Drug Interaction Report

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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GENERALLY AVOID: Due to its serotonergic activity, coadministration of tramadol with serotonin-enhancing drugs such as SSRIs, SNRIs, nefazodone, trazodone, and mirtazapine may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Patients receiving tramadol with serotonin-enhancing drugs may also have an increased risk of seizures due to additive epileptogenic effects of these agents.

MANAGEMENT: In general, the use of tramadol in combination with highly serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when initiating or increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life.

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MONITOR CLOSELY: Concomitant use of opioids with gabapentinoids (e.g., gabapentin, pregabalin) may increase the risk of opioid overdose and serious adverse effects such as profound sedation, respiratory depression, syncope, and death due to potentially additive depressant effects on the central nervous system. Using administrative databases, investigators (Gomes T, et al.) conducted a matched case-control study among residents of Ontario, Canada, who received opioid analgesics for non-cancer pain (n=5875; 1256 cases who died of an opioid-related cause and 4619 matched controls) and found that concomitant gabapentin exposure was associated with a 49% higher risk of death from an opioid overdose after adjustment for potential confounders including opioid dose. Moreover, moderate-dose (900 to 1799 mg daily) and high-dose (>=1800 mg daily) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death compared to no concomitant gabapentin use, and very high-dose (>=2500 mg daily) gabapentin use was associated with a nearly 2-fold increase. By contrast, no significant association between concomitant exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid-related death was observed in a prespecified sensitivity analysis. Concomitant use of opioids has also been reported to increase the risk of gabapentinoid misuse or abuse, particularly in patients with a history of addiction. One retrospective cohort analysis of claims data for a commercially insured U.S. population found that among patients with prolonged gabapentin use (>=120 days over a one year period), concomitant prolonged treatment with opioids increased the risk of misuse of one or both drugs by more than 6-fold. Data from several small studies suggest that in the United States and Europe, approximately 15% to 26% and 7% to 21% of patients with opioid use disorder also misused or abused gabapentin and pregabalin, respectively. Concurrent overuse of both opioids and gabapentin has been reported to quadruple the odds of an emergency department visit or hospital stay for respiratory depression.

Coadministration with opioids may increase the oral bioavailability of gabapentin. The precise mechanism has not been established, but may involve increased gabapentin absorption due to delayed gastrointestinal transit induced by opioids. In 12 healthy male volunteers, single-dose administration of gabapentin 600 mg two hours following controlled-release morphine sulfate 60 mg increased gabapentin systemic exposure (AUC) by 44% and decreased apparent oral clearance and apparent renal clearance by 23% and 16%, respectively, compared to administration with placebo. The pharmacokinetics of morphine and its glucuronides were not altered. Gabapentin has also been reported to reduce the plasma concentrations of hydrocodone in a dose-dependent manner. The mechanism of this interaction is unknown. When immediate-release gabapentin 125 mg or 500 mg was coadministered with hydrocodone 10 mg, hydrocodone Cmax decreased by 3% and 21%, respectively, while AUC decreased by 4% and 22%, respectively. Gabapentin AUC was increased 14% by hydrocodone.

MANAGEMENT: Caution is advised when opioids and gabapentinoids are coadministered, particularly in patients with additional risk factors for respiratory depression such as advanced age, renal insufficiency, or chronic lung disease. The dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Use of additional central nervous system depressants should be avoided if possible. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. For patients who have been receiving extended therapy with both an opioid and a gabapentinoid (either for analgesia or seizure control) and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms and increased seizure risk.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: The efficacy of anticonvulsants may be diminished during coadministration with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs). Antidepressants including SSRIs and SNRIs can reduce seizure threshold. In clinical trials, convulsions have typically been reported in 0.1% to 0.3% of patients receiving SSRIs for major depressive disorders. There have been rare reports of prolonged seizures in patients on fluoxetine receiving electroconvulsive therapy (ECT).

MONITOR: Coadministration of SSRIs or SNRIs may potentiate the central nervous system (CNS) adverse effects of anticonvulsants such as somnolence and cognitive and psychomotor impairment.

MONITOR: Coadministration of SSRIs or SNRIs with some anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and valproic acid, may increase the risk of hyponatremia. Treatment with SSRIs or SNRIs has been associated with hyponatremia, which may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in many cases. While generally reversible following discontinuation of SSRI/SNRI treatment, cases with serum sodium lower than 110 mmol/L have been reported. Hyponatremia and SIADH may also result from treatment with some anticonvulsants. The risk appears to be dose-related, and elderly patients and patients who are volume depleted (e.g., diuretic use) may be at greater risk.

MANAGEMENT: SSRIs and SNRIs should be avoided in patients with unstable epilepsy, and used cautiously in patients with epilepsy controlled with anticonvulsant medications. Treatment with SSRIs and SNRIs should be discontinued if seizures develop or seizure frequency increases. Patients receiving SSRIs or SNRIs with anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and/or valproic acid, should also have serum sodium levels measured regularly and monitored for development of hyponatremia, particularly when higher dosages of these medications are used. Signs and symptoms of hyponatremia include nausea, vomiting, headache, difficulty concentrating, memory impairment, confusion, malaise, lethargy, muscle weakness or spasms, and unsteadiness. In more severe and/or acute cases, hallucination, syncope, seizure, coma, respiratory arrest, and death may occur. Discontinuation of SSRIs and SNRIs should be considered in patients who develop symptomatic hyponatremia, and appropriate medical intervention instituted. All patients receiving concomitant therapy with SSRIs or SNRIs and anticonvulsants should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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GENERALLY AVOID: Acute ethanol ingestion may potentiate the CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy.

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