1. Botulinum Toxin Type A (Botox): Aetna considers botulinum toxin type A (Botox) medically necessary for any of the following conditions:

   1. Strabismus, including gaze palsies accompanying diseases, such as:

      • Neuromyelitis optica;

      • Schilder’s disease.

      Note: Strabismus repair is considered cosmetic in adults with uncorrected congenital strabismus and no binocular fusion.

   2. Blepharospasm, characterized by intermittent or sustained closure of the eyelids caused by involuntary contractions of the orbicularis oculi muscle.
   3. Post-facial (7th cranial) nerve palsy synkinesis (hemifacial spasms), characterized by sudden, unilateral, synchronous contractions of muscles innervated by the facial nerve.
   4. Laryngeal spasm.

   5. Cervical dystonia (spasmodic torticollis) of moderate or greater severity when all of the following criteria are met:

      1. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles); and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and

      4. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures, or other neuromuscular disorders.  

   6. Focal dystonias, including:

      1. Lingual dystonia;
      2. Adductor laryngeal dystonia;
      3. Jaw-closing oromandibular dystonia, characterized by dystonic movements involving the jaw, tongue, and lower facial muscles;
      4. Hand dystonia (i.e., organic writers cramp);
      5. Symptomatic torsion dystonia;

      6. Focal dystonias in corticobasilar degeneration.

   7. Limb spasticity, including:

      1. Hereditary spastic paraplegia;
      2. Limb spasticity due to multiple sclerosis;
      3. Limb spasticity due to other demyelinating diseases of the central nervous system (including adductor spasticity and pain control in children undergoing adductor-lengthening surgery as well as children with upper extremity spasticity);
      4. Spastic hemiplegia, such as due to stroke or brain injury;

      5. Equinus varus deformity in children with cerebral palsy. 

   8. Esophageal achalasia, for individuals who have any of the following:

      1. Have failed conventional therapy; or
      2. Are at high risk of complications of pneumatic dilation or surgical myotomy; or
      3. Have failed a prior myotomy or dilation; or
      4. Have had a previous dilation-induced perforation; or

      5. Have an epiphrenic diverticulum or hiatal hernia, both of which increase the risk of dilation-induced perforation.

   9. Chronic anal fissure unresponsive to conservative therapeutic measures (e.g., nitroglycerin ointment).

   10. Intractable, disabling focal primary hyperhydrosis, when all of the following are met:

       1. Topical aluminum chloride or other extra-strength antiperspirants are ineffective or result in a severe rash; and
       2. Member is unresponsive or unable to tolerate pharmacotherapy prescribed for excessive sweating (e.g., anticholinergics, beta-blockers, or benzodiazepines) if sweating is episodic; and

       3. Significant disruption of professional and/or social life has occurred because of excessive sweating.

   11. Ptyalism / sialorrhea (excessive secretion of saliva, drooling) that is socially debilitating and refractory to pharmacotherapy (including anticholinergics).
   12. Facial myokymia and trismus associated with post-radiation myokymia.
   13. Hirschsprung’s disease with internal sphincter achalasia following endorectal pull-through. 
   14. Medically refractory upper extremity tremor that interferes with activities of daily living (ADLs).  (Additional botulinum toxin injections are considered medically necessary if response to a trial of botulinum toxin enables ADLs or communication.)
   15. Detrusor-sphincter dyssynergia after spinal cord injury.
   16. Neurogenic detrusor overactivity. 

2. Botulinum Toxin Type B (Myobloc): Aetna considers botulinum toxin type B (Myobloc) medically necessary for the treatment of any of the following conditions:

   1. Individuals with cervical dystonia (spasmodic torticollis) of moderate or greater severity when the following criteria are met:

      1. There are clonic and/or tonic involuntary contractions of multiple neck muscles (e.g., sternocleidomastoid, splenius, trapezius and/or posterior cervical muscles); and
      2. There is sustained head torsion and/or tilt with limited range of motion in the neck; and
      3. The duration of the condition is greater than 6 months; and

      4. Alternative causes of the member’s symptoms have been considered and ruled out, including chronic neuroleptic treatment, contractures; or other neuromuscular disorders.

   2. Ptyalism/sialorrhea (excessive secretion of saliva, drooling) that is socially debilitating and refractory to pharmacotherapy (including anticholinergics).

