Tramadol Hcl Er (tramadol HCl)

Available as tramadol hydrochloride; dosage expressed in terms of the salt.

Use the lowest effective dosage and shortest duration of therapy consistent with the treatment goals of the patient.

Individualize initial dosage based on severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse. Dosage should be titrated to a level that provides adequate analgesia and minimizes adverse effects. If level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the dosage.

Tramadol hydrochloride is administered orally as immediate- or extended-release preparations.

Tramadol is commercially available as a single-entity preparation in various dosage forms and in fixed combination with acetaminophen. Consult the prescribing information for additional information on the fixed combination product.

Tramadol hydrochloride is extensively metabolized by cytochrome P-450 (CYP) isoenzymes 2D6 and 3A4, as well as by conjugation. The formation of the active metabolite, O-desmethyl tramadol (M1), is dependent on CYP2D6.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Opioid Analgesics/Opioid Antagonists

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Naltrexone, nalmefene, and samidorphan are opioid antagonists and thus inhibit the effects of opioid analgesics.(1-3)

CLINICAL EFFECTS: Concurrent administration or the administration of naltrexone within 7-10 days of opioids may induce acute abstinence syndrome or exacerbate a pre-existing subclinical abstinence syndrome.(1,4) Patients taking naltrexone may not experience beneficial effects of opioid-containing medications.(4) Samidorphan can precipitate opioid withdrawal in patients who are dependent on opioids. In patients who use opioids, delay initiation of samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids.(3) Concurrent use of nalmefene tablets with opioid agonists may prevent the beneficial effects of the opioid.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of naltrexone states that the administration of naltrexone concurrently with opioids or to patients dependent on opioids is contraindicated.(1,4) Patients previously dependent on short-acting opioids should be opioid-free for a minimum of seven to ten days before beginning naltrexone therapy. Patients previously on buprenorphine or methadone may be vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4) The manufacturer of naltrexone states that the naloxone challenge test, described in the naltrexone prescribing information, can be administered to determine if patients are opioid free.(1) The manufacturer of samidorphan states the concurrent use of samidorphan in patients using opioids or undergoing acute opioid withdrawal is contraindicated. Prior to initiating samidorphan, there should be at least a 7-day opioid free interval from the last use of short-acting opioids, and at least a 14-day opioid free interval from the last use of long-acting opioids.(3) The UK manufacturer of nalmefene tablets (for reduction of alcohol consumption) states the concurrent use of opioid analgesics is contraindicated.(2) Suspend the use of nalmefene tablets for 7 days prior to the anticipated use of opioids (e.g., elective surgery).(2)

DISCUSSION: A double-blind, randomized, placebo-control study evaluated pain relief and side effects of 35 opioid-naive patients undergoing cesarean section. All patients received spinal anesthesia (bupivacaine and morphine) and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone 6 mg. Patients treated with naltrexone experienced shorter duration of pain relief (not statistically significant), however incidence of opioid-induced side effects was reduced. Patients in the naltrexone 6 mg group had lower rates of pruritus, vomiting, and somnolence (all statistically significant) compared to the placebo group.(5) In a double-blind, randomized, placebo-control trial ten recreational opioid users were studied to determine the effects of hydromorphone (4 mg and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after pretreatment with naltrexone (50 mg) or placebo. Results show that lower doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone 16 mg alone caused euphoria and miosis which were blocked by naltrexone. Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared to hydromorphone. Naltrexone partially diminished the euphoria caused by tramadol, while it enhanced some of the unpleasant monoaminergic effects (flushing, malaise, vomiting).(6) A case report describes a 28 year-old ex-heroin addict who was stable on methadone 100 mg daily and simultaneously stopped using heroin and began drinking alcohol. He was admitted to the hospital for alcohol detoxification and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg. The patient experienced withdrawal symptoms including chills, agitation, muscle and abdominal pain, generalized piloerection, and dilated pupils. Treatment of withdrawal was titrated to treat symptoms and required administration 78 mg of parenteral hydromorphone, after which the patient experienced relief for the following six hours.(8) Intentional administration of an opioid antagonist, naloxone, with opioid analgesics has been performed with close monitoring to lower required opioid dose by inducing withdrawal. Three case reports describe patients who had improved pain relief on significantly reduced doses of opioid analgesics.(8) In a double-blind controlled trial, 267 trauma patients were randomized to receive 0.05 mg/kg intravenous morphine either alone or in combination with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction of pain and incidence of side effects. Results indicate that ultra-low dose naltrexone does not alter opioid requirements for pain control, but does lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9)

Propoxyphene; Tramadol/Rasagiline; Selegiline

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tramadol and propoxyphene inhibit neural reuptake of serotonin. MAOIs may increase neuronal serotonin concentrations via inhibition of MAO-A.

CLINICAL EFFECTS: The concurrent use of some opioids with MAOIs has resulted in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: High doses or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The US manufacturers of both rasagiline and selegiline state that use of propoxyphene or tramadol is contraindicated during therapy with and within 14 days of discontinuation of rasagiline or selegiline due to the risk for serotonin syndrome.

