with caution to patients with renal impairment. Impaired renal function affects the rate and extent of excretion of both tramadol and its active metabolite, M1. It may take several days for elevated plasma concentrations and toxicity to develop. Dosage reductions of the immediate-release tablets are recommended if creatinine clearance falls below 30 ml/min (see Dosage). The extended-release tablets are not recommended for use in patients with a creatinine clearance below 30 ml/min. The extended-release tablets have not been studied in patients with a creatinine clearance below 30 ml/min, and the limited availability of dose strengths and once daily dosing do not permit the dosing flexibility required for safe use in patients with severe renal impairment.

    Hepatic disease

    Dosage reductions and an increased dosage interval are recommended for patients with hepatic disease (see Dosage). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. It may take several days for elevated plasma concentrations and toxicity to develop. The extended-release tablets are not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of the extended-release tablets have not been studied in patients with severe hepatic impairment, and the limited availability of dose strengths and once daily dosing do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Data are insufficient to inform a drug-associated risk for major birth defects or miscarriage with tramadol use in human pregnancy. Tramadol crosses the placenta. Based on animal data, tramadol may cause fetal harm; advise pregnant women of the potential risk to the fetus. In animal studies of tramadol, decreased fetal weights and reduced ossification were observed in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Decreased body weight and increased mortality were observed in pups at tramadol doses of 1.2 and 1.9 times the MRHD. Tramadol is not recommended for use in women during and immediately prior to labor and obstetric delivery because oral opioid agonists may cause respiratory depression in the newborn. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol during labor. Opioid analgesics can prolong labor by reducing the strength and frequency of uterine contractions; however, this effect may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of tramadol during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including 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. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported during postmarketing experience with tramadol.

    Breast-feeding

    Because of the potential for serious adverse events, including excess sedation and respiratory depression in a breast-fed infant, breast-feeding is not recommended during treatment with tramadol. Tramadol and its metabolite are excreted into human milk in small amounts. Samples of breast milk taken from 75 women 2 to 4 days postpartum after receiving at least 4 doses of tramadol indicated that an exclusively breast-fed infant would receive 2.24% of the maternal weight adjusted dose of tramadol and 0.64% of its metabolite. Assessments of the infants of these mothers using the Neurologic and Adaptive Capacity Score found no difference when compared to infants in a control group. Forty-nine percent of mothers in the tramadol group and 100% of mothers in the control group were also receiving other opioids (mostly oxycodone). If an infant is breast-fed while receiving tramadol, monitor the infant for adverse reactions, including excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped or when breast-feeding is stopped. Tramadol is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because the safety of tramadol in the exposed infant has not been studied. After a single tramadol 100 mg IV dose, the cumulative excretion in breast milk within 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. Alternative analgesics that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include acetaminophen, ibuprofen, and morphine.

    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.

    Geriatric

    Geriatric patients vary in their tolerance of tramadol. Use all forms of tramadol with caution in patients 65 years and older, with consideration of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Age-based dosage adjustments are recommended in patients older than 75 years of age. In clinical trials, higher general incidence rates of constipation, fatigue, weakness, postural hypotension, and dyspepsia were observed for geriatric patients as compared with younger patients. Healthy elderly subjects aged 65 to 75 years were found to have similar tramadol pharmacokinetics as compared to healthy adults less than 65 years of age. However, in study patients over 75 years, elevated maximum serum concentrations and prolonged elimination half-life have been reported. According to the Beers Criteria, tramadol is considered a potentially inappropriate medication (PIM) for use in geriatric patients with chronic seizures or epilepsy and should generally be avoided in these populations because tramadol lowers the seizure threshold; however, tramadol may be acceptable in geriatric patients with well-controlled seizures in whom alternative agents have not been effective. The Beers expert panel also recommends reducing the immediate-release dose of tramadol and avoiding extended-release tramadol in geriatric patients with a creatinine clearance less than 30 mL/min due to the potential for adverse CNS effects.

    Adenoidectomy, children, infants, neonates, obesity, respiratory infection, sleep apnea, tonsillectomy

    Tramadol is contraindicated for the treatment of pain in neonates, infants, and children younger than 12 years and in postoperative pain management in pediatric patients after a tonsillectomy and/or adenoidectomy. Ultra-rapid metabolizers may convert tramadol to its active metabolite, O-desmethyltramadol, more quickly and completely than usual, leading to higher than normal opioid blood concentrations that can result in fatal respiratory depression. Because some children who are normal metabolizers can covert opioids at similar rates to ultra-rapid metabolizers, this concern extends to all pediatric patients. Do not use tramadol in pediatric patients with obesity or who have conditions which may increase the risk of serious breathing problems (e.g., obstructive sleep apnea, severe lung disease, asthma, respiratory infection). The safety and efficacy of tramadol in neonates, infants, children, and adolescents less than 16 years of age have not been established for any dosage form.

    Driving or operating machinery

    Patients should be warned against driving or operating machinery until they know how tramadol may affect them.

    MAOI therapy

    Use of tramadol is contraindicated in patients who are receiving or who have received MAOI therapy within the past 14 days. Additive CNS depression, drowsiness, dizziness, or hypotension may occur. Concomitant use may also increase the risk for serotonin syndrome.

