Focus on Muscular Pain

Introduction

Back problems account for 16.5% of all disability in the United States. It is estimated that 58% to 80% of adult Americans experience low back pain at some point. Low back pain is one type of pain in a wide range of musculoskeletal pain disorders. These disorders, in aggregate, affect roughly 25% of adults in the United States. A recent study estimated that the economic cost of pain to US employers is $80 billion per year, with the majority of the cost ($64 billion) attributable to loss of productivity. In addition to the economic burden of these conditions, back pain and other musculoskeletal pain disorders severely impair the quality of life of affected individuals. Acute or chronic pain has a deleterious impact on every aspect of patients’ lives and imposes a tremendous burden on society and health-care resources.

It has been proposed that an important cause of chronic pain disorders is ineffective or insufficient treatment of acute pain (7 days to 6 weeks) and subacute pain (6 weeks to 6 months). Ineffectively treated chronic pain may lead to a destructive cycle of continuous pain signaling and subsequent release of inflammatory substances into surrounding soft tissues.

Current pharmacotherapy for musculoskeletal pain disorders includes nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, alpha-adrenergic agonists, anticonvulsants, and opioid analgesics. The limited efficacy and substantial side effects of many pharmacologic treatments either reduce patient compliance or produce serious complications. For example, NSAIDs effectively reduce musculoskeletal pain caused by a number of conditions, including osteoarthritis and chronic back pain, but impose and additional burden due to the high incidence of gastrointestinal adverse effects. In determining the overall cost of treating pain with this class of drugs, the costs of gastrointestinal prophylaxis (if utilized) and the potential costs of treating the side effects should be considered. The side effects of pain medications, fear of addiction and regulatory restrictions relevant to the prescribing of opioid analgesics, and dose-ceiling effects of certain type of analgesics area all barriers to long term recovery.

There has been considerable interest in the efficacy of BoNTs, which are focal nonsystemic therapies, in managing pain, particularly in musculoskeletal pain conditions in which the muscle-relaxing effect of BoNT is likely to be of therapeutic benefit.

Botulinum Neurotoxins

There are seven BoNT serotypes (A-G) produced by Clostridium botulinum. Although all of these serotypes inhibit acetylcholine release, their intracellular target proteins, the characteristics of their actions, and their potencies vary substantially. BoNT-A has been the most widely studied serotype for therapeutic purposes. More recently, BoNT-B became clinically available and has been used predominantly for the treatment of cervical dystonia. BoNT-A, a 900-kDa complex, is the most potent of the neurotoxins and is marketed in the US under the trade name of Botox by Allergen, Inc. Also available in the US is serotype B, which is a 700-kDa complex marketed under the trade name of Myobloc by Elan Pharmaceuticals. Units of the different serotypes of BoNTs cannot be compared or used interchangeably. Therefore, the efficacy dosing, and side-effect profile of one serotype cannot be extrapolated from studies that made use of a different serotype. The majority of clinical trials of BoNT have made use of the A serotype. Accordingly, results of these trials should not be generalized to treatment with BoNT-B.

Mechanism of Action of BoNT in Pain Reduction

The reversible presynaptic blockade of the release of acetylcholine at the motor end plates caused by BoNT and the resulting relaxation of the muscle is well established and is the underlying mechanism for its therapeutic effect on hyperactive muscle disorders. Other processes and pathways that are thought to contribute to reduction of pain sensation with BoNT therapy include altered afferent input to the CNS produced by the effect of BoNT on muscle spindles; inhibition of the release of neurotransmitters and neuropeptides involved in peripheral pain and somatosensory pathways such as glutamate, substance P, and clacitonin gene-related peptide; and direct antinociceptive effects in the central nervous system. For example, BoNT injection has been shown to block formalin-induced release of glutamate in the paws of rats. Inhibition of glutamate release was associated with reduced neuronal activity in the dorsal horn in the tonic nociceptive phase of the formalin response. Cui et al speculated that their results demonstrate a pathway by which suppression of the glutamate-mediated peripheral neurotransmitter release by BoNT inhibits peripheral and central sensitization and thereby reduces the sensation of pain.

Clinical Applications of BoNT-A in Managing Muscular Pain

The use of BoNT-A in pain management is a relatively new area of investigation. As a result, there are few randomized, placebo controlled, double-blind trials. In addition to the well-studied effects of BoNT-A on a pain in dystonia and spasticity, the range of other painful, nonneurologic muscle conditions that are potential targets for BoNT-A therapy include neck pain, back pain, and myofascial pain syndrome.

BACK PAIN

Foster et al investigated the efficacy of BoNT-A in 31 patients with chronic low back pain. Patients were randomized to double-blind treatment with 200 U of BoNT-A (40 U/site at five lumbar paravertebral levels on the side of maximum discomfort) or placebo. Pain and degree of disability were assessed at baseline and at 3 and 8 weeks, using a Visual Analogue Scale (VAS) and the Oswestry Low Back Pain Questionnaire (OLBPQ). At 3 to 8 weeks, a significantly greater proportion of BoNT-A-treated patients experienced >50% pain relief (73.3% and 60% at 3 and 8 weeks, respectively; P<.01) compared with placebo-treated patients (25% and 12.5%). The degree of disability due to back pain measured with the OLBPQ at 8 weeks also showed improvement in more patients in the BoNT-A group(66.7%) compared with the placebo group (18.8%: P=.011). These results confirmed the observations of open-label and uncontrolled studies.