DISCUSSION: The US manufacturer of rasagiline reports a case of serotonin syndrome in a patient treated with both tramadol (dose not stated) and rasagiline 4 mg daily, and also warns that cases of serotonin syndrome have been reported with concomitant use of meperidine, methadone, or propoxyphene. The interaction between meperidine and MAOIs has been well documented. There are two reports of potential interactions between MAOIs and dextromethorphan. There is one case report of serotonin syndrome with concurrent meperidine and linezolid. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Serotonergic Agents/Dapoxetine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Slt Serotonergic Opioids (Extended Release)/Metaxalone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of serotonergic opioids and metaxalone, a weak monoamine oxidase (MAO) inhibitor, may result in additive CNS depression and additive serotonergic effects.(1-3)

CLINICAL EFFECTS: Concurrent use of opioids and metaxalone may result in profound sedation, respiratory depression, coma, and/or death.(1-3) The concurrent use of some opioids with serotonergic properties with metaxalone may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Treatment with multiple medications which increase serotonin levels or inhibit the metabolism of serotonin are risk factors for serotonin syndrome. Higher opioid concentrations, as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for an interaction.

PATIENT MANAGEMENT: Use an alternative analgesic when possible. If concurrent therapy is unavoidable, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1,3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1,3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(7) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(8) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(9) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(10) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(11) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(12) Although documentation is lacking for some opioids, the FDA recommends health professionals monitor and advise patients to report symptoms of serotonin syndrome in patients receiving analgesic opioids and serotonergic agents.(3) Metaxalone is a weak inhibitor of MAO.(2,13)

Tramadol/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tramadol and MAO inhibitors (MAOIs) may lower the seizure threshold.(1-3) Both tramadol and MAOIs may increase serotonin and norepinephrine. Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while MAOIs impair metabolism of serotonin and norepinephrine via inhibition of monoamine oxidase(MAO).(1-3)

CLINICAL EFFECTS: Concurrent use of tramadol and an inhibitor of monoamine oxidase may result in seizures or serotonin syndrome.(1-3) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: CYP2D6 poor metabolizers, or patients also taking strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, terbinafine) will inhibit tramadol metabolism leading higher systemic levels of tramadol. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(3) The risk of seizure may also be increased in patients receiving more than the upper daily dose limit of tramadol or in patients taking other medications that lower seizure threshold.(1-2)

PATIENT MANAGEMENT: The Australian manufacturers of tramadol state that it is contraindicated in patients who are currently receiving monoamine oxidase inhibitors or who have received them in the previous 14 days.(1,2) The US manufacturer of tramadol states that tramadol should be used with caution in patients taking monoamine oxidase inhibitors and in patients receiving antidepressants.(3)

DISCUSSION: The use of tramadol in patients taking monoamine oxidase inhibitors may increase the risk of seizures, serotonin syndrome, and suicide.(3) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(4,5) Metaxalone is a weak inhibitor of MAO.(7,8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Anticholinergics; Opioids/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

Chronic Opioids/Buprenorphine; Pentazocine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Buprenorphine antagonizes mu-opiate receptors.(1) Pentazocine is a mixed agonist-antagonist at opiate receptors.(2) Other opioids agonize mu-opiate receptors.

CLINICAL EFFECTS: Concurrent use of buprenorphine or pentazocine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.

PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses of opioids may be more likely to experience withdrawal symptoms with concurrent use.

PATIENT MANAGEMENT: Use buprenorphine and pentazocine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. The manufacturer of Sublocade states buprenorphine may precipitate opioid withdrawal in patients who are currently physically dependent on full opioid agonists. The risk of withdrawal may be increased if buprenorphine is given less than 6 hours after short-acting opioids (such as heroin, morphine) and less than 24 hours after long-acting opioids (such as methadone).(3)

DISCUSSION: In clinical trials, administration of buprenorphine injection produced withdrawal symptoms in patients maintained on methadone (30 mg daily) when administered 2 hours post-methadone,(4) but not when administered 20 hours post-methadone.(5) In another study, sublingual buprenorphine produced withdrawal symptoms in patients maintained on methadone. Symptoms were more pronounced in patients maintained on 60 mg daily doses than in patients maintained on 30 mg daily doses.(6) In a study of 10 patients maintained on methadone (100 mg daily), only three were able to tolerate escalating sublingual doses of buprenorphine/naloxone up to 32/8 mg. Split doses produced less withdrawal symptoms than full doses.(7) In a case report, a heroin-user maintained in a buprenorphine-maintenance program began stockpiling his buprenorphine instead of ingesting it and began using heroin. He then decided to re-initiate treatment on his own and ingested between 80 and 88 mg of buprenorphine over a two day period and experienced extreme withdrawal symptoms, despite restarting heroin during these symptoms. Methadone relieved his withdrawal symptoms.(8)

Chronic Opioids/Butorphanol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Butorphanol antagonizes mu-opiate receptors.(1) Other opioids agonize mu-opiate receptors.

CLINICAL EFFECTS: Concurrent use of butorphanol with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.

PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses of opioids may be more likely to experience withdrawal symptoms with concurrent use.

PATIENT MANAGEMENT: Use butorphanol with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects.

DISCUSSION: In a study in patients maintained on methadone, butorphanol produced withdrawal symptoms comparable to naloxone.(2) In a case report, the use of remifentanil for conscious sedation in a patient maintained on butorphanol produced severe withdrawal symptoms.(3)

Chronic Opioids/Nalbuphine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Nalbuphine antagonizes mu-opiate receptors.(1) Other opioids agonize mu-opiate receptors.

CLINICAL EFFECTS: Concurrent use of nalbuphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.

PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses of opioids may be more likely to experience withdrawal symptoms with concurrent use. In opioid naive patients, higher doses of nalbuphine may result in decreased analgesic effects.

PATIENT MANAGEMENT: Use nalbuphine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. If nalbuphine is used to reverse opioid anesthesia, monitor patients for renarcotization.

