Myofascial pain syndrome (MPS) is defined as a regional pain disorder of muscular origin characterised by the existence of trigger points within muscles. The myofascial trigger point (MTrP) is, in turn, defined as a palpable and hyperirritable nodule located in a taut band of muscle. Stimulation of this point produces two characteristic phenomena: referred pain and sudden contractions of the taut band, called the local twitch response (LTR). Active MTrPs produce pain, and sometimes referred pain, spontaneously. Latent MTrPs produce referred pain as a response to pressure, but not spontaneously.
A current hypothesis is that the disorder underlying MPS is related to inappropriate activity of acetylcholine (ACh) at the neuromuscular junction, which produces a sustained contraction of the sarcomere. The ACh-related effects are relevant to the development of the taut band. This activity leads to an increase in local energy demand or energy crisis [
The inappropriate activity at the motor endplate has been studied from an electrophysiological perspective. First, the existence of spontaneous electrical activity (SEA), characterised by continuous low-amplitude action potentials and spikes, was demonstrated in the active MTrP. Excessive ACh activity at the TrP (the muscle endplate) is inferred from the electrophysiologic activity (endplate noise and SEA) [
Another factor that plays a determining role in MPS is the sensitization phenomenon. Persistent peripheral muscle nociceptor activation is converted into a permanent stimulus that facilitates pain neurotransmission. This is due both to a local increase in the number of nociceptors and to the opening of silent multisegment spinal cord circuits [
In summary, the disorder underlying MPS is considered to be inappropriate ACh activity at the endplate, producing an energy crisis that favours nociceptive neurotransmitter release. The altered ACh produces active phenomena (taut band), and the nociceptive neurotransmitters initiate the cascade of pain neurotransmission or sensory phenomena: local pain and referred pain.
Botulinum toxin has been used for decades in the treatment of disorders characterised by muscle hyperactivity, such as spasticity or dystonia [
Botulinum toxin blocks neurotransmission at the neuromuscular junction. Several transport proteins participate in the process by which ACh is released; these proteins aggregate to form the SNARE complex (Soluble NSF (N-Ethylmaleimide-Sensitive Factor) Attachment Protein Receptor [
A number of possible mechanisms of action that could explain the antinociceptive effects of BTA have been formulated and investigated [
In myofascial syndrome it is believed that the excessive ACh production is responsible for the characteristic SEA of MTrPs, detectable on electromyography (EMG). The injection of 10 U of onabotulinumtoxinA (Botox) in the area of the dysfunctional motor endplate was found to reduce SEA in experimental animals [
It has been shown that BTA directly inhibits the release of pain mediators such as substance P, bradykinin, CGRP, and glutamate [
Nociceptive sensitization involves an increase in the concentration of substances that facilitate nociceptive neurotransmission, such as substance P, CGRP, and glutamate, both at the peripheral nociceptors and in the posterior horn of the spinal cord. Blockade of the release of these substances peripherally interrupts the first step of sensitization: the accumulation of nociceptive neurotransmitters at the free nerve endings. BTA is therefore considered to be more effective when sensitization phenomena exist [
As a result, BTA has recognised mechanisms based on experimental studies that would enable it to act on three critical aspects of MPS: excess Ach release, local nociception, and sensitization phenomena. These are the three reasons that have driven research into the analgesic potential of BTA in the myofascial pain syndrome and in other pain syndromes.
The first clinical trial on the treatment of MPS with BTA was published in 1994, and the results were promising [
Given this lack of uniformity or, at least, of similarity between the results and conclusions of those articles, the proposal of the present review is to analyse the publications from a clinical perspective to search for clues that could explain the differences. This is not a systematic review, but rather a critical analysis that aims to examine certain factors that could improve our understanding of the data published to date and of the discrepancies between those data.
The objective of this paper was therefore to conduct a qualitative analysis of the possible sources of variability between the different trials and reviews of the use of BTA for the treatment of myofascial pain syndrome.
Literature searches were performed in the PubMed database using the following key words: “botulinum toxin” “myofascial pain”, and “botulinum toxin” “trigger point”. The results obtained were filtered to select those clinical trials and systematic reviews that referred to MPS associated with neck or back pain.
