The Use of Botulinum Toxins for Chronic Pain and HeadachesCharles E. Argoff, MD

AddressCohn Pain Management Center, North Shore University Hospital and New York University School of Medicine, 4300 Hempstead Turnpike, Bethpage, NY 11714, USA.E-mail: pargoff@optonline.net

Current Treatment Options in Neurology 2003, 5:483–492Current Science Inc. ISSN 1092-8480Copyright © 2003 by Current Science Inc.

IntroductionThe number of therapeutic uses of the botulinumtoxins has grown considerably over the past decade.The US Food and Drug Administrat ion (FDA)approved the use of the botulinum toxins for awide variety of clinical states, including for cosmeticpurposes and the treatment of cervical dystonia, andthe treatment of hyperhidrosis has grown dramati-cally recently. This article will focus on the useof these toxins in the management of chronic painand headache.

The botulinum toxins are products of the anaerobicbacterium, Clostridum botulinum. Types A, B, C1, D, E, F,and G are the seven immunologically distinct serotypesof these extremely potent neurotoxins. Only typesA and B are currently available for routine clinicalpractice. Of the two type A preparations commerciallyavailable, Botox and Dysport (Ipsen Ltd., Berkshire,UK), only Botox is available in the US at this time.Type B is currently commercially available as Myoblocin the US and as Neurobloc (Elan Products, Zurich,

Opinion statementThe use of botulinum toxin in the management of various neurologic and non-neurologic disorders has grown considerably over the past decade. At the same time, new informa-tion regarding the mechanism of action of these toxins has evolved allowing for a greater understanding of the versatility of these agents. Although two types of botuli-num toxin (type A Botox [Allergan, Inc., Irvine, CA] and type B Myobloc [Elan Products, New York) are commercially available in the US, most studies of the use of these toxins for the management of chronic pain and headache have been completed with type A. Data from open-label and retrospective studies as well as clinical practice suggest as strongly as possible that there is a role for these agents, especially Botox, in the man-agement of several chronic headache disorders, including chronic migraine, chronic tension-type, cervicogenic, and cluster headache. Emerging data regarding the use of these agents for so-called “analgesic-rebound” headache also appear impressive; however, as of yet, no multicenter, randomized, controlled studies for any headache type have been published that confirm the results seen in noncontrolled studies. Never-theless, the benefit that some patients experience from this agent is impressive, and this drug appears for many to modify the disorder in a very positive manner. In a similar fashion, data for other pain states are often restricted to open-label and case study approaches; however, clinical experience and some of the available studies (even small controlled studies) suggest a role for the toxins in the management of various chronic pain states, such as myofascial pain, low back pain, and neuropathic pain. One of the greatest challenges ahead for all interested in this area is confirming the benefit seen clinically through appropriately designed multicenter, randomized, controlled studies.

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Switzerland) in Europe. Each of these neurotoxins is aprotein that varies in many ways, including molecularweight, mechanism of action, duration of effect, andadverse effects. The bacteria synthesize each toxininitially as a single-chain polypeptide. Bacterial pro-teases then “nick” type A as well as type B proteinsresulting in a di-chain structure consisting of one heavyand one light chain. Each toxin type is nicked in acharacteristic manner; for example, type A is nickedmore than type B and there is less than a 50% homol-ogy between the toxins [1].

Most of the known effects of these toxins have beenattributed to their ability to inhibit the release of acetyl-choline from cholinergic nerve terminals; however, thiseffect alone does not appear to explain the apparentanalgesic activity of some of these toxins [2]. Based onthe results of many laboratory experiments, otherpotential analgesic mechanisms of the botulinumtoxins and, in particular, Botox have been proposed,including the inhibition of the release of glutamate,substance P, and calcitonin gene–related peptide,reduced afferent input to the central nervous systemthrough effects of the toxins on muscle spindles, andother possible effects on pain transmission indepen-dent of the effect on cholinergic transmission of theseneurotoxins [3, Class III; 4,5]. Cui et al. [6••,7] haverecently reported in a placebo-controlled study thatsubcutaneous injections of botulinum toxin type A(BTX-A) into the paws of rats before exposure to theformalin model of inflammatory pain experienced asignificant dose-dependent inhibition of the acute aswell as secondary pain responses. In addition to thedemonstration that glutamate release in the peripherywas reduced in treated, as opposed to control, animals,inhibition of the expression of C-fos in the dorsal spinalcord in treated animals, but not controls, was observed.Nonparalytic doses of Botox were used in this study;therefore, these findings suggest that there are verylikely noncholinergic mechanisms of at least one ofthe botulinum toxins (BTX-A) that help to explain itsanalgesic effect.

