The cytochrome P450s represent the major system for oxidative metabolism of drugs. Today we’re focusing on one in particular: CYP2D6. Multiple drugs are substrates of CYP2D6, including several antidepressants (e.g., most SSRI/SNRIs, all TCAs) and opioids (specifically codeine, hydrocodone, oxycodone, and tramadol). Confusingly, CYP2D6’s function depends on the drug. For instance, consider its impact on codeine and nortriptyline:
- Codeine is a prodrug and its analgesic properties do not manifest until it is metabolized by CYP2D6, primarily to morphine and codeine-6-glucuronide. In contrast, nortriptyline is the active moiety and its metabolism by CYP2D6 results in inactivation of the drug to its primary metabolite.
- At conventional doses, individuals with reduced metabolism based upon CYP2D6 genotype will derive no therapeutic benefit from codeine (because it will not be converted to its active moiety), but they may be “overdosed” with nortriptyline and at increased risk of side effects.
- Conversely, at conventional doses of codeine, individuals with ultra-rapid metabolism based upon CYP2D6 genotype have higher than expected morphine levels (an initial “overdose”), with more side effects and a shorter than expected duration of pain control. On the other hand, these patients may derive no significant therapeutic benefit from nortriptyline because of excessive metabolism.
Further clouding the picture is the number of drugs that inhibit CYP2D6, including 3 antidepressant substrates classified as strong inhibitors (bupropion, fluoxetine, and paroxetine) and 1 antidepressant classified as a moderate inhibitor (duloxetine).
- Strong inhibitors are drugs that increase the area under the concentration time curve (AUC) of substrates by at least 5-fold; moderate inhibitors do so between 2-fold and 5-fold
The example of a patient taking both an opioid and an antidepressant is actually quite common, raising concern for drug-drug interactions via CYP2D6. This interaction has been linked to opioid toxicity and worse pain control, possibly caused by attenuated conversion of these opioids to active forms.
In a recent retrospective cohort study published in the Annals of Internal Medicine, researchers identified 29,000 (!) U.S. nursing home residents (age ≥65) who were prescribed CYP2D6-metabolized opioids plus antidepressants. During 1 year of follow-up after antidepressant initiation, residents who also received CYP2D6-inhibiting antidepressants were more likely to have worsening pain (33% vs 29%), pain-related hospitalizations (1.5% vs 1.1%), and pain-related emergency department visits (0.9% vs. 0.6%) than were residents who received other antidepressants. Rates of opioid overdose were similar between the two antidepressant groups.
Although the above study focused on a specific population, these results are arguably worth considering when selecting antidepressants for any patient who takes opioids. But keep in mind that various confounding factors might have influenced the above study’s findings. For example, because duloxetine often is used to treat both pain and depression, patients who received that drug might have been at higher baseline risk for pain-related complications, independent of its inhibition of CYP2D6.