DISCUSSION: Nalbuphine has been successfully used as an adjunct to morphine without decreasing analgesic effects.(2,3) However, other studies reported increased morphine requirements in patients who had initially received nalbuphine.(4,5) Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however, patients often required additional pain medication(5-7) and some studies reported renarcotization after the effects of nalbuphine wore off.(9,10) Nalbuphine has also been used to prevent epidural fentanyl,(13) morphine(14-16), and hydromorphone induced pruritus;(17,18) however, one study reported shortening of the duration of analgesia(16) and another reported increased PCA demands.(17) In methadone-dependent subjects, administration of nalbuphine produced withdrawal symptoms similar to naloxone.(19,20) Administration of nalbuphine to patients maintained on controlled-release morphine resulted in withdrawal symptoms.(20,21)

Codeine; Tramadol/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3) Codeine and tramadol are converted to their more active opioid metabolites (morphine and O-desmethyltramadol respectively) by CYP2D6.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and opioids such as tramadol, or alcohol may further increase the risk for respiratory depression and profound sedation, syncope or coma.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) In patients receiving codeine or tramadol, ultrarapid metabolizers of CYP2D6 are more likely to have higher than normal systemic concentrations of the active opioid.(4) Other patients at high risk from this interaction include: adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of respiratory depression; and breastfeeding women (due to the risk of serious adverse reactions in breastfed infants).(5)

PATIENT MANAGEMENT: Avoid use of oxybate when concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Codeine and tramadol are converted to their active opioid metabolites by CYP2D6. Ultrarapid metabolizers of CYP2D6 more rapidly convert codeine or tramadol to their active metabolites (morphine and o-desmethyltramadol respectively) and so are more likely to have higher than normal systemic concentrations of the active opioid. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS) and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. FDA reported the case of a 5-year-old patient who received one dose of tramadol following a tonsillectomy and experienced slow, difficult breathing requiring emergency intervention and hospitalization. The child was subsequently found to be an ultrarapid metabolizer of CYP2D6.(4) Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Tramadol/Cyclobenzaprine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tramadol and cyclobenzaprine, a tricyclic compound, both may lower the seizure threshold, have additive effects on serotonin levels,(1) and cause additive CNS depression.(3)

CLINICAL EFFECTS: Concurrent use of tramadol and cyclobenzaprine may result in increased risk of seizures, serotonin syndrome, suicide,(1) profound sedation, respiratory depression, coma, and/or death.(3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tramadol should be used with caution in patients taking tricyclic compounds, including cyclobenzaprine. Monitor patients closely for serotonin syndrome.(1) Limit prescribing opioid analgesics with CNS depressants such as cyclobenzaprine to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(3) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The use of tramadol in patients treated with tricyclic compounds may increase the risk of seizures.(1) A review of 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 23% of the patients were also taking tricyclic antidepressants.(2) Therefore, the manufacturer of tramadol states that tramadol should be used with caution in patients treated with tricyclic compounds.(1) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9)

Tramadol/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tramadol and linezolid may lower the seizure threshold.(1-3) Both tramadol and linezolid may increase serotonin and norepinephrine. Tramadol inhibits neuronal reuptake of serotonin and norepinephrine, while linezolid impairs metabolism of serotonin and norepinephrine via inhibition of monoamine oxidase(MAO).(1-3)

CLINICAL EFFECTS: Concurrent use of tramadol and linezolid may result in seizures or serotonin syndrome.(1-3) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(4)

PREDISPOSING FACTORS: CYP2D6 poor metabolizers,(5) or patients also taking strong CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, terbinafine) will have reduced tramadol metabolism leading higher systemic levels of tramadol. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1) The risk for seizures may also be increased in patients receiving more than the upper daily dose limit of tramadol, or in patients taking additional medications which lower the seizure threshold.(1)

PATIENT MANAGEMENT: Evaluate the patient for predisposing factors (other drugs, diseases or conditions) which may further increase the risk for serotonin syndrome or seizures. When possible and clinically appropriate, change to an alternative analgesic or antibiotic, particularly when predisposing factors are present. If concomitant therapy is necessary, monitor patient for signs of serotonin toxicity (e.g. tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, muscle rigidity) or seizures, especially after tramadol dose increases. Manufacturer prescribing recommendations: The US manufacturer of tramadol states that tramadol should be used with caution in patients taking monoamine oxidase inhibitors.(1) In contrast, an Australian manufacturer of tramadol states that it is contraindicated in patients who are currently receiving monoamine oxidase inhibitors or who have received them in the previous 14 days.(2) The US manufacturer of linezolid does not have specific recommendations regarding concurrent treatment with tramadol but does state that linezolid should not be used in patients receiving serotonergic drugs (e.g. SSRIs, TCAs, meperidine) unless clinically appropriate and patients are carefully observed for signs and symptoms of serotonin syndrome.(3)

DISCUSSION: Tramadol and its M1 metabolite are pharmacologically active. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The active M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP P-450-2D6 converts tramadol to M1.(1,5) A study in surgery patients included 2D6 EM patients who received concomitant treatment with tramadol and 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. Authors noted some EM patients were converted to the PM phenotype.(6)

Tramadol/Meperidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The concurrent administration of tramadol(1) with meperidine(2) may result in additive blockade of serotonin reuptake, leading to central serotonergic hyperstimulation, as well as additive sedation, respiratory depression, coma, and/or death.

CLINICAL EFFECTS: Concurrent administration may increase the risk for adverse events, including serotonin syndrome, sedation, and respiratory depression. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers have accelerated conversion of tramadol to its active metabolite, M1, and may be at higher risk of sedation and respiratory depression.(1) Treatment with multiple medications which increase serotonin levels or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(3) A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may increase the risk for serotonin syndrome due to tramadol. Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine.

