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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ADJUST DOSE: Severe myopathy and rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (i.e., statins) and niacin. The mechanism is unknown; however, the development of myopathy has been associated with both the administration of statins alone and lipid-modifying dosages of niacin (1 g/day or more) alone. Certain populations may be more susceptible to the interaction. In a double-blind, randomized cardiovascular outcomes trial for simvastatin, the incidence of myopathy was found to be higher in patients of Chinese descent (0.43%) compared to patients not of Chinese descent (0.03%) taking 40 mg simvastatin and lipid-modifying dosages of a niacin-containing product. The cause of the increased risk is unknown, and it is also unknown if the increased risk applies to other Asian populations or to other statins when given to Chinese patients.

MANAGEMENT: Concomitant use of statins with lipid-modifying dosages of niacin (1 g/day or more) should be approached cautiously and only if the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Addition of niacin to statin therapy typically provides little additional reduction in LDL cholesterol, but further reductions of triglycerides and increases in HDL cholesterol may be attained. If the combination is prescribed, lower dosages of the statin should be considered. Coadministration of simvastatin with high doses of niacin (1 g/day or more) is not recommended in Chinese patients due to an increased risk of myopathy. Lovastatin labeling recommends that the dosage not exceed 20 mg daily when prescribed with lipid-modifying dosages of niacin. All patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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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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GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including hydrocodone. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of alcohol while taking some sustained-release formulations of hydrocodone may cause rapid release of the drug, resulting in high systemic levels of hydrocodone that may be potentially lethal. Alcohol apparently can disrupt the release mechanism of some sustained-release formulations. In study subjects, the rate of absorption of hydrocodone from an extended-release formulation was found to be affected by coadministration with 40% alcohol in the fasted state, as demonstrated by an average 2.4-fold (up to 3.9-fold in one subject) increase in hydrocodone peak plasma concentration and a decrease in the time to peak concentration. Alcohol also increased the extent of absorption by an average of 1.2-fold (up to 1.7-fold in one subject).

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of hydrocodone. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of hydrocodone by certain compounds present in grapefruit. Increased hydrocodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

MANAGEMENT: Patients taking sustained-release formulations of hydrocodone should not consume alcohol or use medications that contain alcohol. In general, potent narcotics such as hydrocodone should not be combined with alcohol. Patients should also avoid consumption of grapefruit or grapefruit juice during treatment with hydrocodone.

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GENERALLY AVOID: Chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, which has included rare cases of fatal hepatitis and frank hepatic failure requiring liver transplantation. The proposed mechanism is induction of hepatic microsomal enzymes during chronic alcohol use, which may result in accelerated metabolism of acetaminophen and increased production of potentially hepatotoxic metabolites.

MANAGEMENT: In general, chronic alcoholics should avoid regular or excessive use of acetaminophen. Alternative analgesic/antipyretic therapy may be appropriate in patients who consume three or more alcoholic drinks per day. However, if acetaminophen is used, these patients should be cautioned not to exceed the recommended dosage (maximum 4 g/day in adults and children 12 years of age or older).

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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: 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: Ethanol can exacerbate the cutaneous flushing that is a common side effect of niacin. At least one case of delirium and lactic acidosis has been reported with coadministration of these drugs, although data are limited.

MANAGEMENT: Coadministration should probably be discouraged, particularly since chronic consumption of large amounts of alcohol is associated with hyperlipidemia.

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A single case has been reported in which cutaneous flushing and tremors were noted in a woman who was taking niacin while wearing a nicotine patch. The mechanism is suspected to be synergistic cutaneous vasodilatory effects. The clinical significance of this possible interaction is not known.

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