Botulinumtoxin A in der Kopfschmerztherapie

In recent years botulinum toxin type A has been used increasingly more in the treatment of specific headache disorders. Especially regarding chronic migraine with and without combined medication overuse, convincing randomized studies have proven the efficacy of this treatment option and have led to approval for this indication. Regarding other headache entities, such as episodic migraine, tension-type headache, trigeminal autonomic cephalalgia (TAC), neuralgic, neuropathic and myofascial pain, currently available scientific data on the efficacy of botulinum toxin type A are scarce and often ambiguous. The exact underlying mechanisms of the influence of botulinum toxin type A on the pathophysiology of headache are not completely clear but an influence on the release of calcitonin gene-related peptide (CGRP) seems to play a crucial role. This article summarizes the most important studies as well as experiences of treatment with botulinum toxin type A regarding different headache entities.     

Botulinum toxin in migraine prophylaxis

Migraine is a chronic headache disorder manifesting in attacks lasting 4-72 hours. Characteristics of headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia and phonophobia. The migraine aura is a complex of neurological symptoms, which occurs just before or at the onset of migraine headache. Botulinum toxin A represents a completely new option for patients with chronic pain conditions. Numerous retrospective open-label chart reviews and 4 double-blind, placebo-controlled studies have demonstrated that botulinum toxin type A is significantly effective in migraine prophylaxis and reduces the frequency, severity, and disability associated with migraine headaches. Studies have generally reported a good and consistent efficacy. The differential therapeutic use of botulinum toxin appears to be worth attempting in migraine patients with the following characteristic features: (1) Muscular stress as migraine trigger, e. g., in craniocervical dystonia, pericranial painful muscular trigger points or tender points, oromandibular dysfunction, (2) concurrent chronic tension-type headache with the aggravating factors of muscular stress or oromandibular dysfunction, (3) chronic migraine with frequent migraine attacks on more than 15 days per month for longer than 3 months and if other therapeutic options have been either ineffective or have not been tolerated. The use of the agent does not cause CNS side effects. Migraine patients in particular, often suffer greatly, as a result of the adverse effects of the drugs used, from fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair loss and changes in libido. These side effects are not known in association with botulinum toxin A. To date, neither organic damage nor allergic complications have been reported. Thus, both the tolerability and the safety of this therapeutic measure are high. The mode of action by which botulinum toxin is effective in migraine prophylaxis is not fully understood and is under investigation. Currently, a number of other randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A in the prophylaxis of migraine and other headache entities.     

Botulinum toxin: mechanisms of action

This review describes therapeutically relevant mechanisms of action of botulinum toxin (BT). BT's molecular mode of action includes extracellular binding to glycoproteine structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain-barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated through blockade of substance P, glutamate and calcitonin gene related peptide.     

Expanding use of botulinum toxin

Botulinum toxin type A (BTX-A) is best known to neurologists as a treatment for neuromuscular conditions such as dystonias and spasticity and has recently been publicized for the management of facial wrinkles. The property that makes botulinum toxin type A useful for these various conditions is the inhibition of acetylcholine release at the neuromuscular junction. Although botulinum toxin types A and B (BTX-A and BTX-B) continue to find new uses in neuromuscular conditions involving the somatic nervous system, it has also been recognized that the effects of these medications are not confined to cholinergic neurons at the neuromuscular junction. Acceptors for BTX-A and BTX-B are also found on autonomic nerve terminals, where they inhibit acetylcholine release at glands and smooth muscle. This observation led to trials of botulinum neurotoxins in various conditions involving autonomic innervation. The article reviews the emerging use of botulinum neurotoxins in these and selected other conditions, including sialorrhea, primary focal hyperhidrosis, pathological pain and primary headache disorders that may be of interest to neurologists and related specialists.     