PATIENT MANAGEMENT: Use an alternative to meperidine whenever possible, particularly in patients with renal impairment. If concurrent therapy of tramadol with meperidine is warranted, patients should be closely monitored for signs and symptoms of sedation, respiratory depression and serotonin syndrome. One or both agents may need to be discontinued. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(2)

DISCUSSION: There are a number of serotonin syndrome case reports following the addition of tramadol to a stable selective serotonin reuptake inhibitor regimen. The syndrome developed between 12 hours to 3 weeks after the initiation of tramadol therapy. Patients recovered after tramadol and/or the SSRI/SNRI was discontinued.(4-16) One patient also developed mania.(4) Another patient developed nightmares and hallucinations after taking concurrent tramadol and paroxetine for 56 days.(5) One author suggests that although the combination of tramadol and SSRIs or SNRIs is associated with a risk for serotonin syndrome, given the high rate of co-prescribing for the combination it is an uncommon outcome.(17) Case reports describe the interaction between meperidine and serotonin-increasing agents.(18-20) Although there are no reports of serotonin syndrome specifically with the combination of tramadol and meperidine, both drugs inhibit serotonin reuptake and caution is still warranted.

Tramadol/Tricyclic Compounds; Carbamazepine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tramadol and tricyclic compounds may lower the seizure threshold.(1) Tramadol inhibits the reuptake of serotonin and norepinephrine but has weak opioid effects. M1, tramadol's active metabolite, is a stronger opioid and up to 6 times more potent than tramadol in producing analgesia.(1) Carbamazepine induces the metabolism of this tramadol opioid metabolite.

CLINICAL EFFECTS: Concurrent use of tramadol and a tricyclic compound may result in seizures or serotonin syndrome and may increase the risk of suicide.(1) Concurrent use of tramadol and carbamazepine may significantly reduce the analgesic effect of tramadol.(1) Although not used therapeutically as an antidepressant, carbamazepine is a tricyclic compound.

PREDISPOSING FACTORS: Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tramadol should be used with caution in patients taking tricyclic compounds.(1) The use of tramadol and carbamazepine is not recommended.(1) Carbamazepine induces metabolism (glucuronidation) of the tramadol opioid metabolite (M1). In patients on long-term carbamazepine when tramadol is started, achieving adequate analgesia may be difficult. Prescribing higher tramadol doses would be associated with higher parent drug levels which may result in serotonin and norepinephrine associated adverse effects. In patients receiving chronic tramadol treatment when carbamazepine is started, anticipate a reduction in analgesic effects. The maximal effects of carbamazepine on tramadol efficacy may not be seen for 2 or more weeks. Monitor for decreased tramadol efficacy, including symptoms of opioid withdrawal, after carbamazepine is initiated or when carbamazepine dosage is increased. If carbamazepine is to be discontinued in patients stabilized on the combination of tramadol and carbamazepine, gradually decrease the carbamazepine dose to decrease the risk of withdrawal seizures. As carbamazepine induction wanes, systemic tramadol metabolite concentrations will rise. The tramadol dose may need to be decreased to prevent tramadol toxicity.

DISCUSSION: The use of tramadol in patients treated with tricyclic compounds may increase the risk of seizures.(1) A review of 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 23% of the patients were also taking tricyclic antidepressants.(2) Therefore, the manufacturer of tramadol states that tramadol should be used with caution in patients treated with tricyclic compounds.(1) The manufacturer of tramadol also states that the use of tramadol with carbamazepine is not recommended.(1) In a case report, a 79 year-old female developed serotonin syndrome three days after the addition of tramadol to amitriptyline therapy. Over the next four days, her condition deteriorated and she died.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents With Hyponatremia Risk/Desmopressin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Meperidine; Tramadol/Trazodone (<= 50 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Meperidine and tramadol inhibit the reuptake of serotonin.(1,2) Metabolism of trazodone leads to formation of the active metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of serotonin receptors.(3,4) Both tramadol and mCPP are metabolized by CYP2D6.(2,4-6)

CLINICAL EFFECTS: Concurrent administration could increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of meperidine, tramadol or mCPP would be predicted to increase risk for serotonin toxicity. Concomitant therapy with other agents which increase brain serotonin concentrations may also increase risk.(1-3,7) Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine. Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic terbinafine) may also increase mCPP and tramadol concentrations, increasing risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher tramadol and mCPP concentrations compared with extensive metabolizers.(2,3)

PATIENT MANAGEMENT: Assess patient for predisposing risk factors and monitor accordingly. Manufacturers of meperidine, tramadol and trazodone recommend careful monitoring for signs and symptoms of serotonin syndrome when a metabolic inhibitor or another serotoninergic agent is started, or when the dose of either agent is increased.(1-3)

DISCUSSION: Meperidine, tramadol and trazodone have each been associated with serotonin syndrome when given concurrently with one or more serotoninergic agents.(1-3) MCPP has been associated with serotonin syndrome when used as a probe of central serotonin function in human investigational studies.(8) CYP3A4 converts trazodone to mCPP which is then converted to an inactive metabolite via CYP2D6.(3,4)

Meperidine; Tramadol/Trazodone (> 50 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tramadol inhibits the reuptake of serotonin.(1,2) Metabolism of trazodone leads to formation of a common active metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of serotonin receptors.(3-5) Both tramadol and mCPP are metabolized by CYP2D6.(1,3-5)

CLINICAL EFFECTS: Concurrent administration could increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of meperidine, tramadol or mCPP would be predicted to increase risk for serotonin toxicity. Concomitant therapy with other agents which increase brain serotonin concentrations may also increase risk.(1-3,6) Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine. Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic terbinafine) may also increase mCPP and tramadol concentrations, increasing risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher tramadol and mCPP concentrations compared with extensive metabolizers.(1,3)

