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Botulinum toxin therapy in pain management
Anesthesiology Clin N Am 21 (2003) 715 – 731
Botulinum toxin therapy in pain management P. Prithvi Raj, MD, FIPP Texas Tech University Health Sciences Center, International Pain Institute, 4430 South Loop 289, Lubbock, TX 79413, USA
Botulinum toxins are potent neurotoxins produced by Clostridium botulinum that are able to block acetylcholine release at the neuromuscular junction producing a flaccid paralysis. 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. In 1989, the FDA approved BTA for use in treating strabismus, blepharospasm, and hemifacial spasm. In December 2000, botulinum toxin B (BTB) was FDAapproved for use in treating cervical dystonia. Botulinum toxins have been used in a vast array of clinical problems: 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.
History and early clinical development 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 crude form of botulinum toxin (BT) [2], the neurotoxin responsible for food-borne botulism. Early development of BT began during World War II in the course of studying the nature of certain toxins, including BT, and the means for protecting against them. [3]. Although much of this initial work was performed on BTA, other types of
Excerpts from this article were adapted from Dr. Mike A. Royal’s The use of botulinum toxins in the management of pain and headache, published in Pain Practice Vol. 1 (3), September 2001; with permission. E-mail address: [email protected] 0889-8537/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8537(03)00082-8
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Botulinum toxin were also studied, which included B, C, D and E. The purpose was to develop a polyvalent toxoid for immunization purposes. After the war, a crystallized form of BTA became available and stimulated considerable scientific interest. Dr. Alan B Scott, of the Smith-Kettlewell Eye Research Foundation, initiated efforts to study BT in a monkey model of strabismus in the late 1960s [4]. Sufficient data were collected by 1978 to file an IND for human clinical studies [5]. Clinical development was aided by the passage of the Orphan Drug Act of 1983 and FDA approval as an orphan drug was granted in December, 1989.
Pharmacology of botulinum toxins There are two types of BT presently available: Botox (Botulinum toxin type A Purified Neurotoxin Complex, Allergan, Inc., 2525 Dupont Drive, Irvine, CA) is available in the US and Dysport (Botulinum toxin type A, Ipsen Ltd, Berkshire, UK) is available in Europe. Botox is FDA-approved for the treatment of essential blepharospasm, strabismus, and hemifacial spasm in-patients over the age of 12 years. BTB (Myobloc, Elan Pharmaceuticals, and South San South San Francisco, CA) was FDA-approved in early December 2000 for the treatment of cervical dystonia and is presently in clinical trials for other conditions.
Structure, mechanism of action, and pharmacology of botulinum toxins Although there are many reviews of this topic in the recent scientific literature [6,7], the proper clinical use of BT as a therapeutic agent rests on a clear understanding of the relationship between its structure and mechanism of action, dosing techniques of administration, and side effects.
Structure Lyophilized BT 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 kD) and one light chain (L-chain; 50 kD) bound together by at least one disulfide bond and additional non-covalent forces. Botulinum toxin occurs in several subtypes, designated A through G, with sequence homology amounting to about 50% across the subtypes [8,9]. 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 and antigenic crossreactivity [10]. When secreted into culture medium by C botulinum, BT is complexed with two other proteins, a non-toxin protein (150 kD) and a hemagglutinating protein (600 kD); these additional proteins greatly enhance the stability of BT complex over free B [11]. Most relevant to clinical use is that Type A seems to be the most potent of the subtypes [12 –14] and, when injected clinically, has the
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longest duration of action [15,16]. While Type B [17,18] and F [19,20] 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. For this reason, and because much of the preclinical and clinical literature uses BT, this review 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-chains 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 [21]. The binding of BT to the motor endplate pre-synaptic membrane is a two-stage process, with concentration of the toxin occurring through a non-specific affinity for ganglioside-containing, lipid-rich presynaptic membrane [22], followed by specific binding to a protein-containing receptor [23,24]. Binding is irreversible, but not itself toxic to the neurone [25,26]. Internalization of the bound toxin occurs by receptor-mediated endocytosis [27]. 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 [28 –30]. Once in the cytosol, the L-chain of BT effects a long-lasting inhibition of ACh release, which current evidence suggests is accomplished by the cleavage of one or more proteins necessary for the release of ACh by synaptosomes [10]. 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 [10].
