Pharmacogenetics of new analgesics

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Abstract
Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1,PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage‐gated sodium, calcium and potassium channels, for whichSCN9A,CACNA1B,KCNQ2andKCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand‐gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate‐gated receptors and ATP‐gated purinergic P2X receptors with most important subunits coded byCHRNA4,GRIN2BandP2RX7. Among G protein coupled receptors, δ‐opioid receptors (coded byOPRD1), cannabinoid receptors (CNR1andCNR2), metabotropic glutamate receptors (mGluR5 coded byGRM5), bradykinin B1(BDKRB1) and 5‐HT1A(HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro‐psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information.

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