    Phenylketonuria

    Orally disintegrating tablets contain phenylalanine; do not prescribe this dosage form for patients with phenylketonuria or other phenylketone-related sensitivity.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use tramadol 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.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 1.0-4.9
    hepatic failure / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    GI bleeding / Delayed / 0-1.0
    bradycardia / Rapid / 0-1.0
    serotonin syndrome / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    suicidal ideation / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    proteinuria / Delayed / 0-1.0
    cholecystitis / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    myocardial infarction / Delayed / 0.5-0.9
    pulmonary embolism / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    fetal death / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 9.3-46.0
    euphoria / Early / 0-14.0
    hallucinations / Early / 0-14.0
    orthostatic hypotension / Delayed / 0-5.4
    hypertension / Early / 0-5.0
    hypertonia / Delayed / 0-5.0
    depression / Delayed / 0-5.0
    dyspnea / Early / 0-5.0
    urinary retention / Early / 0-5.0
    hyperglycemia / Delayed / 0-5.0
    peripheral vasodilation / Rapid / 1.0-4.9
    hot flashes / Early / 1.0-4.9
    peripheral edema / Delayed / 1.0-4.9
    blurred vision / Early / 1.0-4.9
    confusion / Early / 1.0-4.9
    withdrawal / Early / 1.0-4.9
    dysphagia / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    amnesia / Delayed / 0-1.0
    ataxia / Delayed / 0-1.0
    impaired cognition / Early / 0-1.0
    migraine / Early / 0-1.0
    dysuria / Early / 0-1.0
    hematuria / Delayed / 0-1.0
    cystitis / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    cholelithiasis / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    sinus tachycardia / Rapid / 0.5-0.9
    palpitations / Early / 0.5-0.9
    gout / Delayed / 0.5-0.9
    dysphonia / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    physiological dependence / Delayed / Incidence not known
    tolerance / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 13.0-40.0
    vertigo / Early / 0.5-33.0
    dizziness / Early / 7.0-33.0
    headache / Early / 3.0-32.0
    drowsiness / Early / 5.0-25.0
    vomiting / Early / 3.0-17.0
    flushing / Rapid / 0-15.8
    agitation / Early / 0-14.0
    tremor / Early / 0-14.0
    anxiety / Delayed / 0-14.0
    emotional lability / Early / 0-14.0
    xerostomia / Early / 1.0-13.1
    dyspepsia / Early / 1.0-13.0
    asthenia / Delayed / 0-12.0
    pruritus / Rapid / 3.0-11.9
    insomnia / Early / 1.0-10.9
    diarrhea / Early / 0-10.0
    diaphoresis / Early / 0-9.0
    anorexia / Delayed / 0.7-5.9
    arthralgia / Delayed / 1.0-5.4
    malaise / Early / 0-5.0
    syncope / Early / 0-5.0
    paresthesias / Delayed / 0-5.0
    increased urinary frequency / Early / 0-5.0
    infection / Delayed / 0-5.0
    fever / Early / 0-5.0
    weight loss / Delayed / 0-5.0
    myalgia / Early / 0-5.0
    flatulence / Early / 0.5-4.9
    abdominal pain / Early / 1.0-4.9
    fatigue / Early / 1.0-4.9
    weakness / Early / 1.0-4.9
    lethargy / Early / 1.0-4.9
    sneezing / Early / 1.0-4.9
    nasal congestion / Early / 1.0-4.9
    rhinorrhea / Early / 1.0-4.9
    cough / Delayed / 1.0-4.9
    hypoesthesia / Delayed / 1.0-4.9
    miosis / Early / 1.0-4.9
    restlessness / Early / 1.0-4.9
    rash (unspecified) / Early / 1.0-4.9
    chills / Rapid / 1.0-4.9
    rhinitis / Early / 1.0-4.9
    pharyngitis / Delayed / 1.0-4.9
    sinusitis / Delayed / 1.0-4.9
    influenza / Delayed / 1.0-4.9
    back pain / Delayed / 1.0-4.9
    gastroesophageal reflux / Delayed / 0-1.0
    dental pain / Delayed / 0-1.0
    yawning / Early / 0-1.0
    hyperkinesis / Delayed / 0-1.0
    night sweats / Early / 0-1.0
    irritability / Delayed / 0-1.0
    pallor / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    menstrual irregularity / Delayed / 0-1.0
    tinnitus / Delayed / 0-1.0
    libido decrease / Delayed / 0-1.0
    ecchymosis / Delayed / 0.5-0.9
    muscle cramps / Delayed / 0.5-0.9
    gonadal suppression / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Acetaminophen; Codeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Acetaminophen; Oxycodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. 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; Propoxyphene: (Major) As propoxyphene is a moderate CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6 (and CYP3A4), concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Alfentanil: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Almotriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Amiodarone: (Moderate) Use of amiodarone concurrently with tramadol may inhibit tramadol metabolism. Decreased efficacy and possibly increased side effects may occur due to increased tramadol serum concentrations and decreased serum concentrations of the active metabolite.
    Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Amitriptyline; Chlordiazepoxide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol. (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Amobarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Amoxapine: (Moderate) In vitro drug interaction studies in human liver microsomes suggest that concomitant administration of tricyclic antidepressants could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. It is not clear if amoxapine, a related cyclic antidepressant, would cause these types of interactions. Amoxapine may decrease the seizure threshold and cyclic antidepressants have been associated with increased risk of seizures when given concurrently with tramadol.
    Amphetamine; Dextroamphetamine Salts: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as 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. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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, including tramadol, could result in additive depressant effects. Careful monitoring is recommended during combined use of a CNS depressant and apomorphine. A dose reduction of one or both drugs may be warranted.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if tramadol and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tramadol-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tramadol is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tramadol. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Concurrent use of tramadol and aripiprazole should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and aripiprazole. Similar precautions apply to combination products containing tramadol such as acetaminophen; tramadol.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and tramadol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tramadol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Asenapine: (Moderate) Concurrent use of tramadol and asenapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and asenapine.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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 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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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. (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Atazanavir; Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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. (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including tramadol.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including tramadol.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Barbiturates: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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. (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Belladonna; Opium: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Benzphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as 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. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants and anorectics that may induce seizures, including benzphetamine. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering tramadol with boceprevir due to an increased potential for tramadol-related adverse events. If tramadol 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 tramadol. Tramadol is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated tramadol plasma concentrations.
    Brexpiprazole: (Moderate) Concurrent use of tramadol and brexpiprazole should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and brexpiprazole. Similar precautions apply to combination products containing tramadol such as acetaminophen; tramadol.
    Brigatinib: (Moderate) Monitor for decreased efficacy of tramadol, and signs and symptoms of opioid withdrawal in patients who are physically dependent if coadministration with brigatinib is necessary. Brigatinib induces CYP3A4 in vitro; concurrent use of a CYP3A4 inducer may result in decreased tramadol concentrations.
    Brompheniramine; 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 tramadol.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    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 tramadol. 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. Additionally, concurrent use of opiates with other drugs that modulate serotonergic function, such as tramadol, has resulted in serotonin syndrome in some cases. 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. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. There is also a potential for increased risk of seizures if tramadol is given with other opiates.
    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 tramadol. 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. Additionally, concurrent use of opiates with other drugs that modulate serotonergic function, such as tramadol, has resulted in serotonin syndrome in some cases. 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. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. There is also a potential for increased risk of seizures if tramadol is given with other opiates. (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Bupropion: (Major) Increased serum concentrations of tramadol and reduced serum concentrations of the O-desmethyltramadol metabolite (M1) would be expected from concurrent use of tramadol and a CYP2D6 inhibitor such as bupropion. As the analgesic activity of tramadol is due to both the parent drug and M1, inhibition of CYP2D6 by bupropion may affect the analgesic effect of tramadol; reduced analgesic effects are possible. Also, administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold such as bupropion.
    Bupropion; Naltrexone: (Major) Increased serum concentrations of tramadol and reduced serum concentrations of the O-desmethyltramadol metabolite (M1) would be expected from concurrent use of tramadol and a CYP2D6 inhibitor such as bupropion. As the analgesic activity of tramadol is due to both the parent drug and M1, inhibition of CYP2D6 by bupropion may affect the analgesic effect of tramadol; reduced analgesic effects are possible. Also, administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold such as bupropion. (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Buspirone: (Moderate) Tramadol can cause additive CNS depression when used with other agents that are CNS depressants including buspirone.
    Butabarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as tramadol. 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. There is also a potential increased risk of seizures if tramadol is given with other opiates.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Carbamazepine: (Major) Carbamazepine induces cytochrome P450 isoenzyme 2D6, which induces the metabolism of tramadol. Carbamazepine may also contribute to the CNS depressant effects of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus interfere with the ability of carbamazepine to control seizures.
    Carbetapentane; Chlorpheniramine: (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 tramadol.
    Carbetapentane; Chlorpheniramine; 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 tramadol.
    Carbetapentane; Diphenhydramine; 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 tramadol.
    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 tramadol.
    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 tramadol.
    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 tramadol.
    Carbetapentane; Phenylephrine; Pyrilamine: (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 tramadol.
    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 tramadol.
    Carbetapentane; Pyrilamine: (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 tramadol.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Cariprazine: (Moderate) Concurrent use of tramadol and cariprazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and cariprazine.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Ceritinib: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with ceritinib is necessary; the risk is greatest if ceritinib is added to a stable dose of tramadol. Ceritinib is a CYP3A4 inhibitor and tramadol is metabolized by CYP3A4 and CYP2D6. Coadministration with a CYP3A4 inhibitor may result in a greater amount of tramadol metabolism via CYP2D6, and greater levels of the active metabolite, M1.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS including tramadol.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS including tramadol.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Chlorpheniramine; Codeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Chlorpromazine: (Moderate) Concurrent use of tramadol and chlorpromazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that chlorpromazine has CYP2D6 inhibitory effects and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by chlorpromazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and chlorpromazine.
    Cinacalcet: (Moderate) Coadministration of cinacalcet, a strong CYP2D6 inhibitor, with tramadol, a CYP2D6 substrate, may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering citalopram with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, citalopram is a weak inhibitor of CYP2D6. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. If serotonin syndrome is suspected, citalopram and concurrent serotonergic agents should be discontinued.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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. Additionally, in vivo data suggest clobazam is a CYP2D6 inhibitor. Because the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by clobazam may affect the analgesic response to tramadol. Reduced analgesic effects of tramadol are possible, and the risk for serious adverse effects such as seizures may be increased.
    Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
    Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Codeine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Codeine; Guaifenesin: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Codeine; Promethazine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    COMT inhibitors: (Moderate) COMT inhibitors can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Crizotinib: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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. Additionally, concurrent use of tramadol and cyclobenzaprine increases the possibility of developing serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue cyclobenzaprine and tramadol. Cyclobenzaprine may enhance the risk of seizures in patients taking tramadol.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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: (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Darunavir; Cobicistat: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations.
    Delavirdine: (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as delavirdine, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
    Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol which also decreases the seizure threshold.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In one case, the addition of tramadol to extended-release venlafaxine (300 mg/day) and mirtazapine (30 mg/day) likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful. In addition, although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as tramadol, be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower, or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day.
    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 an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Dexmedetomidine: (Moderate) Concurrent use of dexmedetomidine with other CNS depressants, such as tramadol, could result in additive sedative effects and possibly prolong recovery from anesthesia.
    Dextromethorphan; Promethazine: (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Dextromethorphan; Quinidine: (Moderate) As quinidine is a potent inhibitor of CYP2D6 and tramadol is partially metabolized by CYP2D6, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. 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.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Digoxin: (Moderate) An increased incidence of digoxin toxicity has been reported in some patients during post-marketing reports with the concurrent use of tramadol and digoxin.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Doxepin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Dronabinol, THC: (Moderate) Dronabinol, THC can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Tramadol is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Moderate) Droperidol can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In one case, the addition of tramadol to extended-release venlafaxine (300 mg/day) and mirtazapine (30 mg/day) likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful. Also, duloxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Patients receiving tramadol in combination with an SNRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Efavirenz: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised.
    Elbasvir; Grazoprevir: (Moderate) Administering acetaminophen; tramadol with elbasvir; grazoprevir may result in elevated tramadol plasma concentrations. Tramadol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Eliglustat: (Moderate) Coadministration of tramadol and eliglustat may result in a reduction in the metabolic conversion and clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome. In addition, coadministration of tramadol and eliglustat may result in decreased analgesia. If coadministration is necessary, monitor patients closely for tramadol-related adverse effects and diminished analgesic efficacy. The analgesic activity of tramadol is due to both the parent drug and the pharmacologically active metabolite M1. Because the metabolism of tramadol to M1 is dependent on CYP2D6 and eliglustat is an inhibitor of CYP2D6, therapeutic response may be affected.
    Enzalutamide: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of tramadol as needed. If enzalutamide is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Erythromycin: (Moderate) Administration of CYP3A4 inhibitors such as erythromycin with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Erythromycin; Sulfisoxazole: (Moderate) Administration of CYP3A4 inhibitors such as erythromycin with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering escitalopram with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, CYP2D6 inhibitors can prevent the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. Although escitalopram is a modest inhibitor of CYP2D6, the inhibition of the M1 metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome or other adverse effects.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Eszopiclone: (Moderate) Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants such as anxiolytics, sedatives, and hypnotics. A reduction in the dose of eszopiclone and tramadol, should be considered to minimize additive sedative effects. 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.
    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.
    Ethotoin: (Major) Tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of anticonvulsants to control seizures. The use of tramadol in patients on anticonvulsant medications for seizure therapy is not recommended. In addition, the hepatic metabolism of tramadol may be accelerated by the use of ethotoin, phenytoin, or fosphenytoin.
    Everolimus: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with everolimus is necessary; the risk is greatest if everolimus is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Everolimus is a weak CYP3A4 inhibitor as well as a CYP2D6 inhibitor. Tramadol is metabolized by both CYP3A4 and CYP2D6.
    Ezogabine: (Moderate) Due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur during concurrent use of other centrally-acting medications such as tramadol. Patients should be monitored for excessive somnolence during concurrent therapy with this agent.
    Fentanyl: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as fluoxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as fluoxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects. (Moderate) Concurrent use of tramadol and olanzapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and olanzapine.
    Fluphenazine: (Moderate) Concurrent use of tramadol and fluphenazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that fluphenazine is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by fluphenazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and fluphenazine.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 should be observed when administering fluvoxamine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures.
    Fosphenytoin: (Major) Tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of anticonvulsants to control seizures. The use of tramadol in patients on anticonvulsant medications for seizure therapy is not recommended. In addition, the hepatic metabolism of tramadol may be accelerated by the use of ethotoin, phenytoin, or fosphenytoin.
    Frovatriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Gabapentin: (Moderate) Tramadol may produce additive CNS depression, such as drowsiness and dizziness when given with gabapentin. Counsel patients to limit activity until they are aware of how coadministration affects them.