   3. Intractable, disabling focal primary hyperhydrosis, when all of the following are met:

      1. Topical aluminum chloride or other extra-strength antiperspirants are ineffective or result in a severe rash; and
      2. Member is unresponsive or unable to tolerate pharmacotherapy prescribed for excessive sweating (e.g., anticholinergics, beta-blockers, or benzodiazepines) if sweating is episodic; and

      3. Significant disruption of professional and/or social life has occurred because of excessive sweating.

3. Experimental and Investigational Indications: Aetna considers botulinum toxin (type A or type B) experimental and investigational for all other indications, including any of the following conditions:

   1. Headache, including cervicogenic, cluster, migraine or tension-type or chronic daily  headache; or
   2. Fibromyositis; or
   3. Painful cramps; or
   4. Anal sphincter dysfunction; or
   5. Bell’s palsy; or
   6. Stuttering; or
   7. Irritable colon; or
   8. Biliary dyskinesia; or
   9. Temporomandibular joint disorders; or
   10. Chronic low back pain; or
   11. Chronic neck pain; or
   12. Gastroparesis; or
   13. Clubfoot; or
   14. Cranial/facial pain of unknown etiology; or
   15. Piriformis syndrome; or
   16. Pylorospasm; or
   17. Chronic constipation; or
   18. Benign prostatic hypertrophy; or
   19. Interstitial cystitis; or
   20. Soto's syndrome; or
   21. Knee flexion contracture; or
   22. Tinnitus; or
   23. Lateral epicondylitis (tennis elbow); or
   24. Stiff person syndrome; or
   25. Myofascial pain; or
   26. Chronic pelvic pain; or
   27. Graves ophthalmopathy; or
   28. Palatal myoclonus; or
   29. Post-herpetic neuralgia; or
   30. Schwalbe-Ziehen-Oppenheim disease; or
   31. Tourette's syndrome; or
   32. Detrusor-sphincter dyssynergia asscociated with multiple sclerosis; or
   33. Focal lower limb dystonia; or
   34. Gustatory sweating; or
   35. Head and voice tremor; or 
   36. Hyper-lacrimation; or
   37. Motor tics; or
   38. Phonic tics; or
   39. Brachial plexus injury; or
   40. Restless legs syndrome. 

4. Cosmetic Indications: Aetna considers botulinum toxin cosmetic for the following indications:

   1. Wrinkles, frown lines; or
   2. Aging neck; or

   3. Blepharoplasty (eyelid lift).

5. Neutralizing Antibodies to Botulinum Toxin: Aetna considers testing for neutralizing antibodies to botulinum toxin experimental and investigational.

See also CPB 031 - Cosmetic Surgery, CPB 79 - Benign Prostatic Hypertrophy (BPH) Treatments, CPB 084 - Ptosis Surgery, and CPB 725 - Post-Herpetic Neuralgia.

Local injections of botulinum toxin type A (Botox) have been approved by the FDA for the treatment of strabismus, essential blepharospasm, and hemifacial spasm.  In patients with congenital strabismus who have compromised or absent binocular vision, treatment is cosmetic as ocular realignment is not capable of restoring binocular vision.

Clinical studies indicate that Botox can also provide symptomatic relief in a variety of other conditions characterized by involuntary spasm of certain muscle groups, notably in cervical dystonia (spasmodic torticollis) and spasmodic dysphonia.  Ninety percent of spasmodic torticollis patients show some improvement of pain relief, head position, and disability, and Botox is now the treatment of choice for this condition.  Botox has been shown to result in normal or near normal voice in patients with adductor type (strained or strangled voice) laryngeal dystonia and to be of considerable benefit in patients with abductor type (breathy, whispery voice) laryngeal dystonia.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that while botulinum neurotoxin is probably effective for the treatment of adductor type laryngeal dystonia, there is insufficient evidence to support a conclusion of effectiveness for botulinum neurotoxin in patients with abductor type of laryngeal dystonia. The assessment also stated that while many clinicians utilize electromyographic targeting for laryngeal injections, the utility of this technique is not established in comparative trials.