The manner in which acetylcholine is affected by thetoxin has been much more widely studied than otheractions of the toxin. The mechanism by which acetyl-choline is released by these neurotoxins is a multistepprocess. It must be emphasized that it is much betterunderstood at this point than the mechanism by whichthese neurotoxins may exert their analgesic effects. Thetoxin must be internalized into the synaptic terminalfor it to exert its anticholinergic effect. The first step inthis process is the binding of the toxin to a receptor onthe axon terminals of the cholinergic terminals. Eachspecific botulinum toxin serotype binds specificallyto its own receptor irreversibly and each neither bindsto nor inhibits the other serotypes’ receptor [8,9]. After

the toxin is bound, an endosome is formed that carriesthe toxin into the axon terminal. The final step involvescleavage of one of the known synaptic proteins thatare required for acetylcholine release by the axon.Botulinum toxins A, E, and C cleave synaptosome-associated protein–25. Botulinum toxins B, D, F, and Gcleave synaptobrevin, also known as vesicle-associatedmembrane protein. Botulinum toxin type C also cleavessyntaxin [1]. The specific manner in which each toxintype may cleave the synaptic protein, as well the specificdifferences in effect on inhibiting acetylcholine release,is beyond the scope of this chapter. It has not yet beenconclusively demonstrated how these differences trans-late into varied clinical responses, including beneficialas well as adverse effects.

After the toxin has been injected into a muscle, weak-ness occurs within a few days to a week after injection,peaks most often within 2 weeks, and then graduallymuscle weakness resolves with a slow return to baseline.This recovery is associated with sprouting of the affectedaxon, and the return of synaptic activity to the originalnerve terminals. Regeneration of the cleaved synapticprotein is also required for recovery to occur. The dura-tion of the clinical effect of the currently available neuro-toxins appears approximately 3 months, but may clearlyvary from individual to individual [4,10,11]. Addition-ally, neither the possible differences in duration ofaction of these toxins for different clinical conditions, forexample, cervical dystonia versus migraine headache northe best way to use these differences from a treatmentviewpoint have not been well studied to date.

THE CURRENT US FOOD AND DRUG ADMINISTRATION–APPROVED USES OF THE BOTULINUM TOXINSIn 1989, BTX-A (Botox) became the first botulinum toxinto be approved by the FDA for use in the US. Althoughoriginally approved for the treatment of strabismus,blepharospasm, and hemifacial spasm, it has beensubsequently approved for the treatment of cervicaldystonia and, most recently, for the treatment of glabellarwrinkles. The second botulinum toxin approved bythe FDA, botulinum toxin type B (BTX-B) is currentlyapproved only for cervical dystonia [12,13, Class III]. It isimportant to report that even among initial publishedstudies of the use of BTX-A or BTX-B for cervical dystonia,the analgesic effects of these agents, for example, theability for these toxins to reduce the pain associated withcervical dystonia, was observed. In many studies of cervi-cal dystonia, the analgesic effect of the neurotoxinsappeared to have a greater duration of action than othermore direct neuromuscular effects [13, Class III].

It should be reported that the discussion of the useof BTX-A or BTX-B in the management of painful states,other than those discussed, involves a discussion ofthese agents used in an “off-label” manner.