Pharmacology When injected intramuscularly at therapeutic doses, BT 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 on the underlying condition, dose and site of injection, onset of effect of BT 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 6 weeks up to 6 months
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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 BT administration. Recovery of functional innervation is associated with histologic evidence of neuronal sprouting, reinnervation and enlargement of some endplates, along with the formation of new smaller endplates [12,31,32]. There is also an increase in the number of muscle fibers innervated per axon, with some fibers coming to be innervated by more than one axon [12]. Recovery is complete after allowing sufficient time for regrowth [33,34]. Fiber size, and presumably neuromuscular function, returns to essentially normal, even after multiple cycles of injection and recovery [35]. BTB (Myobloc) is produced by fermentation of C. botulinum type B (Bean strain) as a noncovalently associated neurotoxin complex with hemagglutinin and non-hemagglutinin 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 5000 units BTB per mL in 0.05% human serum albumin, 0.01 M sodium succinate, and 0.1M sodium chloride at a pH of about 5.6. Although biologic activity is maintained at room temperature for 6 months; recommended storage guidelines are for refrigeration at temperatures (2– 8°C.) with stability maintained for 2 years. Similarly 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 units/ng. However, units of biologic activity of BTB cannot be compared with or converted into units of any other BT. Extrapolation from animal data should not be done because of differences in species sensitivity to BT neurotoxin serotypes. Until adequate studies are done, extrapolation from human cervical dystonia dosing data to other conditions in which BT might be used in an off label fashion would not be prudent. The most commonly reported adverse events associated with BTB in clinical trials were dry mouth, dysphagia, dyspepsia and injection site pain with the dry mouth and dysphagia the most common reasons for discontinuation [36]. Doses up to 25,000 units were studied, but most patients received 12,500 units 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 seemed to be much less of a problem with repeat dosing even when higher doses were used.
Antibody formation Tsui [37] reported on the incidence of antibody formation in 32 patients with spasmodic torticollis who received repeated injections of BTA. 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 or spasmodic torticollis, the incidence of antibody formation is far less. Based on the
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data from several studies, the incidence of antibody formation with BTA for the treatment of cervical dystonia is probably less than 5% [38]. The present Botox formulation is ‘‘cleaner’’ (4 versus 9 ng protein) than the older formulation used in much of the published data discussing antibody formation. Based on the present data, general guidelines of keeping the dose as low as is necessary (eg, a maximum of 300 units of BTA) and injecting no more frequently than every 3 months remain. Since BTA and BTB display quite different chemical compositions, it has long been felt that the antibody cross reactivity between the two is small [39]. Nonetheless concern has been expressed over the potential problem of neutralizing antibody formation with lower potency and shorter acting BT serotypes. Higher toxin doses and frequent injections seem to be associated with neutralizing antibody formation [40]. As part of the Myobloc clinical trials, 446 patients were followed by periodic ELISA assays to detect the presence of neutralizing activity against BTB with positive results confirmed by the mouse neutralization assay [41]. Twelve percent of the patients had a positive ELISA response at baseline and by 6, 12, and 18 months, new ELISA responses were seen in 20%, 36%, and 50%, respectively. Estimated rates of serum neutralizing activity were 10% at 1 year and 18% at 18 months. There were no data on whether this neutralizing activity had any effect on efficacy. Additionally, for example, although BTA and BTF have similar potency, increasing doses of BTF to increase duration of response to that seen with BTA may increase antibody formation as demonstrated in a study by Chen et al who reported on 4 of 18 (22%) cervical dystonia patients that became nonresponsive to BTF following 12 to 66 months of treatment [42].
Pain abatement in clinical studies with botulinum toxin type A This review attempts to organize the burgeoning number of clinical studies of BT 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 BT use in a particular subcategory, whereas at the same time identifying principles of practice that may guide the use of BT for neuromuscular pain in general. Considering this, the first general principle for the rational use of BT in pain management is actually a precondition: the patient must be experiencing chronic pain of a known or probable cause for which there is no curative treatment, and chronic pain for which other conservative and non-invasive pain relief strategies have been considered and exhausted. Pain related to involuntary or excessive muscle contraction can be produced by a 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 on the predominance of a movement disorder, primarily the
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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 [35]. 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 [43]. 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 BT 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, BT may prove beneficial even in the generalized dystonias. The focal dystonias for which there is an extensive literature detailing treatment with BT 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. About 70% of patients with cervical dystonia report pain as a principle complaint. Controlled clinical trials in cervical dystonia suggest a dramatic effect of BT 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 BT was used for the treatment of cervical dystonia [44]. 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 BT ranged from 40 to 120 MU (Botox), while per-treatment doses ranged between 100 to 374 m.u. (Botox).
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Writer’s cramp Writer’s cramp, now considered a focal dystonia [45], is the most common form of occupational dystonia. Similar disorders have been described in musicians and others whose daily work involves frequent repetitive movements of the hands [46,47]. 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 populations. 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 a proper grasp cannot 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 [48]. 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 BT 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 BT [49]. A subsequent larger study showed improvement in 16 of 19 patients (84%) [50]. 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 BT therapy [50 –54] the last of these showed pain abatement in all 12 subjects who reported pain as a feature of their condition. Where patients have been observed long enough, some have continued to respond to BT for as long as 6 years [55]. Three published double-blind trials in writer’s cramp have shown some degree of response also, however, pain was not assessed in these studies. In one such study of 17 patients, subjective improvement was noted after 53% of the BT injections compared with only one patient (7%) after placebo injection [56]. 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 BT 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 [57]. A third study in 10 patients used a similar double blind, crossover design, and 80% of patients showed a subjective and objective response [58].