Botox has been evaluated in various spastic disorders.  Botox can be used to reduce spasticity or excessive muscular contractions to relieve pain; to assist in posturing and walking; to allow better range of motion; to permit better physical therapy; and to reduce severe spasm in order to provide adequate perineal hygiene.  It has been shown to improve gait patterns in patients with cerebral palsy with progressive dynamic equinovarus or equinovalgus foot deformities.  Treatment of children with cerebral palsy during the early years when functional skills in walking are being developed improves the outcome and may help to avoid surgery for contracture and bony torsion. In multiple sclerosis, Botox can relieve contractions of thigh adductors that interfere with sitting, positioning, cleaning, and urethral catheterization.

Moore et al (2008) stated that the controlled evidence favoring Botox in the treatment for spasticity in cerebral palsy (CP) is based on short-term studies.  These researchers conducted a randomized, double-blind, placebo-controlled, parallel-group study of Botox for leg spasticity in 64 children with CP.  For 2 years, the children received trial injections of up to 30 mu/kg every 3 months if clinically indicated.  For the primary endpoints of Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Index (PEDI) scaled scores at 2 years (trough rather than peak effect), there were no differences between the mean change scores of each group.  For the GMFM total score, the 95 % CI of -4.81 to 1.90 excluded a 5-point difference in either direction, and a 2-point benefit with 95 % confidence.  There were no differences in adverse events.  The authors concluded that there was no evidence of cumulative or persisting benefit from repeated Botox at the injection cycle troughs at 1 year or 2 years.  The dose was not enough to change spasticity measures and thus GMFM in this heterogeneous group.  Ceiling effects in GMFM and PEDI may have reduced responsiveness.  This finding does not deny the value, individually, of single injection cycles or prove that repeating them is unhelpful.  In this regard, Botox therapy can be viewed in the same light as other temporary measures to relieve spasticity, such as oral or intra-thecal agents: there is no evidence of continuing benefit if the treatment ceases.  The study provided long-term, fully controlled adverse event data and has not revealed any long-term adverse effects.

Treatment with Botox has been shown to be safe and effective in the jaw-closing variant of oromandibular dystonia.  Injections of Botox into the masseter, temporalis, and internal pterygoid muscles result in reduction in the oromandibular and lingual spasms and an improvement in chewing and speech.  Symptoms are reduced in about 70 percent of patients, and treatment may prevent dental complications and temporomandibular joint dysfunction.  Treatment with Botox has been shown to be safe and effective for writer's cramp (local and segmental limb dystonia). This dystonia can be incapacitating and has been exceptionally resistant to treatment with oral medications.  Other occupational cramps, such as musician’s cramp, respond less well to injections as they require very sophisticated neuromuscular performance.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Naumann et al, 2008) stated that while many clinicians advocate electromyography or nerve stimulation guidance to optimize needle localization for injection, further data are needed to establish this recommendation.

Botox has also been shown to be effective in the treatment of achalasia.  Two thirds of patients with this condition respond within six months and effectiveness lasts on an average of a little over one year for an initial treatment, although shorter and longer duration have been reported.  There is some question whether Botox treatments are as good as or better than conventional therapy, pneumatic dilation, or myotomy.

Botox has been shown to be a promising alternative to sphincterotomy in patients with chronic anal fissures.

Some autonomic disorders resulting in hypersecretion of glands such as hyperhydrosis and sialism (ptyalism) respond well to Botox.

Initial reports on the use of Botox in the treatment of migraine headache are promising; however, limitations of the placebo-controlled randomized trials include the lack of a dose-response curve and the lack of a scientific explanation for the treatment effect.  These initial results require further validation to confirm the effectiveness of Botox in migraine prophylaxis.

