The online version of this article (doi:10.1186/s10194-017-0741-2) contains supplementary material, which is available to authorized users.
Calcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been clarified.
We performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials.
The literature search identified 375 citations of which 50 contained relevant original data. An association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain was found. In 13 out of 20 studies in somatic pain conditions, CGRP levels had a positive correlation with pain. Increased CGRP levels were reported in plasma, synovial and cerebrospinal fluid in subjects with musculoskeletal pain. A randomized clinical trial on monoclonal antibody, which selectively binds to and inhibits the activity of CGRP (galcanezumab) in patients with osteoarthritis knee pain, failed to demonstrate improvement of pain compared with placebo. No studies to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions.
The present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act as a neuromodulator in non-headache pain conditions. However, more studies are needed to fully understand the role of CGRP in nociceptive processing and therapy of chronic pain.
Additional file 1: Table S1. Brief overview of used methods and the association between pain and CGRP in each category. (DOC 72 kb)10194_2017_741_MOESM1_ESM.doc
Additional file 2: Table S2. Brief overview of used methods and the association between pain and CGRP in the musculoskeletal category. (DOC 37 kb)10194_2017_741_MOESM2_ESM.doc
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB (2015) Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 14:1081–1090 PubMedCrossRef
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J, ALD403 study investigators (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13:1100–1107 CrossRef
Lin WC, Yeh CH, Chien LC, Morone NE, Glick RM, Albers KM (2015) The anti-inflammatory actions of auricular point acupressure for chronic Low back pain. Evid Based Complement Alternat Med. doi: 10.1155/2015/103570., Epub 2015 Jun 11
Wang H, Zhang X, He JY, Zheng XF, Li D, Li Z, Zhu JF, Shen C, Cai GQ, Chen XD (2015) Increasing expression of substance P and calcitonin gene-related peptide in synovial tissue and fluid contribute to the progress of arthritis in developmental dysplasia of the hip. Arthritis Res Ther 17:4 PubMedPubMedCentralCrossRef
Takeshita M, Nakamura J, Ohtori S, Inoue G, Orita S, Miyagi M, Ishikawa T, Takahashi K (2012) Sensory innervation and inflammatory cytokines in hypertrophic synovia associated with pain transmission in osteoarthritis of the hip: a case–control study. Rheumatology (Oxford) 51:1790–5 CrossRef
Brown MF, Hukkanen MV, McCarthy ID, Redfern DR, Batten JJ, Crock HV, Hughes SP, Polak JM (1997) Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease. J Bone Joint Surg (Br) 79:147–153 CrossRef
Ozawa T, Ohtori S, Inoue G, Aoki Y, Moriya H, Takahashi K (2006) The degenerated lumbar intervertebral disc is innervated primarily by peptide-containing sensory nerve fibers in humans. Spine (Phila Pa 1976) 31:2418–2422 CrossRef
Alpar EK, Onuoha G, Killampalli VV, Waters R (2002) Management of chronic pain in whiplash injury. J Bone Joint Surg (Br) 84:807–811 CrossRef
Takeuchi H, Kawaguchi S, Ohwada O, Kobayashi H, Hayakawa M, Takebayashi T, Troiqoe T, Sato N, Yamashita T (2007) Plasma neuropeptides in patients undergoing lumbar discectomy. Spine (Phila Pa 1976) 32:E79–84 CrossRef
Larsson J, Ekblom A, Henriksson K, Lundeberg T, Theodorsson E (1991) Concentration of substance P, neurokinin A, calcitonin gene related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid from knee joints in patients suffering from rheumatoid arthritis. Scand J Rheumatol 20:326–335 PubMedCrossRef
Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR (1998) Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function. J Neurosci 18:8947–8959 PubMed
Salomon J, Baran E (2008) The role of selected neuropeptides in pathogenesis of atopic dermatitis. J Eur Acad Dermatol Venereol 22:223–228 PubMed
Hou Q, Barr T, Gee L, Vickers J, Wymer J, Borsani E, Rodella L, Getsios S, Burdo T, Eisenberg E, Guha U, Lavker R, Kessler J, Chittur S, Fiorino D, Rice F, Albrecht P (2011) Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms. Pain 152:2036–2051 PubMedPubMedCentralCrossRef
Attal N, de Andrade DC, Adam F, Ranoux D, Teixeira MJ, Galhardoni R, Raicher I, Üceyler N, Sommer C, Bouhassira D (2016) Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial. Lancet Neurol 15:555–565 PubMedCrossRef
Pfizer. Acute Response Capsaicin Flare Study. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 May 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT01147432.
