Botulinum toxin and painful peripheral neuropathies: what should be expected?

Botulinum toxin type A (BTX-A) is a potent neurotoxin that blocks acetylcholine release from presynaptic nerve terminals by cleaving the SNARE complex. BTX-A has been reported to have analgesic effects independent of its action on muscle tone. The most robust results have been observed in patients with neuropathic pain. Neuropathic pain due to peripheral lesions has been the most widely studied. BTX-A has shown its efficacy on pain and allodynia in various animal models of inflammatory neuropathic pain. The only randomized, double-blind, placebo-controlled trial in patients with focal painful neuropathies due to nerve trauma or postherpetic neuralgia demonstrated significant effects on average pain intensity from 2 weeks after the injections to 14 weeks. Most patients reported pain during the injections, but there were no further local or systemic side effects. The efficacy of BTX-A in painful peripheral neuropathies has been more recently studied. Results were positive in the only study in an animal model of peripheral neuropathy. One study in patients with diabetic painful peripheral neuropathy demonstrated a significant decrease in Visual Analog Scale. In conclusion, one session of multiple intradermal injection of BTX-A produces long-lasting analgesic effects in patients with focal painful neuropathies and diabetic neuropathic pain, and is particularly well tolerated. The findings are consistent with a reduction of peripheral sensitisation, the place of a possible central effect remaining to define. Further studies are needed to assess some important issues, i.e. BTX-A efficacy in patients with small fiber neuropathies and the relevance of early and repeated injections. Future studies could also provide valuable insights into pathophysiology of neuropathic pain.     

A randomized,double-masked,crossover comparison of the efficacy and safety of botulinum toxin type A produced from the original bulk toxin source and current bulk toxin source for the treatment of cervical dystonia

In 1997, the US FDA approved a new bulk toxin source (now referred to as current) for the manufacture of botulinum toxin type A (BTX-A). The current BTX-A preparation has a lower neurotoxin complex protein load than the original BTX-A preparation, which may reduce antigenic potential. The present double-masked, multicenter study compared the efficacy and safety of BTX-A (BOTOX) produced from both original and current bulk toxin sources for the treatment of cervical dystonia. Patients (N = 133) were injected with BTX-A produced from original and current bulk toxin sources using a crossover design. Adverse events were assessed at each visit. Efficacy was assessed at 2 and 6 weeks post-injection using the severity and pain-disability subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Mean BTX-A doses were comparable (original: 155 U, current: 156 U). Both BTX-A preparations produced similar, statistically significant reductions in TWSTRS severity and pain-disability scores at weeks 2 and 6 post-injection. The original and current BTX-A preparations showed no significant differences in adverse events, including both treatment-related (34%, 31%) and treatment-unrelated (27%, 32%), respectively. BTX-A produced from the original and current bulk toxin sources showed comparable efficacy and safety in the treatment of cervical dystonia; both significantly reduced dystonia severity and pain.     

Association of antinociceptive action of botulinum toxin type A with GABA-A receptor

The mechanism of botulinum toxin type A (BTX-A) antinociceptive action in the central nervous system is little known. The potential interaction between BTX-A and GABAergic system has not been investigated previously. In the present study, we demonstrate prevention of BTX-A antinociceptive effect on formalin-induced inflammatory pain and partial sciatic nerve transection-induced mechanical allodynia by GABA-A antagonist bicuculline, thus suggesting association of the GABA-A receptors and antinociceptive action of BTX-A.     

A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache

Tension-type headache (TH) is a common condition, the pathophysiology of which remains undetermined. Evidence implicates sustained contraction of pericranial muscles to be a major cause. A recent preliminary study demonstrated the effectiveness of botulinum toxin type A (BTX-A) in patients suffering from chronic TH. To further investigate this, we performed a study to compare the efficacy of BTX-A with the steroid methylprednisolone (both administered with the local anesthetic lidocaine), when administered by injection into the tender points of cranial muscles in patients with TH. A significant decrease in the median pain score (assessed using a standard visual analogue scale ) was observed at 60 days post injection of BTX-A compared with the pain score achieved following steroid therapy. All patients treated with BTX-A experienced a gradual decrease in median pain severity scores at 30 days and 60 days post treatment. The beneficial effects of BTX-A therapy continued to improve 60 days following injection, whereas the effects of steroid therapy at this time point began to decline. This study clearly demonstrates the effectiveness of BTX-A for the treatment of TH.     