Although there is a single randomized controlled single-center study that found benefits of botulinum toxin in the treatment of migraine, no firm conclusions can be drawn from this study because of the marginal statistical significance of the results, the lack of an expected dose-response relationship, and the lack of a valid scientific explanation for treatment effects.  In a randomized double-blind, vehicle-controlled study, 123 subjects with a history of two to eight moderate-to-severe migraine attacks per month were randomized to receive single administration of placebo vehicle or botulinum toxin A 25 or 75 U, injected into multiple sites of pericranial muscles at the same visit.  Study subjects were assessed at 1, 2 and 3 months.  For the 25-U botulinum toxin group, reduction in migraine frequency barely reached statistical significance (p = 0.46) at the 3-month assessment, but did not reach statistical significance at the 1- or 2-month assessments.  The 75-U botulinum toxin group had no statistically significant reduction in migraine frequency at any assessment (Silberstein, et al., 2000).  A commentary on this study (Bandolier, 2001) noted that, because of significant flaws in the design of the study by Silberstein, et al., "[t]he trial would score 2 out of a possible 5 points on a common quality scoring scale in which trials scoring 2 or less may be subject to bias."  The commentary also noted the marginal statistical significance of results and the lack of an expected dose-response relationship.  "The simple fact is that with one or two patients giving different responses, this would have been declared a negative trial.  It does not inspire confidence, especially as this is the only randomised controlled trial for this intervention in this indication and the quality of reporting allows for the possibility of bias, as well as it being financed by the manufacturer."  These results need to be replicated in a longer-term, multicenter randomized clinical study before conclusions about the effectiveness of botulinum toxin in migraine can be drawn.

A subsequent randomized controlled clinical trial found no benefit to botulinum toxin type A in preventing migraine headaches (Evers, et al., 2004).  Researchers evaluated 60 migraine patients for a three-month period; participants received injections of either a high or low dose of botulinum toxin or placebo in muscles in the neck and/or forehead.  During the course of the study, “migraine frequency was halved” for 30% of the participants in the botulinum toxin groups and for 25% of those in the placebo group.  Researchers also found that there were “no significant differences” among the three groups regarding the number of days participants had the migraine or the amount of drugs needed to treat the headaches.  The researchers concluded that their findings “did not support the hypothesis that [Botox] is [an] effective…treatment [for] migraines.”  Phase III clinical trials of botulinum toxin (Botox) for FDA approval of a migraine indication are ongoing.

In a phase II clinical trial (n = 702), Silberstein, et al. (2005) assessed the safety and effectiveness of three different doses of Botox as prophylactic treatment of chronic daily headache (CDH).  Eligible patients were injected with Botox at 225 U, 150 U, 75 U, or placebo and returned for additional masked treatments at day 90 and day 180.  Patients were assessed every 30 days for 9 months.  The primary efficacy end point was the mean change from baseline in the frequency of headache-free days at day 180 for the placebo non-responder group.  The primary efficacy end point was not met.  Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were observed in the placebo non-responder group treated with Botox at 225 U, 150 U, 75 U, or placebo, respectively (p = 0.44).  An a priori-defined analysis of headache frequency revealed that Botox at 225 U or 150 U had significantly greater least squares mean changes from baseline than placebo at day 240 (-8.4, -8.6, and -6.4, respectively; p = 0.03 analysis of covariance).  Only 27 of 702 patients (3.8 %) withdrew from the study because of adverse events, which generally were transient and mild to moderate.  These investigators concluded that although the primary efficacy end point was not met, all groups responded to treatment.  The 225 U and 150 U groups experienced a greater decrease in headache frequency than the placebo group at day 240.  The placebo response was higher than expected.  Botulinum toxin type A was safe and well tolerated.  The authors noted that further study of Botox prophylactic treatment of CDH appears warranted.  The findings of this study were in agreement with those of Mathews, et al. (2005).  A review in Clinical Evidence (Silver, 2005) concluded that botulinum toxin for chronic tension-type headache was “likely to be ineffective or harmful.”

An assessment on use of botulinum toxin in pain associated with neuromuscular disorders, prepared for the Minnesota Health Technology Advisory Committee (2001), concluded that there is insufficient evidence to support the use of botulinum toxin in the treatment of migraine.  A review of the literature on treatments for migraine concluded that "botulinum toxin A ha[s] recently been suggested to be effective [for treatment of migraine]; however, at present, there are insufficient rigorous and reliable controlled data on these drugs for them to be indicated for such use" (Krymchantowski, et al., 2002).  A structured evidence review by the BlueCross BlueShield Association Technology Evaluation Center (2002) concluded “The available evidence does not permit conclusions regarding the prophylactic or abortive effect of [botulinum toxin A] or any other botulinum toxin type on chronic primary headache syndromes”, including migraine, chronic tension, and cluster headache syndromes.  The BlueCross BlueShield Association Technology Evaluation Center reevaluated the use of botulinum toxin for primary headache disorders (BCBSA, 2004) and concluded that this does not meet the TEC criteria.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) stated that botulinum neurotoxin is probably ineffective in episodic migraine and chronic tension-type headache.  Also, there is currently no consistent evidence or strong evidence to allow drawing conclusions on the effectiveness of botulinum neurotoxin in chronic daily headache.  The assessment also noted that the evidence for botulinum neurotoxin in gustatory sweating is suboptimal.

