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Drug overview for TRAMADOL HCL (tramadol hcl):
Generic name: TRAMADOL HCL (TRAH-muh-dall)
Drug class: Opioid Analgesics- IR (with all antitussive opiates)
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Tramadol hydrochloride is a synthetic opiate agonist and inhibitor of norepinephrine and serotonin uptake.
No enhanced Uses information available for this drug.
Generic name: TRAMADOL HCL (TRAH-muh-dall)
Drug class: Opioid Analgesics- IR (with all antitussive opiates)
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Tramadol hydrochloride is a synthetic opiate agonist and inhibitor of norepinephrine and serotonin uptake.
No enhanced Uses information available for this drug.
DRUG IMAGES
TRAMADOL HCL 50 MG TABLET
The following indications for TRAMADOL HCL (tramadol hcl) have been approved by the FDA:
Indications:
Pain
Professional Synonyms:
None.
Indications:
Pain
Professional Synonyms:
None.
The following dosing information is available for TRAMADOL HCL (tramadol hcl):
Opiate agonists should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient. The initial dosage of tramadol must be individualized, taking into account the patient's 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 concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used. (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions: Precautions and Contraindications.)
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and/or drug therapy in geriatric patients, care should be taken in dosage selection for such patients. The manufacturers recommend that geriatric patients receive initial dosages of tramadol hydrochloride alone in the lower end of the usual range and that the dosage not exceed 300 mg daily in those older than 75 years of age. Dosage of tramadol hydrochloride should be titrated slowly in geriatric patients, with close monitoring for CNS and respiratory depression.
Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.
Patients receiving opiate analgesics should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for manifestations of opiate withdrawal and for the development of addiction, abuse, or misuse. During long-term therapy, the continued need for opiate analgesics should be continually reevaluated. Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.
Patients with chronic pain who experience episodes of breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., ''rescue'' therapy with an immediate-release analgesic). If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the dosage.
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).
When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.
If discontinuance of opiate therapy is required in a patient who may be physically dependent on opiates, the dosage should be tapered gradually to avoid manifestations of abrupt withdrawal. When tramadol therapy is discontinued in such patients, dosage generally can be reduced by 25-50% every 2-4 days. If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Dosage of tramadol hydrochloride (as conventional tablets) should be reduced in certain patients with renal or hepatic impairment by decreasing the frequency of administration. Adults with creatinine clearances less than 30 mL/minute may receive oral tramadol hydrochloride conventional tablets in a dosage of 50-100 mg every 12 hours, not to exceed 200 mg daily. Since less than 7% of a dose of tramadol hydrochloride is removed by hemodialysis, patients undergoing dialysis may receive their usual dosage on the day of dialysis.
Adults with hepatic cirrhosis may receive the conventional tablets in a dosage of 50 mg every 12 hours.
Tramadol hydrochloride extended-release oral formulations should not be used in patients with severe renal impairment (creatinine clearances less than 30 mL/minute) or severe hepatic impairment (Child-Pugh class C). The available tablet or capsule strengths and once-daily dosing of these formulations do not provide sufficient dosing flexibility for safe use in these patients.
Adults with creatinine clearances of less than 30 mL/minute may receive tramadol hydrochloride in fixed combination with acetaminophen at a dosing interval of every 12 hours; in such patients, the dosage of tramadol hydrochloride administered as the fixed combination should not exceed 75 mg every 12 hours. Tramadol hydrochloride in fixed combination with acetaminophen should not be used in patients with impaired hepatic function.
If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used. (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions: Precautions and Contraindications.)
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and/or drug therapy in geriatric patients, care should be taken in dosage selection for such patients. The manufacturers recommend that geriatric patients receive initial dosages of tramadol hydrochloride alone in the lower end of the usual range and that the dosage not exceed 300 mg daily in those older than 75 years of age. Dosage of tramadol hydrochloride should be titrated slowly in geriatric patients, with close monitoring for CNS and respiratory depression.
Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.
Patients receiving opiate analgesics should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for manifestations of opiate withdrawal and for the development of addiction, abuse, or misuse. During long-term therapy, the continued need for opiate analgesics should be continually reevaluated. Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.
Patients with chronic pain who experience episodes of breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., ''rescue'' therapy with an immediate-release analgesic). If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the dosage.
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).
When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.
If discontinuance of opiate therapy is required in a patient who may be physically dependent on opiates, the dosage should be tapered gradually to avoid manifestations of abrupt withdrawal. When tramadol therapy is discontinued in such patients, dosage generally can be reduced by 25-50% every 2-4 days. If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Dosage of tramadol hydrochloride (as conventional tablets) should be reduced in certain patients with renal or hepatic impairment by decreasing the frequency of administration. Adults with creatinine clearances less than 30 mL/minute may receive oral tramadol hydrochloride conventional tablets in a dosage of 50-100 mg every 12 hours, not to exceed 200 mg daily. Since less than 7% of a dose of tramadol hydrochloride is removed by hemodialysis, patients undergoing dialysis may receive their usual dosage on the day of dialysis.
Adults with hepatic cirrhosis may receive the conventional tablets in a dosage of 50 mg every 12 hours.
