Chapter 70. Use of Botulinum Toxin in Pain Management

Botulinum toxins are potent neurotoxins produced by the bacteria Clostridium botulinum. The most widely studied effect of botulinum toxins is at the neuromuscular junction where they block the release of acetylcholine preventing muscle contraction and causing local flaccid paralysis (rather than rigid, or tetanic, paralysis caused by a related clostridial protein, tetanus toxin). This results in a temporary (months) chemodenervation and the loss or reduction in activity in the target organ (muscle, sweat gland, or sphincter) with minimal risk of systemic adverse effects. However, botulinum toxins work not only at the neuromuscular junction but also alter the sensory input, producing secondary changes at the central level. The broadening clinical role of botulinum toxins depends on the multiple direct and indirect effects that the toxin exerts in both the peripheral nervous system and in the central nervous system (CNS).

In 1989, the FDA approved botulinum toxin type A (BTX-A) for use in treating strabismus, blepharospasm and hemifacial spasm. In 2000–2001, both BTX-A (Allergan, Inc.) and botulinum toxin type B (BTX-B; Elan Pharmaceuticals) were FDA-approved for use in treating cervical dystonia, and in 2002, BTX-A was approved by the FDA for treatment of glabellar frown lines. Besides the FDA-approved indications, botulinum toxins have been used in a vast array of clinical problems, including achalasia; anismus; benign prostatic hypertrophy; dysphonia; dystonias; essential tremor; hyperhidrosis; kyphoscoliosis; low back pain; migraine and tension-type headache; myofascial pain; pancreatitis; pelvic floor disorders; rectal fissures; sialorrhea; spasticity; temporomandibular joint syndrome; urinary sphincter dysfunction; wrinkles; and various other movement disorders.

Clostridium botulinum was first identified as a causative agent in food poisoning by Van Ermengem following a fatal outbreak in 1895.1 In the 1920s, additional outbreaks lead to the isolation of a relatively crude form of botulinum toxin (BTX),2 the neurotoxin responsible for food-borne botulism.

Early development of BTX began during WW II in the course of studying the nature of certain toxins, including BTX, and the means for protecting against them.3 Although much of this initial work was carried out on BTX-A, other types of botulinum toxin were also studied, including types B, C, D, and E. The purpose was to develop a polyvalent toxoid for immunization purposes. After the war, a crystallized form of BTX-A became available and stimulated considerable scientific interest. Dr. Alan B. Scott, of the Smith-Kettlewell Eye Research Foundation, initiated efforts to study BTX in a monkey model of strabismus in the late 1960s.4 Sufficient data was collected by 1978 to file an investigational new drug (IND) application for human clinical studies.5 The passage of the Orphan Drug Act of 1983 and FDA approval aided clinical development of BTX-A as an orphan drug in December 1989.

There are two types of commercial botulinum toxins presently available in the United States: Botox (Botulinum toxin type A Purified Neurotoxin Complex, Allergan, Inc., 2525 Dupont Drive, Irvine, CA) and BTX-B (Myobloc, Elan Pharmaceuticals, San Diego, CA). Botox is currently FDA-approved for the treatment of essential blepharospasm, strabismus, hemifacial spasm, cervical dystonia and glabellar frown lines in patients older than age 12 years. BTX-B was FDA-approved in December 2000 for the treatment of cervical dystonia and is presently in clinical trials for other conditions. Dysport (Botulinum toxin type A, Ipsen Ltd, Berkshire, UK) is available only in Europe.

While there are many reviews of this topic in the recent scientific literature,6,7 the proper clinical use of BTX as a therapeutic agent rests upon a clear understanding of the relationship between its structure and mechanism of action, as well as dosing, techniques of administration, and side effects.

Structure

As the clinical uses of botulinum toxins expand, it is very important to understand the basic properties of the various serotypes (A, B, C1, D, E, F, and G) of botulinum toxins with sequence homology amounting to approximately 50% across the serotypes. The various subtypes are most similar in regards to their larger structural features and certain functional sites, and somewhat diverse with respect to the finer details of function as well as antigenic cross-reactivity.8 Lyophilized botulinum toxin type A supplied as a pharmaceutical agent is a bipartite protein that is synthesized in bacterial culture as a single, long-chain protein and subsequently nicked by bacterial proteases to form the free toxin. The free toxin consists of one heavy chain (H-chain; 100 kDA) and one light chain (L-chain; 50 kDA) bound together by at least one disulfide bond and additional noncovalent forces (Fig. 70-1). When secreted into culture medium by C. botulinum, BTX is complexed with two other proteins, a nontoxin nonhemagglutinin protein (150 kDA) and a hemagglutinating protein (600 kDA); these additional proteins greatly enhance the stability of BTX complex.9 Most relevant to clinical use is that botulinum toxin type A appears to be the most potent of the subtypes, and, when injected clinically, has the longest duration of action.10–14 While botulinum toxin types B and F have seen limited clinical use, and others are the subject of further study, the multiple differences thus far observed suggest that the subtypes are not interchangeable.15–18 For this reason, and because much of the preclinical and clinical literature employs BTX, this chapter presents results primarily obtained with BTX-A.

