• When choosing pharmacologic therapy, make sure that all medications your patient takes are documented, consider drug-drug interactions, and instruct the patient to notify you of any new medications.
• In addition to toxicity, loss of efficacy of some opiate drugs may occur as a result of metabolic inhibition or induction by psychotropic medications.
• Collaborate with the physician who is prescribing the opioid if psychotropic choices are limited. The patient’s pain may be treated adequately with another analgesic that does not interact with the psychotropic that has been chosen.
As prescribed by his internist, Mr. G, age 44, takes 10 mg of methadone every 4 hours for chronic back pain secondary to a work-related injury 3 years ago. He experiences minimal sedation. Mr. G presents for psychiatric evaluation with complaints of increasing irritability, poor focus, low energy, and lack of interest in usual activities. The psychiatrist diagnoses him with depressive disorder not otherwise specified, and prescribes fluoxetine, 20 mg/d. Three weeks later, Mr. G’s wife contacts the psychiatrist reporting that her husband seems “overmedicated” and describes excess drowsiness and slowed thought processing.
After discussion with Mr. G’s internist and pharmacist, the psychiatrist decides that this oversedation may represent a drug-drug interaction between methadone and fluoxetine resulting in higher-than-expected methadone serum levels. Mr. G is instructed to stop fluoxetine with no taper, and his methadone dose is lowered with good results. Over the next 2 weeks Mr. G is titrated back to his original methadone dose and is re-evaluated by the psychiatrist to discuss medication options to address his depression.
Psychiatrists commonly encounter patients who receive opiate medications for chronic pain. Being aware of potential drug-drug interactions between opiate medications and psychotropics can help avoid adverse effects and combinations that may affect the efficacy of either drug. Pharmacokinetic interactions may affect your choice of psychiatric medication and should be taken into account when addressing adverse effects in any patient who takes opiates and psychotropics.
The primary metabolic pathways for opiate metabolism are the cytochrome P450 (CYP) 2D6 and 3A4 isoenzymes. Depending on the agent used, prescribers may need to consider interactions for both pathways (Table 11,2 and Table 21). For example, oxycodone is metabolized via 2D6 and 3A4 isoenzymes and is a potent analgesic with oxymorphone and noroxycodone as its active metabolites. These metabolites, however, make a negligible contribution to oxycodone’s analgesic effect.3,4 Metabolism by the 3A4 isoenzyme is the principal oxidative pathway and the 2D6 site accounts for approximately 10% of oxycodone metabolism. A randomized, placebo-controlled, crossover study showed that 2D6 inhibition by paroxetine had no significant effect on oxycodone levels; however, a combination of paroxetine and itraconazole, a potent 3A4 inhibitor, resulted in substantial increases in oxycodone plasma levels.5 Remain vigilant for possible opiate toxicity when administering oxycodone with 3A4 inhibitors.
Methadone and meperidine also involve dual pathways. Methadone is metabolized primarily by 3A4 and 2B6, with 2D6 playing a smaller role.6 CYP2D6 seems to play an important part in metabolizing the R-enantiomer of methadone, which is largely responsible for the drug’s opiate effects, such as analgesia and respiratory depression.7,8 Induction of the 3A4 isoenzyme may result in methadone withdrawal, and inhibition may cause methadone toxicity.9 Inducers of 3A4, such as carbamazepine, and inhibitors, such as fluoxetine and fluvoxamine, should be avoided or used very cautiously in patients taking methadone. The 2B6 and 2D6 isoenzymes also may increase or decrease methadone levels and should be treated similarly. In Mr. G’s case, fluoxetine inhibited all 3 isoenzymes that are primarily responsible for methadone metabolism. A better antidepressant choice for Mr. G may have been venlafaxine, which is known to only mildly inhibit 2D6, or mirtazapine, which does not seem to inhibit the major CYP isoforms to an appreciable degree.10
Although the full scope of meperidine metabolism has not been identified,9 an in vitro test demonstrated that 2B6 and 3A4 play important roles in metabolizing meperidine to normeperidine, its major metabolite.11 Normeperidine does not provide analgesia and is associated with neurotoxicity, including anxiety, tremor, muscle twitching, and seizure.12 Agents that induce 3A4—such as carbamazepine or St. John’s wort—may contribute to neurotoxicity.9 Inhibition of these isoenzymes may increase meperidine levels and lead to anticholinergic toxicity or respiratory and central nervous system depression.13,14
Opiates metabolized by the 2D6 isoenzyme include codeine, hydrocodone, and tramadol. The analgesic effect of codeine seems dependent on 2D6 metabolism. Via this pathway, codeine is converted into morphine, which has a 300-times stronger affinity for the μ opioid receptor compared with codeine. 2D6 poor metabolizers have shown codeine intolerance and toxicity.3 Psychotropics known to strongly inhibit 2D6 isoenzyme processes—such as paroxetine, fluoxetine, and bupropion—should be avoided in patients taking codeine to prevent adverse effects and potential loss of efficacy. Better antidepressant choices include citalopram or venlafaxine, which inhibit 2D6 to a lesser degree.