Botulinum toxin in tension-type headache

Botulinum toxin has meanwhile been approved for a number of indications. It is also gaining acceptance in other indications with a major focus on pain. The most common type of headache is tension-type headache (TTH) the pathogenesis of which has not yet been unfolded. As it looks there are vascular, myofascial and supraspinal factors intertwined. It is felt that headache is triggered by myofascial stimuli. The application of botulinum toxin is an intelligent alternative since the favorable effect of pharmacologic and other therapies is limited. Application of BTX should be considered when the pericranial muscles are involved. One of the effects produced lies in the reduction of muscular stress, muscular ischemia and muscle tone. We still don't know whether additional mechanisms such as retrograde uptake and direct antiinflammatory potential are involved. Current data permit the conclusion that headaches are decreased in their frequency and distinctiveness. Significant untoward effects are not to be expected. Neither the ideal dose nor the optimum selection of injection sites have been established as yet, an individual injection scheme is apparently most promising. Injection of the trigger points seems to make sense.     

Status on the use of botulinum toxin for headache disorders

PURPOSE OF REVIEW: Reports and studies on botulinum toxin A in headache treatment are increasing. The studies available from reference systems and published congress contributions on the prophylactic treatment of idiopathic and symptomatic headache with botulinum toxin were analyzed with respect to the study design, the headache diagnosis, and the significance of results. RECENT FINDINGS: For the prophylactic treatment of tension-type headache and migraine, no sufficient positive evidence for a treatment with botulinum toxin A is obtained from randomized, double-blind, and placebo-controlled trials to date. For the treatment of chronic daily headache (including medication overuse headache), there is inconsistent positive evidence for subgroups (e.g. patients without other prophylactic treatment). SUMMARY: The majority of double-blind and placebo-controlled studies do not confirm the assumption that botulinum toxin A is efficacious in the treatment of idiopathic headache disorders. It is possible that subgroups of patients with chronic daily headache benefit from a long-term treatment with this substance. Future clinical trials should focus on these defined patient groups.     

An Update on the Neurologic Applications of Botulinum Toxins

Initially used to treat strabismus in the 1970s, botulinum toxin now has more than a hundred possible medical applications. Its utility in neurologic conditions has largely involved treating movement disorders (particularly dystonia and conditions with muscle hyperactivity), although practically any hyperkinetic movement disorder may be relieved by botulinum toxin, including hemifacial spasm, tremor, tics, myoclonus, and spasticity. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neurotransmitters involved in pain regulation. Thus, their use in neurology has been expanded to include headache and other pain syndromes, as well as hypersecretory disorders. This article highlights some of the common neurologic conditions currently improved by botulinum toxins and reviews the scientific evidence from research studies and clinical experience with these conditions.     

Review of botulinum toxin type A for the prophylactic treatment of chronic daily headache

Botulinum toxin A is increasingly used in the treatment of idiopathic and symptomatic headache disorders. However, only few controlled trials are available and many trials can hardly be compared to each other because of different endpoints and different trial designs. In particular chronic daily headache, which is defined as an idiopathic headache occurring on more than 15 days per month for at least 3 months and a daily duration of at least 4 hours, is considered as a headache disorder with possible efficacy of botulinum toxin A. For the prophylactic treatment of chronic tension-type headache and chronic migraine, no sufficient positive evidence for a successful treatment can be obtained from randomized, double-blind, and placebo-controlled trials to date. For the treatment of chronic daily headache including medication overuse headache, there is some positive evidence for efficacy in a subgroup of patients. To date, the majority of double-blind and placebo-controlled studies do not suggest that botulinum toxin A is efficacious in the treatment of chronic idiopathic headache disorders. However, it is possible that some subgroups of patients with chronic daily headache will benefit from a long-term treatment with botulinum toxin A.     

Botulinum toxin as treatment for focal dystonia: a systematic review of the pharmaco-therapeutic and pharmaco-economic value