PATIENT MANAGEMENT: Assess patient for predisposing risk factors and monitor accordingly. Manufacturers of meperidine, tramadol and trazodone recommend careful monitoring for signs and symptoms of serotonin syndrome when a metabolic inhibitor or another serotoninergic agent is started, or when the dose of either agent is increased.(1-3)

DISCUSSION: Meperidine, tramadol, and trazodone have each been associated with serotonin syndrome when given concurrently with one or more serotoninergic agents.(1-3) MCPP has been associated with serotonin syndrome when used as a probe of central serotonin function in human investigational studies.(7) CYP3A4 converts trazodone to mCPP which is then converted to an inactive metabolite via CYP2D6.(3-4)

Opioids (Extended Release)/Benzodiazepines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)

Opioids (Extended Release)/Muscle Relaxants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Opioids (Extended Release)/Sleep Drugs

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Opioids (Ir & Er)/Gabapentinoids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Opioid-induced reduction in GI motility may increase the absorption of gabapentin and pregabalin.(1) Gabapentin and pregabalin may reverse opioid-induced tolerance of respiratory depression.(2) Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(3)

CLINICAL EFFECTS: Concurrent use of opioids may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-7)

PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an opioid analgesic, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)

DISCUSSION: In a study in 12 healthy males, administration of a single dose of morphine (60 mg sustained release) increased the area-under-curve (AUC) of a single dose of gabapentin (600 mg) by 44%.(1,3,4) There were no affects on the pharmacokinetics of morphine.(1,3,4) The combination of gabapentin plus morphine increased pain tolerance over the combination of morphine plus placebo. Side effects were not significantly different between morphine plus placebo and morphine plus gabapentin.(1) A retrospective, case-control study of opioid users in Ontario, Canada between August 1, 1997 and December 31, 2013 who died of an opioid-related cause matched cases to up to 4 controls who also used opioids. Use of gabapentin in the 120 days prior to death resulted in a significant increase in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared to opioid use alone. Use of moderate dose (900 mg to 1,799 mg daily) or high dose (>= 1,800 mg daily) gabapentin increased the odds of opioid-related death 60% compared to opioid use without gabapentin. Review of gabapentin prescriptions from calendar year 2013 found that 46% of gabapentin users received at least 1 opioid prescription.(3) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function.(7) A retrospective cohort study evaluated the risk of mortality among Medicare beneficiaries aged 65 and older who were taking gabapentin with or without concurrent use of opioids. All-cause mortality in gabapentin users compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per 1,000 person years, respectively. Adjusted for covariates, the risk of all-cause mortality among gabapentin users on high-dose opioids was more than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10)

Select Opioids (Extended Release)/Select Tranquilizers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs or tranquilizers may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as tranquilizers may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as tranquilizers to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9)

Selected Serotonergic Opioids/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of serotonergic opioids such as meperidine or tramadol and antipsychotics such as ziprasidone may result in additive CNS depression or additive risk of serotonin syndrome.(1)

CLINICAL EFFECTS: Concurrent use of serotonergic opioids such as meperidine or tramadol and antipsychotics such as ziprasidone may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity. Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as meperidine or tramadol with CNS depressants such as antipsychotics, including ziprasidone, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness,(1) as well as for signs of serotonin syndrome. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(12-14)

Serotonergic Agents/Centanafadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Serotonergic Agents/Gepirone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gepirone is a serotonin receptor agonist. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents may increase the risk of hypertensive crisis and serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1)

Tramadol (Extended Release)/Antipsychotics; Phenothiazines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids such as tramadol with antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids such as tramadol with other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as tramadol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Tramadol/5-Ht3 Antagonists

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The interaction may involve a reduction in the binding involving 5-HT3 receptors.(1)

CLINICAL EFFECTS: Concurrent use of 5-HT3 antagonists may decrease the effectiveness of tramadol, resulting in increased use of tramadol.(1-3) 5-HT3 antagonists may not be effective in reducing tramadol-induced nausea.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of alternative anti-emetics in patients receiving tramadol, or the use of other opioids in patients receiving 5-HT3 antagonists.

DISCUSSION: In a randomized study in 59 post-surgical patients in recovery, compared to tramadol alone, patients receiving concurrent ondansetron required significantly larger doses of tramadol at four hours (223 mg versus 71 mg), at 8 hours (285 mg versus 128 mg), and at 12 hours (406 mg versus 190 mg). Vomiting rates at 4 hours and 8 hours were significantly higher with tramadol and concurrent ondansetron compared to tramadol alone.(1) In a randomized, double-blind study in 40 surgical patients undergoing lumbar laminectomy, compared to tramadol alone, cumulative tramadol consumption with concurrent ondansetron during the first 24 hours was significantly increased (between 26% and 35%) as well as thereafter (22% to 25%).(2) In another randomized study in 120 post-surgical patients, it was discovered that tramadol consumption was increased in those patients receiving concurrent ondansetron compared to tramadol alone.(3) In a prospective, randomized, double-blinded study in dental patients, patients received one of four treatments: fentanyl and metoclopramide, tramadol and metoclopramide, fentanyl and ondansetron, or tramadol and ondansetron. The patients who received tramadol and ondansetron had the highest nausea scores among the treatment groups. There were no significant differences in the incidences of pain or nausea in the 24 hours following the procedure.(4) In a randomized, controlled trial in 40 surgical patients undergoing hernioplasty or thyroidectomy, compared to tramadol alone, cumulative tramadol consumption was higher at the 2-hour time point with concurrent ondansetron (0.24 +/- 0.1 vs. 0.17 +/- 0.16; p = 0.01).(5) A systematic review and meta-analysis of randomized controlled trials in the postoperative setting comparing tramadol alone and in combination with ondansetron were included. At 4-hours, 8-hours, 12-hours, and 24-hours post-procedure, patients had increased tramadol requirements when administered with concurrent ondansetron compared to tramadol alone.(6) 5-HT3 antagonists linked to this monograph include: alosetron, azasetron, dolasetron, granisetron, ondansetron, palonosetron, ramosetron, and tropisetron.