Mechanism of Action

Pharmacologic effect of BTX-A occurs in three stages, with control of each stage assignably to one of three functional units existing on either the H- or L-chain of the toxin. Each chain performs the functions associated with it in applicable model systems, even when separated from the other; however, the component chains do not block neurotransmission when applied separately.19

The binding of BTX-A to the motor end plate presynaptic membrane is a two-stage process, with concentration of the toxin occurring through a relatively nonspecific affinity for ganglioside-containing, lipid-rich presynaptic membrane, followed by specific binding to a protein-containing receptor.20–22 Binding is irreversible, but not itself toxic to the neurone23 (Fig. 70-2).

Internalization of the bound toxin occurs by receptor-mediated endocytosis.24 Once formed, the contents of the endosome become increasingly acidic, most likely by normal cellular mechanisms. The decrease in pH within the endosome prompts a configurational change in the toxin, which then forms a channel through the membrane. The channel allows all or part of the toxin to enter the cytosol.25–27

Once in the cytosol, the L-chain of BTX effects a long-lasting inhibition of acetylcholine (ACh) release, which current evidence suggests is accomplished by the cleavage of the SNAP-25 (synaptosomal-associated protein, 25 kDA) proteins necessary for the release of ACh by synaptosomes.8 Although all toxin subtypes evidence a high degree of sequence homology associated with a functioning zinc-endopeptidase on the L-chain, and proteolytic activity can be found in all BTX subtypes except C2, each toxin subtype has a characteristic specificity for cleaving a certain spectrum of proteins involved in synaptosomal function.8

Pharmacology

When injected intramuscularly at therapeutic doses, BTX induces a localized chemical denervation. With appropriate dose and proper localization of the target muscle, the injected muscle is only partially denervated, and therefore involuntary contracture diminishes without complete paralysis. Depending upon the underlying condition, dose and site of injection, onset of effect of BTX varies from a few days to 2 weeks. This corresponds roughly to the time it takes for the toxin to reach the cytosol of the targeted synapses and begin its enzymatically mediated cholinergic blockade. Functional denervation is observable for from 6 weeks to 6 months following injection, but typically lasts for 3 to 4 months. During peak effect, muscle histology shows evidence of atrophy and increased variation of fiber size following BTX administration. Recovery of functional innervation is associated with histological evidence of neuronal sprouting, reinnervation and enlargement of some end plates, along with the formation of new smaller end plates.10,28,29 There is also an increase in the number of muscle fibers innervated per axon, with some fibers being innervated by more than one axon.10 Recovery is complete after allowing sufficient time for regrowth.30,31 Fiber size, and presumably neuromuscular function, returns to essentially normal, even after multiple cycles of injection and recovery.32 Botulinum toxin therapy has also been reported to alleviate pain associated with various conditions with or without accompanying muscle contractions. An extensive review of the literature also indicates that BTX-A is effective in reducing pain caused by trigger points, myofascial pain, back pain, and headaches. The degree of response to BTX-A therapy in chronic pain has been variable and therefore warrants further controlled investigations. The potential mechanism of action of botulinum toxin in pain relief is discussed in the following paragraph.