Tramadol hydrochloride extended-release oral formulations should not be used in patients with severe renal impairment (creatinine clearances less than 30 mL/minute) or severe hepatic impairment (Child-Pugh class C). The available tablet or capsule strengths and once-daily dosing of these formulations do not provide sufficient dosing flexibility for safe use in these patients.
Adults with creatinine clearances of less than 30 mL/minute may receive tramadol hydrochloride in fixed combination with acetaminophen at a dosing interval of every 12 hours; in such patients, the dosage of tramadol hydrochloride administered as the fixed combination should not exceed 75 mg every 12 hours. Tramadol hydrochloride in fixed combination with acetaminophen should not be used in patients with impaired hepatic function.
Tramadol hydrochloride alone or in fixed combination with acetaminophen or celecoxib is administered orally. Since food does not affect substantially the rate or extent of absorption of tramadol hydrochloride administered alone as conventional tablets, the manufacturers state that conventional tablets of the drug can be taken without regard to food. Food may decrease the rate and extent of absorption of tramadol when the drug is administered as extended-release tablets (delaying peak plasma concentrations by about 3 hours and decreasing the extent of absorption by about 16%); the manufacturer states that although tramadol hydrochloride extended-release tablets may be administered once daily without regard to food, the extended-release tablets should be administered in a consistent manner relative to food intake.
The manufacturer also recommends that tramadol hydrochloride extended-release capsules be administered in a consistent manner relative to food intake, although the rate and extent of absorption are similar following oral administration with or without food. Food delays absorption of tramadol hydrochloride and acetaminophen administered in fixed combination, increasing times to peak plasma concentrations by about 35 and 60 minutes, respectively. However, food does not affect peak plasma concentrations achieved or the extent of absorption of the drugs, and the clinical importance of the delays in absorption is unknown.
The manufacturers make no specific recommendation regarding administration of the fixed-combination preparation with food. Tramadol hydrochloride extended-release tablets or capsules should be swallowed whole and should not be broken, crushed, chewed, split, or dissolved, since such physical alteration of the tablets or capsules could result in rapid release of the drug and absorption of a potentially fatal overdose. The extended-release preparations should not be used concomitantly with other tramadol-containing preparations.
For patients receiving tramadol hydrochloride conventional tablets alone for the relief of moderate to moderately severe pain and not requiring rapid onset of analgesic effect, the manufacturers recommend a dosage titration regimen to decrease the likelihood of discontinuance secondary to adverse effects (e.g., nausea, vomiting, dizziness, vertigo) associated with administration at higher initial dosages.
The manufacturer also recommends that tramadol hydrochloride extended-release capsules be administered in a consistent manner relative to food intake, although the rate and extent of absorption are similar following oral administration with or without food. Food delays absorption of tramadol hydrochloride and acetaminophen administered in fixed combination, increasing times to peak plasma concentrations by about 35 and 60 minutes, respectively. However, food does not affect peak plasma concentrations achieved or the extent of absorption of the drugs, and the clinical importance of the delays in absorption is unknown.
The manufacturers make no specific recommendation regarding administration of the fixed-combination preparation with food. Tramadol hydrochloride extended-release tablets or capsules should be swallowed whole and should not be broken, crushed, chewed, split, or dissolved, since such physical alteration of the tablets or capsules could result in rapid release of the drug and absorption of a potentially fatal overdose. The extended-release preparations should not be used concomitantly with other tramadol-containing preparations.
For patients receiving tramadol hydrochloride conventional tablets alone for the relief of moderate to moderately severe pain and not requiring rapid onset of analgesic effect, the manufacturers recommend a dosage titration regimen to decrease the likelihood of discontinuance secondary to adverse effects (e.g., nausea, vomiting, dizziness, vertigo) associated with administration at higher initial dosages.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| TRAMADOL HCL 50 MG TABLET | Maintenance | Adults take 1 tablet (50 mg) by oral route every 6 hours as needed |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| TRAMADOL HCL 50 MG TABLET | Maintenance | Adults take 1 tablet (50 mg) by oral route every 6 hours as needed |
The following drug interaction information is available for TRAMADOL HCL (tramadol hcl):
There are 4 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Opioid Antagonists/Opioid Analgesics 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) |
CONTRAVE, LOTREXONE, LYBALVI, NALTREX, NALTREXONE BASE MONOHYDRATE, NALTREXONE HCL, NALTREXONE HCL DIHYDRATE, NALTREXONE HCL MICRONIZED, OPVEE, VIVITROL |
| 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. |
FURAZOLIDONE, MARPLAN, MATULANE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, TRANYLCYPROMINE SULFATE, XADAGO |
| 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. |
AZILECT, EMSAM, RASAGILINE MESYLATE, SELEGILINE HCL, ZELAPAR |
| Slt Serotonergic Opioids (Immediate 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.(1,2) CLINICAL EFFECTS: Concurrent use of opioids and metaxalone may result in profound sedation, respiratory depression, coma, and/or death.(2) 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.(2) 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.(2) 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.(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) 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).(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) The interaction between meperidine and MAOIs has been well documented. There are two reports of potential interactions between MAOIs and dextromethorphan.(13,14) In another case report, the concurrent use of propoxyphene and phenylzine resulted in sedation and somnolence. The patient had previously taken both agents alone with no adverse effects.(15) Although some studies have shown that morphine does not interact with MAOIs,(16,17) other data indicates that MAOIs markedly potentiate the effect of morphine.(18) Metaxalone is a weak inhibitor of MAO.(1,19) |
