• Ichrak Drissi, William Aidan Woods, and Christopher Geoffrey Woods.
• Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.
• Br. Med. Bull. 2020 May 15; 133 (1): 65-78.

Introduction Or BackgroundCongenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids.Sources Of DataPubmed.gov peer-reviewed journal articles and reviews.Areas Of AgreementThe importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway.Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target.There are further Mendelian causes of painlessness to be discovered.Areas Of ControversyWhich NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing?Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids.Why do all CIP phenotypes involve a complete loss of all types of nociception?Areas Timely For Developing ResearchPRDM12 as an analgesic target.Discovery of the function and analgesic potential of new CIP genes.Can NGF-TRKA be used in the treatment of S. aureus?© The Author(s) 2020. Published by Oxford University Press.

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