Botulinum toxins (types A, B, C1, and F) have an inhibitory effect on the in vitro neuropeptide release from rat embryonic dorsal root ganglia neurons and from isolated rabbit iris sphincter and dilatory muscles.33–35 Also, BTX-A was reported to inhibit in vitro release of acetylcholine and substance P (but not norepinephrine) in rabbit ocular tissue.35 Based on these in vitro and limited in vivo observations, it is hypothesized that BTX treatment reduces the local release of nociceptive peptides either from cholinergic neurons or from C- or Ad fibers in vivo. This reduction in neuropeptide release would prevent local sensitization of nociceptors and reduce the local perception of pain. A reduction of nociceptive signals from the periphery could result in reduced central sensitization associated with chronic pain. Preclinical investigation on the local antinociceptive effects of BTX-A was reported by Cui at the Society of Neuroscience annual meeting in 2000, and a follow-up report was submitted more recently by Aoki at the American Academy of Neurology annual meeting in 2003.36 To investigate the mechanism of the antinociceptive effect of subcutaneous BTX-A (Allergan, Inc.), its effect on formalin-induced local glutamate release, electrophysiological activities of dorsal horn neurons and the spinal expression of c-fos, an indicator of activation of neurons, were assessed in the rat model for inflammatory pain (formalin model). Formalin (5%, 50 μL subcutaneous ) OK produces prolonged distinct biphasic excitations (spikes) of dorsal horn neurons, which correspond to early (acute nociceptive) and late (tonic nociceptive) phases of the behavioral formalin pain response. Pretreatment of rats with BTX-A (1 day, sc) significantly inhibited the formalin-induced electrophysiological activities in the late phase but not in the early phase. BTX-A also dose-dependently inhibited formalin-induced glutamate release in the paw and the expression of c-fos in the dorsal horn of the spinal cord. These results demonstrate that the inhibition of neurotransmitter release from primary sensory neurons by subcutaneous BTX-A mediates, at least, some of its antinociceptive effect. Local administration of BTX-A directly inhibits the peripheral sensitization produced by local neurotransmitter release, which then results in an indirect reduction in central sensitization. Inhibition of nociceptive processing at the peripheral site and at the spinal cord level may underline the mechanism of BTX-A effect in alleviating certain chronic pain conditions. In conclusion, the preclinical (in vitro and in vivo) data, coupled with clinical observations strongly supports the theory that botulinum toxin (especially BTX-A) may have antinociceptive properties distinct from its well-documented effects on the neuromuscular junction and other cholinergic nerves.

BTX-B (Myobloc) is produced by fermentation of C. botulinum type B (Bean strain) as a noncovalently associated neurotoxin complex with hemagglutinin and nonhemagglutinin proteins. After the fermentation process, the neurotoxin complex is purified through a series of precipitation and chromatography steps. Myobloc is marketed as a clear to light yellow solution in 3.5 mL glass vials with 5,000 U BTX-B per mL in 0.05% human serum albumin, 0.01 M sodium succinate, and 0.1 M sodium chloride at a pH of about 5.6. Although biological activity is maintained at room temperature for 6 months; recommended storage guidelines are for refrigeration at temperatures of 2°C to 8°C, with stability maintained for 2 years. For Myobloc, one unit corresponds to the calculated median lethal intraperitoneal dose for female Swiss Webster mice weighing 18 to 20 g. The specific activity of Myobloc ranges between 70 and 130 U/ng. However, units of biological activity of BTX-B cannot be compared to or converted into units of any other BTX. Extrapolation from animal data should not be done because of differences in species sensitivity to BTX neurotoxin serotypes. Until adequate studies are done, extrapolation from human cervical dystonia dosing data to other conditions in which BTX might be used in an off-label fashion is not prudent.

The most commonly reported adverse events associated with BTX-B in clinical trials were dry mouth, dysphagia, dyspepsia, and injection site pain, with the dry mouth and dysphagia the most common reasons for discontinuation.37 Doses up to 25,000 U were studied, but most patients received 12,500 U or less. Dysphagia increased with increasing doses injected into the sternocleidomastoid muscle. Dry mouth showed some dose-related increases with injections into the splenius capitis, trapezius, and sternocleidomastoid muscles. Additionally, dry mouth appeared to be much less of a problem with repeat dosing, even when higher doses were used.

Antibody Formation

Tsui reported on the incidence of antibody formation in 32 patients with spasmodic torticollis who received repeated injections of BTX-A.38 Four patients (12.5%) produced antibodies after 2 to 9 months of treatment. Because the dose range used in blepharospasm is much less than that used in cervical dystonia/spasmodic torticollis, the incidence of antibody formation is far less. Based upon data from a number of studies, the incidence of antibody formation with BTX-A for the treatment of cervical dystonia is probably less than 5%.39 It is important to note that the present Botox formulation is “cleaner” (5 ng vs. 25 ng protein) than the older formulation used in much of the published data discussing antibody formation. As a result of its lower neurotoxin complex load, current BTX-A exposes cervical dystonia patients to approximately 12 ng of protein per treatment (or 48 ng of protein per year based on treatment every 3 months) based on a mean effective dose of 236 U. Hatheway and Dang reported that an annual exposure 125 ng or less of BTX-A would result in <5% of patient population with neutralizing antibodies.40 Based upon current data, general guidelines of keeping the dose as low as is necessary (300–600 U for BTX-A) and injecting no more frequently than every 3 months remain. The BTX-B product from Elan Pharmaceuticals contains 50 ng of neurotoxin complex per 5,000 U. As a result of this, BTX-B exposes cervical dystonia patients to ˜100 ng of protein per treatment cycle based on the most effective dose of 10,000 U published in two double-blind studies.41,42 According to the BTX-B product insert (Myobloc, US Product Insert, Elan), at 10,000 U, 18% of patients treated for 18 months developed neutralizing antibodies. There was no data on whether this neutralizing activity had any effect on efficacy. The reasons for such rapid development of neutralizing antibodies remain unclear and may be a result of previous exposure of the patients to BTX-A or the high content of protein in this product. Factors that may influence the risk of botulinum toxin antibody formation include the overall exposure to neurotoxin complex protein, protein load per effective dose of the toxin, and, most importantly, the frequency of exposure.

