Tramadol (brand names ConZip, Ultram, UltramER, Odolo) is an analgesic used to treat moderate to severe pain. It is used for a variety of pain conditions, including post-operative pain, cancer pain, and musculoskeletal pain. Tramadol is a centrally acting opioid analgesic with mu-opioid binding activity as well as weak inhibition of reuptake of norepinephrine and serotonin.
The CYP2D6 enzyme converts tramadol to the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for the mu-opioid receptor than tramadol. The M1 metabolite is up to 6 times more potent than tramadol in producing analgesia.
Individuals who have reduced CYP2D6 activity are known as “intermediate metabolizers” and those with absent CYP2D6 activity are known as “poor metabolizers.” The standard recommended doses of tramadol may not provide adequate pain relief in these individuals because of reduced levels of M1. Whereas in individuals who have increased CYP2D6 activity (“ultrarapid metabolizers”), standard doses of tramadol may result in a higher risk of adverse events because of increased exposure to M1.
The 2021 FDA-approved drug label warns that individuals who are ultrarapid metabolizers (UMs) should not use tramadol because of the risk of life-threatening respiratory depression and signs of opiate overdose (for example, extreme sleepiness, confusion, or shallow breathing) (Table 1) (1).
The prevalence of CYP2D6 UM varies but is thought to be present in approximately 1–10% of Caucasians (European, North American), 3–4% of Blacks (African Americans), and 1–2% of East Asians (Chinese, Japanese, Korean). The frequency of UM phenotype has been reported to be even higher in some groups, including Ashkenazi Jews and regional populations in the Middle East.
Furthermore, tramadol is not recommended in nursing mothers due to the potential exposure to high levels of M1 causing life-threatening respiratory depression, if the mother is a UM. At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an UM of codeine, which—similar to tramadol—is activated by CYP2D6 metabolism.
Tramadol is contraindicated for all children younger than age 12 and for all individuals under the age of 18 when being used for post-operative analgesia following tonsillectomy or adenoidectomy, or both. The label warns that life-threatening respiratory depression and death have occurred in children who received tramadol, and in at least one case, the child was an UM of tramadol.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, a different non-CYP2D6 dependent analgesic should be used to avoid the risk of severe toxicity with standard dosing of tramadol. The CPIC also recommends avoiding tramadol in individuals identified as CYP2D6 poor metabolizers (PMs) due to the possibility of lack of effect (Table 2) (2).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) provides dosing recommendations for tramadol based on CYP2D6 genotype (Table 3). The DPWG states it is not possible to calculate a dose adjustment for tramadol, because when the ratio of tramadol and M1 is altered, the nature and total analgesic effect of tramadol also changes. For CYP2D6 UM, DPWG recommends selecting an alternative drug to tramadol - but not codeine, which is also metabolized by CYP2D6. Alternative drugs include morphine (not metabolized by CYP2D6) and oxycodone (which is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in clinical practice). For CYP2D6 poor (PM) and intermediate metabolizers (IM), DPWG recommends increasing the dose of tramadol, and if this does not have the desired effect, selecting an alternative drug (not codeine) (Table 3) (3).