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Considering that pain is infrequently mentioned in studies of writer’s cramp, most attempts at gauging the efficacy of BT in this condition showed better response with subjective responses than with objective ones, even in the doubleblind studies. Nevertheless, BTX-A seems to be the best treatment available at present for writer’s cramp, especially for patients who also experience pain.
Spastic disease states with pain Two other subgroups of pain patients detailed in this review 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 sometimespainful spasticity in certain patients with cerebral palsy, multiple sclerosis, stroke, and traumatic brain injury, whereas 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 [59]. 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 [59]. Burke et al [60] suggest that this view is no longer entirely accurate. 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 [60 – 62]. The most fundamental component of this sequence is the abnormal intraspinal response to sensory input. Modulation of local spinal cord activity occurs by way of the descending pathways, such as the rubrospinal tract [63,64]. In general, positive symptoms such as hyper-reflexa 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 [65]. Though they can interfere with rehabilitation, they are also more amenable to clinical intervention than are negative signs.
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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 [66 – 69]. Initially, physical therapeutic modalities should be tried, such as avoidance of noxious stimuli, passive movement exercises, thermal agents, vibratory treatment, and serial inhibitive casting [69]. Oral medications can be tried in conjunction with physical measures or alone, but neither neural depressants (eg, oral or intrathecal baclofen, benzodiazepines, clonidine, and tizanidine) nor muscle relaxants (eg, dantrolene) have proved very satisfactory by reason of limited efficacy and intolerable side effects [70 – 72]. For the more seriously affected or unresponsive patient, invasive procedures such as phenol and alcohol nerve blocks [73,74], spinal cord stimulation, rhizotomies, and intrathecal baclofen administration have been tried [65,75 – 79]. The cost of prolonged care and relative lack of benefit of conservative management have lead to the suggestion that BT be tried in the management of spasticity. BT can be used therapeutically to produce a reversible, partial, chemical denervation when injected directly into the suggestion that BT be tried in the management of spasticity. BT 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, BT 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 BT have been reported in spasticities of varying etiology. Although the focus of this review is on pain management, 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 control design and in these 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. Though the current literature contains at least a dozen studies reporting the benefits of BT in the improvement of muscle tone in spastic conditions, fewer than half of those included formal measures of pain relief. Even in these studies, 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 six 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 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 seemed to have obtained significant reduction in pain. Taken together, these results support the use of BT for pain relief in all spastic conditions in which it has thus far been tested. About 75% of such patients may expect to obtain pain relief.
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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 [80]. The condition is associated with regional pain and is most typically revealed by deep palpation of 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, as 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 [81]. 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 [82]. The nodular trigger points of MPS are believed to develop after trauma, 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 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. Injection of trigger points with analgesics, saline [83], and even distilled water [84], can produce temporary relief. In a small but carefully designed double blind, crossover study of six patients with myofascial pain syndrome, injections of BT or placebo showed a clear benefit of BT [85]. Patients were selected based on 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 neurologic deficits were excluded. Patients were randomly injected with either BT (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
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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 BT injection, but not at the 30-minute observation time. Mean duration of response was 5 to 6 weeks. One subject responded to both BT and Saline, and one subject’s pain threshold following BT had not returned to baseline by the time of the placebo injection. Results between the two treatment regimens were statistically significant in favor of BT 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 BT 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 BT 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 BTs only in more refractory cases until the treatment becomes established and pharmacoeconomics data are 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 BTs 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 BT 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
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through the involved muscle. It has also been demonstrated that 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 tensiontype headache management, most investigators have chased the tenderness and injected posterior neck muscles (upper trapezius, levator scapulae, and suboccipitals) and, if tender, temporalis, frontalis, and temporalis forward or included suboccipitals as well.
How much to inject? Cervical and seventh-nerve dystonia data have been used as a starting point for BT dose calculations with adjustments depending on the size of the muscle and degree of spasm. Clinical experience with BTA would seem to support this extrapolation to MPS or headache, but with BTB it will be important to be cautious and start at a maximum of 2500 to 5000 units and move upward depending on clinical response until data from current studies provides doseresponse information. The total maximum dose per visit for BT (Botox) typically should not exceed 300 to 400 unit range (although many have gone as high as 600 –700 units safely for numerous involved muscles as in diffuse spasticity or dystonia) and intervals between doses should be no more frequent than every 3 months. Following these general guidelines will reduce adverse events (primarily weakness) and antibody formation. Little data are available to help one decide on BTB dosing outside of cervical dystonia. It seems to be about 40 to 50 times less potent than BT with very few patients having received doses at or above 20,000 units, though these doses seem to be well tolerated. In the cervical dystonia data, BTB produced duration of effect between 12 and 16 weeks. Larger volumes of Injectate and doses of neurotoxin may influence the tendency for excess BT to diffuse to non-targeted sites (adjacent muscles or remote sites). This becomes a concern especially with anterior neck injections where EMG guidance and low volumes of Injectate (BTA 100 units per cc or BTB 5000 units per cc) should be used. The technique of using multiple injection sites within the muscle seems to reduce unwanted side effects as does using EMG 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 once it is added to reconstitute Botox it should be used within 4 hours because of dual concerns of protein denaturation and infection risk. Elan Pharmaceuticals also recommends that PFNS be used if one desires a more dilute concentration of Myobloc than 5000 units per cc and, although the toxin is stable
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for months at room temperature, if the vial is violated, the toxin should be used within 4 hours because of infection concern. The use of preservative-free local anesthetic as a diluent, though 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 helps to decrease local injection pain [86]. In MPS, numerous studies have documented 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 known, although studies are in progress to answer this question. Is targeting of injections needed? The use of fluoroscopic or EMG guidance to identify the muscle or localize the motor endplate before injections seems 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.
