Genetic mutations that prevent pain: implications for future pain medication.

Part of the interindividual variability in pain therapy has been associated with genetic polymorphisms. Several genetic variants prevent or at least decrease pain in their carriers as compared with carriers of the respective wild-type or common alleles by impeding the generation, transmission and processing of nociceptive information or by increasing the local availability of active analgesics or their pharmacodynamic effects. Complete prevention of pain has so far been seen in six distinct rare hereditary syndromes, namely the 'channelopathy-associated insensitivity to pain', caused by 13 currently identified variants in the SCN9A gene coding for the alpha-subunit of the voltage-gated sodium channel, and five maladies belonging to the hereditary sensory and autonomic neuropathy (HSAN) I-V syndromes, caused by various mutations in several genes. Reduced pain in the average population has been associated with frequent variants in the micro-opioid receptor gene (OPRM1), catechol-O-methyltransferase gene (COMT), guanosine triphosphate cyclohydrolase 1/dopa-responsive dystonia gene (GCH1), transient receptor potential cation channel, subfamily V, member 1 gene (TRPV1) or the melanocortin-1 receptor gene (MC1R). Duplications/amplifications of the cytochrome P450 2D6 (CYP2D6) gene leading to increased enzyme function may cause intense opioid effects of codeine up to toxicity. The COMT V158M variant has been associated with decreased morphine requirements for analgesia. Inactivating MC1R variants have been associated with increased opioid analgesia of the micro-opioid receptor agonist morphine-6-glucuronide and, in women only, of kappa-opioid agonists. Finally, variants in the P-glycoprotein gene (ABCB1) conferring decreased transporter function have been associated with increased respiratory depressive effects of fentanyl. In summary, a finite number of genetic variants that prevent pain by decreasing nociception or increasing analgesia have been identified. Given the complex biological and psychological nature of pain, we will see in the near future how much of the interindividual variance in pain and analgesia is due to identifiable genetic causes, and to what extent genetics enters clinical pain therapy.