METAXALONE |
There are 7 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Sodium Oxybate/Codeine; Tramadol 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) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| 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) |
LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, ZYVOX |
| Iobenguane I 123/Agents that Affect Catecholamines 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) |
ADREVIEW |
| 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. |
DEMEROL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL |
| Eluxadoline/Anticholinergics; Opioids 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) |
VIBERZI |
| 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) |
AMITRIPTYLINE HCL, AMOXAPINE, ANAFRANIL, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, EQUETRO, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TEGRETOL, TEGRETOL XR, TRIMIPRAMINE MALEATE |
| 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) |
AMRIX, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, FEXMID, TONMYA |
There are 22 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Slt Anticoagulants (Vit K antagonists)/Tramadol 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) |
ANISINDIONE, JANTOVEN, WARFARIN SODIUM |
| Opioids/Buprenorphine; Pentazocine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opiate receptors, exhibiting a ceiling effect at which higher doses produce no further effect. Pentazocine is a mixed agonist-antagonist at opiate receptors.(1) Full mu-opioid agonists (e.g., morphine, methadone) continue to have increased effects at higher doses without ceiling effects.(2) 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 and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids or who take higher dosages 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: Concurrent use of buprenorphine with other opioids in opioid dependent patients could result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.(2) 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) |
BELBUCA, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, PENTAZOCINE-NALOXONE HCL, SUBLOCADE, SUBOXONE, ZUBSOLV |
| 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. |
AKYNZEO, ALOSETRON HCL, GRANISETRON HCL, GRANISOL, LOTRONEX, MKO (MIDAZOLAM-KETAMINE-ONDAN), ONDANSETRON HCL, ONDANSETRON HCL-0.9% NACL, ONDANSETRON ODT, PALONOSETRON HCL, POSFREA, SANCUSO, SUSTOL |
| Gabapentinoids/Opioids (IR & ER) 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) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER, RELGAABI |
| Opioids/Butorphanol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Butorphanol antagonize mu-opiate receptors. Other opioids agonize mu-opiate receptors.(1) 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 and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. Patients using higher doses of opioids may also be at a higher risk. 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: Because butorphanol antagonizes mu-opiate receptors and other opioids agonize mu-opiate receptors, concurrent use of buprenorphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.(1) 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) |
BUTORPHANOL TARTRATE |
| Opioids/Nalbuphine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nalbuphine(1) antagonizes mu-opiate receptors. 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 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) |
NALBUPHINE HCL |
| 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, 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) |
ABIRATERONE ACETATE, ABIRTEGA, AKEEGA, APLENZIN, APTIVUS, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CERDELGA, CINACALCET HCL, CONTRAVE, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, FLUOXETINE DR, FLUOXETINE HCL, MIRABEGRON ER, MULTAQ, MYRBETRIQ, NUEDEXTA, OLANZAPINE-FLUOXETINE HCL, ORLADEYO, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PROZAC, QUINIDINE GLUCONATE, QUINIDINE SULFATE, SENSIPAR, TERBINAFINE HCL, TRUQAP, VARUBI, VIZIMPRO, WELLBUTRIN SR, WELLBUTRIN XL, YONSA, ZYTIGA |
| Trazodone (Greater Than 50 mg)/Meperidine; Tramadol 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) |
RALDESY, TRAZODONE HCL |
| Opioids (Immediate 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 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) 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) |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| Opioids (Immediate 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) |
AMBIEN, AMBIEN CR, BELSOMRA, DAYVIGO, EDLUAR, ESZOPICLONE, LUNESTA, QUVIVIQ, RAMELTEON, ROZEREM, ZALEPLON, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Opioids (Immediate 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) |
ATMEKSI, BACLOFEN, CARISOPRODOL, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHLORZOXAZONE, DANTRIUM, DANTROLENE SODIUM, FLEQSUVY, MEPROBAMATE, METHOCARBAMOL, NORGESIC, NORGESIC FORTE, ONTRALFY, ORPHENADRINE CITRATE, ORPHENADRINE CITRATE ER, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OZOBAX, OZOBAX DS, REVONTO, ROBAXIN, RYANODEX, SOMA, TANLOR, TIZANIDINE HCL, VANADOM, ZANAFLEX |
| Desmopressin/Agents with Hyponatremia Risk 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) |
DDAVP, DESMODA, DESMOPRESSIN ACETATE, NOCDURNA |
| Amphetamines/Tramadol 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: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, 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) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE ER ODT, AMPHETAMINE SULFATE, ARYNTA, DESOXYN, DEXEDRINE, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, HYDROXYAMPHETAMINE HBR, LISDEXAMFETAMINE DIMESYLATE, METHAMPHETAMINE HCL, MYDAYIS, PROCENTRA, VYVANSE, XELSTRYM, ZENZEDI |
| Trazodone (Less Than or Equal To 50 mg)/Meperidine; Tramadol 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) |
TRAZODONE HCL |
| Tramadol (IR)/Selected 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 and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and 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) |
MOLINDONE HCL |
| Tramadol (IR)/Selected 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 and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as tramadol and 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) |