Summary BTs seem to be a useful treatment in refractory MPS and headache. Presumably BTs work by breaking the spasm or 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 BTs compared with standard therapies is duration of response. We do not advocate that BTs 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. 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.
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[5] Scott AB. Botulinum toxin injection into extra-ocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044 – 9. [6] Tsui JKC. Botulinum toxin as a therapeutic agent. Pharmacol Ther 1996;72:13 – 24. [7] Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker Inc.; 1994. [8] Whelan SM, Elmore MJ, Bodsworth NJ, Brehm JK, Atkinson T, Minlon NP. Molecular cloning of the Closiridium bolulinun structural gene encoding the type B neurotoxin and determination of its entire nucleotide sequence. Appl Environ Microbiol 1992;58:2345 – 54. [9] East AK, Richardson FT, Allaway D, Collins MD, Roberts TA, Thompsun DE. Sequence of the gene encoding type F neurotoxin of Closiridium bolulinum. FEMS Microbiol Lett 1992;96: 225 – 30. [10] DasGupta BR. Structures of botulinum neurotoxin, its functional domains, and perspectives on the crystaline type A toxin. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker Inc.; 1994. p. 15 – 39. [11] Hesse S, Lucke D, Malezic M, et al. Botulinum toxin treatment for lower limb extensor spasticity in chronic hemiparetic patients. J Neurol Neurosurg Psychol 1994;57:1321 – 4. [12] Sellin LC, Thesless S, Dasgupta BR. Different effects of types A and B botulinum toxin on transmitter release at the rat neuromuscular junction. Acta Physiol Scand 1983;119(2): 127 – 33. [13] Sellin LC, Kauffman JA, Dasgupta BR. Comparison of the effects of botulinum neurotoxin types A and E at the rat neuromuscular junction. Med Biol 1983;61(2):120 – 5. [14] Kauffman JA, Way JF, Siegel LS, Sellin LC. Comparison of the action of types A and F botulinum toxin at the rat neuromuscular juntion. Toxicol Appl Pharmacol 1985;79(2): 211 – 7. [15] Schantz EJ, Johnson EA. Preparation and characterization of botulinum toxin type A for human treatment. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker Inc.; 1994. p. 41 – 9. [16] Sugiyama H. Clostridium botulinum neurotoxin. Microbiol Rev 1980;44:419 – 48. [17] Moyor E, Settler PE. Botulinum toxin type B: experimental and clinical experience. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker; 1994. p. 71 – 86. [18] Borodic GE, Pearce LB, Smith KL, et al. Botulinum B toxin as an alternative to botulinum A toxin: a histology study. Ophthal Plast Reconstr Surg 1993;9:182 – 90. [19] Greene P, Fahn S. Use of botulinum toxin type F injections to treat torticollis in patients with immunity to botulinum toxin type A. Mov Disord 1993;8:479 – 83. [20] Ludlow CL, Hallett M, Rhew K, et al. Therapeutic use of type F botulinum toxin. NEJM 1992; 326:349 – 50. [21] DasGupta BR. Structure and biological activity of botulinum neurotoxin. J Physiol (Paris) 1990;84:220 – 8. [22] Montccucco C. How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem Sci 1986;11:314 – 7. [23] Evans DM, Williams RS, Shone CC, Hambleton P, Melling J, Dolly JO. Botulinum neurotoxin type B: its purification, radioiodination and interaction with rat-brain synaptosomal membranes. Eur J Biochem 1986;154:409 – 16. [24] Black JD, Dolly JO. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol 1986;103:521 – 34. [25] Burgen AS, Dickens VF, Zatman LJ. The action of botulinum toxin on the neuromuscular junction. J Physiol (London) 1949;109:10 – 24. [26] Sudhof TC. The synaptic vesicle cycle: A cascade of protein-protein interactions. Nature 1995; 375:645 – 53. [27] Simpson LL. The study of clostridial and related toxins. The search for unique mechanisms and common denominators. J Physiol (Paris) 1990;84:143 – 51.
