Congenital Pain Insensitivity

A syndrome characterized by indifference to PAIN despite the ability to distinguish noxious from non-noxious stimuli. Absent corneal reflexes and INTELLECTUAL DISABILITY may be associated. Familial forms with autosomal recessive and autosomal dominant patterns of inheritance have been described. (Adams et al., Principles of Neurology, 6th ed, p1343)

Also Known As:

Networked: 117 relevant articles (1 outcomes, 9 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Hypohidrosis
2.	Pain (Aches)
3.	Hereditary Sensory and Autonomic Neuropathies (HSAN)
4.	Intellectual Disability (Idiocy)
5.	Erythromelalgia (Erythermalgia)

Experts

1.	Waxman, Stephen G: 5 articles (01/2020 - 12/2007)
2.	Dib-Hajj, Sulayman D: 3 articles (01/2020 - 06/2010)
3.	Baskozos, Georgios: 2 articles (10/2022 - 01/2019)
4.	Bennett, David L: 2 articles (10/2022 - 01/2019)
5.	Themistocleous, Andreas C: 2 articles (10/2022 - 01/2019)
6.	Weir, Greg A: 2 articles (10/2022 - 01/2019)
7.	Wood, John N: 2 articles (10/2022 - 12/2015)
8.	Capsoni, Simona: 2 articles (01/2021 - 02/2014)
9.	Woods, C Geoffrey: 2 articles (01/2019 - 06/2014)
10.	Dion, Patrick A: 2 articles (03/2016 - 11/2014)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Congenital Pain Insensitivity:

1.	Analgesics (Analgesic Drugs)IBA 10/01/2015 - "Genomic study of congenital insensitivity to pain provides new avenues for the development of analgesics." 01/01/2022 - "Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target." 10/01/2012 - "By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. " 06/01/1969 - "[Somatosensory evoked response in patients with congenital analgesia and the neurochemically induced analgesic state]." 01/01/2020 - "These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings "Nav1.7 total loss-of-function leads to painlessness." Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics."
2.	Amino AcidsFDA Link 04/15/1969 - "In vitro uptake of labelled amino acids by the skin of children with generalized congenital analgesia." 01/01/2020 - "These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings "Nav1.7 total loss-of-function leads to painlessness." Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics." 11/01/2017 - "Novel 9 amino acid in-frame deletion in the NTRK1 tyrosine kinase domain in a patient with congenital insensitivity to pain with anhydrosis."
3.	Nerve Growth Factor (NGF)IBA 01/01/2016 - "The purpose of the present study was to investigate the effects of reduced NGF signaling in patients with hereditary sensory and autonomic neuropathies type V, congenital insensitivity to pain, caused by a mutation of the NGFβ gene, including a characterization of single nociceptive fibers using microneurography (MNG). " 01/01/2019 - "In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. " 02/25/2023 - "A point mutation in the NGFB gene (leading to the amino acid substitution R100W) is responsible for Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), leading to a congenital pain insensitivity with no clear cognitive impairments, but with alterations in the NGF/proNGF balance. " 01/01/2021 - "Here we shall review the consequences of these NGF mutations, each of which results in specific clinical signs: R221W determines congenital pain insensitivity with no overt cognitive disabilities, whereas V232fs and R121W also result in intellectual disability, thus showing similarities to HSAN IV, which is caused by mutations in TrkA, rather than to HSAN V. Comparing the cellular, biochemical and clinical findings of these mutations could help in better understanding not only the possible mechanisms underlying HSAN V, but also mechanisms of NGF signalling and roles. " 02/01/2014 - "Interestingly, alterations in NGF signalling, due to mutations in the NGF TRKA gene, have also been involved in another congenital insensitivity to pain, HSAN IV, characterized not only by absence of reaction to painful stimuli, but also anhidrosis and mental retardation. "
4.	Voltage-Gated Sodium ChannelsIBA 10/21/2022 - "Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. " 03/01/2016 - "Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9." 12/04/2015 - "Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. " 08/01/2015 - "The clinically overlapping "congenital insensitivity to pain (CIP)" is caused by mutations in voltage-gated sodium channels, which control the excitability of nociceptors. " 10/22/2013 - "Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. "
5.	Naloxone (Narcan)FDA LinkGeneric 12/01/1978 - "In an electrophysiological study on a nociceptive flexion reflex of the lower limb, the effects of naloxone and of placebo were compared in 8 normal subjects and in a patient with congenital insensitivity to pain. " 04/01/1978 - "Electrophysiological studies of the nociceptive reflex (R3) were carried out in eight normal subjects, and one patient with congenital insensitivity to pain, in order to compare the effects of naloxone and a placebo. " 01/01/1986 - "Moreover, patients with congenital analgesia show pronounced elevation of nociceptive reflex thresholds which can be reduced to within almost normal levels by dosing with naloxone. " 11/01/1981 - "[Effect of naloxone on somatosensory evoked potentials in congenital insensitivity to pain]." 09/30/1978 - "Congenital insensitivity to pain and naloxone."
6.	Proteins (Proteins, Gene)FDA Link 12/01/2020 - "Structural and functional annotation of PR/SET Domain (PRDM) protein family: In-silico study elaborating role of PRDM12 mutation in congenital insensitivity to pain." 12/01/2020 - "One of the PR/SET Domain Proteins, PRDM12, has been identified in recent past as a candidate gene for congenital insensitivity to pain. " 01/01/2012 - "Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). " 11/01/2012 - "Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. " 10/01/2012 - "Recent studies have revealed that mutations in the NGFB gene-encoding NGF protein also cause congenital insensitivity to pain. "
7.	Nonsense Codon (Nonsense Mutation)IBA 11/01/2014 - "A novel nonsense mutation in SCN9A in a Moroccan child with congenital insensitivity to pain." 01/01/2010 - "A nonsense mutation in the SCN9A gene in congenital insensitivity to pain." 11/01/2014 - "In this report we present a previously unreported homozygous nonsense mutation present in a consanguineous Moroccan congenital insensitivity to pain patient with anosmia. " 12/01/2007 - "Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. " 01/01/2014 - "Genetic studies in families demonstrating recessively inherited channelopathy-associated insensitivity to pain have identified nonsense mutations that result in truncation of the voltage-gated sodium channel type IX subunit (SCN9A), a 113.5-kb gene comprising coding 26 exons. "
8.	3-(2-carboxyindol-3-yl)propionic acidIBA 09/01/2012 - "Congenital Insensitivity to Pain and Anhydrosis (CIPA) Syndrome; A Report of 4 Cases." 01/01/2011 - "Congenital Insensitivity to pain with anhydrosis (CIPA) is a rare inherited disease. " 03/01/2008 - "Because no clear cause for the Charcot spine could be determined from the patient's history or initial evaluation, an extensive diagnostic work-up was undertaken, which ultimately led to a diagnosis of congenital insensitivity to pain with anhydrosis (CIPA). " 11/01/2007 - "Sensory phenotype was assessed in a young girl affected by congenital insensitivity to pain (CIPA) scheduled for an open surgical drainage. " 11/01/2007 - "Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA)."
9.	Sodium Channels (Sodium Channel)IBA 07/01/2013 - "We now know that mutations of sodium channels cause not only rare genetic 'model disorders' such as inherited erythromelalgia and channelopathy-associated insensitivity to pain but also common painful neuropathies. " 06/08/2010 - "A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain. " 06/01/2014 - "For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. " 11/07/2012 - "Sodium channel Nav1.7 has emerged as a target of considerable interest in pain research, since loss-of-function mutations in SCN9A, the gene that encodes Nav1.7, are associated with a syndrome of congenital insensitivity to pain, gain-of-function mutations are linked to the debiliting chronic pain conditions erythromelalgia and paroxysmal extreme pain disorder, and upregulated expression of Nav1.7 accompanies pain in diabetes and inflammation. " 06/01/2011 - "From human genetics, a small number of patients with mutations in the genes encoding nerve growth factor/TrkA signaling and in a particular sodium channel subunit (SCN9a, encoding Nav1.7) show congenital analgesia with limited other effects. "
10.	Anesthetics (Anesthetic Agents)IBA 02/01/2017 - "This case report describes the anesthetic management of a parturient with congenital insensitivity to pain presenting for cesarean delivery." 10/01/2013 - "Anesthetic management of a patient with congenital insensitivity to pain: a case report." 01/01/2011 - "We report a family case of a 5 years old girl and 2 years old boy with congenital insensitivity to pain, while discussing the clinical features and the anesthetic strategy of such patients. " 05/01/2009 - "Anesthetic management of a pediatric patient with congenital insensitivity to pain." 06/01/2005 - "Anesthetic management of a child with congenital insensitivity to pain with anhydrosis."