ABILIFY, ABILIFY ASIMTUFII, ABILIFY MAINTENA, ADASUVE, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, ARISTADA, ARISTADA INITIO, ASENAPINE MALEATE, BARHEMSYS, CAPLYTA, CHLORPROMAZINE HCL, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, COMPAZINE, COMPRO, DROPERIDOL, ERZOFRI, FANAPT, FLUPHENAZINE DECANOATE, FLUPHENAZINE HCL, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL LACTATE, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, LATUDA, LOXAPINE, LURASIDONE HCL, NUPLAZID, OLANZAPINE, OLANZAPINE ODT, OLANZAPINE-FLUOXETINE HCL, OPIPZA, PALIPERIDONE ER, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PERSERIS, PHENERGAN, PIMOZIDE, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, REXULTI, RISPERDAL, RISPERDAL CONSTA, RISPERIDONE, RISPERIDONE ER, RISPERIDONE ODT, RYKINDO, SAPHRIS, SECUADO, SEROQUEL, SEROQUEL XR, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, THIOTHIXENE, TRIFLUOPERAZINE HCL, UZEDY, VERSACLOZ, VRAYLAR, ZYPREXA, ZYPREXA RELPREVV, ZYPREXA ZYDIS |
| 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. |
CELEXA, CITALOPRAM HBR, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, EFFEXOR XR, ESCITALOPRAM OXALATE, FETZIMA, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, LEXAPRO, MILNACIPRAN HCL, PRISTIQ, SAVELLA, SERTRALINE HCL, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, ZOLOFT |
| Select Opioids (Immediate 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 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) |
PENTOBARBITAL SODIUM |
| Nefazodone/Tramadol 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) |
NEFAZODONE HCL |
| Gepirone/Serotoninergic Agents 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) |
EXXUA |
| 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: Concurrent use of opioids and methylphenidate may have unpredictable effects and may mask overdose symptoms of the opioid, 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) |
APTENSIO XR, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, FOCALIN, FOCALIN XR, JORNAY PM, METADATE CD, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN |
| 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) |
GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE |
The following contraindication information is available for TRAMADOL HCL (tramadol hcl):
Drug contraindication overview.
Tramadol is contraindicated in patients with substantial respiratory depression; acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; or known hypersensitivity (e.g., anaphylaxis) to the drug, other opiates, or any ingredient in the formulation. Tramadol also is contraindicated during or within 14 days following treatment with an MAO inhibitor. Tramadol is contraindicated in children younger than 12 years of age for the management of pain and in those younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy. (See Cautions: Pediatric Precautions.)
Tramadol is contraindicated in patients with substantial respiratory depression; acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; or known hypersensitivity (e.g., anaphylaxis) to the drug, other opiates, or any ingredient in the formulation. Tramadol also is contraindicated during or within 14 days following treatment with an MAO inhibitor. Tramadol is contraindicated in children younger than 12 years of age for the management of pain and in those younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy. (See Cautions: Pediatric Precautions.)
There are 10 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute asthma attack |
| Adenoidectomy in pediatric patient |
| Alcohol intoxication |
| Benzodiazepine overdose |
| CYp2d6 poor metabolizer |
| CYp2d6 ultrarapid metabolizer |
| Gastrointestinal obstruction |
| Opioid overdose |
| Serotonin syndrome |
| Tonsillectomy in pediatric patient |
There are 19 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| 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 |
| Intracranial hypertension |
| Lower seizure threshold |
| Respiratory depression |
| Seizure disorder |
| Sleep apnea |
| Suicidal |
| Suicidal ideation |
There are 5 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Adrenocortical insufficiency |
| Biliary tract disorder |
| CYp2d6 intermediate metabolizer |
| Hypoglycemic disorder |
| Hyponatremia |
The following adverse reaction information is available for TRAMADOL HCL (tramadol hcl):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 32 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Respiratory depression |
| Rare/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 |
There are 82 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Constipation Dizziness Drowsy Flushing Headache disorder Insomnia Nausea Pruritus of skin Vertigo Vomiting Xerostomia |
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/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 |
The following precautions are available for TRAMADOL HCL (tramadol hcl):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate 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. Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.
The onset, duration, and severity of the syndrome vary depending on the specific opiate 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 opiates in pregnant women 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. Opiate 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 opiates during labor should be monitored for excessive sedation and respiratory depression. An opiate antagonist must be available for reversal of opiate-induced respiratory depression.
Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared with maternal veins was 0.83 for women given tramadol during labor.
Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis. The manufacturers state that available data regarding use of tramadol in pregnant women are insufficient to establish the risk of major birth defects and spontaneous abortion with the drug. Based on animal data, women of childbearing potential should be advised of the potential for tramadol to cause fetal harm.
Although there are no adequate and controlled studies to date in humans, 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. Embryotoxicity and fetotoxicity have been demonstrated in rats when tramadol and acetaminophen were administered in fixed combination at maternally toxic doses of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.
Embryonic and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Tramadol was not teratogenic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6,
and 3.6 times, respectively, the maximum human daily dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg 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.
Tramadol and acetaminophen in fixed combination was not teratogenic in rats at a maternally toxic dose of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs. In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol hydrochloride doses of 50 mg/kg or higher had decreased weights, and pup survival was decreased early in lactation at tramadol hydrochloride doses of 80 mg/kg (1.2-1.6 or 1.9-2.6 times, respectively, the maximum human dose).
