Calcitonin gene-related peptide and pain: a systematic review

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Electronic supplementary material

The online version of this article (doi:10.1186/s10194-017-0741-2) contains supplementary material, which is available to authorized users.

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Most cited references 105

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Sensitization in patients with painful knee osteoarthritis.

Lars Arendt-Nielsen, Hongling Nie, Mogens B Laursen … (2010)

Pain is the dominant symptom in osteoarthritis (OA) and sensitization may contribute to the pain severity. This study investigated the role of sensitization in patients with painful knee OA by measuring (1) pressure pain thresholds (PPTs); (2) spreading sensitization; (3) temporal summation to repeated pressure pain stimulation; (4) pain responses after intramuscular hypertonic saline; and (5) pressure pain modulation by heterotopic descending noxious inhibitory control (DNIC). Forty-eight patients with different degrees of knee OA and twenty-four age- and sex-matched control subjects participated. The patients were separated into strong/severe (VAS>or=6) and mild/moderate pain (VAS<6) groups. PPTs were measured from the peripatellar region, tibialis anterior (TA) and extensor carpi radialis longus muscles before, during and after DNIC. Temporal summation to pressure was measured at the most painful site in the peripatellar region and over TA. Patients with severely painful OA pain have significantly lower PPT than controls. For all locations (knee, leg, and arm) significantly negative correlations between VAS and PPT were found (more pain, more sensitization). OA patients showed a significant facilitation of temporal summation from both the knee and TA and had significantly less DNIC as compared with controls. No correlations were found between standard radiological findings and clinical/experimental pain parameters. However, patients with lesions in the lateral tibiofemoral knee compartment had higher pain ratings compared with those with intercondylar and medial lesions. This study highlights the importance of central sensitization as an important manifestation in knee OA.

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CGRP and its receptors provide new insights into migraine pathophysiology.

Tony Ho, Lars Edvinsson, Peter J Goadsby (2010)

Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

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CGRP may play a causative role in migraine.

Annette Jacobsen, Jes Olesen, Lene Iversen … (2002)

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.

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Author and article information

Contributors

Messoud Ashina: + 45 38 63 33 85 , ashina@dadlnet.dk

Journal

Journal ID (nlm-ta): J Headache Pain

Journal ID (iso-abbrev): J Headache Pain

Title: The Journal of Headache and Pain

Publisher: Springer Milan (Milan )

ISSN (Print): 1129-2369

ISSN (Electronic): 1129-2377

Publication date (Electronic): 16 March 2017

Publication date PMC-release: 16 March 2017

Publication date Collection: 2017

Volume: 18

Issue: 1

Electronic Location Identifier: 34

Affiliations

[1 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, , University of Copenhagen, ; Copenhagen, Denmark

[2 ]Department of Neurology, NYU Lutheran Headache Center, New York University School of Medicine, NYU Langone Medical Center, New York, NY USA

[3 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, , Basic & Clinical Neuroscience, and NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, ; London, UK

Article

Publisher ID: 741

DOI: 10.1186/s10194-017-0741-2

PMC ID: 5355411

PubMed ID: 28303458

SO-VID: dfce4673-4e28-4027-a8ea-a81da97d8e7e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 7 January 2017

Date accepted : 28 February 2017

Funding

Funded by: Lundbeckfonden (DK)

Award ID: R155-2014-171

Award Recipient : Messoud Ashina

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ScienceOpen disciplines: Anesthesiology & Pain management

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ScienceOpen disciplines: Anesthesiology & Pain management

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Calcitonin gene-related peptide and pain: a systematic review

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Irish Journal of Paramedicine

Most cited references 105

Sensitization in patients with painful knee osteoarthritis.

CGRP and its receptors provide new insights into migraine pathophysiology.

CGRP may play a causative role in migraine.

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

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Cited by 73

Most referenced authors 1,057