Botox has been shown to reduce muscle tone and increase range of movement in upper extremity spasticity or in spastic foot drop after stroke.  However, whether this translates into functional improvement has yet to be substantiated.

The value of Botox in treating conditions other than those listed above is under investigation.

Unit dosing of botulinum toxin type A (Botox) and botulinum toxin type B (Myobloc) or other botulinum toxin serotypes are not interchangeable. According to the U.S. Food and Drug Administration (FDA), "[u]nits of biologic activity of Botox cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other assay method."

If concomitant neuromuscular disorders, such as myasthenia gravis and certain myopathies exist, Botox may be harmful.  Thus, diagnosis is crucial before undertaking botulinum toxin type A injections.

Botox is not indicated in patients receiving aminoglycosides, which may interfere with neuromuscular transmission.

Botulinum toxin type B (Myobloc) was approved by the Food and Drug Administration for symptomatic treatment of patients with cervical dystonia (i.e., spasmodic torticollis) to reduce the severity of abnormal head position and neck associated with cervical dystonia.  Botulinum toxin type B is antigenically distinct and has a different mechanism of action than botulinum toxin type A. Although the U.S. Pharmacopeial Convention (2004) has stated that treatment of spasticity caused by stroke or brain injury is an accepted off-label indication for botulinum toxin type B, based in part on the positive results of an uncontrolled prospective study of botulinum toxin type B (Bradshear, et al., 2003), a subsequently published randomized controlled clinical trial by the same investigator group failed to demonstrate a statistically significant effect of botulinum toxin type B (Bradshear, et al., 2004), perhaps due to the small size of the study.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of spasticity (Simpson et al, 2008a) recommended botulinum neurotoxin as a treatment option to reduce muscle tone and improve passive function in adults with spasticity.  The assessment also recommended botulinum neurotoxin for equinus varus deformity in children with cerebral palsy, adductor spasticity and pain control in children undergoing adductor-lengthening surgery, and children with upper extremity spasticity.  Furthermore, the assessment stated that there is insufficient evidence to recommend an optimum technique for muscle localization at the time of injection.  It noted that further studies on injection methodology including the use of electromyographic guidance, ultrasonography, and electrical stimulation are needed to optimize treatment technique.

Both Botox and Myobloc are neurotoxins produced by fermentation of the bacterium Clostridium botulinum.  They interfere with neuromuscular transmission, temporarily paralyzing the affected muscle. Clostridium botulinum is a gram-positive, spore-forming obligate anaerobe that is widely distributed in nature and frequently found in soil, marine environments, and agricultural products. Each strain produces one of eight antigenically distinct toxins designated A through H.  Human disease is caused by types A, B, E, and (rarely) F. After repeated use of high doses, antibodies can develop in some individuals, making further treatment ineffective indefinitely. Because of Myobloc’s unique mechanism of action and antigenicity, Myobloc may be effective in patients with cervical dystonia who have developed antibodies to or who have not responded to Botox.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that the role of electromyography has not been established for cervical dystonia.  It also stated that while a few patients in one Class II study suggested that botulinum neurotoxin may be effective for lower extremity dystonia, the data are inadequate to provide a recommendation.

A randomized controlled clinical trial (n = 16) demonstrated significant reductions in sialorrhea without compromising dysphagia in persons with Parkinson’s disease and problematic sialorrhea (Ondo, et al., 2004).

Baumann, et al. (2005) reported on the results of a pilot study of botulinum toxin type B for axillary hyperhidrosis. Twenty patients were randomly assigned to botulinum toxin type B (n = 15) or to placebo injection (n = 5). The investigators explained that this trial was initially conceived as a placebo-controlled study; however, owing to the insufficient size of the placebo group (one placebo subject failed to return for follow up and one responded to placebo injections), the placebo arm of this trial was dropped during data analysis. The investigators reported a significant difference in subject and physician assessed measures of treatment response at one month in the participants receiving Myobloc (botulinum toxin type B) injections. Duration of action ranged from 2.2 to 8.1 months (mean 5.0 months).