The clinical trials were studied from a qualitative point of view, recording specific data on the following aspects: diagnostic criteria, muscles injected, injection procedure, treatment for control group, and outcome measures. All these categories were studied using content analysis to search for possible sources of variability.
The conclusions of the reviews were studied and, after qualitative analysis of each category, a panel of discordant points was drawn up in order to highlight the sources of variability and suggest ways to achieve uniformity.
Nineteen clinical trials [
Below we describe the possible sources of variability according to the established categories.
Given that there is no definitive consensus on the diagnostic criteria of MPS, it is not surprising that studies on the use of BTA for the treatment of MTrPs apply different criteria. There are expert recommendations that propose a series of clinical criteria to make the diagnosis [
Although efforts are being made to establish diagnostic imaging for MPS, particularly with elastography techniques [
However, the diagnostic criteria used were not detailed in the majority of studies, and it was simply stated that the patients suffered myofascial pain [
There was also very marked variability between the trials with regard to the concept of pain topography. It must be realised that although MPS has traditionally been defined as specific to each muscle, it is actually a form of regional or widespread pain [
An example of how the selection criteria can group together apparently similar but in reality profoundly different samples can be seen if we analyse two of the most detailed studies that have been published to date. In the study by Ferrante et al. there were 142 patients with myofascial pain of the neck or shoulder [
Another aspect that was not detailed in the studies was whether the syndromes detected in the patients were primary or secondary. Primary MPS is an independent medical entity, whereas secondary MPS develops in association with other diseases, such as vertebral disc disease, nerve root disease, osteoarthritis, facet joint disease, cervical whiplash or after a muscle lesion [
In summary, the following sources of variability in the diagnosis were detected: lack of uniformity in the criteria used to diagnose MPS, variability in the regional pain topographies included in the studies and in the minimum and maximum numbers of MTrPs in any given patient in order to satisfy the recruitment criteria, and a lack of information about the clinical characteristics of the MPS and possible associated abnormalities.
In view of the diagnostic and topographic variability, we cannot expect greater uniformity in the muscles or muscle groups injected. One aspect that makes it difficult to reproduce certain studies is that the specific muscles injected are not identified in the study reports [
Such discrepancies in the muscles injected for each pain topography demonstrate either a difference between the different samples or else a difference between authors regarding the muscles considered to be the cause of each patient’s pain.
Furthermore, it would probably be difficult to compare the results of studies that injected four different muscles with those that injected only one muscle. The lack of detail about the muscles injected does not help in the interpretation of the data obtained.
There is also the possibility that the treatments could be useful in a specific muscle but not in another. This idea is based on the fact that the studies performed on piriformis syndrome have reported the superiority of BTA while studies performed on another single muscle, infraspinatus [
For physicians familiarised with MPS, the selection of the target muscles for therapy is crucial. Identification of the most important active MTrPs and of other MTrPs in synergic or antagonistic muscles is a determining factor for obtaining satisfactory clinical results [
In summary, the marked differences in the selection of the muscle or muscles to be injected constitute another source of variability that could explain the differences in the results between trials.
The myofascial injection procedure is different from any other type of injection, as it requires, insofar as is possible, injection into the nucleus of the trigger point. It means that the needle will be inserted in part of the taut band that is the hardest and most tender, and that gives the most prominent twitch response. A number of techniques have been described to confirm that the injection enters the MTrP: the recommendable clinical procedure requires the LTR to be reproduced on piercing the MTrP. Hong demonstrated that the efficacy of the injection is greater when this response is obtained [
On this basis, authors have referred to injections “into trigger point” and “nearby trigger point,” that is, into the nucleus of the MTrP or close to the MTrP [
This is a crucial issue, as the myofascial injection is specific and, as far as possible, must be performed in accordance with the standard procedure described that guarantees closest approximation to the MTrP. However, the majority of studies do not give details of the injection procedure employed and simply state “injection into the MTrP.” Some give details of the depth reached with the needle (between 1 and 3 cm) [
Two other very important matters are the
There were also differences in the
The variability in these three aspects—the injection procedure, the number of trigger points injected, and the dose per injection point or total dose—makes it very difficult to interpret the data in a unified manner. Citing once again the two largest trials, there were marked differences between treatments, one with 5 injection sites and a total dose of 250 U of onabotulinumtoxinA [
Another procedure-related factor is the
In summary, very significant variations have been detected in the injection procedure. Only a few studies have reported using a standardised procedure to locate the MTrP. The number of MTrPs injected varied considerably, with between 1 and 10 injection sites. There was a sevenfold variation in the total dose of onabotulinumtoxinA between the studies with the lowest and highest total doses, and studies performed with abobotulinumtoxinA presented a 16-fold difference in this parameter. This dose variability makes it very difficult to compare results between trials. There have also been up to 10-fold differences in the dilutions used in the different studies. Finally, the gauge of the needles could also affect results.