The safety and efficacy of BoNT-A therapy were evaluated in patients with low back pain in a retrospective single-center study. The records of 33 patients with a history of chronic low back pain who underwent BoNT-A injections in the piriformis, lumbar paraspinals, psoas, or both piriformis and lumbar paraspinals for treatment of low back pain were reviewed. The primary outcome measure was reduction in pain as evaluated by change in VAS scores. VAS scores were recorded prior to treatment and at each follow up visit. Overall, BoNT-A therapy with a median dose of 200 units (U) provided significant reduction in pain, with a mean reduction of 2.6 points (P<.001). Peak pain relief was observed 22 to 60 days postinjection (mean reduction of 3.0 points, P<.001). Significant reductions in pain were reported following injections in all evaluated muscles (P<.04). Treatment was well tolerated with no reported adverse events. This retrospective analysis supports the safe and effective use of BoNT-A in chronic low back pain.

NECK PAIN

Two randomized, controlled, double-blind trials evaluated the clinical efficacy of BoNT-A therapy for neck pain. Wheeler et al did not detect any significant differences in pain relief as a result of placebo and BoNT-A injections into cervical paraspinal, trapezius, and thoracic paraspinal muscles. In contrast, Freund and Schwartz studied BoNT-A treatment of whiplash-associated neck pain in a randomized, double-blind, placebo-controlled study of 26 patients with chronic neck pain subsequent to a motor vehicle accident. Fourteen of the patients received 100 U BoNT-A, while 12 received saline. Out come measures included total subjective neck, shoulder, and head pain based on VASs. Follow-up assessments were carried out at 2 and 4 weeks posttreatment. At 4 weeks postinjection, the treatment group was significantly improved form preinjection pain levels (P<.01). The placebo group showed no statistically significant changes at any posttreatment time.

MYOFASCIAL PAIN SYNDROME

Myofascial pain syndrome (MPS) is characterized by the presence of localized, hyperirritable trigger points. A trigger point is a palpable knot or mass (usually 3-6 mm in diameter) in a taut band of muscle, associated with tenderness and referred pain into well-defined areas remote from the trigger-point area. The etiology of MPS is uncertain, but it is hypothesized that the trigger points involve sustained muscle contraction, providing a rationale for BoNT-A treatment.

There have been varying efficacy results in clinical trials of BoNT in the treatment of MPS. Cheshire et al in a small (N=6) controlled trial injected 50 U of BoNT or saline into 2-3 trigger points in the cervical paraspinal or shoulder girdle muscles in the 6 patients. Eight weeks later patients were injected with the treatment in a cross over design. Four for of the six patients responded (defined as a 30% reduction in pain) to BoNT-A but not to saline; one patient did not respond to either treatment and one patient responded to both treatments.

In a somewhat larger group of patients, Wheeler et al treated 33 MPS patients with 50 or 100 U of BoNT-A or placebo and noted significant changes from baseline in the posttreatment assessment at 4 months in all treatment groups, without significant differences among treatment groups.

Lang reported an open-label, exploratory pilot study (N=7) for treatment of MPS. Treatment consisted of one or more injections of BoNT-A into the cervicothoracic and/or lumbosacral regions using a novel injection technique. The injections were either unilateral or bilateral, and spread evenly throughout the midbelly of surface muscles in a gridlike pattern. Most patients received injections into multiple muscles (total dose range, 20-600 U; mean total dose, 236 U; mean volume/treatment, 10 mL; mean U/mL = 20 U/mL). Physician’s global outcome ratings were “excellent” for 13 treatments (18%), “good” for 34 treatments (47%), “fair” for 18 treatments (25%), and “poor” for 7 treatments (10%). Twenty of the 95 follow-up visits occurred between days 22 and 60 post injection.

Ferrante et al in a 12-week, randomized, double-blind, placebo-controlled trail assessed the effect of 10 U, 25, U and 50 U BoNT-A injections in 132 patients with cervical or shoulder myofascial pain and active trigger points. BoNT-A-treated patients demonstrated improvements in three variables associated with quality of life compared to placebo (Vitality, Social Functioning, and Role Emotional, SF-36, QoL) but no significant effect on pain scores.

Conclusion

Clinical trials of BoNT in a variety of muscular pain disorders have yielded encouraging results, but there have been few controlled trials and some inconsistent findings. There is emerging evidence suggesting that BoNT may alleviate pain through a series of complex pathways that extend beyond the muscle-relaxing effect achieved by inhibition of neuromuscular transmission. Further study is needed to enhance our current understanding of the pathophysiology of chronic pain disorders and the mechanisms by which BoNT may modify pain, as well as to quantify the benefits of BoNT therapy in these disorders.