No toxicity was observed for progeny of dams receiving doses of 8, 10, 20, 25, or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
The onset, duration, and severity of the syndrome vary depending on the specific opiate 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 opiates in pregnant women 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. Opiate 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 opiates during labor should be monitored for excessive sedation and respiratory depression. An opiate antagonist must be available for reversal of opiate-induced respiratory depression.
Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared with maternal veins was 0.83 for women given tramadol during labor.
Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis. The manufacturers state that available data regarding use of tramadol in pregnant women are insufficient to establish the risk of major birth defects and spontaneous abortion with the drug. Based on animal data, women of childbearing potential should be advised of the potential for tramadol to cause fetal harm.
Although there are no adequate and controlled studies to date in humans, 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. Embryotoxicity and fetotoxicity have been demonstrated in rats when tramadol and acetaminophen were administered in fixed combination at maternally toxic doses of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.
Embryonic and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Tramadol was not teratogenic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6,
and 3.6 times, respectively, the maximum human daily dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg 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.
Tramadol and acetaminophen in fixed combination was not teratogenic in rats at a maternally toxic dose of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs. In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol hydrochloride doses of 50 mg/kg or higher had decreased weights, and pup survival was decreased early in lactation at tramadol hydrochloride doses of 80 mg/kg (1.2-1.6 or 1.9-2.6 times, respectively, the maximum human dose).
No toxicity was observed for progeny of dams receiving doses of 8, 10, 20, 25, or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
Tramadol is distributed into 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. Because the safety of tramadol in infants and neonates has not been established, the drug is not recommended for obstetrical preoperative medication or for use in nursing women, including use for post-delivery analgesia.
FDA review of available medical literature did not reveal evidence of an increased frequency of adverse effects in nursing infants of women receiving tramadol; however, because the drug is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, FDA recommends that tramadol not be used in nursing women. (See Pharmacogenomics under Cautions: Precautions and Contraindications. Also see Cautions: Precautions and Contraindications, in Codeine Phosphate and Codeine Sulfate 28:08.08.) Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia). If clinical manifestations of opiate toxicity occur, caregivers should seek immediate medical treatment for the infant. Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.
FDA review of available medical literature did not reveal evidence of an increased frequency of adverse effects in nursing infants of women receiving tramadol; however, because the drug is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, FDA recommends that tramadol not be used in nursing women. (See Pharmacogenomics under Cautions: Precautions and Contraindications. Also see Cautions: Precautions and Contraindications, in Codeine Phosphate and Codeine Sulfate 28:08.08.) Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia). If clinical manifestations of opiate toxicity occur, caregivers should seek immediate medical treatment for the infant. Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for TRAMADOL HCL (tramadol hcl):
WARNING: Tramadol has a risk for abuse and addiction, which can lead to overdose and death. Tramadol may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of tramadol that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have medication available to treat opioid overdose (such as naloxone, nalmefene). Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of tramadol from your body, which may affect how tramadol works.
Be sure you know how to take tramadol and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits.
Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy.
Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms.
Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight. Children younger than 18 years should not use products that contain tramadol. Some children are more sensitive to tramadol and have had very serious (rarely fatal) breathing problems such as slow/shallow breathing (see also Side Effects section).
The risk is greater in children who are obese or have breathing problems, or after certain surgeries (including tonsil/adenoid removal). Talk with your doctor or pharmacist about the risks and benefits of this medication.
WARNING: Tramadol has a risk for abuse and addiction, which can lead to overdose and death. Tramadol may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of tramadol that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have medication available to treat opioid overdose (such as naloxone, nalmefene). Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of tramadol from your body, which may affect how tramadol works.
Be sure you know how to take tramadol and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits.
Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy.
Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms.
Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight. Children younger than 18 years should not use products that contain tramadol. Some children are more sensitive to tramadol and have had very serious (rarely fatal) breathing problems such as slow/shallow breathing (see also Side Effects section).
The risk is greater in children who are obese or have breathing problems, or after certain surgeries (including tonsil/adenoid removal). Talk with your doctor or pharmacist about the risks and benefits of this medication.