Because BTX-A and BTX-B display quite different chemical compositions, it has long been felt that the antibody cross-reactivity between the two is extremely small.43 Nonetheless, concern has been expressed over the potential problem of neutralizing antibody formation with lower potency and shorter-acting BTX serotypes.44 Preliminary data based on the amino acid sequences of botulinum neurotoxin serotypes and tetanus toxin, which provide the molecular basis for cross-reactivity, indicate that there is a molecular basis for cross-reactivity between the proteins. However, the exact clinical significance of these findings has yet to be determined.45 Additionally, for example, although BTX-A and BTX-F have similar potency, increasing doses of BTX-F to increase duration of response to that seen with BTX-A may increase antibody formation to BTX-F. This was demonstrated in a study by Chen and colleagues, who reported that 4 of 18 (22%) cervical dystonia patients treated with BTX-F became nonresponsive to BTX-F following 12 to 66 months of treatment.46

Botulinum toxin therapy has also been reported to alleviate pain associated with various conditions with or without accompanying muscle contractions. Early reports in cervical dystonia patients treated with BTX-A suggested that the pain relief was much greater than the benefits gained by decreasing excess muscle contraction.30,41,47,48 Pain associated with myoclonus of spinal cord origin was also successfully treated with BTX-A.49 Furthermore, tension-type headaches were also reported to improve following BTX-A therapy.50,54 Intramuscular BTX-A administered prior to adductor release surgery in children with cerebral palsy resulted in significant antinociceptive effects. The children treated with BTX-A reported a reduced need for narcotics, were discharged earlier and had better outcomes than the placebo group. The results of this trial were so dramatic that the trial was terminated earlier than scheduled.55 An extensive review of the literature also indicates that BTX-A is effective in reducing pain caused by trigger points, myofascial pain, back pain, and headaches. The degree of response to BTX-A therapy in chronic pain has been variable and therefore warrants further controlled investigations.

This review organizes the burgeoning number of clinical studies of BTX into a few medically useful categories into which the same or similarly classified patients have been grouped for treatment. It is thereby hoped to make evident the essential features of BTX use in a particular subcategory, while at the same time identifying principles of practice that may guide the use of BTX for neuromuscular pain in general. Considering this, the first general principle for the rational use of BTX in pain management is actually a precondition: the patient must be experiencing chronic pain of a known or highly probable etiology for which there is no curative treatment, and for which other conservative and noninvasive pain relief strategies have been considered and exhausted.

Pain related to involuntary or excessive muscle contraction can be produced by an extremely wide range of clinical conditions, some of which are associated with movement disorders, and others in which pain, spasm, and cramping are the only symptoms present. For the purpose of establishing categories among the multiple reports describing the use of BTX-A in musculoskeletal pain, one may divide case studies into categories based upon the predominance of a movement disorder, primarily the focal dystonias, or the predominance of spasticity, primarily of the CNS origin; myofascial pain syndrome can be considered in a distinct category.

Focal Dystonias with Pain

Dystonia generalized or focal, is defined as a condition of increased muscular tone that leads to abnormal fixed postures or shifting postures resulting from irregular, forceful twisting movements of the trunk and extremities. The mobile spasms of generalized dystonia are similar to those of athetosis but are usually slower and involve the larger muscle groups of the trunk, extremities and neck. Dystonic movements increase during volitional motor activity, nervousness, and emotional stress, and diminish during relaxation and sleep.55

Focal dystonias are more common than generalized dystonias and include such disorders as cervical dystonia, writer’s cramp (occupational dystonia), blepharospasm, and spastic dysphonia. In the focal dystonias, a single area of the body is affected. Focal dystonias occur more frequently in adults than in children, remain stable over time, and rarely spread to involve other body parts.56

Both generalized and focal dystonias may be associated with pain, either from the extremes of posture, excessive tendon and joint tension, or from muscle contraction. The focal dystonias are more readily treated with BTX than are the generalized dystonias because of the greater number of muscles involved and consequent larger doses required in the treatment of the latter; larger doses may cause systemic toxicity and possibly lead to development of resistance. Nevertheless, if pain can be localized to one or two muscle groups, BTX may prove beneficial even in the generalized dystonias. The focal dystonias for which there is an extensive literature detailing treatment with BTX and for which pain represents an important element of response, include cervical dystonia (spasmodic torticollis) and occupational dystonia (writer’s cramp).