Focal dystonia is a common, invalidating neurologic condition characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures in one body part. Currently, botulinum toxin is the treatment of first choice. We performed a systematic review towards the pharmaco-therapeutic and pharmaco-economic value of botulinum toxin as treatment for focal dystonia, which yielded the following results. Botulinum toxin is the most effective treatment for reducing dystonic symptoms measured with dystonia-specific and general questionnaires, and pain in patients with focal dystonia. Seventy-one percent of patients with cervical dystonia had a reduction in neck pain compared to 12?% in placebo groups. Adverse events occur in 58?% of patients during treatment with botulinum toxin compared to 46?% treated with placebo. Especially dry mouth, neck weakness, dysphagia, and voice changes are common. Adverse events are usually mild and self-limiting. Health-related quality of life, measured with the SF-36 is 20?C50 points lower in patients with focal dystonia compared to controls and the effect of botulinum toxin on health-related quality of life is unclear. Botulinum toxin treatment is expensive because the drug itself is expensive. Yearly costs for treating a patient with focal dystonia with botulinum toxin range from EUR 347 to EUR 3,633 and the gain in QALYs with BTX treatment is small. Focal dystonia impairs the productivity and the ability to work. At start of botulinum toxin treatment only 47?C50?% was working. Botulinum toxin partly improves this. Overall, we conclude that botulinum toxin is an expensive drug with good effects. From a societal perspective, the costs may well weigh up to the regained quality of life. However, the available literature concerning costs, health-related quality of life and labor participation is very limited. An extensive cost-effectiveness study should be performed incorporating all these aspects.     

Change in the pattern of cervical dystonia might be the cause of benefit loss during botulinum toxin treatment

The muscular patterns of cervical dystonia were identified by polymyographic recordings in 76 patients before botulinum toxin treatment. The leading muscles were considered to be those which started dystonic movement and which showed constant and maximal activity during all dystonic movements. The dystonic muscles were repeatedly treated by local Injections of botulinum toxin. Sixteen patients showed (after repeated injections) loss of the benefit of local applications of botulinum toxin after various periods of time. Repeated polymyographic recordings were performed in these patients during the loss of the benefit of injected botulinum toxin. In four patients repeated polymyographic recordings showed an Identical pattern of cervical dystonia, but the activity of previously injected muscles was apparently decreased. In 12 patients only minimum or no activity was recorded in muscles which had previously been treated with botulinum toxin, but the pattern of cervical dystonia was changed. Different patterns of cervical dystonia with different leading muscles, but with identical directions of head deviation, were observed in six patients. In another six patients, the head deviation direction was to the opposite side and was accompanied by a change of the leading muscle and a change of the muscular pattern of dystonia. These results suggest either that dystonic activity from the cerebral generator changes to new effectors during the peripheral blockade of primary dystonic muscles, or that a change of generators at different levels of the CNS occurs. It may be neccessary to carry out repeated polymyographic recordings throughout the period of loss of benefit of previously successful local botulinum toxin injections.     

Botulinum toxin type A in chronic migraine

The use of botulinum toxin type A continues to be investigated by the US FDA for potential use in the treatment of headache. As part of this process there has been extensive research conducted by individual study sites as well as multicenter trials. To date, the majority of the focus has been on migraine headache as well as on tension-type headache. The results of these studies have been mixed. A variety of issues may contribute to the mixed results, including difference in the dose of toxin used, the number of injection sites utilized, the treatment paradigm itself, confounding medications, high and prolonged placebo response, as well as patient selection issues. Currently, the focus on botulinum toxin type A is on those patients who have chronic daily headache with a migraine component to their clinical picture. The results of two large trials in this population produced positive findings, especially when consideration is given to the a priori additional analyses of this complex patient population. The results of these studies have allowed a more focused program to be undertaken in the Phase III evaluation. At the same time, additional work has been performed to understand the mechanism by which botulinum toxin type A may work to alleviate migraine. This work may contribute substantially to improving outcomes with botulinum toxin type A. Characterization of the mechanism of action in pain may be crucial to outcomes because many issues are related to central sensitization.     

Neck pain in chronic whiplash syndrome treated with botulinum toxin. A double-blind,placebo-controlled clinical trial