Tramadol/Amphetamines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS.(1) Amphetamines may affect serotonin release and/or reuptake, depending on their molecular structure. Ring substitution tends to increase amphetamine-induced release of endogenous serotonin. However, the effect on serotonin release may also be dose related and is more likely if the amphetamine is taken in doses greater than those approved and generally employed in treating attention-deficit-hyperactivity-disorder, or if abused, especially over long periods of time.(2) Concurrent administration of amphetamines with tramadol may result in additive effects on serotonin, resulting in serotonin syndrome.(3,4)

CLINICAL EFFECTS: Opposing CNS effects of opioids and stimulants may compromise the effectiveness of both agents and mask opioid overdose symptoms such as drowsiness and inability to focus. Concurrent use of amphetamines with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. High doses or long-term abuse of amphetamines may increase the risk of serotonin syndrome. Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Limit prescribing tramadol with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Consider initiating amphetamines or tramadol at lower doses and monitor for signs and symptoms of serotonin syndrome. Concurrent use of amphetamines with tramadol should be approached with appropriate monitoring. Discontinue medication if symptoms occur.(3,4) Instruct patients receiving concurrent therapy to report any signs or symptoms of serotonin syndrome immediately. Monitor patients receiving concurrent therapy for signs of substance abuse. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with stimulants.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(1)

DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(7) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(6)

Tramadol/Methylphenidate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Opioids and methylphenidate exhibit opposing effects on the CNS.(1)

CLINICAL EFFECTS: Opposing CNS effects of opioids and stimulants may compromise the effectiveness of both agents and mask opioid overdose symptoms such as drowsiness and inability to focus.

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing tramadol with CNS stimulants such as methylphenidate to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Concurrent use of methylphenidate with tramadol should be approached with appropriate monitoring. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)

Tramadol/Nefazodone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tramadol inhibits the reuptake of serotonin.(1) Metabolism of nefazodone leads to formation of a common active metabolite, m-chlorophenylpiperazine (mCPP) which is an agonist at a variety of serotonin receptors.(2-3) Both tramadol and mCPP are metabolized by CYP2D6.(1,3-5)

CLINICAL EFFECTS: Concurrent administration could increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of tramadol or mCPP would be predicted to increase risk for serotonin toxicity. Concomitant therapy with other agents which increase brain serotonin concentrations may also increase risk.(1,2,6) Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine. Concomitant treatment with inhibitors of CYP2D6 (e.g. bupropion, cinacalcet, duloxetine, fluoxetine, paroxetine, quinidine, or systemic terbinafine) may also increase mCPP and tramadol concentrations, increasing risk for serotonin toxicity. Patients who are poor metabolizers at CYP2D6 would be expected to have higher tramadol and mCPP concentrations compared with extensive metabolizers.(1)

PATIENT MANAGEMENT: Assess patient for predisposing risk factors and monitor accordingly. The manufacturer of tramadol recommends careful monitoring for signs and symptoms of serotonin syndrome when a metabolic inhibitor or another serotoninergic agent is started, or when the dose of either agent is increased.(1)

DISCUSSION: Nefazodone and tramadol have each been associated with serotonin syndrome when given concurrently with one or more serotoninergic agents.(1-2) MCPP has been associated with serotonin syndrome when used as a probe of central serotonin function in human investigational studies.(7) Nefazodone has several active metabolites, including mCCP. Although systemic mCPP concentrations are low relative to nefazodone concentrations, in animal studies the ratio of brain:blood concentrations for mCPP to nefazodone were 47:1 and 10:1 in the mouse and rat respectively.(3)

Tramadol/Selected Moderate To Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine, hydroquinidine, levomepromazine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1)

CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)

PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14)

PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12)

DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)

Tramadol/Selected Ssris; Snris

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The concurrent administration of tramadol with a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) may result in additive blockade of serotonin reuptake, leading to central serotonergic hyperstimulation.(1) The combination of tramadol and SSRIs or SNRIs may also lower the seizure threshold.(1)

CLINICAL EFFECTS: Concurrent administration may increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Concurrent administration may increase the risk for seizures, especially in susceptible individuals.(1)

PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(2) Predisposing factors for a lower seizure threshold include a history of seizures, epilepsy, or a recognized risk for seizures (e.g. head trauma, metabolic disorders, alcohol, drug withdrawal, infections of the central nervous system). A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may increase the risk for serotonin syndrome due to tramadol.