Cervical Dystonia

Cervical dystonia is the most common focal dystonia. There are intermittent or continuous spasms of the sternocleidomastoid, trapezius, and other cervical muscles, usually more prominent on one side than on the other. Approximately 70% of patients with cervical dystonia report pain as a principle complaint. Controlled clinical trials in cervical dystonia suggest a dramatic effect of BTX injections in controlling the pain component of this syndrome; not surprisingly, objective improvements in movement were similarly improved. Supporting these findings is a survey of 19 studies in which BTX was used for the treatment of cervical dystonia.57 The mean weighted percent of patients reporting an improvement in pain was 76% (range: 50%–100% for the 16 studies reporting pain results; N = 938 patients). Per-muscle doses of BTX ranged from 40 to 120 mU (Botox), while per-treatment doses ranged between 100 and 374 mU (Botox).

Writer’s Cramp

Writer’s cramp, now considered a focal dystonia, is the most common form of occupational dystonia.58 Similar disorders have been described in musicians and others whose daily work involves frequent repetitive movements of the hands.59,60 In one large survey, the incidence of writer’s cramp accounted for 25% of all focal dystonias, with an incidence of 2.7 per million population.

The syndrome typically begins with a feeling of clumsiness during writing or other fine motor activity, and there is a loss of speed and fluency of movement. The grip may be too tight, causing the hand to become quickly fatigued. Tightness and aching can extend to the forearm or shoulder and abnormal muscle contraction lead to a distortion of normal posture. In some cases, the wrist flexes or extends and the fingers curl into the palm or pull away, so that there cannot be a proper grasp, as in cervical dystonia, but it is significant in some patients. Spontaneous remission is rare and probably occurs in fewer than 5% of patients. Writer’s cramp responds poorly to conventional drug, physical, and behavioral therapy.61 Of the many pharmacotherapies tried in this focal dystonia, the most effective appear to be systemic anticholinergics. Unfortunately, these medications rarely work and must frequently be used at such high doses that the side effects become intolerable. In contrast, numerous studies of BTX in the occupational dystonias have proved effective in relieving hyperactive muscle contracture, and have provided pain relief when pain was associated with this condition.

In an early study of dystonia of diverse forms, one patient with writer’s cramp showed modest motor improvement along with significant pain relief following injection with BTX.62 A subsequent larger study showed improvement in 16 of 19 patients (84%).63 The results of three open-label trials indicate that 83% to 92% of patients with focal hand dystonia derive at least some subjective benefit of BTX therapy the last of these showed pain abatement in all 12 subjects who reported pain as a feature of their condition.63–67 Where patients have been observed long enough, some have continued to respond to BTX for as long as 6 years.68

Three published double-blind trials in writer’s cramp have shown some degree of response as well; however, pain was not assessed in these studies. In one such study of 17 patients, subjective improvement was noted after 53% of the BTX injections, as compared to only one patient (7%) after placebo injection.68 Subjective improvement lasted for 1 to 4 months in 82% of the patients following a single dose of toxin; however, objective assessments based on videotapes of patient performance failed to demonstrate a significant difference between toxin and placebo. A second double-blind study with a crossover design treated 20 patients with writer’s cramp with either BTX or placebo, administered in random order. Patients were assessed subjectively and by three objective tests of pen control and writing. Of these 20 patients, 6 had subjective improvement in writing, 7 had improved writing speed, 4 had improved writing by “blinded” rating, and 12 had better pen control on quantitative testing.69 A third study in 10 patients employed a similar double-blind, crossover design, and 80% of patients shows both a subjective and objective response.70

Considering that pain is relatively infrequently mentioned in studies of writer’s cramp, it is interesting to note that most attempts at gauging the efficacy of BTX in this condition showed better response with subjective responses than with objective ones, even in the double-blind studies. Nevertheless, BTX-A seems to be the best treatment available at present for writer’s cramp and is especially for patients who also experience pain.

Spastic Disease States with Pain

Two other subgroups of pain patients detailed in this chapter are those in whom there is a known cause of spasticity tracing its origin to either the peripheral or central nervous systems. CNS dysfunction may lead to the sometimes-painful spasticity in certain patients with cerebral palsy, multiple sclerosis, stroke, and traumatic brain injury, while peripheral lesions may cause myofascial pain syndrome.