Therapies and Procedures

1.	Anesthesia 01/01/2017 - "Congenital insensitivity to pain: How should anesthesia be managed? " 01/01/2017 - "Congenital insensitivity to pain: How should anesthesia be managed?" 08/01/1975 - "[Anesthesia in congenital analgesia]." 02/01/2002 - "Anesthesia for patients with congenital insensitivity to pain and anhidrosis: a questionnaire study in Japan." 01/01/2017 - "Anesthesia Procedure for Congenital Insensitivity to Pain in a Child with Anhidrosis Syndrome: A Rare Case."
2.	Analgesia 06/01/1996 - "The congenital insensitivity-to-pain syndrome (analgesia congenita): report of a case." 12/15/1984 - "Intracerebroventricular injection of cerebrospinal fluid (CSF) from a patient with congenital indifference to pain induces analgesia in rats." 12/15/1984 - "CSF from a patient with congenital indifference to pain was found to produce analgesia in the rat following intracerebroventricular injections. " 04/01/1958 - "[Congenital insensitivity to pain with analgesia & agnosia during labor]." 04/01/1986 - "Bilateral amputations were performed without analgesia on a patient with congenital insensitivity to pain (congenital analgesia). "
3.	Surgical Amputation (Amputations) 09/01/1986 - "A case of a variant of congenital indifference to pain, in which the patient initially developed lower extremity neurogenic arthropathy ultimately requiring bilateral above-the-knee amputations, is presented. " 04/01/1986 - "Bilateral amputations were performed without analgesia on a patient with congenital insensitivity to pain (congenital analgesia). " 01/01/2015 - "The patient suffered from congenital insensitivity to pain without anhidrosis and presented with full blown sequelae of the condition in the form of oral self-mutilation leading to loss of teeth, tongue tip amputation, finger tips destruction, and lower limb wound infections. " 09/01/1998 - "Hereditary sensory neuropathy type IV is an autosomal-recessive disorder characterized by congenital insensitivity to pain and anhidrosis and resulting in recurrent hyperpyrexia, self-mutilation, recurrent infections, chronic osteomyelitis, bone and joint deformities, and limb amputations. "
4.	Injections 12/15/1984 - "CSF from a patient with congenital indifference to pain was found to produce analgesia in the rat following intracerebroventricular injections. " 01/01/1986 - "Spontaneously elevated nociceptive threshold levels were markedly diminished after Naloxone injections in 4 patients with congenital insensitivity to pain. " 10/01/2000 - "Examples of osteoarthropathy from diverse causes are presented including syringomyelia, spinal cord injury, meningomyelocele, diabetes mellitus, congenital insensitivity to pain, steroid injections, syphilis, leprosy, and others. "
5.	Transjugular Intrahepatic Portasystemic Shunt 03/01/1980 - "The muscolo-cutaneous nerve, and skin biopsies from 3rd and 5th finger-tips and the back were studied in a 8-year-old girl with congenital indifference to pain, and in a control child of the same age. " 01/01/2015 - "The patient suffered from congenital insensitivity to pain without anhidrosis and presented with full blown sequelae of the condition in the form of oral self-mutilation leading to loss of teeth, tongue tip amputation, finger tips destruction, and lower limb wound infections. "