Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain Management

The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems. ¹
The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c- fos , expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin.
These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine.     

Other noncosmetic uses of BOTOX

Botulinum toxin A has a wide variety of clinical applications, which are related by blockade of acetylcholine and often are related to abnormal muscle contractures. These applications include ocular disorders, disorders of the upper aerodigestive tract, dystonia and hemifacial spasm, cosmetic, gastrointestinal disorders, genitourinary disorders, management of pain, and use in autonomic nervous system disorders. Many of these diseases will be discussed with regard to their treatment with botulinum toxin compared to conventional treatments. Advantages and disadvantages of botulinum toxin use are delineated. General guidelines for adult and pediatric dosing will also be discussed.     

Potential antinociceptive mechanisms of botulinum toxin

Botulinum toxin has been used in pain therapy for several years. Its application in migraine and headaches is particularly interesting. Clinical results have not yet been definitely conclusive, and a uniform model of the mode of action has not been established either. Apart from a purely muscular effect, a direct antinociceptive effect of botulinum toxin has been found in patients, in the preclinical model, and in a clinical pain model. This is contradicted by negative observations in the clinical model of pain, which might be related to methodological deficits. Further basics need to be worked out before arriving at any final result. Clinical studies with patients and pain models should then follow. Studying botulinum toxin within the context of pain will also provide many new insights into pain therapy in general. In which pain model botulinum toxin may play a role in the future, has to be awaited.     

Mögliche antinozizeptive Mechanismen von Botulinumtoxin

Botulinum toxin has been used in pain therapy for several years. Its application in migraine and headaches is particularly interesting. Clinical results have not yet been definitely conclusive, and a uniform model of the mode of action has not been established either. Apart from a purely muscular effect, a direct antinociceptive effect of botulinum toxin has been found in patients, in the preclinical model, and in a clinical pain model. This is contradicted by negative observations in the clinical model of pain, which might be related to methodological deficits. Further basics need to be worked out before arriving at any final result. Clinical studies with patients and pain models should then follow. Studying botulinum toxin within the context of pain will also provide many new insights into pain therapy in general. In which pain model botulinum toxin may play a role in the future, has to be awaited.     

The effect of small doses of botulinum toxin a on neck-shoulder myofascial pain syndrome: a double-blind, randomized, and controlled crossover trial

OBJECTIVES: Myofascial pain syndrome is a common cause of muscular pain in the shoulder-neck region. Injections of large amounts of botulinum toxin A have been found to be beneficial for the alleviation of myofascial pain, but large doses of this toxin may cause paresis of the muscle and other adverse events. The aim of this work was to determine the effect of small doses (5 U) of botulinum toxin A (BTA) injected directly into the painful trigger points of the muscles, using a double-blind crossover technique. METHODS: On the basis of the empirical criteria proposed for diagnosis of myofascial pain syndrome, 31 patients suffering from myofascial pain in the neck-shoulder region were studied. The patients received either botulinum toxin A or physiological saline injections on 2 occasions 4 weeks apart. The total dose varied from 15 to 35 U of botulinum toxin A [28+/- 6 U (mean+/- SD)]. The follow-up measurements were carried out at 4 weeks after each treatment. Neck pain and result of treatment were assessed with questionnaires. The pressure pain threshold was determined using a dolorimeter. RESULTS: Neck pain values decreased from 4.3+/- 2.4 to 3.3+/- 2.0 after saline injections and from 4.1+/- 2.1 to 3.3+/- 2.2 after botulinum toxin A. The pressure pain threshold values increased from 5.2+/-1.6 to 5.9+/-1.5 and from 5.7+/-1.6 to 5.9+/-1.6 after injections with saline and botulinum toxin A, respectively. No statistically significant changes in the neck pain and pressure pain threshold values occurred between the botulinum toxin A and saline groups. After the first injections, the subjective result of treatment was significantly (P=0.008) in favor of botulinum toxin A, and after the second injections, the subjective result was better for saline, but the difference was not statistically significant (P=0.098). There was no significant difference in the prevalence of side effects between saline and botulinum toxin A. CONCLUSIONS: Our study shows that there was no difference between the effect of small doses of botulinum toxin A and those of physiological saline in the treatment of myofascial pain syndrome.     