Upper Motor Neuron Disease Syndromes and Pain

Patients experiencing acute or long-standing insults and degenerative processes of the CNS may display a wide variety of signs that together constitute the upper motor neuron syndrome. Spasticity, a velocity-dependent increase in muscle tone characterized by hyperactive stretch reflexes, is but one sign. Additional positive and negative signs characterize the syndrome. Among those classed as positive are such signs as hyperactive tendon reflexes, increased resistance to passive movement, flexed posture in the arm and extension in the leg, excessive contraction of antagonistic muscles, and stereotypic movement synergies; negative signs include weakness, lack of dexterity, and paresis.70

Until recently, spasticity was viewed as a consequence of overactive muscle spindles or fusimotor fibers, resulting from disruption of descending inhibitory tracts, the corticospinal and corticobulbar tracts, and sensory afferents.71 O’Brien and colleagues suggest that this view is no longer entirely accurate.72 Spastic paresis or spastic dystonia may be better understood as an imbalance of inhibition and excitation occurring at the motor neuron level of the spinal cord, not unlike focal hypertonia with dystonic features.73,74 The most fundamental component of this sequence is the abnormal intraspinal response to sensory input. Modulation of local spinal cord activity occurs via the descending pathways, such as the rubrospinal tract.75,76 In general, positive symptoms such as hyperreflexia are caused by the disinhibition of local cord excitatory circuits. Negative symptoms, such as paresis or loss of dexterity, reflect dysfunction of corticospinal pathways. The positive signs of spasticity interfere with the activities of daily living, can cause fractures or contractures, increase the frequency of pressure sores, and are often associated with pain.77 Although they can interfere with rehabilitation, they are also more amenable to clinical intervention than are negative signs.

Spasticity as described above, is a prominent clinical feature of several important afflictions of the CNS, including stroke, cerebral palsy, multiple sclerosis, Parkinson’s disease, and traumatic brain injury. For chronic or degenerative states, the management of spasticity is an ongoing task, which is best begun with conservative measures and accelerated as needed.78–81 Initially, physical therapeutic modalities should be tried, such as avoidance of noxious stimuli, passive movement exercises, thermal agents, vibratory treatment, and serial inhibitive casting.81 Oral medications can be tried in conjunction with physical measures or alone, but neither neural depressants (e.g., oral or intrathecal baclofen, benzodiazepines, clonidine, and tizanidine) nor muscle relaxants (e.g., dantrolene) have proved very satisfactory by reason of limited efficacy and intolerable side effects.82–84 For the more seriously affected or unresponsive patient, invasive procedures such as phenol and alcohol nerve blocks cord stimulation, rhizotomies, and intrathecal baclofen administration have been tried.77,85–90

The cost of prolonged care and relative lack of benefit of conservative management have lead to the suggestion that BTX be tried in the management of spasticity. BTX can be used therapeutically to produce a reversible, partial, chemical denervation when injected directly into the suggestion that BTX be tried in the management of spasticity. BTX can be used therapeutically to produce a reversible, partial, chemical denervation when injected directly into a contracted muscle. Because of its potentially pronounced paralytic action, BTX can be as effective as certain surgeries presently in use for the management of spasticity, yet it has the advantage of being reversible and generally repeatable as needed, in accord with the fluctuating state of the patient.

Quite a few preliminary studies with BTX have been reported in spasticities of varying etiology. Although the focus of this review is on pain management, it is worthwhile to note that all of these reports have shown a clinical benefit in the control of muscle tone in patients with severe spasticity. Three studies followed a randomized, double-blind, placebo-controlled design and in these studies, the results were statistically significant.

Pain is a somewhat variable feature of spasticity, depending on the degree of impairment and the specific regions of the anatomy affected. Although there are at least a dozen studies reporting the benefits of BTX in the improvement of muscle tone in spastic conditions, fewer than half include formal measures of pain relief. Even in those studies that include formal measures of pain relief, the number of patients experiencing pain at the start of study was frequently less than the total number of patients studied. There were a total of 130 patients treated in the 6 studies. Of these, 106 (82%; range: 25%–100%) had clinically significant pain at the start of study. Within the group experiencing significant pain at the start of treatment, 77% (range: 63%–90%) obtained relief. The study of Parkinson’s disease patients was notable in that it contained a relatively large sample of patients similarly affected by a particularly painful lower leg cramp. In this sample, 70% of patients reported complete pain relief while the balance appeared to have obtained significant reduction in pain. Taken together, these results support the use of BTX for pain relief in all spastic conditions in which it has thus far been tested. Approximately 75% of such patients may expect to obtain pain relief.

