Coverage from EHF 2019

The neuropeptide calcitonin gene-related peptide (CGRP) plays a significant role in chronic neuropathic pain, and the therapeutic benefits of anti-CGRP monoclonal antibodies (mAbs) in migraine treatment are well established. However, CGRP is not only expressed in the central nervous system, but also in nearly all human organs.1 In a presentation at the 13th annual congress of the European Headache Federation, Prof. David W. Dodick (Mayo Clinic, USA) provided a brief overview of recent studies on the use of anti-CGRP mAbs in non-migraine pain conditions.

Primary headache

Thus far, clinical trial results have not demonstrated a therapeutic benefit of anti-CGRP mAbs in cluster headache. Prof. Dodick questioned whether patient population and outcome measure selection could be improved to properly answer the research question, and emphasised that additional studies of anti-CGRP mAbs in cluster headache should be conducted.

“We are tracking patients from a migraine standpoint, but what we haven’t been doing – and what I think we should be doing – is tracking other pain syndromes as well.”

 – David W. Dodick, Mayo Clinic, USA

Secondary headache

Animal studies have shown that concussions lead to headache and pain-related behaviours, and that the administration of anti-CGRP mAbs prevents allodynia in murine models of post-traumatic headache (PTH).2,3 Prof. Dodick highlighted an ongoing clinical trial (NCT03347188) that investigates anti-CGRP mAbs in patients with PTH. The results of this study are expected in October 2020.

Non-headache pain

A recent systematic literature review showed an association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain.4 In particular, CGRP levels had a positive correlation with pain in somatic pain conditions. However, an initial investigation of anti-CGRP mAbs in patients with osteoarthritis knee pain failed to demonstrate a therapeutic benefit compared with placebo.5 In Prof. Dodick’s opinion, this was an unexpected result and he questioned whether the correct joint was targeted in this study. Prof. Dodick further commented that other pain syndromes that could be potentially addressed with anti-CGRP are those of visceral, inflammatory and neuropathic etiology.4,6

Non-pain syndromes

The prophylactic administration of anti-CGRP antibodies was found to block CGRP-induced diarrhoea in mice.7 These preclinical results illustrate the potential of anti-CGRP mAbs as a novel therapeutic strategy for infectious diarrhoea and other gastro-intestinal pathologies, such as colitis and inflammatory bowel disease.

Prof. Dodick concluded his presentation with a call to action to track patients in clinical trials not only from a migraine standpoint, but to integrate measures that record other pain syndromes as well. Patient-reported outcome questionnaires were highlighted as appropriate tools for this purpose.

References

  1. Russell FA, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94:1099–1142.
  2. Bree D, et al. Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia. 2018;38:246–258.
  3. Porreca F, et al. manuscript in preparation
  4. Sophie Schou W, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18:34.
  5. Jin Y, et al. CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial. Osterarthritis Cartilage. 2018;26:1609–1618.
  6. Bowler KE, et al. Evidence for anti-inflammatory and putative analgesic effects of a monoclonal antibody to calcitonin gene-related peptide. Neuroscience. 2013;228:271–282.
  7. Kaiser EA, et al. Anti-CGRP antibodies block CGRP-induced diarrhea in mice. Neuropeptides. 2017;64:95–99.