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[53] Rivest J, Lees AJ, Marsden CD. Writer’s cramp: treatment with botulinum toxin injections. Mov Discord 1991;6:55 – 9. [54] Jankovic J, Schwartz KS. Use of botulinum toxin in the treatment of hand dystonia. J Hand Surg 1993;18A:883 – 7. [55] Karp BI, Cole RA, Cohen LG, Grill S, Lou J-S, Hallett M. Long-term botulinum toxin treatment of focal hand dystonia. Neurology 1994;44:70 – 6. [56] Yoshimura DM, Aminoff MJ, Olney RK. Botulinum toxin therapy for limb dystonias. Neurology 1992;42:627 – 30. [57] Tsui JKC, Bhatt M, Calne S, Clane DB. Botulinum toxin in the treatment of writer’s cramp: a double-blind study. Neurology 1993;43:183 – 5. [58] Cole R, Hllett M, Cohen LG. Double-blind trial of botulinum toxin for treatment of focal hand dystonia. Move Discord 1995;10:466 – 71. [59] Young RR. Treatment of spastic paresis. NEJM 1989;320:1553 – 5. [60] Burke D. Critical examination of the case for or against fusimotor involvement in disorder of muscle tone. In: Desmedt JE, editor. Motor control mechanisms in health and disease. New York: Raven Press; 1983. p. 133 – 50. [61] Dimitrijevic MR. Spasticity and rigidity. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. 2nd edition. Baltimore: Williams and Wilkins; 1993. p. 443 – 53. [62] Simpson DM, Alexander DN, O’Brien CF, et al. Botulinum toxin type A in the treatment of upper extremity spasticity: A randomized, double-blind, placebo-controlled trial. Neurology 1996;46(5):1306 – 10. [63] Gordon J. Spinal mechanisms of motor coordination. In: Kandel ER, Schwartz JH, Jessell TM, editors. Principles of neural science. 3rd edition. Norwalk: Appleton & Lange; 1991. p. 581 – 95. [64] Delwaide PJ, Yoiung RR, editors. Clinical neurophysiology in spasticity. Amsterdam: Elsevier; 1985. [65] Young RR. Physiologic and pharmacologic approaches to spasticity. Neurol Clin 1987;5:529 – 39. [66] Katz RT. Management of spasticity. Am J Phys Med Rehabil 1988;67:108 – 16. [67] Gans BM, Glenn MB. Introduction. In: Glenn MB, Whyte J, editors. The practical management of spasticity in children and adults. Philadelphia: Lea & Febiger; 1990. p. 1 – 7. [68] Mayer NH. Functional management of spasticity after head injury. J Neuro Rehab 1991;5:S1 – 4. [69] Lehmkuhl LD, Thoi Ll, Baize C, Kelley CJ, Krawcryk L, Bontke CF. Multunodality treatment of joint contractures in patients with severe brain injury: cost, effectiveness, and integration of therapies in the application of seria Vinhibitive casta. J Head Trauma Rehabil 1990;5:23 – 42. [70] Carthidge NE, Hudgson P, Weightman D. A comparison of baclofen and diazepam in the treatment of spasticity. J Neurol Sci 1974;23:17 – 24. [71] Whyte J, Robinson KM. Pharmacologic management. In: Glenn MB, Whyte J, editors. The practical management of spasticity in children and adults. Philadelphia: Lea & Febiger; 1990. p. 201 – 26. [72] Chan CH. Dantrolene sodium and hepatic injury. Neurology 1999;40:1427 – 32. [73] Reeves KD, Baker A. Mixed somatic peripheral nerve block for painful or intractable spasticity: a review of 30 years of use. AJPM 1992;2:205 – 10. [74] Glenn MB. Nerve blocks. In: Glenn MB, Whyte J, editors. The practical management of spasticity in children and adults. Philadelphia: Lea & Febiger; 1990. p. 227 – 58. [75] Kasdon KL, Abromovitz JN. Neurosurgical approaches. In: Glenn MB, Whyte J, editors. The practical management of spasticity in children and adults. Philadelphia: Lea & Febiger; 1990. p. 259 – 67. [76] Albright AL, Barron WB, Fasick MP, Polinko P, Janosky J. Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993;270:2476 – 7. [77] Bowers DN, Averill A. Intrathecal baclofen for Intractable spasticity due to severe traumatic brain injury [abstract]. Arch Phy Med Rehabil 1991;72:816. [78] Meythaler JM. Use of intrathecal baclofen in brain injury patient’s abstract. Arch Phys Med Rehabil 1994;75:1036. [79] Shaari CM, Sanders I. Assessment of the bilogical activity of botulinum toxin. In: Jankovic J,
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Botulinum toxin therapy in pain management P. Prithvi Raj, MD, FIPP Texas Tech University Health Sciences Center, International Pain Institute, 4430 South Loop 289, Lubbock, TX 79413, USA
Botulinum toxins are potent neurotoxins produced by Clostridium botulinum that are able to block acetylcholine release at the neuromuscular junction producing a flaccid paralysis. 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. In 1989, the FDA approved BTA for use in treating strabismus, blepharospasm, and hemifacial spasm. In December 2000, botulinum toxin B (BTB) was FDAapproved for use in treating cervical dystonia. Botulinum toxins have been used in a vast array of clinical problems: 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.