    Gefitinib: (Major) Monitor for an increased incidence of tramadol-related adverse effects as well as changes in the efficacy of tramadol if given concurrently with gefitinib. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tramadol. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily). The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as tramadol.
    General anesthetics: (Moderate) Tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants, such as general anesthetics. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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, use caution when administering granisetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Haloperidol: (Major) Haloperidol can competitively inhibit the metabolism of tramadol by CYP2D6. Concurrent use of haloperidol and tramadol increases plasma levels of tramadol and decreases the concentration of the active tramadol metabolite. This may lead to decreased analgesic effects of tramadol and possibly increased tramadol-induced side effects, including seizures, due to increased tramadol concentrations and the decrease in seizure threshold caused by haloperidol. Additive CNS depression may also be seen with the concomitant use of tramadol and haloperidol.
    Homatropine; Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Hydantoins: (Major) Tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of anticonvulsants to control seizures. The use of tramadol in patients on anticonvulsant medications for seizure therapy is not recommended. In addition, the hepatic metabolism of tramadol may be accelerated by the use of ethotoin, phenytoin, or fosphenytoin.
    Hydrocodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Hydromorphone: (Major) Tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists such as hydromorphone. Concomitant use of tramadol and opiate agonists may also increase the risk of seizures; avoid concurrent use whenever possible. Prior to concurrent use of hydromorphone 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 hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tramadol, a CYP3A substrate, as tramadol toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Coadministration should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and iloperidone.
    Imatinib: (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as imatinib, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
    Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Iohexol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopamidol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopromide: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ioversol: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tramadol may result in increased serum concentrations of tramadol. Tramadol is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. (Moderate) Tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6. Higher doses of tramadol may be required when it is given concurrently with other agents that induce this isoenzyme, such as rifampin.
    Isoniazid, INH; Rifampin: (Major) Use tramadol cautiously, if at all, in patients also receiving a MAOI or a drug with MAO-inhibiting activity such as isoniazid, INH. International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy. An increased risk of seizures and serotonin syndrome exists in patients receiving tramadol and MAOIs concurrently. Postmarketing reports of serotonin syndrome with use of tramadol and MAOIs and alpha-2-adrenergic blockers exist. If concomitant treatment of tramadol with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. (Moderate) Tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6. Higher doses of tramadol may be required when it is given concurrently with other agents that induce this isoenzyme, such as rifampin.
    Isosulfan Blue: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Moderate) Administration of CYP3A4 inhibitors such as ketoconazole with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS including tramadol.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and tramadol should be discontinued.
    Levorphanol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Linezolid: (Severe) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
    Lisdexamfetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as 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. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and tramadol. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Lopinavir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, tramadol. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome (NMS) like signs and symptoms.
    Loxapine: (Major) Loxapine can potentiate the actions of other CNS depressants such as tramadol. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. In addition, loxapine therapy may be associated with an increased risk of seizures when given concurrently with tramadol due to decreases in the seizure threshold.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the analgesic effect of tramadol by decreasing its systemic exposure. If used together, monitor patients closely for loss of tramadol efficacy; a tramadol dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
    Lurasidone: (Moderate) Concurrent use of lurasidone and tramadol or combination products containing tramadol (e.g., acetaminophen; tramadol) should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and lurasidone.
    Maprotiline: (Moderate) Concomitant use of tramadol increases the seizure risk in patients taking tricyclic antidepressants and other tricyclic compounds. Tramadol use may increase the seizure risk in patients taking drugs that reduce the seizure threshold. Maprotiline is pharmacologic similar to the tricyclic antidepressants, may decrease the seizure threshold, and causes CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. In vitro drug interaction studies in human liver microsomes suggest that concomitant administration of tricyclic antidepressants could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. It is not clear if maprotiline, a related cyclic antidepressant, would cause these types of interactions.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Meperidine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Meperidine; Promethazine: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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. (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Mephobarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Meprobamate: (Moderate) Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants such as meprobamate. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Mesoridazine: (Moderate) Due to the primary CNS effects of phenothiazines, caution should be used when given in combination with other centrally acting medications, such as tramadol. Both of these medications can lower the seizure threshold when used alone, therefore there is an even greater risk when they are used concomitantly.
    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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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 tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Methamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as 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. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants and anorectics that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Methohexital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Methscopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Methylene Blue: (Severe) Tramadol 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 tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as tramadol, should be used with caution. Additive drowsiness and/or dizziness is possible.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 should be observed when administering milnacipran and levomilnacipran with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The combination of other serotonergic medications and tramadol has been associated with serotonin syndrome and seizures. Several cases of serotonin syndrome have been reported following the administration of tramadol with SSRIs such as paroxetine or sertraline. Levomilnacipran, a serotonin-norepinephrine reuptake inhibitor, has actions similar to the SSRIs and thus may also have the potential to interact with tramadol. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or other adverse effects. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tramadol may be increased when co-administered with mirabegron. Tramadol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as 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. Additive sedative effects may also occur. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or other adverse effects. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Mitotane: (Major) Use caution if mitotane and tramadol are used concomitantly, and monitor for decreased efficacy of tramadol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. The metabolism of tramadol is stereoselective; the (+) enantiomer preferentially undergoes N-demethylation, mediated by CYP3A4 and CYP2B6, and the (-) enantiomer undergoes O-demethylation via CYP2D6. O-demethylation leads to the production of the active metabolite M1, which is critical to tramadol activity. Because of the role of CYP3A4 in tramadol metabolism, coadministration with mitotane may affect patient response to tramadol.
    Molindone: (Moderate) Due to the primary CNS effects of molindone, caution should be used when given in combination with other centrally acting medications, such as tramadol. Both of these medications can lower the seizure threshold when used alone, therefore there is an even greater risk when they are used concomitantly.
    Monoamine oxidase inhibitors: (Severe) Tramadol use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of tramadol with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome or seizures. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as tramadol.
    Morphine: (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.
    Morphine; Naltrexone: (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.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, including tramadol, can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as tramadol. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. 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. There is also a potential increased risk of seizures if tramadol is given with other opiates.
    Nalmefene: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Naloxone: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Naltrexone: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Naproxen; Sumatriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Naratriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Nefazodone: (Major) Although clinical data for some interactions is lacking, medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin (tramadol) may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome.
    Netupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Nilotinib: (Moderate) Tramadol is a substrate of CYP2D6 and CYP3A4. Nilotinib is a competitive inhibitor of CYP3A4 and CYP2D6. As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect analgesic effects; reduced analgesic effects are possible. Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor and/or CYP3A4 inhibitor. The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Caution should be exercised when coadministering nilotinib with CYP3A4 and CYP2D6 substrates; a tramadol dose reduction may be necessary. Monitor patients closely for tramadol toxicity and efficacy if these drugs are used together.
    Non-Ionic Contrast Media: (Major) Tramadol lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Nortriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Olanzapine: (Moderate) Concurrent use of tramadol and olanzapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations.
    Ondansetron: (Moderate) Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from a few small studies indicate that ondansetron may reduce the analgesic effects of tramadol. Since adverse effects may occur when tramadol is administered in excessive dosage as patients try to obtain pain relief, clinicians should be alert to increases in the patient reported frequency of tramadol administration during concurrent use.
    Opiate Antagonists: (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Oritavancin: (Moderate) Tramadol is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of tramadol may be reduced if these drugs are administered concurrently.
    Orphenadrine: (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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Oxazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Oxybutynin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Oxycodone: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Oxymorphone: (Major) Tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists such as oxymorphone. Concomitant use of tramadol and opiate agonists may also increase the risk of seizures; avoid concurrent use whenever possible. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxymorphone 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 oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or the CNS depressant is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
    Palbociclib: (Moderate) If coadministration of palbociclib is necessary, monitor for increased tramadol-related adverse effects (e.g., seizures, serotonin syndrome and opioid toxicity including potentially fatal respiratory depression). Consider a tramadol dose reduction until stable drug effects are achieved. If palbociclib is discontinued, monitor for opioid withdrawal symptoms and consider increasing the tramadol dose. Coadministration of palbociclib, a weak time-dependent CYP3A4 inhibitor, may increase tramadol plasma concentrations and may result in increased metabolism of tramadol through 2D6 resulting in higher levels of the active metabolite, M1.
    Paliperidone: (Moderate) Concurrent use of tramadol and paliperidone should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and paliperidone.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as tramadol. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Panobinostat: (Major) Avoid the concomitant use of panobinostat and tramadol as increased tramadol levels and an increased risk of adverse effects may occur if these agents are used together. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tramadol toxicity including seizures and serotonin syndrome. Panobinostat is a CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as paroxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tramadol, a CYP3A4 substrate, may cause an increase in systemic concentrations of tramadol. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to tramadol if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while tramadol is a CYP2D6 substrate.
    Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. 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.
    Pentazocine; Naloxone: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as tramadol. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. There is also a potential increased risk of seizures if tramadol and pentazocine are given concurrently. 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. (Moderate) Naloxone should be used cautiously in situations of tramadol overdose. Naloxone administration may increase the risk of seizures in these patients. Furthermore, naloxone will reverse some but not all symptoms caused by tramadol overdosage. It is not clear if such precautions would also apply to the use of other opiate antagonists with tramadol.
    Pentobarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as tramadol.
    Perphenazine: (Major) Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. Concomitant use of tramadol and antipsychotics may increase the risk of seizures and result in other additive CNS effects. The manufacturer of tramadol cautions that serotonin syndrome may occur during use of drugs that impair the metabolism of tramadol such as CYP2D6 inhibitors, including antipsychotics like perphenazine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may in theory also decrease tramadol efficacy.
    Perphenazine; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol. (Major) Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. Concomitant use of tramadol and antipsychotics may increase the risk of seizures and result in other additive CNS effects. The manufacturer of tramadol cautions that serotonin syndrome may occur during use of drugs that impair the metabolism of tramadol such as CYP2D6 inhibitors, including antipsychotics like perphenazine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may in theory also decrease tramadol efficacy.
    Phenobarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Phentermine; Topiramate: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    Phenylephrine; Promethazine: (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Phenytoin: (Major) Tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of anticonvulsants to control seizures. The use of tramadol in patients on anticonvulsant medications for seizure therapy is not recommended. In addition, the hepatic metabolism of tramadol may be accelerated by the use of ethotoin, phenytoin, or fosphenytoin.
    Pimozide: (Major) Concurrent use of tramadol and pimozide should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and pimozide.
    Posaconazole: (Major) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with posaconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of posaconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Pramipexole: (Moderate) Tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants, such as pramipexole. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Pregabalin: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including tramadol, can potentiate the CNS effects (e.g., increased sedation) of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Primidone: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Procarbazine: (Major) Avoid use of tramadol concurrently or within 14 days of discontinuing a drug with monamine oxidase inhibitor (MAOI)-like activity, such as procarbazine. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases. International recommendations contraindicate the use of tramadol within 14 days of an MAOI. There is an increased risk of seizures and serotonin syndrome in patients receiving these drugs currently. In animal studies, an increased number of deaths was noted with the combination due to interference with detoxification mechanisms.
    Prochlorperazine: (Moderate) Concurrent use of tramadol and prochlorperazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and prochlorperazine.
    Promethazine: (Moderate) Caution is advisable during concurrent use of tramadol and promethazine. Seizures have been reported in patients receiving monotherapy with both tramadol and promethazine at recommended doses. Concomitant use of tramadol and promethazine may increase the risk of seizures. In addition, due to the primary CNS effects of promethazine, caution is advisable during use of other centrally acting medications such as tramadol. Impairment of metabolism of tramadol by CYP2D6 inhibitors, such as promethazine, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6 inhibitor may decrease tramadol analgesic efficacy.
    Propafenone: (Moderate) As propafenone is a moderate CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Decreased analgesia might occur. Inhibition of either CYP2D6 and/or CYP3A4 is also expected to reduce the metabolic clearance of tramadol and may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Propantheline: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Propoxyphene: (Major) As propoxyphene is a moderate CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6 (and CYP3A4), concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Protriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Quazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Quetiapine: (Moderate) Due to the primary CNS effects of quetiapine, caution should be used when given in combination with other centrally acting medications, such as tramadol. Both of these medications can lower the seizure threshold when used alone, therefore there is an even greater risk when they are used concomitantly.
    Quinidine: (Moderate) As quinidine is a potent inhibitor of CYP2D6 and tramadol is partially metabolized by CYP2D6, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Quinine: (Moderate) Quinine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme including tramadol.
    Ranolazine: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Rasagiline: (Severe) Rasagiline is contraindicated for use with tramadol due to the risk of serotonin syndrome. 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. At least 14 days should elapse between the discontinuation of rasagiline and the initiation of tramadol.
    Remifentanil: (Major) Concomitant use of tramadol and remifentanil increases the risk of adverse effects including seizures, serotonin syndrome, and additive opioid toxicity. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected or significant adverse events occur.
    Ribociclib: (Moderate) Use caution with coadministration of ribociclib and tramadol, as the systemic exposure of tramadol may be increased resulting in an increase in treatment-related adverse reactions including seizures, sedation, and respiratory depression. Ribociclib is a moderate CYP3A4 inhibitor. Tramadol is primarily metabolized by CYP2D6 to an active O-demethylated metabolite (M1) that is critical for its analgesic activity; CYP3A4 is involved in tramadol metabolism to inactive metabolites. Inhibition of CYP3A4 may increase formation of the active metabolite via CYP2D6 metabolism.