PATIENT MANAGEMENT: If concurrent therapy of tramadol with a SSRI or SNRI is warranted, patients should be closely monitored for signs and symptoms of serotonin syndrome and increased seizure activity.(1)

DISCUSSION: There are a number of serotonin syndrome case reports following the addition of tramadol to a stable selective serotonin reuptake inhibitor regimen. The syndrome developed between 12 hours to 3 weeks after the initiation of tramadol therapy. Patients recovered after tramadol and/or the SSRI/SNRI was discontinued.(3-14) One patient also developed mania.(3) Another patient developed nightmares and hallucinations after taking concurrent tramadol and paroxetine for 56 days.(15) One author suggests that although the combination of tramadol and SSRIs or SNRIs is associated with a risk for serotonin syndrome, given the high rate of co-prescribing for the combination it is an uncommon outcome.(16) A review of the 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 20 patients were receiving concurrent therapy with an selective serotonin reuptake inhibitor.(17) The manufacturer of tramadol states that the risk of seizure is increased in patients receiving concurrent therapy with selective serotonin reuptake inhibitors.(1) Selected SSRIs and SNRIs linked to this monograph include: citalopram, desvenlafaxine, escitalopram, fluvoxamine, levomilnacipran, milnacipran, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.

Tramadol/Slt Anticoagulants (Vit K Antagonists)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of propoxyphene or tramadol may result in increased effects of some anticoagulants, including bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on warfarin who begin therapy with propoxyphene or tramadol containing medication should be monitored closely for signs of increased warfarin effects. The dosage of warfarin may need to be adjusted or a different opioid may need to be used. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There have been four case reports of increased INR values following the addition of tramadol to warfarin-containing regimens.(1-4) In one case, a patient was hospitalized due to hematochezia with an increased INR of 5.4 after concomitant use of tramadol with warfarin. The patient was switched to gabapentin to prevent future bleeding.(1) Another case report identified this interaction in a patient on a stable warfarin regimen whose INR increased to 10.6 after the addition of tramadol for 2 weeks to treat musculoskeletal pain. After discontinuation of tramadol, it took approximately 4 months for INR to normalize after adjustments were made to their warfarin regimen.(2) A different case report examines concomitant tramadol and warfarin use which required a 30% reduction in warfarin dose allowing the patient to remain on both therapies while maintaining INR goal.(3) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with opioid analgesics (OR=2.81; 95% CI 1.89-4.17).(5) A retrospective review associated tramadol use with episodes of major bleeding in patients receiving phenprocoumon or acenocoumarol.(6) In contrast, a study in 19 patients receiving phenprocoumon found no effect on INR values following the addition of tramadol.(7) There have been three case reports of patients developing hematuria following the addition of a combination product containing propoxyphene and acetaminophen.(8-10)

*Known hypersensitivity (e.g., anaphylaxis) to tramadol, any ingredient in the formulation, or opioid agonists.

*Significant respiratory depression.

*Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

*Known or suspected GI obstruction, including paralytic ileus.

*Current or recent (within 14 days) therapy with a monoamine oxidase inhibitor (MAOI).

*In children <12 years of age for pain.

*In children <18 years of age for postoperative pain following tonsillectomy and/or adenoidectomy.

• Acute asthma attack
• Adenoidectomy in pediatric patient
• Alcohol intoxication
• Benzodiazepine overdose
• CYp2d6 poor metabolizer
• CYp2d6 ultrarapid metabolizer
• Opioid overdose
• Serotonin syndrome
• Tonsillectomy in pediatric patient

• Acute pancreatitis
• Alcohol use disorder
• Alcohol withdrawal syndrome
• Central nervous system infection
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Depression
• Disease of liver
• Drug abuse
• Exacerbation of chronic obstructive pulmonary disease
• Familial dysautonomia
• Gastrointestinal obstruction
• Intracranial hypertension
• Lower seizure threshold
• Respiratory depression
• Seizure disorder
• Sleep apnea
• Suicidal
• Suicidal ideation

• Adrenocortical insufficiency
• Biliary tract disorder
• CYp2d6 intermediate metabolizer
• Hypoglycemic disorder
• Hyponatremia

The most common adverse effects of tramadol hydrochloride immediate-release preparations (>=15%) reported in clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, and pruritus.

The most common adverse effects of tramadol hydrochloride extended-release tablets (>=10% and >=2 times that of placebo) include dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth.

The most common adverse effects of tramadol hydrochloride extended-release capsules (>=10% and >=2 times that of placebo) include nausea, constipation, dry mouth, somnolence, dizziness, and vomiting.

Less Frequent

• Respiratory depression

Rare or Very Rare

• Abnormal ECG
• Accidental fall
• Accidental injury
• Adrenocortical insufficiency
• Anaphylaxis
• Androgen deficiency
• Anemia
• Angioedema
• Bronchospastic pulmonary disease
• Drug dependence
• Dyspnea
• Hearing loss
• Hepatic failure
• Hepatitis
• Hypoglycemic disorder
• Hyponatremia
• Increased urinary frequency
• Myocardial ischemia
• Peripheral ischemia
• Prolonged QT interval
• Pulmonary edema
• Pulmonary thromboembolism
• Seizure disorder
• Serotonin syndrome
• SIADH syndrome
• Sleep apnea
• Spasm of sphincter of oddi
• Stevens-johnson syndrome
• Suicidal
• Tachycardia
• Toxic epidermal necrolysis

More Frequent

• Constipation
• Dizziness
• Drowsy
• Flushing
• Headache disorder
• Insomnia
• Nausea
• Pruritus of skin
• Vertigo
• Vomiting
• Xerostomia

Less Frequent

• Acute abdominal pain
• Acute cognitive impairment
• Anorexia
• Arthralgia
• Blurred vision
• Diarrhea
• Dyspepsia
• Flatulence
• General weakness
• Hyperhidrosis
• Hypertension
• Nervousness
• Orthostatic hypotension
• Skin rash
• Symptoms of anxiety
• Urinary retention
• Vasodilation of blood vessels

