BOTULINUM toxin type A (BoNT-A) was approved by the U.S. Food and Drug Administration in 1989 for the treatment of strabismus and blepharospasm. It was subsequently approved for cervical dystonia and, most recently, for hyperhydrosis. It provides effective symptomatic relief of these conditions for several months, and repeated treatments usually provide similar benefits when symptoms recur. It has been reported to be effective for a variety of off-label indications, including other dystonias, myoclonus, spasticity associated with stroke, head injury, multiple sclerosis and cerebral palsy, sialorrhea, and smooth muscle hyperactivity.1For the past several years, there has been increasing interest in the use of BoNT-A for the treatment of pain. Myofascial pain syndrome would seem to be a logical condition to study, because it has been proposed that motor hyperactivity is involved in the development and possibly maintenance of this painful condition. Previously published open-label studies have shown mainly positive results. This is not surprising given the fact that saline injection and dry needling of trigger points are accepted therapeutic interventions. Placebo-controlled studies have yielded conflicting results. In this issue of Anesthesiology, Ferrante et al. 2report the results of a randomized, double-blind, placebo-controlled trial of BoNT-A for the treatment of cervical and shoulder myofascial pain. It is a robust study involving 132 patients, saline placebo and three different BoNT doses, and a 12-week follow-up period. All previous medications were stopped before the study, and identical postinjection therapy was given to all patients. There were no significant differences in pain scores, pressure algometry, or analgesic use among the control and three BoNT groups.
The negative results of this study are unexpected because there is reason to predict reduction of pain given the pharmacologic effects attributed to BoNT. Reduction in muscle tone and activity is a predictable result of intramuscular injection, and it would seem reasonable to postulate that a period of prolonged muscle inactivity would be of benefit for a condition characterized by muscle shortening and tenderness. In addition, there is evidence that BoNT interferes with the release of substance P, calcitonin gene–related protein (CGRP), and other neurotransmitters or neuromodulators found in nociceptors.3The so-called SNARE protein, which is necessary for exocytosis of acetylcholine vesicles and is inhibited by BoNT, is also present in substance P and CGRP-containing neurons.4
As the authors indicate, the site of trigger point injection may not be the optimal site for BoNT injection of the muscle. The motor endplate is the most effective location for injection, but that site is not known for many of the muscles susceptible to myofascial pain. Nevertheless, BoNT diffuses throughout the muscle and should provide some effect at the higher doses.
Another concern is the accuracy of the diagnosis and the possible heterogeneity of the cohort selected. Not all patients who have muscle tenderness have myofascial pain syndrome. Also, patients who have myofascial pain that is secondary to other painful disorders such as radiculopathy, facet arthropathy or complex regional pain syndrome are much more resistant to treatment than patients with primary myofascial pain syndrome. It might be useful to limit study participation to patients who experience complete but temporary relief from local anesthetic trigger point injections.
The effect of BoNT on several other painful disorders has been investigated. Foster et al. 5conducted a double-blind, placebo-controlled trial of BoNT for the treatment of low back pain. At both 4 and 8 weeks, the treatment group had significantly more patients reporting pain relief, and at 8 weeks, functional improvement was greater in the treatment group. I was able to find five placebo-controlled trials of BoNT injection for chronic tension type headache published between 1999 and 2004. Only one of these studies indicated a significantly better response for BoNT. There have been a few case reports on the use of BoNT in neuropathic pain states, including complex regional pain syndrome and spinal cord injury, but no controlled trials. The fact that preganglionic sympathetic neurons are cholinergic has led to speculation that prolonged sympathetic denervation by BoNT may be feasible.
Although BoNT has been shown to block the release of substance P, CGRP, and glutamate in vitro , there has been little evidence that BoNT produces clinically relevant reduction in release of neurotransmitters or neuromodulators in nociceptors. Two studies have failed to demonstrate changes in cutaneous pain thresholds in human volunteers after subcutaneous BoNT infiltration.6,7It is possible that the dose requirements for these effects are not met using clinically appropriate doses.
Compared with the dramatic benefits seen for patients with dystonia, spasticity, and hyperhydrosis, the outcomes for treatment of patients with chronic pain have been mixed at best. This is typical for new therapies for chronic pain, because most cohorts of patients with a given diagnosis contain individuals with diverse pain mechanisms and psychosocial backgrounds. We often find individual patients within a group who respond dramatically while the group as a whole does not have significant improvement. Refinement of indications, injection technique, and dose may eventually better define criteria for successful treatment of certain pain syndromes using botulinum toxin.
Medical College of Wisconsin, Milwaukee, Wisconsin. sabram@mcw.edu