Botulinum Neurotoxin for the Treatment of Migraine and Other Primary Headache Disorders: From Bench to Bedside

Botulinum toxin type A, a neurotoxin, is effective for treating a variety of disorders of involuntary muscle contraction including cervical dystonia, blepharospasm, and hemifacial spasm. It inhibits neuromuscular signaling by blocking the release of acetylcholine at the neuromuscular junction. The biological effects of the toxin are transient, with normal neuronal signaling returning within approximately 3 to 6 months postinjection.
Recent clinical findings suggest that botulinum toxin type A may inhibit pain associated with migraine and other types of headache. However, the mechanism by which this toxin inhibits pain is not fully understood and is under investigation. Research findings suggest that botulinum toxin type A inhibits the release of neurotransmitters from nociceptive nerve terminals and, in this way, may possess an analgesic effect. A number of retrospective open-label chart reviews and 3 double-blind, placebo-controlled trials have demonstrated that localized injections of botulinum toxin type A significantly reduce the frequency, severity, and disability associated with migraine headaches. Although the majority of patients in these studies experienced no botulinum toxin type A-mediated side effects, a small percentage of patients did report transient minor side effects including blepharoptosis, diplopia, and injection-site weakness. Currently, 4 randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A as a novel treatment for migraine and other types of headache. These studies may provide further evidence that botulinum toxin type A is an effective option for the preventive treatment of migraine.     

Botulinum neurotoxin for the treatment of migraine and other primary headache disorders: from bench to bedside

Botulinum toxin type A, a neurotoxin, is effective for treating a variety of disorders of involuntary muscle contraction including cervical dystonia, blepharospasm, and hemifacial spasm. It inhibits neuromuscular signaling by blocking the release of acetylcholine at the neuromuscular junction. The biological effects of the toxin are transient, with normal neuronal signaling returning within approximately 3 to 6 months postinjection. Recent clinical findings suggest that botulinum toxin type A may inhibit pain associated with migraine and other types of headache. However, the mechanism by which this toxin inhibits pain is not fully understood and is under investigation. Research findings suggest that botulinum toxin type A inhibits the release of neurotransmitters from nociceptive nerve terminals and, in this way, may possess an analgesic effect. A number of retrospective open-label chart reviews and 3 double-blind, placebo-controlled trials have demonstrated that localized injections of botulinum toxin type A significantly reduce the frequency, severity, and disability associated with migraine headaches. Although the majority of patients in these studies experienced no botulinum toxin type A-mediated side effects, a small percentage of patients did report transient minor side effects including blepharoptosis, diplopia, and injection-site weakness. Currently, 4 randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A as a novel treatment for migraine and other types of headache. These studies may provide further evidence that botulinum toxin type A is an effective option for the preventive treatment of migraine.     

Botulinum toxin type A in the healing of ulcer following oro-mandibular dyskinesia in a patient in a vegetative state.

OBJECTIVE: Use of botulinum toxin is expanding as clinical studies demonstrate new potential therapeutic applications. In rehabilitation, botulinum toxin is predominantly used as adjunct therapy for the treatment of spasticity, but it may prove useful for other atypical clinical situations. CASE HISTORY: A 73-year-old man had a severe sub-arachnoid haemorrhage following the rupture of a giant aneurism of the middle left cerebral artery. Clinically, the patient presented a vegetative state and an oro-mandibular dyskinesia that produced a chronic ulcer on the lower lip. As treatment for this dyskinesia, a total of 320 U botulinum toxin type A were injected into the upper and lower orbicularis oris and masseter muscles. RESULTS AND DISCUSSION: This treatment allowed for application of topical medication and subsequently, ulcer healing. Botulinum toxin type A may be an important therapeutic aid for clinicians faced with treating persistent pathological conditions caused by dyskinesia.     