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Treatment

• The botulinum toxins have been used in several different headache types with varying responses according to the individual studied. Rather seren-dipitously, the initial observation that Botox could be an effective headache management tool was made by Dr. William Binder, a plastic surgeon.Dr. Binder observed that many of his patients who had undergone BTX-A injections for the treatment of glabellar lines reported substantial improve-ment in their headache frequency and severity. After making these initial observations, he helped to design and complete a multicenter open-label trial of BTX-A in patients with migraine [14, Class III]. Of the 77 patients studied, 36 (51%) patients with migraine (as defined by the International Headache Society [IHS]) reported complete relief of their headaches. The mean duration of the effect of the Botox was 4.1 months, and 27 of 77 (38%) reported a partial response. The site of injections was determined based on the particular needs of the patient, but generally included the frontalis, temporalis, corrugator, and procerus muscles and, in a few patients, the suboccipital muscles. In addition, the dose of BTX-A also varied from patient to patient. Except for brow ptosis, no significant adverse effects were experienced. In a separate study, Silberstein et al. [15, Class I] reported the results of a multicenter, randomized, controlled study of BTX-A involving 123 patients with IHS-defined migraine who experienced between two and eight severe migraine headaches each month. Patients were randomized to one of three groups—placebo, 25 U BTX-A, or 75 U BTX-A. Eleven standard injection sites were used, including the frontalis, temporalis, corrugator, and procerus muscles. Bilateral injections were performed. Compared with placebo, the patients receiving 25 U BTX-A experienced the following effects after Botox injections: 1) significantly fewer and less severe migraine headaches each month, 2) a reduction in the amount of acute headache medication used, and 3) a lower incidence of emesis. There were no differences between the group receiving 75 U of BTX-A and those receiving placebo. No adverse effects were reported except for two cases of diplopia and 13 cases of ptosis [15]. Brin et al. [16], in a sepa-rate study, presented the results of a randomized, placebo-controlled, multicenter study of BTX-A in the migraine prophylaxis. In this study, several injection site patterns were used. Patients received Botox injections in the frontal and temporal regions, frontal only with placebo injections into the temporal region, temporal only with placebo injections into the frontal region, or placebo injections for each region. Those patients who received BTX-A injections into temporal and frontal regions experienced significantly greater pain relief than the placebo group only as well as those who received placebo and Botox injections.

• Many other studies have been more recently reported; however, essentially as abstracts only. Regardless, several interesting observations have been made in these from these studies. In a study of 30 patients with IHS-defined migraine headache, experiencing between two and eight attacks each month, patients were randomized to receive 50 U BTX-A or placebo injections. The 15 injection sites used included the temporalis, frontalis, corrugator, procerus, trapezius, and splenius capitis muscles bilaterally. Patients were observed for up to 90 days. Compared with placebo-treated patients who did not experience any significant change in their headache frequency or severity, those who received BTX-A injections had a significant reduction in headache frequency (at 90 days 2.5 vs 5.8; P<0.01) as well as severity. No significant adverse effects were reported [17].

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• In an open-label study evaluating the effects of Botox on disability in episodic and chronic migraine, treatment with 25 U BTX-A (frontalis, temporalis, and corrugator muscles) resulted in decreased migraine-associated disability in 58% of patients [18]. Two retrospective studies have emphasized that an additional potential benefit of Botox may be that it can serve as a “disease-modifying” treatment for patients with chronic migraine [19,20, Class III]. Each of these reports concluded that there may be increasing benefit experienced with repeated treatments with BTX-A for patients with chronic migraine; these clinical observa-tions, although not derived from randomized, controlled studies, are important to consider, because many injectors have empirically discov-ered for maximal benefit to be realized from Botox, a patient may need treatment at least several times.

• Compared with Botox in which many studies have been reported, only one open-label study involving the use of BTX-B (Myobloc) for the treat-ment of chronic migraine headache has been reported. Forty-seven patients with at least four migraine headaches within a 4-week period were treated with a total of 5000 U BTX-B into at least three injection sites. Injection sites were chosen on the basis of pain distribution, “trigger points” and glabellar lines. Thirty patients (64%) reported improvement in headache intensity and severity. One adverse effect experienced with BTX-B treatment in this study that was not experienced with BTX-A treatment was dry mouth [21, Class III].