The control treatment in the majority of studies has been normal saline injection. Almost all authors considered this treatment to be a placebo [
The effect of dry needling (DN) on inactivation of MPTs is now well known. Many authors have demonstrated the usefulness of DN in MPS [
This is an important issue, as the treatments with which BTA has been compared were not placebos but active treatments. Normal saline injection, local anaesthetic injection, and dry needling are all effective procedures, and it must therefore be taken into account that comparative studies using these techniques are trials investigating the superiority of one treatment over another, they are not placebo-controlled trials; this has implications for the determination of study sample size and for the calculation of the expected differences in improvement between the experimental group and the control group.
In addition, certain biases regarding the control treatment must be taken into account. For example, a cost-benefit study that compared the efficacy of BTA versus bupivacaine demonstrated that the two treatments produced similar improvements in the pain but that treatment with the local anaesthetic was much less expensive than BTA [
Other important details that could help to explain the variability in the results of the studies are the concomitant treatments used. For example, in one study, patients in the two treatment arms, BTA and normal saline, also received treatment with amitriptyline, ibuprofen and, when necessary, propoxyphene-acetaminophen. Myofascial release techniques were also applied to all patients for the duration of the study. It is possible that the importance of these associated treatments was not taken sufficiently into account in the evaluation of the improvement achieved in the experimental and control groups [
In summary, control treatments considered to be placebos have actually been treatments of known efficacy. In some studies, patients who had previously responded to one of the treatments could have been selected. Finally, some trials have included pharmacological and physical treatments administered concomitantly with the experimental and control treatments and these additional treatments could have masked the improvements observed.
The principal outcome variable in the majority of the studies was the difference between the pain measurements before treatment and during followup. In general, a visual analogue scale (VAS) was used [
The majority of the studies reported that BTA was not superior to the treatments with which it was compared [
In the study by Ferrante et al. [
Another of the differences detected was in the
In summary, there are contradictory results in the different trials in terms of pain improvement, with some trials that do not demonstrate superiority of BTA over alternative treatments and other trials that do confirm the superiority of BTA. Improvements have also been detected in some quality of life measures; these have been considered to be possible errors, but further explanation is required. In addition, there was considerable variation in the times at which the outcomes were measured and this may not have been ideal based on our knowledge of the duration of action of BTA.
The contradictory results in terms of superiority or nonsuperiority of BTA in the different clinical trials are the main source of doubt regarding the true efficacy of BTA in MPS associated with neck and back pain.
The use of BT for the treatment of pain of myofascial origin has been analysed in specific systematic reviews and also in joint reviews on the usefulness of BTA in pain [
The conclusions of the reviewers can be grouped into three types: BTA not recommended, a lack of data to be able to recommend or not recommend the treatment, and recommendation for use in specific conditions.
Some reviews concluded that BTA is not superior to other injection therapies, such as saline or local anaesthetic injection, and that current evidence therefore did not support the use of BTA injection into MTrPs for myofascial pain in general [
Another group of reviewers concluded that the available data were not sufficiently strong either to recommend or to reject the use of botulinum toxin in MPS [
Finally, another group of reviewers concluded that botulinum toxin can be useful in MPS in certain clinical conditions.