Does botulinum toxin A make prosthesis use easier for amputees?

Four post-amputation patients (1 with phantom pain, 3 with stump pain) were each treated with 100 IU botulinum toxin A, divided between several trigger points in the distal stump musculature. In 1 female patient (along with a pronounced reduction in phantom pain) hyperhidrosis of the stump ceased completely, probably after diffusion of the drug into the dermal sweat glands, leading to longer and safer use of the prosthesis. Intentional intradermal injection for this issue therefore could be valuable. Another patient was able to use her prosthesis for the whole day again after botulinum toxin A treatment for substantial stump pain, compared with only 4 hours a day before treatment. In 2 male patients, stump pain while wearing the prosthesis subsided to a considerable extent, 1 of the 2 reported an improvement in steadiness of gait. We suggest that stump treatment with botulinum toxin in rehabilitative medicine should be investigated in more detail.     

Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A

Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain-processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin–neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons’ activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice, we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R-expressing neurons and also cleaves the target of botulinum toxin, a component-docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a murine model of Taxol-induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods, and that BoNT/A-LC:SP may be a useful agent for treating chronic pain.     

Cost-effectiveness of botulinum toxin type a in the treatment of post-stroke spasticity.

OBJECTIVE: Treatment strategies for post-stroke spasticity include oral anti-spastic drugs, surgery, physiotherapy and botulinum toxin type A injection. The objective of this study was to compare the cost-effectiveness and outcomes of oral therapy vs. botulinum toxin type A treatment strategies in patients with flexed wrist/clenched fist spasticity. METHODS: Treatment outcome and resource use data were collected from an expert panel experienced in the treatment of post-stroke spasticity. A decision tree model was developed to analyse the data. RESULTS: Thirty-five percent of patients receiving oral therapy showed an improvement in pre-treatment functional targets which would warrant continuation of therapy, compared with 73% and 68% of patients treated with botulinum toxin type A first- and second-line therapy, respectively. Botulinum toxin type A treatment was also more cost-effective than oral therapy with the "cost-per-successfully-treated month" being 942 pounds, 1387 pounds and 1697 pounds for botulinum toxin type A first-line, botulinum toxin type A second-line and oral therapy, respectively. CONCLUSION: In conclusion, botulinum toxin type A is a cost-effective treatment for post-stroke spasticity.     

Is botulinum toxin type A effective in the treatment of spastic shoulder pain in patients after stroke? A double-blind randomized clinical trial.

OBJECTIVE: To determine the efficacy of botulinum toxin type A for the treatment of spastic shoulder pain in patients after stroke. DESIGN: Double-blind randomized clinical trial. PATIENTS: Of 31 patients enrolled from an acute-care hospital in Spain, 2 cases dropped out (drop-out rate 6.5%). Fourteen subjects were treated with infiltration of 500 units of botulinum toxin type A in the pectoralis major muscle of the paretic side, and 15 with a placebo. METHODS: After infiltration, both groups received transcutaneous electrical nerve stimulation for 6 weeks. Patients were assessed by the use of the Visual Analogue Scale for pain. A good result concerning pain was considered when the Visual Analogue Scale score was below 33.3 mm or less than half the initial score. The patients were followed-up for 6 months. RESULTS: The patients treated with botulinum toxin type A showed a significantly greater pain improvement from the first week post-infiltration. Persistent shoulder pain was observed more frequently in the placebo group, with relative risks in the range 0.32-0.41 during the follow-up period. CONCLUSION: Patients with spastic shoulder pain treated with a botulinum toxin type A infiltration in the pectoralis major muscle of the paretic side have a higher likelihood of pain relief (between 2.43- and 3.11-fold).     