The following icd codes are available for TRAMADOL HCL (tramadol hcl)'s list of indications:
| Pain | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.001 | Migraine without aura, not intractable, with status migrainosus |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.011 | Migraine without aura, intractable, with status migrainosus |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.101 | Migraine with aura, not intractable, with status migrainosus |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.111 | Migraine with aura, intractable, with status migrainosus |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.401 | Hemiplegic migraine, not intractable, with status migrainosus |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.411 | Hemiplegic migraine, intractable, with status migrainosus |
| G43.419 | Hemiplegic migraine, intractable, without status migrainosus |
| G43.5 | Persistent migraine aura without cerebral infarction |
| G43.50 | Persistent migraine aura without cerebral infarction, not intractable |
| G43.501 | Persistent migraine aura without cerebral infarction, not intractable, with status migrainosus |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.511 | Persistent migraine aura without cerebral infarction, intractable, with status migrainosus |
| G43.519 | Persistent migraine aura without cerebral infarction, intractable, without status migrainosus |
| G43.6 | Persistent migraine aura with cerebral infarction |
| G43.60 | Persistent migraine aura with cerebral infarction, not intractable |
| G43.601 | Persistent migraine aura with cerebral infarction, not intractable, with status migrainosus |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.611 | Persistent migraine aura with cerebral infarction, intractable, with status migrainosus |
| G43.619 | Persistent migraine aura with cerebral infarction, intractable, without status migrainosus |
| G43.7 | Chronic migraine without aura |
| G43.70 | Chronic migraine without aura, not intractable |
| G43.701 | Chronic migraine without aura, not intractable, with status migrainosus |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.711 | Chronic migraine without aura, intractable, with status migrainosus |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.801 | Other migraine, not intractable, with status migrainosus |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.811 | Other migraine, intractable, with status migrainosus |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.821 | Menstrual migraine, not intractable, with status migrainosus |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.831 | Menstrual migraine, intractable, with status migrainosus |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.901 | Migraine, unspecified, not intractable, with status migrainosus |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.911 | Migraine, unspecified, intractable, with status migrainosus |
| G43.919 | Migraine, unspecified, intractable, without status migrainosus |
| G43.B | Ophthalmoplegic migraine |
| G43.B0 | Ophthalmoplegic migraine, not intractable |
| G43.B1 | Ophthalmoplegic migraine, intractable |
| G43.C | Periodic headache syndromes in child or adult |
| G43.C0 | Periodic headache syndromes in child or adult, not intractable |
| G43.C1 | Periodic headache syndromes in child or adult, intractable |
| G43.D | Abdominal migraine |
| G43.D0 | Abdominal migraine, not intractable |
| G43.D1 | Abdominal migraine, intractable |
| G43.E | Chronic migraine with aura |
| G43.E0 | Chronic migraine with aura, not intractable |
| G43.E01 | Chronic migraine with aura, not intractable, with status migrainosus |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E11 | Chronic migraine with aura, intractable, with status migrainosus |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| G44 | Other headache syndromes |
| G44.00 | Cluster headache syndrome, unspecified |
| G44.001 | Cluster headache syndrome, unspecified, intractable |
| G44.009 | Cluster headache syndrome, unspecified, not intractable |
| G44.01 | Episodic cluster headache |
| G44.011 | Episodic cluster headache, intractable |
| G44.019 | Episodic cluster headache, not intractable |
| G44.02 | Chronic cluster headache |
| G44.021 | Chronic cluster headache, intractable |
| G44.029 | Chronic cluster headache, not intractable |
| G44.03 | Episodic paroxysmal hemicrania |
| G44.031 | Episodic paroxysmal hemicrania, intractable |
| G44.039 | Episodic paroxysmal hemicrania, not intractable |
| G44.04 | Chronic paroxysmal hemicrania |
| G44.041 | Chronic paroxysmal hemicrania, intractable |
| G44.049 | Chronic paroxysmal hemicrania, not intractable |
| G44.05 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt) |
| G44.051 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), intractable |
| G44.059 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), not intractable |
| G44.1 | Vascular headache, not elsewhere classified |
| G44.2 | Tension-type headache |
| G44.20 | Tension-type headache, unspecified |
| G44.201 | Tension-type headache, unspecified, intractable |
| G44.209 | Tension-type headache, unspecified, not intractable |
| G44.21 | Episodic tension-type headache |
| G44.211 | Episodic tension-type headache, intractable |
| G44.219 | Episodic tension-type headache, not intractable |