Botulinum toxin type A: new therapeutic directions

Intramuscular injections of botulinum toxin type A (BTX-A) have been used successfully to treat disorders such as cerebral palsy and cervical dystonia for many years. New and exciting directions for the toxin are currently under clinical investigation for a number of unlicensed indications including tension-type headache, myofascial pain and hyperhidrosis. Although research on BTX-A is prolific, there is still much to be learnt regarding the toxin's mode of action, clinical application and perhaps more importantly, its place in the overall treatment strategy implemented by physicians to ensure treatment is a success for both the patient and the physician. This review will focus on these issues, by outlining some of the future directions for BTX-A research.     

Prophylactic treatment of chronic tension-type headache using botulinum toxin type A

Chronic tension-type headache is a common condition, the pathophysiology of which is not well understood. Over-activity of the pericranial muscles is thought to play a role, although sustained muscle contraction is probably a consequence, rather than a cause, of headache. Botulinum toxin type A (BTX-A) is useful in many conditions involving excessive muscle contraction and may therefore be effective in relieving the pain associated with this type of headache. To investigate the efficacy of BTX-A in relieving pain associated with chronic tension-type headache, a double-btind, randomised, placebo-controlled study was carried out, in which 37 patients received BTX-A, injected into the temporalis or cervical muscles of the neck. Clinical outcome was measured over a 4-month study period using headache diaries and chronic pain index scores. Patients treated with BTX-A showed an improvement in headache severity over the 4-month study period, with 13 out of 22 patients showing a 25, 50 or >50% improvement in headache score at Month 3 compared with two out of 15 patients in the placebo group. The number of headache-free days increased significantly in the BTX-A-treated patient group, and patients recorded an improvement in quality of life following BTX-A injection. It can be concluded that intramuscular injection of BTX-A is an effective treatment for chronic tension-type headache.     

Botulinum toxin treatment in cerebral palsy: evidence for a new treatment option

Intramuscular injections of botulinum toxin type A (BTX-A) have increasingly been used to reduce spasticity in specific muscle groups in children with cerebral palsy. Targets of therapeutic efforts are improvement of gross motor function, alleviation of pain or facilitation of hygienic care. Placebo-controlled studies have shown the local and functional effectiveness of BTX-A for the treatment of dynamic pes equinus. Whether long-term treatment with BTX-A improves motor development and delays contractures is still under investigation.

     

Botulinum toxin treatment in cerebral palsy: evidence for a new treatment option

Intramuscular injections of botulinum toxin type A (BTX-A) have increasingly been used to reduce spasticity in specific muscle groups in children with cerebral palsy. Targets of therapeutic efforts are improvement of gross motor function, alleviation of pain or facilitation of hygienic care. Placebo-controlled studies have shown the local and functional effectiveness of BTX-A for the treatment of dynamic pes equinus. Whether long-term treatment with BTX-A improves motor development and delays contractures is still under investigation.     

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 type A injections for myofascial pain syndrome and tension-type headache

Myofascial pain syndrome (MPS) is characterised by acute and specific pain affecting the piriformis, iliopsoas or scalenus anterior muscles. Tension-type headache (TH) is a common pathological condition, which can be chronic or episodic. Based on its muscle-relaxant properties, botulinum toxin type A (BTX-A) has demonstrated efficacy in a variety of conditions involving dysregulated muscle contractions. Patients with MPS ( n = 40) or TH (n = 20) were recruited to two randomised, single-blind studies, respectively. Each patient received either BTX-A or methylprednisolone, injected into the affected muscles after administration of a local anaesthetic. Pain was assessed at baseline, and 30 and 60 days post-treatment using a standard visual analogue scale. At 30 days post-injection, the mean pain score in all treatment groups was reduced compared with baseline in both studies, although the difference between treatment groups was not significant at this time in either study. However, by 60 days post-injection, the mean pain score has continued to fall in the BTX-A treatment groups, compared with a waning of the steroid therapeutic activity in the controls. The net effect was a highly significant difference between the two treatments in both the MPS ( P < 0.0001) and TH ( P < 0.0005) studies. No major adverse events were reported. In conclusion, BTX-A produces a more prolonged pain relief than methylprednisolone in patients suffering from MPS or TH.     

Botulinum toxin A in functional popliteal entrapment syndrome: a new approach to a difficult diagnosis

Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle–brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.     