History and early clinical development 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 crude form of botulinum toxin (BT) [2], the neurotoxin responsible for food-borne botulism. Early development of BT began during World War II in the course of studying the nature of certain toxins, including BT, and the means for protecting against them. [3]. Although much of this initial work was performed on BTA, other types of
Excerpts from this article were adapted from Dr. Mike A. Royal’s The use of botulinum toxins in the management of pain and headache, published in Pain Practice Vol. 1 (3), September 2001; with permission. E-mail address: [email protected] 0889-8537/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8537(03)00082-8
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Botulinum toxin were also studied, which included B, C, D and E. The purpose was to develop a polyvalent toxoid for immunization purposes. After the war, a crystallized form of BTA became available and stimulated considerable scientific interest. Dr. Alan B Scott, of the Smith-Kettlewell Eye Research Foundation, initiated efforts to study BT in a monkey model of strabismus in the late 1960s [4]. Sufficient data were collected by 1978 to file an IND for human clinical studies [5]. Clinical development was aided by the passage of the Orphan Drug Act of 1983 and FDA approval as an orphan drug was granted in December, 1989.
Pharmacology of botulinum toxins There are two types of BT presently available: Botox (Botulinum toxin type A Purified Neurotoxin Complex, Allergan, Inc., 2525 Dupont Drive, Irvine, CA) is available in the US and Dysport (Botulinum toxin type A, Ipsen Ltd, Berkshire, UK) is available in Europe. Botox is FDA-approved for the treatment of essential blepharospasm, strabismus, and hemifacial spasm in-patients over the age of 12 years. BTB (Myobloc, Elan Pharmaceuticals, and South San South San Francisco, CA) was FDA-approved in early December 2000 for the treatment of cervical dystonia and is presently in clinical trials for other conditions.
Structure, mechanism of action, and pharmacology of botulinum toxins Although there are many reviews of this topic in the recent scientific literature [6,7], the proper clinical use of BT as a therapeutic agent rests on a clear understanding of the relationship between its structure and mechanism of action, dosing techniques of administration, and side effects.
Structure Lyophilized BT 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 kD) and one light chain (L-chain; 50 kD) bound together by at least one disulfide bond and additional non-covalent forces. Botulinum toxin occurs in several subtypes, designated A through G, with sequence homology amounting to about 50% across the subtypes [8,9]. 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 and antigenic crossreactivity [10]. When secreted into culture medium by C botulinum, BT is complexed with two other proteins, a non-toxin protein (150 kD) and a hemagglutinating protein (600 kD); these additional proteins greatly enhance the stability of BT complex over free B [11]. Most relevant to clinical use is that Type A seems to be the most potent of the subtypes [12 –14] and, when injected clinically, has the
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longest duration of action [15,16]. While Type B [17,18] and F [19,20] 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. For this reason, and because much of the preclinical and clinical literature uses BT, this review 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-chains 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 [21]. The binding of BT to the motor endplate pre-synaptic membrane is a two-stage process, with concentration of the toxin occurring through a non-specific affinity for ganglioside-containing, lipid-rich presynaptic membrane [22], followed by specific binding to a protein-containing receptor [23,24]. Binding is irreversible, but not itself toxic to the neurone [25,26]. Internalization of the bound toxin occurs by receptor-mediated endocytosis [27]. 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 [28 –30]. Once in the cytosol, the L-chain of BT effects a long-lasting inhibition of ACh release, which current evidence suggests is accomplished by the cleavage of one or more proteins necessary for the release of ACh by synaptosomes [10]. 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 [10].
Pharmacology When injected intramuscularly at therapeutic doses, BT 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 on the underlying condition, dose and site of injection, onset of effect of BT 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 6 weeks up to 6 months
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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 BT administration. Recovery of functional innervation is associated with histologic evidence of neuronal sprouting, reinnervation and enlargement of some endplates, along with the formation of new smaller endplates [12,31,32]. There is also an increase in the number of muscle fibers innervated per axon, with some fibers coming to be innervated by more than one axon [12]. Recovery is complete after allowing sufficient time for regrowth [33,34]. Fiber size, and presumably neuromuscular function, returns to essentially normal, even after multiple cycles of injection and recovery [35]. BTB (Myobloc) is produced by fermentation of C. botulinum type B (Bean strain) as a noncovalently associated neurotoxin complex with hemagglutinin and non-hemagglutinin 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 5000 units BTB per mL in 0.05% human serum albumin, 0.01 M sodium succinate, and 0.1M sodium chloride at a pH of about 5.6. Although biologic activity is maintained at room temperature for 6 months; recommended storage guidelines are for refrigeration at temperatures (2– 8°C.) with stability maintained for 2 years. Similarly 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 units/ng. However, units of biologic activity of BTB cannot be compared with or converted into units of any other BT. Extrapolation from animal data should not be done because of differences in species sensitivity to BT neurotoxin serotypes. Until adequate studies are done, extrapolation from human cervical dystonia dosing data to other conditions in which BT might be used in an off label fashion would not be prudent. The most commonly reported adverse events associated with BTB in clinical trials were dry mouth, dysphagia, dyspepsia and injection site pain with the dry mouth and dysphagia the most common reasons for discontinuation [36]. Doses up to 25,000 units were studied, but most patients received 12,500 units 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 seemed to be much less of a problem with repeat dosing even when higher doses were used.
