Pharmacogenetics of new analgesics

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 which SCN9A, CACNA1B, KCNQ2 and KCNQ3, 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 by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, d-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), 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. AbbreviationsAMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; COX-2, prostaglandin endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase); FAAH, fatty acid amide hydrolase; Il-1, interleukin 1; MAO, monoamine oxidase; mGluR5, metabotropic glutamate receptor 5; nAChR, neuronal nicotinic acetylcholine receptors; Nav, voltage-gated sodium channels; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; NR2B, NR2B Subunit of the NMDA receptor; P2X7, purinergic receptor P2X, ligand-gated ion channel, 7; TRPV1, transient receptor potential cation channel, subfamily V, member 1; TRPV3, transient receptor potential cation channel, subfamily V, member 3

A machine‐learned analysis of human gene polymorphisms modulating persisting pain points to major roles of neuroimmune processes

“…These mainly include genes found, in at least three independent studies in transgenic mice, to contribute to the modulation of pain and identified using PubMed searches, with the addition of further genes (Lötsch et al., ) comprising those causally implicated in human hereditary diseases associated with extreme pain phenotypes (summarized in, e.g. Lötsch et al., ), and genes coding for the targets of approved analgesic drugs or of novel analgesics currently in clinical phases of development (Lötsch and Geisslinger, ). This provided a set of n = 535 ‘pain genes’ (Fig.…”

Modeling the Influence of the A118G Polymorphism in the OPRM1 Gene and of Noxious Stimulation on the Synergistic Relation between Propofol and Remifentanil

“…15 Based on this observation, we studied 207 patients with the aim to include between 20 and 40 patients who could have the A118G SNP. All patients were enrolled under Institutional Review Board of the Hospital CLINIC de Barcelona, Barcelona, Spain, approval of the study protocol and they signed an informed consent.…”

Considerations when using pharmacokinetic/pharmacodynamic modeling to determine the effectiveness of simple analgesics in children

“…Signal transmission from opioid receptors requires involvement of ion channels (K, Na, Ca) and polymorphisms of these channels have also been noted to have an influence on pain sensitivity. Mutations in voltage-gated transient receptor potential channels have been identified and may modulate the effects of analgesics [95]. Efflux transporters like the P-glycoproteins are also associated with polymorphisms and may affect transport into or out of the brain [96].…”