Myofascial Pain Syndrome

Chronic myofascial pain syndrome (MPS) is one of the most common findings in patients presenting at pain clinics, varying between 30% and 85% of people presenting to pain clinics, and being more prevalent in women than in men.91 The condition is associated with regional pain and is most typically revealed by deep palpation of highly localized hyperirritable spots, which are termed trigger points. Trigger points appear as nodular masses within taut bands of skeletal muscle and cause referred pain upon palpation.

The locations of tender nodules in MPS are remarkably constant, being most frequently found at the base of the head, and in the neck, shoulders, extremities, and low back. Nodules in similar locations may be present in normal persons but are not tender (latent trigger points).

The differential diagnosis of MPS is rather critical because it can mimic the outward signs of other diseases, such as chronic headache, shoulder bursitis, or, more seriously, lumbar herniated disc with radiculopathy, angina pectoris, and appendicitis.92

The trigger points found in MPS should also be distinguished from the tender sites found in fibromyalgia because treatment strategies are different. The most important distinction is that the tender sites of fibromyalgia represent a widespread, nonspecific, soft-tissue pain, and when palpated, cause only local pain.93 The nodular trigger points of MPS are thought to develop after trauma, or after overuse or prolonged spasm of muscles, and cause local and referred pain when palpated. Fibromyalgia is a systemic disease process, possibly caused by dysfunction of the limbic system and/or neuroendocrine axis and responding to a multidisciplinary treatment approach, including psychotherapy, low-dose antidepressant medication, and a moderate exercise program. The trigger points of MPS often respond to structured medical management. If there is any doubt, relief of pain by injection of local anesthetic into a suspected trigger point will relieve the pain of MPS, and confirms the diagnosis. Curiously, injection of trigger points with analgesics, saline, and even distilled water can produce temporary relief.94,95

In a small but carefully designed double-blind, crossover study of six patients with myofascial pain syndrome, injections of BTX-A or placebo showed a clear benefit of BTX-A.96 Patients were selected on the basis of focal pain involving the cervical paraspinal or shoulder girdle muscles, and had discrete trigger points, which when palpated, reproduced a typical pattern of radiating pain for that patient. Patients with diffuse pain or neurological deficits were excluded. Patients were randomly injected with either BTX-A (50 mU in 4 mL normal saline) or normal saline alone on two occasions separated by at least 8 weeks. Trigger points were identically injected in the two or three sites affected on both occasions. Subjects were not told when to expect any relief, and were followed up at weekly intervals for 4 weeks and at 8 weeks after treatment. During the study, other medications for pain relief were not permitted. In addition to investigator palpation and grading of trigger points, pain was assessed both subjectively (visual analog scale) and by the application of a pressure algometer to determine pain threshold in kilograms. A positive response was defined as a reduction from baseline of more than 30% on at least two occasions. Four of six patients responded in this manner. Onset of response occurred within the first week following BTX-A injection, but not at the 30-minute observation time. Mean duration of response was 5 to 6 weeks. One subject responded to both BTX-A and saline, and one subject’s pain threshold following BTX-A had not returned to baseline by the time of the placebo injection. Results between the two treatment regimens were statistically significant in favor of BTX and suggest that additional clinical testing for this indication is warranted.

The goal of treatment in MPS should be the restoration of function. Circumspect measures consisting of massage and physical therapy, preferably without using narcotic or nonnarcotic analgesics, are preferred, with the addition of lifestyle change to reduce psychosocial stressors in the home and at work where needed. If these measures fail, local anesthetics with steroids should be injected up to a maximum of three times in 6 weeks. If the pain is relieved but returns quickly, a trial of BTX injection therapy may provide longer lasting benefit. Besides providing a longer period of pain relief, this strategy may facilitate physical therapy and promote long-term improvement in quality of life.

Dosing Considerations

Once the decision is made to consider BTX for the treatment of MPS or headache, the key questions are which patient will best benefit from this therapy, what dose to administer (in what concentration and in what diluent), and how to do it. Unfortunately, the answers to these questions are still uncertain. Until more studies are performed, only general guidelines are available from the currently available literature.

Whom to Inject?

As with any new therapy, especially one that is expensive, it makes sense to use BTXs only in more refractory cases until the treatment becomes established and pharmacoeconomics data is supportive. In the case of headache management, avoiding a single emergency room visit or multiple office visits, or seeing a significant reduction in expensive tripton use could easily sway the economic balance to using BTXs if the preliminary study results are confirmed in subsequent trials. In MPS, the potential for significant reduction in medication use and complete resolution of symptoms in a substantial portion of refractory cases is a strong argument in support of BTX use. In both conditions, quality of life and functional improvement can be measurably improved.