The first of these involves pain topography. Based on high-quality clinical trials on the treatment of the lumbar pain using the toxin [
Another of the clinical situations is the treatment risk of the patient, for example, when the analgesic regimen carries a high potential for adverse effects [
One further important aspect is the difference between chronic pain and refractory pain. Refractory pain refers to pain that does not respond to other treatments. There are clinical trials and reviews that have focused exclusively on refractory pain, that is, on chronic pain that has not responded to other treatments [
In summary, the different systematic reviews on the use of botulinum toxin in MPS and in regional axial pain (cervical, lumbar and pelvic) associated with this diagnosis, vary from no recommendation for use, through the absence of a recommendation in favour or against, or finally, to use only in specific conditions: pain refractory to treatment, and pain at specific sites (cervical, lumbar, and pelvic).
The use of botulinum toxin in MPS has a pharmacological and pathophysiological basis. In MTrPs there is excessive Ach release and an increase in the concentration of nociceptive neurotransmitters in the biochemical milieu of the MTrPs. BTA appears to be effective on both targets, reducing ACh release and blocking nociceptive neurotransmission.
This rational basis has been the justification for a number of clinical trials, but there are marked discrepancies between the results of those trials. Looking at the most important ones, some do not demonstrate the superiority of BTA over other treatments [
In this paper, content analysis has been used to scrutinise the trials from a clinical perspective in order to identify sources of variability that could explain the differences in the results. The most significant findings were the following. Diagnostic selection and criteria: the trials have used different diagnostic criteria for MPS. There is insufficient standardisation of the different topographies of pain, with studies that have focused on a single area of the vertebral column and others that include several areas. In addition, there are very relevant discrepancies in the number of MTrPs treated and a lack of information on clinical characteristics, such as the type of myofascial pain and its associated abnormalities. The selection criteria for some studies would have led to the exclusion of their patients from other studies [ Muscles injected: in general, the different studies do not coincide in the target muscles. Even in patients with the same pain topography, different muscles were injected. And in some studies, the muscles treated were not even mentioned. Injection procedure, number of trigger points injected, and dose used: in many studies, it was not stated whether a myofascial type injection procedure was used, with robust criteria for injection into or nearby the MTrP. The number of trigger points treated showed little uniformity, as between 1 and 10 were injected, depending on the study. The doses used varied by up to 16-fold between the trials with the highest and lowest total doses. There was also variability in other factors, such as the dilution and the type of needle used. Control group treatments: the groups treated with placebo received treatments of known efficacy, such as normal saline, local anaesthetics, or dry needling. The investigations were therefore comparative studies between two treatments rather than an experimental group versus placebo. Outcome measures: the results of the trials are contradictory. In some, superiority of BTA over other treatments was not observed whereas others reported the superiority of BTA. Improvements were also detected in some quality of life measurements, and these require further explanation. Finally, the length of followup was often suboptimal if the duration of the effect of botulinum toxin is taken into account.
These marked differences have led reviewers to reach contradictory conclusions: BTA not recommended, neither recommended nor rejected or, finally, recommended for use in specific conditions of refractory pain or for pain with a specific topographic diagnosis.
The contradictory results in terms of superiority or nonsuperiority of BTA in the different clinical trials are the main source of doubt about the true efficacy of BTA in myofascial pain syndrome associated with neck and back pain.
In reality, no study has demonstrated that BTA does not improve a patient’s pain. In all of them, the pre- and post-treatment outcome measures showed significant improvements. What has not been possible to demonstrate in some studies is the superiority (or inferiority) of BTA versus other treatments.
To resolve these issues, further studies must be performed that take into account these and other sources of variability described in the literature [
In addition, in the light of all these findings, it must be concluded that there are insufficient data either to recommend or reject treatment with BTA in MPS. Many reviews close with this statement after an extensive analysis and the use of complex statistical methods, and physicians who study those reviews may therefore be left with an uncomfortable feeling that their reading has not helped to resolve the complex task of clinical decision taking.
Although this is a particularly controversial subject, some additional arguments may perhaps be given. At the present time, the treatment of MPS with BTA is an off-label indication. Some trials conclude that BTA is neither superior nor inferior to other treatments injected into the MTrPs, whereas other trials show that BTA is superior to other injection treatments. There is evidence that BTA could be useful in at least some subgroups of patients in which the most relevant characteristic is therapeutic refractoriness [