Nelson, et al. (2005) reported on the results of botulinum toxin type B injections in 13 patients with axillary hyperhidrosis. The investigators reported a significant reduction in hyperhidrosis at 4-week, 8-week, and 12-week follow-up compared to baseline.

Dressler, et al. (2002) reported on a self-controlled study comparing the efficacy of botulinum toxin A and botulinum toxin type B in persons with bilateral axillary hyperhidrosis. Nineteen subjects with axillary hyperhidrosis received botulinum toxin type B in one axilla and botulinum toxin type A in the other axilla. The investigators reported that all subjects except one reported excellent improvement in hyperhidrosis in both axillae, and that none of the subjects had residual hyperhidrosis on clinical examination. The duration of effect was not statistically significantly different between botulinum toxin type A and botulinum toxin type B.

Baumann and Halem (2004) reported on a randomized controlled clinical study of botulinum toxin B in palmar hyperhidrosis. Twenty persons with hyperhidrosis were randomly assigned to injection with botulinum toxin type B (n = 15) or placebo (n = 5). The investigators reported a significant difference in treatment response (as determined by participant assessment) between the subjects injected with botulinum toxin B and placebo. The duration of cessation of palmar sweating ranged from 2.3 months to 4.9 months, with a mean duration of 3.8 months. The investigators reported, however, that 18 of 20 participants reported dry mouth/throat, 60 percent reported indigestion/heartburn, 60 percent reported muscle weakness, and 50 percent reported decreased grip strength. The investigators concluded that botulinum toxin B was safe and effective in treating bilateral palmar hyperhidrosis. However, the side effect profile was substantial.

A number of studies have evaluated the effectiveness of botulinum toxin type A in the treatment of back and neck pain, and the manufacturer is planning on pursuing FDA approval of botulinum toxin for this indication.  Two small double blind studies (Foster, et al., 2000; Foster, et al., 2001) of botulinum toxin for back pain have been published, one involving 28 patients, and another involving 31 patients.  However, both of these studies were small and from a single investigator, raising questions about the generalization of the findings.  In addition, both of the studies were short term, with no comparisons to other treatments for back pain.  Thus, there is currently insufficient scientific evidence of the effectiveness of botulinum toxin in the treatment of back pain.

According to a systematic review of the evidence for botulinum toxin for essential tremor (Ferreira & Sampaio, 2003), there is evidence of short-term reduction of tremor but no consistent improvement in disability and function.  The review noted that botulinum toxin injections cause hand weakness, resulting in a "trade off" between benefits and harms.  The review concluded that "RCTs [randomized controlled clinical trials] comparing botulinum A toxin-haemagglutinin complex versus placebo found short term improvement of clinical rating scales, but no consistent improvement of motor task performance or functional disability.  Hand weakness, which is dose dependent and transient, is a frequent adverse effect."  The American Academy of Neurology (Zesiewicz, et al,, 2005) has stated that botulinum toxin A injections for limb, head, and voice tremor associated with essential tremor may be considered in medically refractory cases.  This recommendation was categorized as Level C, given the limited strength of the available evidence.  The American Academy of Neurology concluded that “[t]he effect of BTX A [botulinum toxin A] on limb tremor in ET [essential tremor] is modest and is associated with dose-dependent hand weakness.  BTX A may reduce head tremor and voice tremor associated with ET, but data are limited. When used to treat voice tremor, BTX A may cause breathiness, hoarseness, and swallowing difficulties.” 

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that botulinum neurotoxin should be considered a treatment option for essential hand tremor in those patients who fail treatment with oral agents.  On the other hand, there is insufficient evidence to draw a conclusion on the use of botulinum neurotoxin in the treatment of head and voice tremor.

The evidence of botulinum toxin in the treatment of piriformis syndrome is limited to a small, controlled short-term study and a small pilot cross-over study reporting on the impact of botulinum toxin on pain, but not on disability and function (Fishman, et al., 2002; Childers, et al., 2002).  In addition, the placebo-controlled study had a significant drop-out rate.  The existence of piriformis syndrome as a clinical entity is controversial (NHS, 2002).