Rare or Very Rare

• Agitation
• Anticholinergic toxicity
• Ataxia
• Bruising
• Cataracts
• Chills
• Cramps in legs
• Delirium
• Depersonalization
• Depression
• Dream disorder
• Dysgeusia
• Dysphagia
• Dysuria
• Ecchymosis
• Erectile dysfunction
• Euphoria
• Fever
• Flu-like symptoms
• Gastroenteritis
• Hallucinations
• Hematuria
• Hyperglycemia
• Hyperkinesis
• Hypertonia
• Hypotension
• Indifference
• Infertility
• Libido changes
• Menstrual disorder
• Miosis
• Mood changes
• Muscle fasciculation
• Myalgia
• Neck stiffness
• Night sweats
• Non-cardiac chest pain
• Opioid induced allodynia
• Opioid induced hyperalgesia
• Palpitations
• Paresthesia
• Peripheral edema
• Pharyngitis
• Sinusitis
• Sleep disorder
• Stomatitis
• Syncope
• Tinnitus
• Tremor
• Urinary tract infection
• Urticaria
• Visual changes
• Weight loss
• Yawning

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The safety and efficacy of tramadol has not been established in pediatric patients. Life-threatening respiratory depression and death have occurred in pediatric patients who have received tramadol. In some cases, these events followed tonsillectomy and/or adenoidectomy, and one patient had evidence of being an ultrarapid metabolizer. Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol.

Because of the risk of life-threatening respiratory depression and death, tramadol is contraindicated in all pediatric patients <12 years of age and for the post-operative management of pain in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

There are insufficient data available regarding tramadol in pregnant females to establish the associated risk of major birth defects and spontaneous abortion. Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6, and 3.6 times, respectively, the maximum daily human dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits). Embryo and fetal toxicity consisted mainly of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters also were seen in pups from rat dams allowed to deliver. Embryo and fetal lethality was reported in only one rabbit study, in which rabbits received tramadol hydrochloride 300 mg/kg, a dose that would cause extreme maternal toxicity in rabbits. No drug-related teratogenic effects were observed in progeny of mice, rats, or rabbits receiving tramadol (up to 140, 80, or 300 mg/kg or 1.7, 1.9, or 14.6 times, respectively, the maximum daily human dosage) by various routes. In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol doses of 50 mg/kg (1.2 times the maximum human dose) or higher had decreased weights, and pup survival was decreased early in lactation at tramadol doses of 80 mg/kg (1.9 times the maximum human dose).

Prolonged maternal use of opioid agonists during pregnancy can result in neonatal opioid withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Females who require prolonged opioid therapy during pregnancy should be advised of the risk of neonatal opioid withdrawal syndrome, and availability of appropriate treatment should be ensured. The onset, duration, and severity of the syndrome vary depending on the specific opioid agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported with tramadol during postmarketing experience. The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.

Use of opioids in pregnant females during labor can result in neonatal respiratory depression. Use of tramadol is not recommended immediately before or during labor, when other analgesic techniques may be more appropriate. Opioid agonists may prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is inconsistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Neonates exposed to opioids during labor should be monitored for excessive sedation and respiratory depression. An opioid antagonist must be available for reversal of opioid-induced respiratory depression.

Tramadol and its metabolite, O-desmethyl tramadol (M1), are distributed into human milk. Following a single IV tramadol dose of 100 mg, the cumulative distribution into milk within 16 hours after dosing was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. Published studies have reported tramadol and M1 in colostrum with administration of tramadol to nursing mothers in the early postpartum period. Females who are ultrarapid metabolizers of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk that can be dangerous to breast-fed infants. In females with normal tramadol metabolism, the amount of tramadol distributed into human milk is low and dose-dependent. There is no information on the effects of tramadol on the breast-fed infant or the effects on milk production. Because of the potential for serious adverse effects, including excess sedation and respiratory depression in a breast-fed infant, advise patients that breast-feeding is not recommended with tramadol. Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opioid toxicity (e.g., excess sedation, 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.

Select the dosage of tramadol with caution and consider regular evaluation of renal function. Titrate the dosage carefully, starting at the low end of the dosage range and monitor closely for signs of CNS and respiratory depression.

Do not exceed a total daily dosage of 300 mg in patients >75 years of age.

In controlled clinical trials of tramadol immediate-release tablets, 455 patients who received tramadol were >=65 years of age and 145 patients were >=75 years of age. In patients >=75 years of age receiving immediate-release tramadol, maximum serum tramadol concentrations were elevated (208 ng/mL) and the elimination half-life was prolonged (7 hours) compared with patients 65-75 years of age (162 ng/mL and 6 hours, respectively). Treatment-limiting adverse GI effects occurred in 30% of patients >75 years of age compared with 17% of those <65 years of age, and constipation resulted in discontinuance of treatment in 10% of those >75 years of age.

In clinical trials of tramadol extended-release tablets, 901 patients who received tramadol were >=65 years of age and 156 patients were >=75 years of age. In these studies, the incidence of adverse effects was higher in patients >65 years of age compared with younger adults; adverse effects reported more frequently in older adults included constipation, fatigue, weakness, postural hypotension, and dyspepsia.

In clinical trials of tramadol extended-release capsules, 812 patients who received tramadol were >=65 years of age and 240 patients were >=75 years of age. In these studies, the incidence of adverse effects was higher in patients >65 years of age compared with younger adults; adverse effects reported more frequently in older adults included nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia, sweating, fatigue, weakness, postural hypotension, and dyspepsia.

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse effects may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dosage of tramadol with caution and consider regular evaluation of renal function. Titrate the dosage carefully, starting at the low end of the dosage range and monitor closely for signs of CNS and respiratory depression.