Pain Polymorphisms and Opioids: An Evidence Based Review

Mol Med Rep. 2019 Mar;19(3):1423-1434. doi: 10.3892/mmr.2018.9792. Epub 2018 Dec 24.


Despite the various different candidate genetic polymorphisms of potential clinical relevance, there is not enough understanding of the inter‑individual variability in analgesic administration. The cytochrome P450 2D6 (CYP2D6) genotype is thought to be one of the most studied. The aim of the present evidence‑based review was to determine if there is now sufficient evidence to make clinical recommendations based on a specific genomic profile. The data sources utilized were as follows: PubMed (NLM) database, Evidence Based Medicine Guidelines and Google. Research on clinical guidance standards, systematic reviews, meta‑analyses and clinical trials, published prior to January 2018, were evaluated in English, using the MeSH terms 'cancer pain', 'polymorphism', 'genetic' and 'gene polymorphism'. To assess the level of evidence, the Strength of Recommendation Taxonomy of the American Family Physician was applied. From the initial search, 12 systematic reviews and/or meta‑analyses, 5 clinical trials and 10 guidelines were selected. The results indicated that genetic variation of µ‑opioid receptor 1 (OPRM1) may contribute to inter‑individual differences in morphine consumption with recommendation grade A for OPRM A118G single nucleotide polymorphism (rs1799971). Polymorphisms associated with the metabolization process of morphine and other opioid drugs are very relevant in opioid titration and ethnic subgroup differences which have to be taken into account (particularly, for the recommendation grade A for the CYP2D6 polymorphism). In human studies, the catechol‑O‑methyl transferase (COMT) genotype affects the efficacy of opioids in acute and chronic pain under different settings, with recommendation grade B to the COMT single nucleotide polymorphism rs4680 (Val/Met). Finally, polymorphisms of the ATP‑binding cassette family of efflux transporters were highlighted. Consistent data on pain polymorphisms is now widely available; however, these results have had very little impact on clinical guidelines and daily oncologist practice. Persisting pain, side effects of grade 3 (NCI‑CTCAE v4.0) and breakthrough pain with more than 4 episodes/day should be considered the criteria for pain multidisciplinary team discussions and for polymorphism screening.

MeSH terms

  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / therapeutic use
  • Cancer Pain / drug therapy
  • Cancer Pain / genetics*
  • Cancer Pain / physiopathology
  • Catechol O-Methyltransferase / genetics*
  • Cytochrome P-450 CYP2D6 / genetics*
  • Genotype
  • Humans
  • Morphine / adverse effects
  • Morphine / therapeutic use
  • Pain / drug therapy
  • Pain / genetics*
  • Pain / physiopathology
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Opioid, mu / genetics*


  • Analgesics, Opioid
  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • Morphine
  • Cytochrome P-450 CYP2D6
  • COMT protein, human
  • Catechol O-Methyltransferase