    Ribociclib; Letrozole: (Moderate) Use caution with coadministration of ribociclib and tramadol, as the systemic exposure of tramadol may be increased resulting in an increase in treatment-related adverse reactions including seizures, sedation, and respiratory depression. Ribociclib is a moderate CYP3A4 inhibitor. Tramadol is primarily metabolized by CYP2D6 to an active O-demethylated metabolite (M1) that is critical for its analgesic activity; CYP3A4 is involved in tramadol metabolism to inactive metabolites. Inhibition of CYP3A4 may increase formation of the active metabolite via CYP2D6 metabolism.
    Rifampin: (Moderate) Tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6. Higher doses of tramadol may be required when it is given concurrently with other agents that induce this isoenzyme, such as rifampin.
    Risperidone: (Major) Concurrent use of tramadol and risperidone should be avoided if possible due to a possible increased risk of seizures. Seizures have been reported in patients receiving monotherapy with tramadol or antipsychotics at recommended doses. In addition, due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally-acting medications such as tramadol.
    Ritonavir: (Major) Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations.
    Rizatriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Rolapitant: (Major) Use caution if tramadol and rolapitant are used concurrently, and monitor for tramadol-related adverse effects as well as possible changes to the efficacy of tramadol. Rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Ropinirole: (Moderate) Ropinirole can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Safinamide: (Severe) Safinamide is contraindicated for use with tramadol due to the risk of serotonin syndrome. 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. At least 14 days should elapse between the discontinuation of safinamide and the initiation of tramadol.
    Scopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Secobarbital: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Sedating H1-blockers: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including tramadol.
    Serotonin-Receptor Agonists: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. SSRIs that are CYP2D6 inhibitors, including sertraline, can prevent the formation of the active M1 metabolite of tramadol. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tramadol, which is partially metabolized by CYP3A4. Monitor patients for adverse effects of tramadol, such as seizures and serotonin syndrome.
    Sodium Oxybate: (Major) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with drugs that are known to lower seizure threshold such as tramadol.
    Solifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of tramadol 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.
    St. John's Wort, Hypericum perforatum: (Moderate) Concurrent use of St. John's Wort with other agents that decrease the neuronal uptake of serotonin, such as tramadol, may increase the risk of a serious serotonin syndrome reaction.
    Sufentanil: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, 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.
    Sumatriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tapentadol: (Major) Because of the potential risk and severity of serotonin syndrome and/or seizures, use tramadol with extreme caution, if at all, in patients receiving immediate-release tapentadol; discontinue tramadol prior to initiating and while taking extended-release tapentadol. Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. In addition, the risk of seizure is increased in patients receiving tramadol with other opioids. These effects may occur within therapeutic dose ranges. 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. Additive CNS depressant effects and respiratory depression are also possible.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and tramadol. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity, including tramadol.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering tramadol with telaprevir due to an increased potential for tramadol-related adverse events. If tramadol dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tramadol. Tramadol is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated tramadol plasma concentrations.
    Telithromycin: (Moderate) Increased serum concentrations of tramadol would be expected from concurrent use of tramadol and a CYP3A4 inhibitor, such as telithromycin (see tramadol Pharmacokinetics). The risk for serious adverse effects such as seizures and serotonin syndrome may be increased.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and tramadol is necessary, as the systemic exposure of tramadol may be decreased resulting in reduced efficacy and in some patients, may result in signs and symptoms of opioid withdrawal. If these drugs are used together, monitor patients for suboptimal efficacy of tramadol; consider increasing the dose of tramadol if necessary. The discontinuation of telotristat ethyl may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression. Tramadol is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Terbinafine: (Moderate) As terbinafine inhibits CYP2D6 and tramadol is partially metabolized by CYP2D6, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Tetrabenazine: (Moderate) Additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression. Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as tramadol, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as tramadol due to the potential for additive sedative effects.
    Thiethylperazine: (Major) Administration of tramadol may enhance the seizure risk in patients taking other medications, such as thiethylperazine, that decrease the seizure threshold. Additive CNS depression may also occur when thiethylperazine is given concurrently with tramadol.
    Thiopental: (Moderate) Tramadol can cause additive CNS depression when used with barbiturates. Phenobarbital may induce the metabolism of tramadol. In addition, tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of phenobarbital to control seizures.
    Thioridazine: (Major) Concurrent use of tramadol and thioridazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, thioridazine has clinically significant CYP2D6 inhibitory effects and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by thioridazine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and thioridazine.
    Thiothixene: (Major) Concurrent use of tramadol and thiothixene should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that thiothixene is a weak CYP2D6 inhibitor and has the potential to decrease the metabolism of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by thiothixene may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and thiothixene.
    Tizanidine: (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 an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Tolterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of tramadol 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.
    Topiramate: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    Trazodone: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tramadol, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Triazolam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Trifluoperazine: (Moderate) Concurrent use of tramadol and trifluoperazine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and trifluoperazine.
    Trihexyphenidyl: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug. The concomitant use of tramadol 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.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like tramadol, may potentiate the effects of either trimethobenzamide or tramadol.
    Trimipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as tramadol. Both tramadol and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro drug interaction studies in human liver microsomes indicate that amitriptyline may inhibit the metabolism of tramadol via CYP2D6, suggesting that concomitant administration of TCAs could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tricyclic antidepressants may decrease the seizure threshold and have been associated with increased risk of seizures when given concurrently with tramadol.
    Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as trospium. The concomitant use of tramadol 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.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and tramadol may result in altered concentrations of tramadol. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tramadol is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In one case, the addition of tramadol to extended-release venlafaxine (300 mg/day) and mirtazapine (30 mg/day) likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful. Also, duloxetine and venlafaxine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Patients receiving tramadol in combination with an SNRI should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Vigabatrin: (Moderate) Tramadol may decrease the seizure threshold and thus, interfere with the ability of anticonvulsants to control seizures. Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given in combination with tramadol.
    Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as 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. Patients receiving vilazodone and tramadol should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as tramadol.
    Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with serotonergic antidepressants. Patients receiving tramadol in combination with vortioxetine should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Warfarin: (Major) Elevation of prothrombin times during concurrent tramadol and warfarin usage has been reported rarely during the post-marketing period. Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol. For example, a patient stabilized on warfarin 5 mg/daily had an increased INR from 3.5 to 7.1. He had begun tramadol 50 mg three times daily 1 month earlier. In another case, addition of tramadol 50 mg every 6 hours to a stable dose of warfarin 45 mg/week resulted in an INR of 10.6. The patient had begun tramadol about 2 weeks before presentation and stopped tramadol 2-3 days earlier. Cessation of warfarin and slow reinstitution of 45 mg/week led to a therapeutic INR. The mechanism of the interaction is unknown; tramadol is not highly protein bound and is not known to affect enzymes associated with the metabolism of warfarin. Closely monitor patients who require the combination of tramadol and warfarin for changes in INR and bleeding. Another alternative analgesic agent may be warranted in patients receiving warfarin.
    Zaleplon: (Moderate) Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants such as zaleplon. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Ziconotide: (Moderate) Tramadol is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary.
    Ziprasidone: (Moderate) Concurrent use of tramadol and ziprasidone should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and ziprasidone.
    Zolmitriptan: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Zolpidem: (Moderate) Extreme caution is needed in using tramadol at the same time as zolpidem. Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants like tramadol than with zolpidem alone. In addition, tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants.

