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Opioids play a fundamental role in chronic pain, especially considering when 1 of 5 Europeans adults, even more in older females, suffer from it. However, half of them do not reach an adequate pain relief. Could pharmacogenomics help to choose the most appropriate analgesic drug? The objective of the present narrative review was to assess the influence of cytochrome  P450 2D6  ( CYP2D6 ) phenotypes on pain relief, analgesic tolerability, and potential opioid misuse. Until December 2021, a literature search was conducted through the  MEDLINE, PubMed  database, including papers from the last 10 years.  CYP2D6  plays a major role in metabolism that directly impacts on opioid (tramadol, codeine, or oxycodone) concentration with differences between sexes, with a female trend toward poorer pain control. In fact,  CYP2D6  gene variants are the most actionable to be translated into clinical practice according to regulatory drug agencies and international guidelines. CYP2D6  genotype can influence opioids’ pharmacokinetics, effectiveness, side effects, and average opioid dose. This knowledge needs to be incorporated in pain management. Environmental factors, psychological together with genetic factors, under a sex perspective, must be considered when you are selecting the most personalized pain therapy for your patients.

CYP2D6 phenotypes and opioid metabolism: the path to personalized analgesia