Objectives Neck pain in chronic whiplash syndrome is a major burden for patients, healthcare providers and insurance companies. Randomized data on treatment of botulinum toxin in chronic whiplash syndrome are scarce. We conducted a randomized, placebo-controlled clinical trial to prove efficacy of botulinum toxin for neck pain in chronic whiplash syndrome. Methods 40 patients with chronic whiplash syndrome (whiplash associated disorders grade 1 and 2) were randomly assigned to receive botulinum toxin (maximum 100 units) or placebo (saline) in muscles with increased tenderness. Results After 12 weeks there was no significant difference between the two treatment groups in decrease of neck pain intensity on VAS (−7.0 mm, 95% confidence interval (CI) [−20.7 to +6.7]), mean number of neck pain days (−1%; 95% CI [−15% to +13%]), neck pain hours per day (−0.14; 95% CI [−3.0 to +2.7]), days on which symptomatic treatment was taken (−0.7%; 95% CI [−15% to +13%]) number of analgesics taken per day (−0.14; 95% CI [−0.6 to +0.4]) and total cervical range of motion (−11 degrees; 95% CI [−40 to +17]). There also was no significant difference in patient’s assessment of improvement after week 4, 8 and 12. Conclusions Botulinum toxin was not proven effective in treatment of neck pain in chronic whiplash syndrome. Increased muscle tenderness alone might not be the major cause of neck pain in whiplash syndrome. Received in revised form: 7 June 2006     

Comparison of analgesic effects of single versus repeated injection of botulinum toxin in orofacial formalin test in rats

Long-term effectiveness and repeated administration of botulinum toxin A are the basis for its use in both neuromuscular disorders and certain painful conditions. Botulinum toxin A has been recently approved for migraine treatment, and its off-label use extends to other craniofacial pain disorders. However, recently it was reported that, after repeated injection, botulinum toxin loses its antinociceptive efficacy in rats. In present study with a similar design, we compared the effects of single and repeated injections of botulinum toxin in formalin-induced orofacial pain. No statistically significant differences were found between single or repeatedly treated animal groups. Our results are in line with the clinical experience and suggest that botulinum toxin can be re-administered in orofacial pain treatment.     

Botulinum toxin in tension-type headache

Despite the controversy regarding specific mechanism of botulinum toxin action in pain relief, clinical results suggest that botulinum toxin type A may be promising treatment options for patients with primary chronic headache. To investigate this, we included sixteen patients with chronic tension-type headache in a prospective double blind, placebo-controlled crossover study and thirty patients in an open-label long-term study. All of the patients showed reduced severity of headache, reduced pericranial muscle tenderness and increased headache-free days during botulinum toxin A treatment. Moreover, constant and cumulative trend of improvement was present during long-term study indicating better quality of life during botulinum toxin treatment. There is need for further placebo-controlled clinical studies to identify the optimal dose, optimal number and place of injection sites as well as optimal injection techniques.     

Botulinum toxins in neurological disease

Botulinum toxins are among the most potent neurotoxins known to humans. In the past 25 years, botulinum toxin has emerged as both a potential weapon of bioterrorism and as a powerful therapeutic agent, with growing applications in neurological and non-neurological disease. Botulinum toxin is unique in its ability to target peripheral cholinergic neurons, preventing the release of acetylcholine through the enzymatic cleavage of proteins involved in membrane fusion, without prominent central nervous system effects. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical use, and have been shown to be safe and effective for the treatment of dystonia, spasticity, and other disorders in which muscle overactivity gives rise to symptoms. This review focuses on the pharmacology, electrophysiology, immunology, and application of botulinum toxin in selected neurological disorders.     

Updates on the antinociceptive mechanism hypothesis of botulinum toxin A

Botulinum toxin A has been traditionally viewed as a motor nerve specific treatment. However, clinical uses for botulinum toxin A have continued to expand, with increased use in conditions implicating sensory pain nerve dysfunction. Chronic pain is associated with excess pain fiber activity. When the site of this excess activity resides in the peripheral portion of the pain pathway, a condition of peripheral sensitization can establish. During this state, excess pain signaling reaches the central nervous system, which can then lead to a condition of central sensitization, manifesting as the symptoms associated with chronic pain (i.e. burning, electric pain, lowered pain threshold to normal stimuli, etc). Experimentally, botulinum toxin type A has been shown to reduce neuropeptides and neurotransmitter release from treated cells or nerve endings and to attenuate nociception in both neuropathic and non-neuropathic pain models. This review summarizes the literature to update the hypothesis for the mechanism by which botulinum toxin type A can modulate chronic pain.     