    PREGNANCY AND LACTATION

    Pregnancy

    Because of the potential for serious adverse events, including excess sedation and respiratory depression in a breast-fed infant, breast-feeding is not recommended during treatment with tramadol. Tramadol and its metabolite are excreted into human milk in small amounts. Samples of breast milk taken from 75 women 2 to 4 days postpartum after receiving at least 4 doses of tramadol indicated that an exclusively breast-fed infant would receive 2.24% of the maternal weight adjusted dose of tramadol and 0.64% of its metabolite. Assessments of the infants of these mothers using the Neurologic and Adaptive Capacity Score found no difference when compared to infants in a control group. Forty-nine percent of mothers in the tramadol group and 100% of mothers in the control group were also receiving other opioids (mostly oxycodone). If an infant is breast-fed while receiving tramadol, monitor the infant for adverse reactions, including excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped or when breast-feeding is stopped. Tramadol is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because the safety of tramadol in the exposed infant has not been studied. After a single tramadol 100 mg IV dose, the cumulative excretion in breast milk within 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. Alternative analgesics that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include acetaminophen, ibuprofen, and morphine.

    MECHANISM OF ACTION

    Mechanism of Action: Tramadol has a unique dual mechanism of pain relief. It has central opiate receptor agonist activity and, thus, exerts an analgesic effect from binding of the parent drug and the O-desmethyltramadol metabolite (M1) to mu-receptors. The relative contribution of tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics). There are limited data available on the efficacy of tramadol for pain in poor versus extensive CYP2D6 metabolizers. Data from a randomized, double-blind, crossover study suggest that receipt of tramadol 2 mg/kg orally produces a greater analgesic effect, especially after the first 4 hours after dosing in extensive metabolizers whereas the analgesic effect in poor metabolizers is more modest but is sustained up to 10 hours after dosing. The threshold for pressure pain detection, tolerance, nociceptive reflex, and peak pain as compared with placebo was greater in extensive metabolizers as compared with the difference between placebo and tramadol receipt in poor metabolizers. The affinity of tramadol for mu-receptors is 10-fold less than codeine, 60-fold less than propoxyphene, and 6000-fold less than morphine. The M1 metabolite has 4—200 times greater affinity for the µ-receptor than tramadol. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone (see Interactions). Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists decrease intracellular cAMP by inhibiting adenylate cyclase which modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood.In addition to central opiate receptor agonist activity, tramadol exerts norepinephrine and serotonin reuptake inhibition in the CNS, which inhibits pain transmission in the spinal cord. The monoaminergic reuptake blockade, similar to MAOIs, is an important contribution to the analgesic and adverse event profile of tramadol. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100—1000 times less than those of imipramine.

    PHARMACOKINETICS

    Tramadol is administered orally, rectally, or intravenously; however, only the oral formulations are available in the United States. Tramadol has a high tissue affinity. Minimum protein binding occurs (about 20%) and appears to be independent of concentration up to 10 mcg/ml. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. The drug volume of distribution ranges from 2.6 to 2.9 l/kg. Tramadol is known to cross the placenta; in 40 women given tramadol during labor, a mean ratio of tramadol serum concentration in umbilical veins as compared to maternal veins was 0.83. Approximately 0.1% of the maternal dose of the dose is distributed into breast milk.
     
