Comparative Effectiveness of Botulinum Toxin Injection for Chronic Shoulder Pain: A Meta-Analysis of Randomized Controlled Trials

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Abstract

Botulinum toxin (BoNT) injection is regarded as a promising treatment for musculoskeletal pain. However, its efficacy for treating chronic shoulder pain remains unclear. We investigated the effectiveness of BoNT injections for chronic shoulder pain by conducting a systematic search of electronic databases up to March 2020 for randomized control trials (RCTs) that used BoNT injections for chronic shoulder pain treatment. The primary outcome was the between-group comparison of pain reduction, quantified by the standardized mean difference (SMD). Nine RCTs comprising 666 patients were included and divided into two groups: one group with shoulder joint pain ( n = 182) and the other group with shoulder myofascial pain ( n = 484). Regarding shoulder joint pain, the efficacy of BoNT injections was similar to that of the reference treatment (SMD: −0.605, 95% confidence level [CI]: −1.242 to 0.032 versus saline; SMD: −0.180, 95% CI: −0.514 to 0.153 versus corticosteroids) at one month post-intervention, and was superior (SMD: −0.648, 95% CI: −0.1071 to −0.225 versus corticosteroids) between one and three months. Likewise, in terms of shoulder myofascial pain, the effectiveness of BoNT injections did not differ from the reference treatment (SMD: −0.212, 95% CI: −0.551 to 0.127 versus saline; SMD: 0.665, 95% CI: −0.260 to 1.590 versus dry needling and SMD: 1.093; 95% CI: 0.128 to 2.058 versus lidocaine) at one month post- intervention, and appeared superior (SMD: −0.314, 95% CI: −0.516 to −0.111 versus saline) between one and three months. Our meta-analysis revealed that BoNT injections could be a safe and effective alternative for patients with chronic shoulder pain.

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Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy.

Paul L Durham, Ryan J Cady, Roger Cady (2004)

To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.

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Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential.

Jianghui Meng, Saak Ovsepian, Jiafu Wang … (2009)

Excessive release of inflammatory/pain mediators from peripheral sensory afferents renders nerve endings hyper-responsive, causing central sensitization and chronic pain. Herein, the basal release of proinflammatory calcitonin gene-related peptide (CGRP) was shown to increase the excitability of trigeminal sensory neurons in brainstem slices via CGRP1 receptors because the effect was negated by an antagonist, CGRP8-37. This excitatory action could be prevented by cleaving synaptosomal-associated protein of M(r) 25,000 (SNAP-25) with botulinum neurotoxin (BoNT) type A, a potent inhibitor of exocytosis. Strikingly, BoNT/A proved unable to abolish the CGRP1 receptor-mediated effect of capsaicin, a nociceptive TRPV1 stimulant, or its elevation of CGRP release from trigeminal ganglionic neurons (TGNs) in culture. Although the latter was also not susceptible to BoNT/E, apparently attributable to a paucity of its acceptors (glycosylated synaptic vesicle protein 2 A/B), this was overcome by using a recombinant chimera (EA) of BoNT/A and BoNT/E. It bound effectively to the C isoform of SV2 abundantly expressed in TGNs and cleaved SNAP-25, indicating that its /A binding domain (H(C)) mediated uptake of the active /E protease. The efficacy of /EA is attributable to removal of 26 C-terminal residues from SNAP-25, precluding formation of SDS-resistant SNARE complexes. In contrast, exocytosis could be evoked after deleting nine of the SNAP-25 residues with /A but only on prolonged elevation of [Ca(2+)](i) with capsaicin. This successful targeting of /EA to nociceptive neurons and inhibition of CGRP release in vitro and in situ highlight its potential as a new therapy for sensory dysmodulation and chronic pain.

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Corticosteroid injections for shoulder pain.

Rachelle Buchbinder, Sally E. Green, Joanne Youd (2003)

While many treatments, including corticosteroid injections in and around the shoulder, are advocated to be of benefit for shoulder pain, few are of proven efficacy. This review of corticosteroid injections for shoulder pain is one in a series of reviews of varying interventions for shoulder disorders. To determine the efficacy and safety of corticosteroid injections in the treatment of adults with shoulder pain. MEDLINE, EMBASE, CINAHL, Central and Science Citation Index were searched up to and including June 2002. Randomised and pseudo-randomised trials in all languages of corticosteroid injections compared to placebo or another intervention, or of varying types and dosages of steroid injection in adults with shoulder pain. Specific exclusions were duration of shoulder pain less than three weeks, rheumatoid arthritis, polymyalgia rheumatica and fracture. Trial inclusion and methodological quality was assessed by two independent reviewers according to predetermined criteria. Results are presented separately for rotator cuff disease, adhesive capsulitis, full thickness rotator cuff tear and mixed diagnoses, and, where possible, combined in meta-analysis. Twenty-six trials met inclusion criteria. The number, site and dosage of injections varied widely between studies. The number of participants per trial ranged from 20 to 114 (median 52 participants). Methodological quality was variable. For rotator cuff disease, subacromial steroid injection was demonstrated to have a small benefit over placebo in some trials however no benefit of subacromial steroid injection over NSAID was demonstrated based upon the pooled results of three trials. For adhesive capsulitis, two trials suggested a possible early benefit of intra-articular steroid injection over placebo but there was insufficient data for pooling of any of the trials. One trial suggested short-term benefit of intra-articular corticosteroid injection over physiotherapy in the short-term (success at seven weeks RR=1.66 (1.21, 2.28). Despite many RCTs of corticosteroid injections for shoulder pain, their small sample sizes, variable methodological quality and heterogeneity means that there is little overall evidence to guide treatment. Subacromial corticosteroid injection for rotator cuff disease and intra-articular injection for adhesive capsulitis may be beneficial although their effect may be small and not well-maintained. There is a need for further trials investigating the efficacy of corticosteroid injections for shoulder pain. Other important issues that remain to be clarified include whether the accuracy of needle placement, anatomical site, frequency, dose and type of corticosteroid influences efficacy.

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Journal ID (nlm-ta): Toxins (Basel)

Journal ID (iso-abbrev): Toxins (Basel)

Journal ID (publisher-id): toxins

Title: Toxins

Publisher: MDPI

ISSN (Electronic): 2072-6651

Publication date (Electronic): 12 April 2020

Publication date Collection: April 2020

Volume: 12

Issue: 4

Electronic Location Identifier: 251

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[1 ]Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 10845, Taiwan; myronrbman@ 123456gmail.com (P.-C.H.); wwtaustin@ 123456yahoo.com.tw (W.-T.W.); dshan1121@ 123456yahoo.com (D.-S.H.)

[2 ]Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan

[3 ]Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei 10048, Taiwan

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[* ]Correspondence: kvchang011@ 123456gmail.com ; Tel.: +886-2-2371-7101

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Ke-Vin Chang https://orcid.org/0000-0002-7558-5651

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Publisher ID: toxins-12-00251

DOI: 10.3390/toxins12040251

PMC ID: 7232231

PubMed ID: 32290577

SO-VID: 33649dc8-3f8d-42c8-b854-c43c43e3e5fc

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Comparative Effectiveness of Botulinum Toxin Injection for Chronic Shoulder Pain: A Meta-Analysis of Randomized Controlled Trials

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Most cited references 48

Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy.

Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential.

Corticosteroid injections for shoulder pain.

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