A型肉毒毒素治疗难治性三叉神经痛临床观察

目的：评价A型肉毒毒素（BTX-A）治疗难治性三叉神经痛的疗效。方法：选取难治性三叉神经痛患者6例,其中原发性5例,继发性1例。采用视觉模拟评分（VAS）于局部多点注射BTX-A,予治疗前及治疗后2周、2个月和6个月时进行疼痛测评。结果：VAS评分：BTX-A治疗前为（8.86±0.75）分;BTX-A注射后2周和2个月分别降至（1.00±1.26）分和（2.00±2.45）分,与治疗前比,差异均有统计学意义（P〈0.05）;6个月时为（5.33±2.16）分,与治疗前比,差异仍有统计学意义（P〈0.05）。6例患者均无明显并发症出现。结论：BTX-A注射治疗难治性三叉神经痛是一种安全有效的新疗法。     

Predictable variables for short- and long-term botulinum toxin treatment response in patients with cervical dystonia

We retrospectively evaluated 118 patients with cervical dystonia (CD) treated with botulinum toxin type A (BTX-A) for the following variables: gender, age at evaluation, age at symptom onset, disease duration, presence of head/neck pain and/or tremor, pattern of head deviation, disease progression (spreading of symptoms), etiology (primary vs. secondary), pretreatment with oral medication, and Tsui score. We investigated whether these parameters could predict the clinical outcome in a short- (<30 days) and long-term basis. On short-term treatment, there were no clinically significant differences between BTX-A responsive and non-responsive patients. On long-term treatment, however, intake of oral medication previously to BTX-A injection and higher Tsui scores were predictors of favorable response. These results suggest that the greater CD severity the more likely patients will respond to BTX-A.     

Pharmacological treatments of neuropathic pain: The latest recommendations

We provide an up-to-date review of the pharmacological treatment of neuropathic pain with emphasis on the latest evidence-based recommendations for its pharmacological treatment. Drugs proposed as first line include tricyclic antidepressants (particularly amitriptyline), serotonin–norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin and gabapentin. Second line treatments include lidocaine plasters and capsaicin high concentration patches for peripheral neuropathic pain only, and tramadol. Third line treatments include strong opioids and botulinum toxin A (for peripheral neuropathic pain). Perspectives include the development of new compounds and a more personalized therapeutic approach, which is made possible by recent progress in the assessment and understanding of neuropathic pain.     

Treatment of chronic limb spasticity with botulinum toxin A.

The purpose of this open study was to find out whether botulinum toxin A (BTX-A) relieves the signs and symptoms of chronic limb spasticity. The study comprised 40 patients, aged 12-82 years, with moderate to severe spasticity of the upper (13) or lower limbs (27) refractory to conventional physical and medical treatments. Outcome measures were clinical and blinded videotape assessments of spasticity and motor function. Electromyography guided BTX-A injections were given in one or two sessions at total doses averaging 175 U in the upper limb (range 70-270 U) and 221 U in the lower limb (range 100-500 U). Thirty four patients (85%) derived worthwhile benefit, with improved limb posture and increased range of passive motion in 31, pain reduction in 28 of 31 with pain, and improved function in 16. Side effects were limited to local and usually mild discomfort from the injections (19), symptomatic local weakness (one), and local infection (one). Preliminary experience indicates that BTX-A is a promising adjunctive treatment for selected patients with spasticity.     

Botulinum toxin A in the treatment of trigeminal neuralgia

Aims: The aims of this study were to investigate the clinical effects and safety of botulinum toxin A (BTX-A) in treating trigeminal neuralgia and its influences on accompanied depression, anxiety, sleep disorders, and quality of life. Methods and Material: Eighty-seven patients with one-branch classical trigeminal neuralgia were injected with BTX-A in the pain area. The visual analogic scale score, sleep interference score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, and side effects were assessed at 1 week prior to and 8 weeks after treatment, respectively. Results: The effective rates after 1, 2, 4, and 8 weeks of treatment were 48.28%, 66.67%, 78.16%, and 80.46%, respectively. The effective rates of anxiety and depression were 90.32% and 96.77%, respectively. When compared to that before treatment, the quality of life was significantly better in terms of role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health (all P < 0.01), while physical function was not significantly improved (P = 0.317). Conclusion: BTX-A treatment can significantly relieve the pain in trigeminal neuralgia patients; improve anxiety, depression, and sleep; and increase the quality of life. BTX-A treatment is a safe and effective method to treat classical trigeminal neuralgia.     

