Use of tramadol is not advised for people who are CYP2D6 poor metabolizers; this is because CYP2D6 enzymes are crucial to the therapeutic effects of tramadol, because they metabolize tramadol to its more active form, O-desmethyltramadol. The FDA states that based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol itself were approximately 20% higher in CYP2D6 poor metabolizers compared to extensive metabolizers, while concentrations of O-desmethyltramadol were 40% lower. This implies that the dosage should be increased (by ~60%) to achieve an equivalent dose of the active metabolite in CYP2D6 poor metabolizers.PGK
A guideline from the Dutch Pharmacogenetics Working Group includes dose recommendations for CYP2D6 poor metabolizers (either select an alternative drug—not oxycodone or codeine—or be alert to the symptoms of insufficient pain relief) as follows:NCBI
- For Ultrarapid metabolizers (those with more than two functional copies): Reduce tramadol dose by 30% and be alert to ADEs (e.g., nausea, vomiting, constipation, respiratory depression, confusion, urinary retention) or select alternative drug (e.g., acetaminophen, NSAID, morphine—not oxycodone or codeine)
- For Intermediate metabolizers (having one active allele and one inactive allele, or two decreased activity alleles, or one decreased activity allele and one inactive allele): Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug—not oxycodone or codeine—or be alert to symptoms of insufficient pain relief
- For Poor metabolizers (those with two inactive alleles): Select alternative drug—not oxycodone or codeine—or be alert to symptoms of insufficient pain relief.
This source defines the activity levels for the CYP2D6 alleles as follows:
- Active alleles: *1, *2, *33, *35
- Decreased activity: *9, *10, *17, *29, *36, *41
- Inactive: *3-*8, *11-*16, *19-*21, *38, *40, *42
The most clinically significant variants are shown in bold.