Where to Inject?

With MPS, most investigators have injected active trigger points directly or used a grid pattern (Lang’s method) around them to get more diffuse spread through the involved muscle.44 Scalene or psoas compartment injections under fluoroscopic guidance can be used with success to target adjacent muscles. In the lower back, trigger points in deeper paraspinals are not as easily felt and the limited studies that have been published have either chased tenderness or spasm as their guide for which muscles to inject. In tension-type headache management, most investigators have chased the tenderness and injected posterior neck muscles (upper trapezius, levator scapulae, and suboccipitals), and, if tender, temporalis, frontalis, suboccipitals also have been injected.

How Much to Inject?

Cervical and VII nerve dystonia data has been used as a starting point for BTX-A dose calculations with adjustments depending upon the size of the muscle and degree of spasm. Extensive clinical experience with BTX-A supports this extrapolation to MPS/headache, but with BTX-B, it will be important to be cautious and start at a maximum of 2,500 U to 5,000 U and move upward, depending upon clinical response until data from current studies provides dose-response information.

The total maximum dose per visit for BTX (Botox) typically should not exceed 300 to 400 U (although many have gone as high as 600–700 U safely for numerous involved muscles as in diffuse spasticity/dystonia) and intervals between doses should be no less than 3 months. Following these general guidelines will reduce adverse events (primarily weakness) and antibody formation. Little data is available to help one decide on BTX-B dosing outside of cervical dystonia. It appears to be about 40 to 50 times less potent than BTX-A, with very few patients having received doses at or above 20,000 U, although these doses appear to be well tolerated. In the cervical dystonia data, BTX-B produced duration of effect between 12 and 16 weeks.

Larger volumes of injectant and doses of neurotoxin may influence the tendency for excess BTX to diffuse to nontargeted sites (adjacent muscles or remote sites). This becomes a concern especially with anterior neck injections where electromyogram guidance and low volumes of injectant (BTX-A 100 U/cc or BTX-B 5,000 U/cc) should be used. The technique of using multiple injection sites within the muscle appears to reduce unwanted side effects as does using electromyogram guidance to target motor end plates, thus allowing one to use fewer toxins.

What to Use as Diluent?

Allergan recommends that only preservative-free saline (PFNS) is used as the diluent, and that once it is added to reconstitute Botox, it should be used within 4 hours because of concerns of compromised sterility and infection risk. Elan Pharmaceuticals also recommends that PFNS be used if one desires a more dilute concentration of Myobloc than 5,000 U/cc and, although the unopened toxin is stable for months at room temperature, once opened, the toxin should be used within 4 hours because of infection concern.

The use of preservative-free local anesthetic as a diluent, although outside of labeling from the manufacturers, does not denature the protein (as long as bicarbonate is not added to neutralize the acidic pH of the local anesthetic) and certainly helps to decrease local injection pain.97 In MPS, numerous studies document that local anesthetics seem not to interfere with toxin efficacy, although studies comparing local anesthetics versus PFNS have not been done. Additionally, whether volume of diluent makes a difference in efficacy is not know, although studies are in progress to answer this question.98

Is Targeting of Injections Needed?

The use of fluoroscopic or electromyogram guidance to identify the muscle or localize the motor end plate prior to injections appears to be a benefit in some situations (particularly in the anterior neck and the deep paraspinal muscles, and possibly to reduce unwanted remote spread by targeting motor end plates with lower toxin doses), but other clinicians have not shown that this technique is necessary when the muscles and trigger points are easily palpable.

Conclusion

BTXs appear to be a useful treatment in refractory MPS and headache. Presumably BTXs work by breaking the spasm–pain cycle, giving the patient a “window of opportunity” for traditional conservative measures to have a greater beneficial impact, but several studies suggest that a direct antinociceptive effect distinct from any reduction in muscle spasm may be at play. The major benefit of BTXs compared with standard therapies is duration of response.

We do not advocate that BTXs be used as a first-line treatment for MPS or headache. However, in refractory cases where nothing else has worked, it may offer a chance for improvement or cure not otherwise available. Data from studies presently being conducted will help us decide where to place BTX in our pain treatment continuum. For now, it remains an off-label, but increasingly accepted, approach in patients with refractory myofascial pain and headache, who, despite multidisciplinary approaches, continue to suffer.

We are grateful to Mike A. Royal, MD, OK for allowing us to take excerpts from his article “The use of botulinum toxins in the management of pain and headache” (Pain Practice 2001;1(3):215–235).