    Tramadol undergoes significant first-pass metabolism following oral administration. Hepatic metabolism takes place via two metabolic, phase I pathways to form N- and O-demethylated tramadol. Of a tramadol dose, 60% is metabolized by the liver. The metabolism is also stereoselective; the (-) enantiomer undergoes O-demethylation selectively, and the (+) enantiomer preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. O-demethylation is mediated by CYP2D6, and the O-demethylated metabolites are further conjugated (phase II reactions). Of eleven identified metabolites, only the O-demethylated metabolite (M1) has analgesic activity, which appears to be critical to the activity of tramadol. The production of M1 depends on CYP2D6. Patients with impaired CYP2D6 activity or those receiving concurrent medications that affect CYP2D6 or CYP3A4 enzymes (see Drug Interactions) may experience an altered response to tramadol. Excretion of tramadol and its metabolites is mostly renal. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. In normal healthy adults, the mean terminal plasma elimination half-lives of racemic tramadol and racemic M1, respectively, are approximately 6.3 and 7.4 hours after administration of immediate-release tramadol (either ODT or regular tablets), 7.9 and 8.8 hours after administration of coated extended-release tablets, 6.5 and 7.5 hours after administration of dual-matrix extended-release tablets, and 10 and 11 hours after administration of extended-release capsules.

    Oral Route

    Immediate-release tablets (e.g., Ultram): Absorption of immediate-release tablets is rapid and bioavailability is 68% after single doses and approaches 100% after multiple doses; the increase in bioavailability with multiple doses is thought to be due to saturable first-pass metabolism. The rate and extent of oral absorption of the immediate-release tablets is not significantly affected by food. Tramadol is detected in plasma within 15—45 minutes of oral dosing, with peak plasma concentrations of tramadol occurring at about 1.5 hours post-dose and peak plasma concentrations of the active metabolite M1 occurring at about 2 hours post-dose. Analgesia onset is within 1 hour of administration of the immediate-release tablets with a peak effect around 2—3 hours; analgesia lasts about 6 hours. Similar to the orally disintegrating tablets and the dual-matrix extended-release tablets, steady state concentrations are achieved after two days of multiple dosing with the immediate-release tablets.
    Orally disintegrating tablets (Rybix ODT): The absolute bioavailability of orally disintegrating tramadol is approximately 75% following the administration of a single 100 mg dose. The rate and extent of oral absorption of the orally disintegrating tablets is not significantly affected by food. There are no studies to indicate that the onset of action of tramadol orally disintegrating tablets (time unstated) is any faster than that of the immediate-release tablets (within 1 hour). Following administration of orally disintegrating tablets, peak plasma concentrations of tramadol occur at approximately 2 hours post-administration and peak plasma concentrations of the active metabolite M1 occur at approximately 3 hours post-dose. As with the immediate-release tablet and the dual-matrix extended-release tablets, steady state concentrations are achieved after two days of multiple dosing with the orally disintegrating tablets. At equipotent doses of immediate-release and orally disintegrating tablets, the AUC, Cmax, time to peak exposure, and half-life of tramadol are similar.
    Dual-matrix extended-release tablets (Ryzolt): The dual-matrix release tablet has characteristics of both the immediate-release and the coated extended-release formulations. The bioavailability of a 200 mg dual-matrix extended-release tablet, relative to a 50 mg immediate-release tablet every 6 hours, was 95%. The rate and extent of oral absorption of the dual-matrix extended-release tablets is not significantly affected by food. Following administration of dual matrix extended-release tablets, peak plasma concentrations of tramadol occur at about 4 hours post-dose and the peak plasma concentrations of the active metabolite M1 occur at about 5 hours post-dose. Steady state concentrations are achieved after two days of multiple dosing with the dual-matrix extended-release tablets compared to 2 days of either immediate-release tablet or orally disintegrating tablet therapy and 4 days of coated extended-release tablet use. In healthy patients, pharmacokinetic parameters are approximately dose proportional over a 100—300 mg dose range.
    Coated extended-release tablets (e.g., Ultram ER): The bioavailability of a 200 mg coated extended-release tablet, relative to a 50 mg immediate-release tablet every 6 hours, was approximately 85—90%. Unlike other oral dosage formulations, coated extended-release tablets are recommended to be taken in a consistent manner with or without food, as the Cmax and systemic exposure of tramadol decreased 28% and 16%, respectively, when a single 200 mg dose was taken with a high fat meal as compared with fasting conditions. Further, the mean Tmax increased from 14 hours under fasting conditions to 17 hours under fed conditions. Following administration of coated extended-release tablets, peak plasma concentrations of tramadol occur at about 12 hours post-dose and peak plasma concentrations of the active metabolite M1 occur at about 15 hours post-dose. The mean Cmax and systemic exposure at steady state are similar for 200 mg coated extended-release tablets administered once daily and 50 mg immediate-release tablets administered every six hours. Steady state concentrations are achieved after 4 days of therapy with the coated extended-release tablets compared to 2 days of therapy with the dual-matrix extended-release tablets. In healthy patients, pharmacokinetic parameters are approximately dose proportional over a 100—400 mg dose range. However, systemic exposure after tramadol 400 mg oral dose of coated extended-release tablet was 26% higher than predicted based on systemic exposure after a 200 mg dose.
    Extended-release capsules (ConZip): Extended-release tramadol capsules contain both immediate-release (IR) and extended-release (ER) tramadol in the following specific amounts: 100 mg capsules contain 25 mg IR and 75 mg ER, 200 mg capsules contain 50 mg IR and 150 mg ER, and the 300 mg capsules contain 50 mg IR and 250 mg ER. The rate and extent of oral absorption is not significantly affected by food. Following administration, peak plasma concentrations of tramadol occur at 5.9 hours post-dose and the peak plasma concentrations of the active metabolite M1 occur at 11 hours post-dose. Steady state concentrations of both tramadol and M1 are achieved after four days of once-daily dosing. In healthy patients, pharmacokinetic parameters are approximately dose proportional over a 100—300 mg dose range.

    Intramuscular Route

    NOTE: This dosage form is not available in the U.S.
     
    Following IM administration, the bioavailability of tramadol is 100%.

    Other Route(s)

    Rectal Route
    NOTE: This dosage form is not available in the U.S.
     
    Following rectal administration, the bioavailability of tramadol is 78%.