The use of botulinum toxins for chronic pain and headaches
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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: email@example.com
Current Treatment Options in Neurology 2003, 5:483492Current 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.
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 .
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 . 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 generelated 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 protein25. Botulinum toxins B, D, F, and Gcleave synaptobrevin, also known as vesicle-associatedmembrane protein. Botulinum toxin type C also cleavessyntaxin . 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 ADMINISTRATIONAPPROVED 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.
The Use of Botulinum Toxins for Chronic Pain and Headaches Argoff 485
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 groupsplacebo, 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 . Brin et al. , 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
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 . 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 . A randomized, controlled study of 37 patients with tension-type headache was completed by Smuts et al. . In this study, patients received 100 U BTX-A or placebo into six injection sitestwo 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 te...