• Several studies involving the use of botulinum toxin for the treatment of IHS-defined tension-type headache have been reported [22]. A randomized, controlled study of 37 patients with tension-type headache was completed by Smuts et al. [23]. In this study, patients received 100 U BTX-A or placebo into six injection sites—two in the temporalis muscles and four in the cervi-cal region. Analysis of the results indicated by the 3rd month postinjection, the treated group experienced by a statistically significant reduction in headache severity compared with the placebo-treated group. A retrospective study of 21 patients with chronic tension-type headache with concurrent tenderness of the scalp or neck was conducted by Freund and Schwartz [22]. The total dose of Botox used was 100 U and the five injection sites chosen based on the patient’s report of maximal tenderness to palpation. Of the 21 patients studied, 18 experienced at least a 50% reduction in headache frequency and 20 of 21 experienced at least a 50% reduction in scalp/neck tenderness to palpation [23]. Although there are other clinical reports of small numbers of successfully treated patients [24–26, Class III], in contrast, a small study reported by Zwart et al. [27, Class III] of six patients with tension-type headache who were treated with Botox failed to report any improvement in pain intensity after injection. One reason for this outcome may have been that patients received injections only into their temporalis muscle unilaterally. In another small randomized controlled study of 10 patients with tension-type headache, Botox was no more effective than placebo [28]. Porta [29, Class III] evaluated the difference in response between BTX-A injections and methylprednisolone injections in patients with tension-type headaches. Although the groups improved, patients who had undergone botulinum toxin injections experienced improvement for a greater duration of time (>60 days) compared with patients treated with methylprednisolone.

Tension-type headache therapy

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• There have been three reports of treatment of cluster headache with botuli-num toxin. A single patient with cluster headache refractory to other treat-ment to the injection of Botox was reported by Ginies et al. [30]. Freund and Schwartz [31] reported on two patients with intractable cluster headache who were reported after they responded to the unilateral injection of 50 U BTX-A into five sites within the temporalis muscle on the affected side. Within nine days of treatment, the headaches abated for the patients [31]. In another non-randomized study of seven patients with chronic cluster headache who were treated with BTX-A or BTX-B, Robbins [32] reported that treatment was at least moderately effective in four of seven patients and not effective in the remain-ing three patients. He also treated three patients with episodic cluster head-ache with botulinum toxin and two of three patients had at least moderate improvement [32].

• One open-label study, one randomized, controlled study, and one case series have been reported regarding the use of botulinum toxin for the manage-ment of chronic daily headache (CDH). Four of five treated patients in an open-label study by Klapper and Klapper [33, Class III] benefited from injec-tions. In a randomized trial of 56 patients with CDH, patients were divided into four groups involving forehead and suboccipital injections. Only patients who received botulinum toxin injections into each region experi-enced significant benefit [34, Class III]. Argoff [35] reported three patients with CDH who were successfully treated with a total of 5000 U BTX-B injected into the frontalis, temporalis, corrugator, splenius capitis, splenius cervicis, levator scapular, and trapezius muscles.

• Chronic temporomandibular joint dysfunction, chronic myofascial pain, chronic cervicothoracic pain, and chronic low back pain are among the painful musculoskeletal conditions that have been treated with the botulinum toxins.

• Botulinum toxin type A has been used for several temporomandibular disorders including myofascial dysfunction affecting this joint, bruxism, oromandibular dystonia, and masseter/temporalis hypertrophy [36]. Forty-six patients with chronic temporomandibular pain were studied by Freund et al. [37]. In their nonrandomized study, they injected BTX-A into the mas-seter muscles (50 U each) and into the temporalis muscles (25 U each) under electromyogram (EGM) guidance. Outcome measures that showed improve-ment included pain level as assessed by visual analog scale scores, interincisal oral opening, and tenderness to palpation. Approximately 60% of those treated experienced at least 50% improvement in these areas. In contrast, Nixdorf et al. [38, Class II] recently completed and reported a double-blind, placebo-controlled crossover trial evaluating the use of BTX-A in the manage-ment of chronic moderate to severe orofacial pain believed of myogenic origin. Similar to the Freund et al. [37] open-label study, 25 U of toxin were injected into each temporalis muscle and 50 U were injected into each mas-seter muscle. Crossover occurred at 16 weeks. Pain intensity and unpleasant-ness was the primary outcome variable utilized. No significant difference was determined between placebo versus active treatment in this study; however,