| G44.22 | Chronic tension-type headache |
| G44.221 | Chronic tension-type headache, intractable |
| G44.229 | Chronic tension-type headache, not intractable |
| G44.3 | Post-traumatic headache |
| G44.30 | Post-traumatic headache, unspecified |
| G44.301 | Post-traumatic headache, unspecified, intractable |
| G44.309 | Post-traumatic headache, unspecified, not intractable |
| G44.31 | Acute post-traumatic headache |
| G44.311 | Acute post-traumatic headache, intractable |
| G44.319 | Acute post-traumatic headache, not intractable |
| G44.32 | Chronic post-traumatic headache |
| G44.321 | Chronic post-traumatic headache, intractable |
| G44.329 | Chronic post-traumatic headache, not intractable |
| G44.4 | Drug-induced headache, not elsewhere classified |
| G44.40 | Drug-induced headache, not elsewhere classified, not intractable |
| G44.41 | Drug-induced headache, not elsewhere classified, intractable |
| G44.5 | Complicated headache syndromes |
| G44.51 | Hemicrania continua |
| G44.52 | New daily persistent headache (NDPh) |
| G44.53 | Primary thunderclap headache |
| G44.59 | Other complicated headache syndrome |
| G44.8 | Other specified headache syndromes |
| G44.81 | Hypnic headache |
| G44.82 | Headache associated with sexual activity |
| G44.83 | Primary cough headache |
| G44.84 | Primary exertional headache |
| G44.85 | Primary stabbing headache |
| G44.86 | Cervicogenic headache |
| G44.89 | Other headache syndrome |
| G50.1 | Atypical facial pain |
| G89 | Pain, not elsewhere classified |
| G89.0 | Central pain syndrome |
| G89.1 | Acute pain, not elsewhere classified |
| G89.11 | Acute pain due to trauma |
| G89.12 | Acute post-thoracotomy pain |
| G89.18 | Other acute postprocedural pain |
| G89.2 | Chronic pain, not elsewhere classified |
| G89.21 | Chronic pain due to trauma |
| G89.22 | Chronic post-thoracotomy pain |
| G89.28 | Other chronic postprocedural pain |
| G89.29 | Other chronic pain |
| G89.3 | Neoplasm related pain (acute) (chronic) |
| G89.4 | Chronic pain syndrome |
| G90.5 | Complex regional pain syndrome I (CRPS i) |
| G90.50 | Complex regional pain syndrome i, unspecified |
| G90.51 | Complex regional pain syndrome I of upper limb |
| G90.511 | Complex regional pain syndrome I of right upper limb |
| G90.512 | Complex regional pain syndrome I of left upper limb |
| G90.513 | Complex regional pain syndrome I of upper limb, bilateral |
| G90.519 | Complex regional pain syndrome I of unspecified upper limb |
| G90.52 | Complex regional pain syndrome I of lower limb |
| G90.521 | Complex regional pain syndrome I of right lower limb |
| G90.522 | Complex regional pain syndrome I of left lower limb |
| G90.523 | Complex regional pain syndrome I of lower limb, bilateral |
| G90.529 | Complex regional pain syndrome I of unspecified lower limb |
| G90.59 | Complex regional pain syndrome I of other specified site |
| H57.1 | Ocular pain |
| H57.10 | Ocular pain, unspecified eye |
| H57.11 | Ocular pain, right eye |
| H57.12 | Ocular pain, left eye |
| H57.13 | Ocular pain, bilateral |
| H92 | Otalgia and effusion of ear |
| H92.0 | Otalgia |
| H92.01 | Otalgia, right ear |
| H92.02 | Otalgia, left ear |
| H92.03 | Otalgia, bilateral |
| H92.09 | Otalgia, unspecified ear |
| K14.6 | Glossodynia |
| M25.5 | Pain in joint |
| M25.50 | Pain in unspecified joint |
| M25.51 | Pain in shoulder |
| M25.511 | Pain in right shoulder |
| M25.512 | Pain in left shoulder |
| M25.519 | Pain in unspecified shoulder |
| M25.52 | Pain in elbow |
| M25.521 | Pain in right elbow |
| M25.522 | Pain in left elbow |
| M25.529 | Pain in unspecified elbow |
| M25.53 | Pain in wrist |
| M25.531 | Pain in right wrist |
| M25.532 | Pain in left wrist |
| M25.539 | Pain in unspecified wrist |
| M25.54 | Pain in joints of hand |
| M25.541 | Pain in joints of right hand |
| M25.542 | Pain in joints of left hand |
| M25.549 | Pain in joints of unspecified hand |
| M25.55 | Pain in hip |
| M25.551 | Pain in right hip |
| M25.552 | Pain in left hip |
| M25.559 | Pain in unspecified hip |
| M25.56 | Pain in knee |
| M25.561 | Pain in right knee |
| M25.562 | Pain in left knee |
| M25.569 | Pain in unspecified knee |
| M25.57 | Pain in ankle and joints of foot |
| M25.571 | Pain in right ankle and joints of right foot |
| M25.572 | Pain in left ankle and joints of left foot |
| M25.579 | Pain in unspecified ankle and joints of unspecified foot |
| M25.59 | Pain in other specified joint |
| M26.62 | Arthralgia of temporomandibular joint |
| M26.621 | Arthralgia of right temporomandibular joint |
| M26.622 | Arthralgia of left temporomandibular joint |
| M26.623 | Arthralgia of bilateral temporomandibular joint |
| M26.629 | Arthralgia of temporomandibular joint, unspecified side |
| M54 | Dorsalgia |
| M54.2 | Cervicalgia |
| M54.4 | Lumbago with sciatica |
| M54.40 | Lumbago with sciatica, unspecified side |
| M54.41 | Lumbago with sciatica, right side |
| M54.42 | Lumbago with sciatica, left side |
| M54.5 | Low back pain |
| M54.50 | Low back pain, unspecified |
| M54.51 | Vertebrogenic low back pain |
| M54.59 | Other low back pain |
| M54.6 | Pain in thoracic spine |
| M54.8 | Other dorsalgia |
| M54.89 | Other dorsalgia |
| M54.9 | Dorsalgia, unspecified |
| M77.4 | Metatarsalgia |
| M77.40 | Metatarsalgia, unspecified foot |
| M77.41 | Metatarsalgia, right foot |