Several studies have tested the effects of pyloric injection of botulinum toxin in patients with diabetic and idiopathic gastroparesis (Parkman, et al., 2004).  These studies have all been unblinded with small numbers of patients from single centers and have observed mild improvements in gastric emptying and modest reductions in symptoms for several months.  Moreover, the American Gastroenterological Association (2004) has concluded that double-blind controlled studies are needed to support the efficacy of this treatment (Parkman, et al., 2004).

Bromer et al (2005) reviewed the use of BTX-A in the treatment of patients with gastroparesis.  Response was defined as improvement or resolution of the patient's major symptom and/or two minor symptoms for 4 weeks.  Of 115 patients treated, 63 patients met the study criteria.  There were 53 women, 10 men, mean age 42 years.  Most patients (56 %) had idiopathic gastroparesis.  Twenty-seven of 63 (43 %) patients experienced a symptomatic response to treatment.  By stepwise logistic regression, male gender was associated with response to treatment (OR 3.27: 95 % CI[1.31, 8.13], p = 0.01).  Vomiting as a major symptom was associated with a lack of response (OR 0.16: 95 % CI[0.04, 0.67], p = 0.01).  Despite the association of male gender with response, the mean duration of response for those patients responding, with a minimum of 3 months' follow-up was 4.9 months (+/- 2.7 months) for women and 3.5 months (+/- 0.71 months) for men (p = 0.59).  The corresponding medians and inter-quartile ranges (IQR) were 5 (IQR 3 - 6) for females and 3.5 (IQR 3 - 4) for males.  The authors concluded that of the patients, 43 % had a response to BTX treatment that lasted a mean of approximately 5 months.  Male gender was associated with a response to this therapy; however, durability of response was unrelated to gender.  Vomiting as a major symptom predicted no response.

The major drawbacks of this study were: (i) it was a retrospective study, (ii) the lack of a validated symptom questionnaire or a visual analog scale before for pre- and post-injection estimation of improvement, (iii) subjects were not prescribed a standardized diet and/or medication regimen for gastroparesis following BTX injection, (iv) a high number of patients (n = 27) were lost to follow-up that may have influenced the response rate, (v) issues with experimental design -- selection bias as well as recall bias.

Ezzeddine et al (2002) reported their findings of pyloric injection of BTX for the treatment of diabetic gastroparesis.  A total of 6 patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study underwent upper endoscopy during which 100 units of BTX were injected into the pyloric sphincter.  Gastric emptying studies were obtained at 48 hours and 6 weeks after injection.  Patients were questioned about symptoms of gastroparesis, and a symptom score was obtained at baseline and at 2 weeks and 6 weeks after injection.  There was a mean improvement in the subjective symptom score at 2 weeks of 55 % (range of 14 to 80 %).  This improvement was maintained at 6 weeks.  There was a 52 % improvement in gastric emptying at 2 and 6 weeks.  The authors concluded that pyloric injection of BTX can improve symptoms and gastric emptying in patients with diabetic gastroparesis.  They stated that further evaluation of pyloric injection of BTX as a treatment for diabetic gastroparesis is warranted.

Gupta and Rao (2002) noted that well-designed, prospective, double-blinded, placebo-controlled studies are needed to establish the role of BTX in selected patients with diabetic gastroparesis.

Yeh and Triadafilopoulos (2006) reviewed injection therapies for non-bleeding disorders of the gastrointestinal tract.  With regards to the use of BTX for the treatment of gastroparesis, the authors noted that data from a randomized, sham-controlled study are needed to draw firm conclusion on the utility of this treatment.

Reddymasu et al (2007) examined the use of endoscopic pyloric injection of BTX in the treatment of patients with post vagotomy gastroparesis (n = 11).  The authors concluded that this approach appears to be safe; but randomized trials are needed.