Antibody formation Tsui [37] reported on the incidence of antibody formation in 32 patients with spasmodic torticollis who received repeated injections of BTA. 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 or spasmodic torticollis, the incidence of antibody formation is far less. Based on the
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data from several studies, the incidence of antibody formation with BTA for the treatment of cervical dystonia is probably less than 5% [38]. The present Botox formulation is ‘‘cleaner’’ (4 versus 9 ng protein) than the older formulation used in much of the published data discussing antibody formation. Based on the present data, general guidelines of keeping the dose as low as is necessary (eg, a maximum of 300 units of BTA) and injecting no more frequently than every 3 months remain. Since BTA and BTB display quite different chemical compositions, it has long been felt that the antibody cross reactivity between the two is small [39]. Nonetheless concern has been expressed over the potential problem of neutralizing antibody formation with lower potency and shorter acting BT serotypes. Higher toxin doses and frequent injections seem to be associated with neutralizing antibody formation [40]. As part of the Myobloc clinical trials, 446 patients were followed by periodic ELISA assays to detect the presence of neutralizing activity against BTB with positive results confirmed by the mouse neutralization assay [41]. Twelve percent of the patients had a positive ELISA response at baseline and by 6, 12, and 18 months, new ELISA responses were seen in 20%, 36%, and 50%, respectively. Estimated rates of serum neutralizing activity were 10% at 1 year and 18% at 18 months. There were no data on whether this neutralizing activity had any effect on efficacy. Additionally, for example, although BTA and BTF have similar potency, increasing doses of BTF to increase duration of response to that seen with BTA may increase antibody formation as demonstrated in a study by Chen et al who reported on 4 of 18 (22%) cervical dystonia patients that became nonresponsive to BTF following 12 to 66 months of treatment [42].
Pain abatement in clinical studies with botulinum toxin type A This review attempts to organize the burgeoning number of clinical studies of BT 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 BT use in a particular subcategory, whereas at the same time identifying principles of practice that may guide the use of BT for neuromuscular pain in general. Considering this, the first general principle for the rational use of BT in pain management is actually a precondition: the patient must be experiencing chronic pain of a known or probable cause for which there is no curative treatment, and chronic pain for which other conservative and non-invasive pain relief strategies have been considered and exhausted. Pain related to involuntary or excessive muscle contraction can be produced by a 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 on the predominance of a movement disorder, primarily the
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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 [35]. 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 [43]. 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 BT 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, BT may prove beneficial even in the generalized dystonias. The focal dystonias for which there is an extensive literature detailing treatment with BT 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. About 70% of patients with cervical dystonia report pain as a principle complaint. Controlled clinical trials in cervical dystonia suggest a dramatic effect of BT 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 BT was used for the treatment of cervical dystonia [44]. 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 BT ranged from 40 to 120 MU (Botox), while per-treatment doses ranged between 100 to 374 m.u. (Botox).
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Writer’s cramp Writer’s cramp, now considered a focal dystonia [45], is the most common form of occupational dystonia. Similar disorders have been described in musicians and others whose daily work involves frequent repetitive movements of the hands [46,47]. 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 populations. 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 a proper grasp cannot 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 [48]. 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 BT 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 BT [49]. A subsequent larger study showed improvement in 16 of 19 patients (84%) [50]. 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 BT therapy [50 –54] the last of these showed pain abatement in all 12 subjects who reported pain as a feature of their condition. Where patients have been observed long enough, some have continued to respond to BT for as long as 6 years [55]. Three published double-blind trials in writer’s cramp have shown some degree of response also, however, pain was not assessed in these studies. In one such study of 17 patients, subjective improvement was noted after 53% of the BT injections compared with only one patient (7%) after placebo injection [56]. 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 BT 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 [57]. A third study in 10 patients used a similar double blind, crossover design, and 80% of patients showed a subjective and objective response [58].
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Considering that pain is infrequently mentioned in studies of writer’s cramp, most attempts at gauging the efficacy of BT in this condition showed better response with subjective responses than with objective ones, even in the doubleblind studies. Nevertheless, BTX-A seems to be the best treatment available at present for writer’s cramp, especially for patients who also experience pain.
Spastic disease states with pain Two other subgroups of pain patients detailed in this review 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 sometimespainful spasticity in certain patients with cerebral palsy, multiple sclerosis, stroke, and traumatic brain injury, whereas 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 [59]. 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 [59]. Burke et al [60] suggest that this view is no longer entirely accurate. 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 [60 – 62]. The most fundamental component of this sequence is the abnormal intraspinal response to sensory input. Modulation of local spinal cord activity occurs by way of the descending pathways, such as the rubrospinal tract [63,64]. In general, positive symptoms such as hyper-reflexa 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 [65]. Though they can interfere with rehabilitation, they are also more amenable to clinical intervention than are negative signs.