Cluster headache therapy

Chronic daily headache therapy

Management of musculoskeletal pain

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15 patients entered the study and only 10 patients completed it, suggesting that these small numbers may have made it difficult to see a statistical differ-ence between the two groups [38].

• The doses of botulinum toxin used for treatment of the temporomandibu-lar disorders depend on the size(s) of the muscle(s) involved, as well as the type of toxin used. For the temporalis and medial pterygoid muscles, the recommended doses of BTX-A are between 5 and 25 U in multiple injection sites. For the masseter muscle, the recommended dose of BTX-A is 25 to 50 U also in multiple injection sites. For the lateral pterygoid muscle, the recommended dose of BTX-A is between 5 and 10 U [36]. For each of these muscles, the recommended doses of BTX-B is between 1000 and 3000 U with multiple injection sites within each muscle [39].

• Many studies have examined the role of botulinum toxin in the treatment of chronic cervical or thoracic pain most often associated with myofascial dysfunction. In a randomized study by Wheeler et al. [40•, Class I] on the use of Botox injections into cervical paraspinal, trapezius, and thoracic para-spinal muscles, no significant differences were detected in pain reduction among treated and placebo patients. In their randomized controlled study of 26 patients with chronic neck pain after “whiplash” injuries, Freund and Schwartz [41, Class III] demonstrated a statistically significant reduction in pain for the patients who were treated with BTX-A compared with placebo. One hundred units of toxin were injected into five “tender” sites, and these were compared with a similar number of saline injections. Improvement was observed after 4 weeks. Cheshire et al. [42, Class II] injected myofascial trigger points in the cervical paraspinal or shoulder girdle area in six patients with BTX-A (50 U spread out over two or three areas) or saline. In this random-ized, controlled, crossover study, crossover occurred at 8 weeks. Four of the six patients experienced at least 30% pain reduction to toxin, but not saline injections. In a previous study by Wheeler et al. [43, Class I], 33 patients with cervical myofascial pain were injected with 50 or 100 U of BTX-A or placebo. No significant differences were seen between the two groups.

• Lang [44, Class III], in an open-label study of the use of BTX-A in the treat-ment of myofascial pain reported that 60% of patients experienced good to excellent results 22 to 60 days after injection. What is interesting about this study is that Lang had used a novel injection technique, injecting the whole muscle in a grid like pattern instead of the areas of tenderness only. In addi-tion, she used doses of BTX-A ranging from 20 to 600 U. Ferrante et al. [45] completed a 12-week randomized, double-blind, placebo-controlled study of 132 patients with cervicothoracic myofascial pain treated with BTX-A or saline injections. No significant differences in outcome were seen in the groups. Patients receiving BTX-A were treated with 50 to 250 U of toxin total divided among five injection sites [45].

• In a single-blinded study, Porta [46] evaluated the potential difference between lidocaine and methylprednisolone injections compared with Botox injections in affected myofascial trigger points within the psoas, piriformis, or scalenus anterior muscles. Eighty to 150 U of toxin were used. Each group received benefit, but the patients treated with toxin experienced a greater duration of relief. Opida [47] presented 31 patients with post-traumatic neck pain who were treated with BTX-B injections in an open-label study. Seventy-one percent of patients reported significant reductions in pain and headache frequency and severity. Taqi et al. [48,49] showed in two separate open-label studies that botulinum toxin (type A or B) may be effective in the treatment of myofascial pain.