Adjuvant treatments associated with botulinum toxin injection for managing spasticity: An overview of the literature

Background and objectiveA wide range of adjunct therapies after botulinum toxin administration have been proposed. The aim of the present paper is to provide an overview of major writings dealing with adjuvant (non-pharmacological) treatments associated with botulinum toxin for managing spasticity in order to provide some up-to-date information about the usefulness of the most commonly used procedures.MethodsThe literature in PubMed was searched with the MeSH terms botulinum toxins, muscle spasticity, physical therapy modalities, and rehabilitation. The results were limited to studies focusing on adjuvant treatments associated with botulinum toxin for managing spasticity. We excluded papers on the use of non-drug treatments for spasticity not associated with botulinum toxin serotype A (BoNT-A) injection. Relevant literature known to the authors along with this complementary search represented the basis for this overview of the literature.ResultsAdhesive taping and casting effectively improved the botulinum toxin effect in patients with upper- and lower-limb spasticity. There is level 1 evidence that casting is better than taping for outcomes including spasticity, range of motion and gait. However, consensus about their most appropriate timing, duration, target and material is lacking. In terms of physical modalities combined with botulinum toxin injection, we found level 1 evidence that extracorporeal shock wave therapy is better than electrical stimulation for some post-injection outcomes including spasticity and pain. Furthermore, electrical stimulation of injected muscles might be useful to boost the toxin effect. However, the best stimulation protocol has not been defined. In addition, we found level 2b evidence that whole-body vibration therapy might reduce spasticity with cerebral palsy.ConclusionFuture research in this field should focus on investigating the most appropriate post-injection treatment protocol for each goal to achieve.     

The use of botulinum toxin in the treatment of headaches

The use of botulinum toxin for movement disorders and cosmesis led to an accidental discovery of its beneficial effect on headaches. Extensive anecdotal evidence and several controlled trials suggest that intermittent and chronic migraines and chronic tension headaches may respond to this treatment. The effect of a single treatment, which is simple to administer, can last for 3 months. Botulinum toxin does not cause systemic or any other serious side effects. Prophylactic pharmacotherapy of migraine headaches is limited in its efficacy and has a potential for systemic side effects. This makes botulinum toxin a preferred treatment for many patients. The large controlled trials that are underway may lead to a wider acceptance of this treatment by neurologists and pain specialists.     

Mechanism of botulinum toxin in the relief of chronic pain

For many years, the use of botulinum toxin in the management of dystonia and associated conditions, has been recognized as not only having a beneficial effect on muscle tone and activity, but also to be associated with significant and prolonged pain relief. It is difficult to understand how this effect could be mediated solely on the basis of the toxin’s well-known property of chemodenervation of motor end plates. A second mode of action is demonstrated, in which effects on the muscle spindle play a prominent role, and which may enhance analgesia. A hypothesis is presented that a toxin degradation product may provide pain relief by mechanisms yet to be elucidated.     

Botulinum toxin for the treatment of musculoskeletal pain and spasm

The impressive pain relief experienced by sufferers of dystonia and spasticity from intramuscular injections of botulinum toxin suggested that patients with other chronic, musculoskeletal pain conditions also may benefit. However, there have been relatively few placebo-controlled studies of botulinum toxin in such non-neurologic conditions as myofascial pain syndrome, chronic neck and low back pain, and fibromyalgia; the results of these studies have not been impressive. One explanation for the lack of positive findings may be the lack of clinically evident muscle spasms (overactivity), despite the presence of muscle tenderness, tightness, or trigger points. Clinical observations of pain relief from injections of botulinum toxin for dystonia and spasticity and its apparent efficacy in treating migraine suggest an anti-nociceptive action independent of its neuromuscular junction-blocking action. Evidence from animal experiments supports this notion, and other data provide plausible physiologic mechanisms in the periphery and central nervous systems. These involve modulation of the activity of the neurotransmitters glutamate, substance P, calcitonin gene-related peptide, enkephalins, and others. However, even if botulinum toxin is firmly established as an analgesic, there is insufficient clinical evidence of its efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.     