Muscle activity changes in spasmodic torticollis after botulinum toxin treatment

We assessed electromyographic (EMG) activity in neck muscles before and after botulinum toxin injections in 28 patients with spasmodic torticollis (ST) to investigate possible changes in muscle activation after treatment. A six-channel EMG with surface electrodes was used to record activity of sternocleiodomastoid, trapezius and splenius capitis bilaterally. Objective benefit (>25% reduction in Tsui's score) occurred in 22 patients (78%). Of the 168 muscles studied before botulinum toxin injections, 90 presented EMG activity. Sixty-eight of these muscles were injected and a decrease in EMG activity occurred in 44 (65%) of them. A decrease in EMG activity was also detected in 15 (68%) of those which were not injected. On the other hand, 70 of the 78 muscles without pre-botulinum toxin EMG activity were not injected. However, after treatment, EMG activity increased in 37 (52%) of these muscles. These changes involved 18 patients and occurred without concomitant change in the main direction of head deviation despite the improvement observed in most cases. These results suggest that in ST head turning results from an abnormal central motor program which results in non-specific neck muscle activation.     

Beneficial effects of botulinum toxin type a for patients with painful tic convulsif

Botulinum toxin is a well-known therapy for patients with diverse movement disorders. Its application has been extended to other disorders. Here, we document the case of a 70-year-old man with hemifacial spasm associated to trigeminal neuralgia secondary to an ectatic basilar artery. He was treated with botulinum toxin type A, 2.5 mouse units over five sites at the orbicularis oculi and one over the buccinator muscle. After botulinum toxin injections, relief was gained not only from twitching but also from pain. When the effects of the toxin vanished, spasms and pain recurred. Further infiltrations were given every 12 weeks following the same response pattern. This observation further validates the increasing role of botulinum toxin in pain management.     

Botulinum toxin in motor disorders: practical considerations with emphasis on interventional neurophysiology.

After a brief review of the pharmacological properties of the botulinum toxin (BT), its mechanism of action on the nerve endings of the neuromuscular junctions, and the general therapeutic principles and adverse side effects, we discuss the advantages of interventional neurophysiology for the treatment of focal motor disorders by means of botulinum toxin A (BTA) muscle infiltration. Electromyography (EMG) provides a valuable objective information in the diagnosis of many motor disturbances and enables the precise identification of the muscles that contribute to the abnormal movement or posture. The use of EMG guidance for BTA injection seems advisable in every muscle but it become indispensable in those difficult to access, deeply located or partially atrophied by previous toxin infiltrations. The EMG study also serves to localise the areas with the highest abnormal activity and the motor point of the muscle, where the injection of toxin exerts its maximal effect. Consequently, lower doses of BTA can be employed without decreasing the efficacy of treatment but reducing the potential risk of side effects, antibody production and the cost of treatment. Electrophysiological diagnosis and BTA treatment may be performed during the same exploration. Considerations on the particular aspects and lines of action are given referring to the main focal muscular hyperactivity motor disorders such as cervical, oromandibular and laryngeal dystonias, blepharospasm, writer's cramp, hemifacial and hemimasticatory spasms, infantile and adult forms of spasticity and some other focal disturbances such as strabismus, detrusor-sphincter dyssynergia and anismus.     

Experience with botulinum toxin type A in medically intractable pediatric chronic daily headache

In adults, botulinum toxin type A has been studied as a potentially effective treatment for chronic daily headache. For pediatric chronic daily headache, the literature evaluating efficacy of botulinum toxin type A is sparse, with no studies assessing tolerability. The purpose of this retrospective case series study was to assess tolerability and efficacy of botulinum toxin type A in the treatment of pediatric chronic daily headache. The series comprises 10 patients (ages 11-17 years) who received a standard 100-unit dose of onabotulinumtoxinA (trade name, Botox) for refractory chronic daily headache. Attention was given to therapeutic history, efficacy, and tolerability. The patients had attempted an average of 8.0 ± 2.40 S.D. therapies prior to botulinum toxin type A. Most patients reported adverse events from at least one of these prior medications. With botulinum toxin type A, four patients (40%) reported subjective but clinically meaningful relief, consisting of a decrease in headache intensity, and two patients additionally noted a decrease in headache frequency. The four responders noted improvements in quality of life. Three patients experienced minor adverse events from botulinum toxin type A. This case series suggests that botulinum toxin type A can be well tolerated and may be a useful therapeutic in pediatric patients with highly medically intractable chronic daily headache.