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• The use of botulinum toxin in the management of chronic low back pain has also been explored. Foster et al. [50••, Class I] in a randomized controlled study involving 31 patients with chronic low back pain studied the effect of 200 U of BTX-A (five sites in the paravertebral levels L1 through L5 or L2 through S1; 40 U per site) compared with placebo injections. Pain and extent of disability were reported at baseline, as well as at 3 and 8 weeks, using the visual analogue scale as well as the Owestry Low Back Pain Questionnaire. At 3 and 8 weeks, more patients who had received botulinum toxin injections (73.3% or 60%) experienced 50% or more pain relief compared with the placebo-treated group (25% or 12.5%). At 8 weeks, there was less disability in the botulinum toxin–treated group compared to the placebo-treated group. Knusel et al. [51] treated patients with low back pain associated with painful muscle spasm with different doses of BTX-A and observed that only those treated with the highest doses (240 U) experienced greater relief than those treated with placebo.

• There have been reports of the use of botulinum toxin for the treatment of piriformis muscle syndrome as well. Childers et al. [52] concluded that there was a trend toward greater pain relief for patients after receiving toxin as opposed to placebo at the completion of a randomized, controlled, crossover study of nine patients with piriformis muscle syndrome who were treated with BTX-A (100 U) and placebo. EMG and fluoroscopic guidance were used for the injections. Fannucci et al. [53] reported that 26 of 30 patients with piriformis syndrome who were injected with BTX-A under computed tomography guidance obtained relief of their symptoms within 5 to 7 days. Fishman [54] has performed a dose ranging study with BTX-B in the management of piriformis syndrome using EMG guidance with notable symptom improvement as well.

• Several case reports of using BTX-B injections in the management of chronic myofascial pain have suggested generally good results [55–57].

• The use of botulinum toxin for the treatment of neuropathic pain is consid-ered novel, and there are only a few reports describing initial results in the management of postherpetic neuralgia, complex regional pain syndrome, and spinal cord injury pain [58]. Given that it has been determined at least for Botox that noncholinergic mechanisms, most notably the inhibition of the release of glutamate, have been reported for Botox, further studies of nonparalytic doses of Botox, even subcutaneous doses in the management of neuropathic pain states, need completion. In addition, although reduc-tion of pain is not the usual primary outcome measurement used in studies of botulinum toxin and spasticity, a study of patients treated with BTX-A for spasticity by Wissel et al. [59] has reported the analgesic benefit of this treatment for 54 of 60 patients.

• Currently, neither of the available botulinum toxins is FDA approved for a specific painful state; therefore, use is in an off-label manner. Patients should be informed of such before treatment.

• Significant side effects are uncommon. Pain, muscle weakness, and a flu-like syndrome have been reported. Spread of toxin has been observed with weakness sometimes involving muscles, which were not directly injected. Autonomic side effects appear more commonly with BTX-B.

Management of neuropathic pain and other painful conditions

General considerations for treatment

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• Contraindications to treatment with botulinum toxin include pregnancy (category C), the concurrent use of aminoglycoside antibiotics, myasthenia gravis, Eaton-Lambert syndrome, or known sensitivity to the toxins.

• Treating more frequently than the recommended interval of 12 weeks may lead to the development of antibodies to the toxin, which also may be associated with the development of clinical resistance.

• There is no valid way to reliably and consistently convert doses of BTX-A to doses of BTX-B at present.

• The use of botulinum toxin for pain management is as part of a comprehensive treatment program that has been developed based on an accurate diagnosis.

• Be aware of current storage or handling recommendations for each of the toxins.

• Whenever possible, use an injection technique including needle size that is the least likely to cause additional pain.

• Guidance techniques such as EMG, computed tomography, or fluoroscopy should be used at the discretion of the injector.

• Prolonged observation after the injections is generally not warranted.• Follow-up should be arranged for 4 to 6 weeks after injections.• More than one series of injections may be required to achieve maximal

analgesic response.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

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53. Fannucci E, Masala S, Sodani G, et al.: CT-guided injec-tion of botulinum toxin for percutaneous therapy of piriformis muscle syndrome with preliminary MRI results about denervation process. Eur Radiol 2001, 11:2543–2548.

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