Long-term effects of combined botulinum toxin treatment and rehabilitation on upper limb muscle spasms: a case report

[Purpose] We report our experience with a patient with a central spinal cord injury who showed improved finger and upper limb functions after long-term treatment with a combination of rehabilitation and botulinum toxin type A. [Participants and Methods] The patient had spasms and pain that gradually became more profound and was given botulinum toxin type A at 1 year 3 months after sustaining a spinal cord injury. We administered 14 botulinum toxin type A injections periodically for 7 years 4 months after the injury. We administered the injections at an average interval of 5.6 months. Splints that allowed extension and improved finger muscle tone and contracture were made for the patient. [Results] The patient experienced gradual alleviation of the spasms in the proximal upper limb muscles and improved range of motion after receiving five doses of botulinum toxin type A. The spasms and range of motion in the fingers gradually improved around 4 years after the injury through splint therapy and a combination of botulinum toxin type A administration and rehabilitation. [Conclusion] The combination of botulinum toxin type A, splint, and rehabilitation therapies can lead to positive improvements in finger spasticity and range of motion and is recommended for hypertonia cases with severe contractures.Key words: Carry-over effect, Concomitant use of splint, Restoration of hand function     

A prospective randomized controlled study of the role of botulinum toxin in whiplash-associated disorder

OBJECTIVES: To investigate the effectiveness of botulinum toxin in preventing the development of chronic whiplash-associated disorder. DESIGN: Prospective, randomized, placebo-controlled double-blind study. SETTING: Regional Neurological Rehabilitation Centre with participants being at home. SUBJECTS: Thirty-seven patients with whiplash-associated disorder who remained symptomatic two months after injury. INTERVENTIONS: Patients were randomized to receive either 250 units botulinum toxin type A (Dysport) or placebo (normal saline). Four trigger points were injected with 0.625 mL of injectant. OUTCOME MEASURES: Tenderness to palpation scores, visual analogue pain scale, Vernon-Mior Neck Pain and Disability Index and cervical range of motion. Follow-up assessments were carried out at four weeks and three months after treatment. RESULTS: Twenty participants received botulinum toxin and 17 received placebo. Both groups showed a tendency towards improvement in pain scores, Vernon-Mior Index and range of motion at four weeks and three months, with the changes being more pronounced in the toxin group. The change in Vernon-Mior Index in the toxin group was both statistically and clinically significant (i.e. a change of score of > or = 5 from baseline to follow-up). Group comparisons did not meet statistical significance. CONCLUSION: The improvements in outcome measures suggest that botulinum toxin type A may have a role to play in the management of whiplash-associated disorder but larger studies are required to clarify the situation.     

Effect of intramuscular botulinum toxin injection on upper limb spasticity in stroke patients

OBJECTIVE: To evaluate the therapeutic effect of intramuscular injection of botulinum toxin on spasticity of the upper limb, with emphasis on its influence over limb function. DESIGN: An open-label, noncontrolled trial with a duration of 12 wk was designed to determine the safety and efficacy of intramuscular botulinum toxin A injection in the treatment of 16 patients with stroke with spastic hemiparesis. Electromyographically guided intramuscular botulinum toxin A injections were applied to the spastic limbs. A detailed scale system was used for the evaluation of muscle tone and functional changes induced by botulinum toxin A treatment. RESULTS: No major side effect secondary to botulinum toxin A injection was reported. Statistically significant (P < 0.05) improvements of muscle tone, joint range of motion, hand muscle strength, and muscular pain were seen after the injection. The improvements lasted up to 8-12 wk after the treatment. However, there was no significant functional improvement except in two of the patients. CONCLUSIONS: Botulinum toxin A injection may help relieve upper limb spasticity and pain in patients with stroke. Its effect on function is probably determined by case selection.