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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 [66 – 69]. Initially, physical therapeutic modalities should be tried, such as avoidance of noxious stimuli, passive movement exercises, thermal agents, vibratory treatment, and serial inhibitive casting [69]. Oral medications can be tried in conjunction with physical measures or alone, but neither neural depressants (eg, oral or intrathecal baclofen, benzodiazepines, clonidine, and tizanidine) nor muscle relaxants (eg, dantrolene) have proved very satisfactory by reason of limited efficacy and intolerable side effects [70 – 72]. For the more seriously affected or unresponsive patient, invasive procedures such as phenol and alcohol nerve blocks [73,74], spinal cord stimulation, rhizotomies, and intrathecal baclofen administration have been tried [65,75 – 79]. The cost of prolonged care and relative lack of benefit of conservative management have lead to the suggestion that BT be tried in the management of spasticity. BT can be used therapeutically to produce a reversible, partial, chemical denervation when injected directly into the suggestion that BT be tried in the management of spasticity. BT 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, BT 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 BT have been reported in spasticities of varying etiology. Although the focus of this review is on pain management, 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 control design and in these 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. Though the current literature contains at least a dozen studies reporting the benefits of BT in the improvement of muscle tone in spastic conditions, fewer than half of those included formal measures of pain relief. Even in these studies, 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 six 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 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 seemed to have obtained significant reduction in pain. Taken together, these results support the use of BT for pain relief in all spastic conditions in which it has thus far been tested. About 75% of such patients may expect to obtain pain relief.
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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 [80]. The condition is associated with regional pain and is most typically revealed by deep palpation of 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, as 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 [81]. 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 [82]. The nodular trigger points of MPS are believed to develop after trauma, 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 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. Injection of trigger points with analgesics, saline [83], and even distilled water [84], can produce temporary relief. In a small but carefully designed double blind, crossover study of six patients with myofascial pain syndrome, injections of BT or placebo showed a clear benefit of BT [85]. Patients were selected based on 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 neurologic deficits were excluded. Patients were randomly injected with either BT (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
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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 BT injection, but not at the 30-minute observation time. Mean duration of response was 5 to 6 weeks. One subject responded to both BT and Saline, and one subject’s pain threshold following BT had not returned to baseline by the time of the placebo injection. Results between the two treatment regimens were statistically significant in favor of BT 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 BT 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 BT 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 BTs only in more refractory cases until the treatment becomes established and pharmacoeconomics data are 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 BTs 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 BT 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
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through the involved muscle. It has also been demonstrated that 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 tensiontype headache management, most investigators have chased the tenderness and injected posterior neck muscles (upper trapezius, levator scapulae, and suboccipitals) and, if tender, temporalis, frontalis, and temporalis forward or included suboccipitals as well.
How much to inject? Cervical and seventh-nerve dystonia data have been used as a starting point for BT dose calculations with adjustments depending on the size of the muscle and degree of spasm. Clinical experience with BTA would seem to support this extrapolation to MPS or headache, but with BTB it will be important to be cautious and start at a maximum of 2500 to 5000 units and move upward depending on clinical response until data from current studies provides doseresponse information. The total maximum dose per visit for BT (Botox) typically should not exceed 300 to 400 unit range (although many have gone as high as 600 –700 units safely for numerous involved muscles as in diffuse spasticity or dystonia) and intervals between doses should be no more frequent than every 3 months. Following these general guidelines will reduce adverse events (primarily weakness) and antibody formation. Little data are available to help one decide on BTB dosing outside of cervical dystonia. It seems to be about 40 to 50 times less potent than BT with very few patients having received doses at or above 20,000 units, though these doses seem to be well tolerated. In the cervical dystonia data, BTB produced duration of effect between 12 and 16 weeks. Larger volumes of Injectate and doses of neurotoxin may influence the tendency for excess BT to diffuse to non-targeted sites (adjacent muscles or remote sites). This becomes a concern especially with anterior neck injections where EMG guidance and low volumes of Injectate (BTA 100 units per cc or BTB 5000 units per cc) should be used. The technique of using multiple injection sites within the muscle seems to reduce unwanted side effects as does using EMG 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 once it is added to reconstitute Botox it should be used within 4 hours because of dual concerns of protein denaturation and infection risk. Elan Pharmaceuticals also recommends that PFNS be used if one desires a more dilute concentration of Myobloc than 5000 units per cc and, although the toxin is stable
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for months at room temperature, if the vial is violated, the toxin should be used within 4 hours because of infection concern. The use of preservative-free local anesthetic as a diluent, though 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 helps to decrease local injection pain [86]. In MPS, numerous studies have documented 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 known, although studies are in progress to answer this question. Is targeting of injections needed? The use of fluoroscopic or EMG guidance to identify the muscle or localize the motor endplate before injections seems 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.
Summary BTs seem to be a useful treatment in refractory MPS and headache. Presumably BTs work by breaking the spasm or 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 BTs compared with standard therapies is duration of response. We do not advocate that BTs 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. 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.
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