The Effect of Fremanezumab on Pain in Patients with Complex Regional Pain Syndrome

Background & Aims

Complex Regional Pain syndrome (CRPS) is a debilitating primary pain condition in the limbs which rarely develops after a trauma. Despite significant progress in understanding the pathophysiology, treatment of CRPS is challenging. Preclinical and clinical studies suggest that the neuropeptide Calcitonin Gene-Related Peptide (CGRP) might be a mediator of both pain and inflammation in CRPS (1-8) which makes CGRP a possible target for a mechanism-based treatment. Recently, drugs targeting CGRP including Fremanezumab have become available and have been shown to be effective in the treatment of migraine (9, 10).

The primary outcome of our study is the change of pain intensity from baseline to the last week of Fremanezumab treatment compared to placebo in CRPS patients. Secondary outcomes are to assess pain relief and differences in clinical signs and function between both groups and if the effect can be predicted by CRPS biomarkers.

Methods

This is a randomized, double-blind, placebo-controlled, proof-of-concept study where 60 adult patients with CRPS according to the International Association for the Study of Pain (IASP) research criteria (11, 12) with disease lasting from 3-18 months are randomized to treatment for eight weeks with Fremanezumab 225 mg or placebo (saline) at a 1:1 rate. Study procedures include patient-reported outcome measures such as pain diary and questionnaires, medical and medication history, demography, physical examination, a restricted version of quantitative sensory testing by the German Research Network on Neuropathic Pain, CRPS severity score, blood samples (inflammatory markers), skin biopsies and measurement of cutaneous blood flow at different time points. Adverse effects and blinding will also be assessed.

Results

Enrollment of patients began in December 2023. As of January 2024, three patients have been included in the study, two of whom have been randomized. It is expected that more patients will be included in the study and undergo randomization before the IASP 2024 World Congress on Pain in August, and baseline data of these patients will be presented at the congress.

Conclusions

This study will hopefully elucidate the pathogenesis of CRPS, and the assessment of the efficacy of Fremanezumab may result in a mechanism-based treatment option for patients with CRPS.

References

1.Birklein F, Schmelz M, Schifter S, Weber M. The important role of neuropeptides in complex regional pain syndrome. Neurology. 2001;57(12):2179-84.
2.Schlereth T, Drummond PD, Birklein F. Inflammation in CRPS: role of the sympathetic supply. Auton Neurosci. 2014;182:102-7.
3.Li WW, Guo TZ, Shi X, Birklein F, Schlereth T, Kingery WS, Clark JD. Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome. J Neuroinflammation. 2018;15(1):105.
4.Guo TZ, Wei T, Shi X, Li WW, Hou S, Wang L, et al. Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome. Mol Pain. 2012;8:85.
5.Shi X, Wang L, Li X, Sahbaie P, Kingery WS, Clark JD. Neuropeptides contribute to peripheral nociceptive sensitization by regulating interleukin-1? production in keratinocytes. Anesth Analg. 2011;113(1):175-83.
6.Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.
7.Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS. Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I. Pain. 2004;108(1-2):95-107.
8.Li WW, Guo TZ, Li XQ, Kingery WS, Clark DJ. Fracture induces keratinocyte activation, proliferation, and expression of pro-nociceptive inflammatory mediators. Pain. 2010;151(3):843-52.
9.Deng H, Li GG, Nie H, Feng YY, Guo GY, Guo WL, Tang ZP. Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – an updated systematic review and meta-analysis. BMC Neurol. 2020;20(1):57.
10.Han L, Liu Y, Xiong H, Hong P. CGRP monoclonal antibody for preventive treatment of chronic migraine: An update of meta-analysis. Brain Behav. 2019;9(2):e01215.
11.Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326-31.
12.Goebel A, Birklein F, Brunner F, Clark JD, Gierthmühlen J, Harden N, et al. The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria. Pain. 2021;162(9):2346-8.