| M77.42 | Metatarsalgia, left foot |
| M79.1 | Myalgia |
| M79.10 | Myalgia, unspecified site |
| M79.11 | Myalgia of mastication muscle |
| M79.12 | Myalgia of auxiliary muscles, head and neck |
| M79.18 | Myalgia, other site |
| M79.6 | Pain in limb, hand, foot, fingers and toes |
| M79.60 | Pain in limb, unspecified |
| M79.601 | Pain in right arm |
| M79.602 | Pain in left arm |
| M79.603 | Pain in arm, unspecified |
| M79.604 | Pain in right leg |
| M79.605 | Pain in left leg |
| M79.606 | Pain in leg, unspecified |
| M79.609 | Pain in unspecified limb |
| M79.62 | Pain in upper arm |
| M79.621 | Pain in right upper arm |
| M79.622 | Pain in left upper arm |
| M79.629 | Pain in unspecified upper arm |
| M79.63 | Pain in forearm |
| M79.631 | Pain in right forearm |
| M79.632 | Pain in left forearm |
| M79.639 | Pain in unspecified forearm |
| M79.64 | Pain in hand and fingers |
| M79.641 | Pain in right hand |
| M79.642 | Pain in left hand |
| M79.643 | Pain in unspecified hand |
| M79.644 | Pain in right finger(s) |
| M79.645 | Pain in left finger(s) |
| M79.646 | Pain in unspecified finger(s) |
| M79.65 | Pain in thigh |
| M79.651 | Pain in right thigh |
| M79.652 | Pain in left thigh |
| M79.659 | Pain in unspecified thigh |
| M79.66 | Pain in lower leg |
| M79.661 | Pain in right lower leg |
| M79.662 | Pain in left lower leg |
| M79.669 | Pain in unspecified lower leg |
| M79.67 | Pain in foot and toes |
| M79.671 | Pain in right foot |
| M79.672 | Pain in left foot |
| M79.673 | Pain in unspecified foot |
| M79.674 | Pain in right toe(s) |
| M79.675 | Pain in left toe(s) |
| M79.676 | Pain in unspecified toe(s) |
| N23 | Unspecified renal colic |
| N64.4 | Mastodynia |
| N94 | Pain and other conditions associated with female genital organs and menstrual cycle |
| N94.0 | Mittelschmerz |
| N94.3 | Premenstrual tension syndrome |
| N94.4 | Primary dysmenorrhea |
| N94.5 | Secondary dysmenorrhea |
| N94.6 | Dysmenorrhea, unspecified |
| R07 | Pain in throat and chest |
| R07.0 | Pain in throat |
| R07.1 | Chest pain on breathing |
| R07.2 | Precordial pain |
| R07.81 | Pleurodynia |
| R07.82 | Intercostal pain |
| R07.89 | Other chest pain |
| R07.9 | Chest pain, unspecified |
| R10 | Abdominal and pelvic pain |
| R10.0 | Acute abdomen |
| R10.1 | Pain localized to upper abdomen |
| R10.10 | Upper abdominal pain, unspecified |
| R10.11 | Right upper quadrant pain |
| R10.12 | Left upper quadrant pain |
| R10.2 | Pelvic and perineal pain |
| R10.20 | Pelvic and perineal pain unspecified side |
| R10.21 | Pelvic and perineal pain right side |
| R10.22 | Pelvic and perineal pain left side |
| R10.23 | Pelvic and perineal pain bilateral |
| R10.24 | Suprapubic pain |
| R10.3 | Pain localized to other parts of lower abdomen |
| R10.30 | Lower abdominal pain, unspecified |
| R10.31 | Right lower quadrant pain |
| R10.32 | Left lower quadrant pain |
| R10.33 | Periumbilical pain |
| R10.8 | Other abdominal pain |
| R10.83 | Colic |
| R10.84 | Generalized abdominal pain |
| R10.85 | Abdominal pain of multiple sites |
| R10.9 | Unspecified abdominal pain |
| R10.A | Pain localized to flank |
| R10.A0 | Flank pain, unspecified side |
| R10.A1 | Flank pain, right side |
| R10.A2 | Flank pain, left side |
| R10.A3 | Flank pain, bilateral |
| R51 | Headache |
| R51.0 | Headache with orthostatic component, not elsewhere classified |
| R51.9 | Headache, unspecified |
| R52 | Pain, unspecified |
| R68.84 | Jaw pain |
| T82.84 | Pain due to cardiac and vascular prosthetic devices, implants and grafts |
| T82.847 | Pain due to cardiac prosthetic devices, implants and grafts |
| T82.847A | Pain due to cardiac prosthetic devices, implants and grafts, initial encounter |
| T82.847D | Pain due to cardiac prosthetic devices, implants and grafts, subsequent encounter |
| T82.848 | Pain due to vascular prosthetic devices, implants and grafts |
| T82.848A | Pain due to vascular prosthetic devices, implants and grafts, initial encounter |
| T82.848D | Pain due to vascular prosthetic devices, implants and grafts, subsequent encounter |
| T83.84 | Pain due to genitourinary prosthetic devices, implants and grafts |
| T83.84xA | Pain due to genitourinary prosthetic devices, implants and grafts, initial encounter |
| T83.84xD | Pain due to genitourinary prosthetic devices, implants and grafts, subsequent encounter |
| T84.84 | Pain due to internal orthopedic prosthetic devices, implants and grafts |
| T84.84xA | Pain due to internal orthopedic prosthetic devices, implants and grafts, initial encounter |
| T84.84xD | Pain due to internal orthopedic prosthetic devices, implants and grafts, subsequent encounter |
| T85.84 | Pain due to internal prosthetic devices, implants and grafts, not elsewhere classified |
| T85.840 | Pain due to nervous system prosthetic devices, implants and grafts |
| T85.840A | Pain due to nervous system prosthetic devices, implants and grafts, initial encounter |
| T85.840D | Pain due to nervous system prosthetic devices, implants and grafts, subsequent encounter |
| T85.848 | Pain due to other internal prosthetic devices, implants and grafts |
| T85.848A | Pain due to other internal prosthetic devices, implants and grafts, initial encounter |
| T85.848D | Pain due to other internal prosthetic devices, implants and grafts, subsequent encounter |
Formulary Reference Tool