Eli Lilly and Company. A Study of LY2951742 in Participants With Mild to Moderate Osteoarthritis Knee Pain. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 May 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02192190.
Jin Y, Smith C, Monteith D, Brown R, Camporeale A, McNearney T, Deeg M, Raddad E, de la Pena A, Kivitz A, Schnitzer T (2016) LY2951742, a monoclonal antibody against CGRP, failed to reduce signs and symptoms of knee osteoarthritis. Osteoarthritis Cartilage 24:S50 CrossRef
Odense University Hopsital. Remote Ischemic Conditioning in Patients With Ulcerative Colitis. In ClinictalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 May 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02445365.
Chakravarty P, Suthar TP, Coppock HA, Nicholl CG, Bloom SR, Legon S, Smith DM (2000) CGRP and adrenomedullin binding correlates with transcript levels for calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) in rat tissues. BrJ Pharmacol 130:189–195 CrossRef
Cottrell GS, Roosterman D, Marvizon JC, Song B, Wick E, Pikios S, Wong H, Berthelier C, Tang Y, Sternini C, Bunnett NW, Grady EF (2005) Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. J Comp Neurol 490:239–255 PubMedCrossRef
Gibson SJ, Polak JM, Bloom SR, Sabate IM, Mulderry PM, Ghatei MA, McGregor GP, Morrison JF, Kelly JS, Evans RM (1984) Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J Neurosci 4:3101–3111 PubMed
Morion CR, Hutchison WD (1989) Release of sensory neuropeptides in the spinal cord: Studies with calcitonin gene-related peptide and galanin. Neuroscience 31:807–815 CrossRef
Levine JD, Fields HL, Basbaum AI (1993) Peptides and the primary afferent nociceptor. J Neurosci 13:2273–2286 PubMed
Weihe E, Schäfer MK, Nohr D, Persson S (1994) Expression of neuropeptides, neuropeptide receptors and neuropeptide processing enzymes in spinal neurons and peripheral non-neural cells and plasticity in models of inflammatory pain. In: Hokfelt T, Schaible HG, Schmidt RF (eds) Neuropeptides, nociception and Pain. Chapman & Hall, London
Pereira da Silva JA, Carmo-Fonseca M (1990) Peptide containing nerves in human synovium: Immunohistochemical evidence for decreased innervation in rheumatoid arthritis. J Rheumatol 17:1592–1599 PubMed
Wang H, Ehnert C, Brenner GJ, Woolf CJ (2006) Bradykinin and peripheral sensitization. Biol Chem 387:11–14 PubMed
Axelsson HE, Minde JK, Sonesson A, Toolanen G, Högestätt ED, Zygmunt PM (2009) Transient receptor potential vanilloid 1, vanilloid 2 and melastatin 8 immunoreactive nerve fibers in human skin from individuals with and without Norrbottnian congenital insensitivity to pain. Neuroscience 162:1322–1332 PubMedCrossRef
Van der Schueren BJ1, Rogiers A, Vanmolkot FH, Van Hecken A, Depré M, Kane SA, De Lepeleire I, Sinclair SR, de Hoon JN (2008) Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model. J Pharmacol Exp Ther 325:248-255.
Li CC, Vermeersch S, Denney WS, Kennedy WP, Palcza J, Gipson A, Han TH, Blanchard R, De Lepeleire I, Depré M, Murphy MG, Van Dyck K, de Hoon JN (2015) Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist. Br J Clin Pharmacol 79:831–837 PubMedPubMedCentralCrossRef
- Calcitonin gene-related peptide and pain: a systematic review
Wendy Sophie Schou
Faisal Mohammad Amin
Peter J. Goadsby
- Springer Milan
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