Factors affecting the health-related quality of life of patients with cervical dystonia and the impact of botulinum toxin type A injections

The purpose of this study was to analyze the health-related quality of life (HRQL) of patients with cervical dystonia (CD) and the impact of botulinum toxin A (BTX-A) therapy in these patients. The authors recruited 101 patients with CD, all previously treated with BTX-A. Both before and 4 weeks after injection of BTX-A the patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a Visual Analogue Scale for pain (VAS: 0-100%), the Short Form 36 health survey questionnaire (SF-36), and the Montgomery-Asberg Depression Rating Scale (MADRS). A control group of 84 healthy volunteers was also evaluated. The patients? baseline SF-36 scores were worse in all the domains when compared with those of the controls. Depression was found in 47.5% of the patients. Improvements were noticed 4 weeks after the single BTX-A injections in all the SF-36 domains, and in the VAS, TWSTRS and MADRS scores. The TWSTRS results did not correlate with any of the SF-36 subscores. Stepwise backward regression analysis revealed depression as the main predictor of poor HRQL, as well as female sex, poor financial situation, and living alone. On contrary, longer treatment with BTX-A was associated with better scores. Cervical dystonia has a marked impact on HRQL and treatment with BTX-A injections has a beneficial effect, seen both in objective and in subjective measures. Depression in CD patients is a main predictor of worse HRQL.     

The botulinum toxins in the treatment of cervical dystonia

The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of toxins, botulinum toxin type A (BTX-A) and botulinum toxin type B (BTX-B), have each been studied in large multicenter trials in subjects with CD. A study of BTX-A demonstrated improvement of 5.15 to 10.65 degrees in head position using the Cervical Dystonia Severity Scale (CDSS) in those treated with BTX-A (trade name BOTOX) compared with placebo. A study in patients who continued to respond to BTX-A and a similarly designed study in patients who were resistant to BTX-A demonstrated statistical improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in those treated with BTX-B (evaluated as NeuroBloc) compared with placebo. The potential availability of both forms of toxin will allow physicians to offer further treatment options to patients with CD.     

Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure

One of the main goals when treating spasticity is to relieve pain and improve function. Intramuscular injection of botulinum toxin type A (BTX-A) has gained widespread acceptance in the treatment of spastic cerebral palsy. Several studies have clearly shown the short-term functional benefit of BTX-A treatment. Information is limited, however, on the efficacy of medium and long-term regimens, using repeated injection of BTX-A. The aim of the present open-label, prospective study was to evaluate functional outcome in children with spastic cerebral palsy after 1 year of treatment with BTX-A, using the Gross Motor Function Measure (GMFM) as a validated outcome measure. Patients ( n =25, age 1.5–15.5 years) were treated with BTX-A for adductor spasm ( n =12) or pes equinus ( n =13). The local effect was evaluated using passive range of motion and modified Ashworth Scale. Apart from a significant improvement in joint mobility and reduction of spasticity compared to pretreatment values ( P  < 0.01), we demonstrated a significant improvement of gross motor function after 12 months of treatment, with a median gain of 6% in total and goal scores ( P  < 0.001). An increase in GMFM scores was particularly evident in younger and moderately impaired children (Gross Motor Function Classification System level III). Whether the observed improvement in gross motor function in children with cerebral palsy is specifically related to therapy with BTX-A or represents at least in part the natural course of motor development still needs clarification.     

Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents' view of functional outcome

Botulinum toxin type A (BTX-A) has been used successfully to manage spasticity in children with cerebral palsy. Little has been done to evaluate treatment outcome and satisfaction from the patients' and parents' points of view. The aim of this study was to investigate the parents' perceptions of the benefits of BTX-A on movement disorders in children with cerebral palsy. Twenty-six children with adductor spasticity were enrolled into an open-label, prospective study. Patients received intramuscular injections of BTX-A, and assessments of joint mobility (passive range of motion), degree of spasticity (Modified Ashworth Scale) and functional benefit (Gross Motor Function Measure) were made before and 12–18 weeks after treatment. Parents' assessment of treatment outcomes were evaluated using a standardised questionnaire. BTX-A was shown to be effective in reducing muscular hyperactivity and functional limitations. Parents' satisfaction with the treatment outcome was high. For non-ambulatory patients, the reported benefits included facilitation of daily care, ease of positioning and reduction of pain. For patients who were disabled to a lesser extent, improvements in gait and posture included sitting with improved comfort, standing for longer periods of time and/or walking longer distances. The parents' responses supported the impressions of the therapists, demonstrating that BTX-A produced beneficial effects on daily activities, according to both objective measures and parents' observation.