Friedenberg and colleagues (2008) noted that observational data suggest that intra-pyloric injection of botox reduces symptoms and accelerates gastric emptying in idiopathic and diabetic gastroparesis. These researchers examined if Botox would improve symptoms to a significantly greater extent than placebo. An additional objective was to ascertain if there is an acceleration of gastric emptying after injection. A single-institution, randomized, double-blind, placebo-controlled study was carried out. Eligible patients had a Gastroparesis Cardinal Symptom Index score greater than or equal to 27 with randomization to intra-pyloric botulinum toxin, 200 units, or saline placebo. Re-assessment of symptoms and repeat gastric emptying scan at 1-month follow-up were done. A total of 32 patients were randomized to botulinum toxin (n = 16) and placebo (n = 16). At 1-month follow-up, 37.5 % randomized to Botox and 56.3 % randomized to placebo achieved improvement as defined by this study. There were no identifiable clinical predictors of response. The Botox group reported improvement in gastric emptying; however, this was not superior to placebo. No serious adverse events were attributable to Botox. The authors concluded that intra-pyloric injection of Botox improves gastric emptying in patients with gastroparesis, although this benefit was not superior to placebo at 1 month. Also, in comparison to placebo, symptoms do not improve significantly by 1 month after injection. These investigators stated that they could not recommend Botox for widespread use in the treatment of delayed gastric emptying until more data are available.

Lembo and Camilleri (2003) do not recommend botulinum injection for the management of patients with chronic constipation.  Furthermore, Talley (2004) stated that a novel approach for the management of chronic constipation is injection of Botox into the puborectalis muscle of patients with pelvic floor dysfunction.  However, there is insufficient evidence to support the effectiveness of this approach.

Botulinum toxin is currently being studied for the management of patients with lower urinary tract dysfunctions such as detrusor-sphincter dyssynergia and detrusor overactivity.  Botulinum toxin is injected into the external urethral sphincter to treat detrusor sphincter dyssynergia, while intra-detrusal injections of botulinum toxin is employed in treating detrusor overactivity and symptoms of the overactive bladder (OAB).  In a single treatment, randomized, placebo-controlled study (n = 59), Schurch, et al., (2005) found that intramuscular injections of Botox into the detrusor can provide rapid, well-tolerated, clinically significant decreases in the signs and symptoms of urinary incontinence caused by neurogenic detrusor overactivity during a 24-week study period.  These researchers noted that Botox is a potential candidate for the management of neurogenic urinary incontinence.

In a randomized, double-blind, placebo-controlled crossover clinical trial, Ghei and colleagues (2005) examined the safety and effectiveness of botulinum toxin B for the treatment of OAB.  A total of 20 patients 18 to 80 years old with detrusor overactivity unresponsive to oral anti-muscarinic agents participated in the study.  They were injected with either placebo (20 ml normal saline) or botulinum toxin B (5,000 IU diluted up to 20 ml) intravesically in a day case setting.  After 6 weeks the treatments were crossed over without washout in line with previous findings.  The primary outcome was the paired difference in change in average voided volumes.  Frequency, incontinence episodes and paired differences in quality of life measured by the King's Health Questionnaire were the secondary outcome measures.  Little carryover was noted in the second arm placebo and the placebo data from both arms were included in analysis.  There were clinically statistically significant paired differences in the change in average voided volume, urinary frequency and episodes of incontinence between active treatment and placebo.  There were similarly significant paired differences in the change in quality of life affecting 5 domains of the King's Health Questionnaire.  These investigators concluded that the findings of this study provided evidence of the efficacy of botulinum toxin B in the treatment of OAB.  Autonomic side effects were observed in 4 patients.  Moreover, they noted that the short duration of action will presumably limit the use to patients who have experienced tachyphylaxis with Botox.

In an editorial that accompanied the study by Ghei, et al., Chancellor (2005) stated that “one undesirable feature of the study was that the hypothesis was tested on a mixed population of patients (patients with mixed etiologies of detrusor overactivity, 3 neurogenic and 17 nonneurogenic with detrusor overactivity).  This limits the generalizability of the findings.  The authors made a strong argument why a crossover design was appropriate and their data were valid.  However, since almost all studies have shown that botulinum toxin A has a duration of efficacy of approximately 6 months, most experts in the field would still question the merit of a crossover at 6 weeks as not all the patients returned to pre-injection clinical and urodynamic values done at 6 weeks.  Most experts would submit that a washout period after the crossover may have been appropriate.  Since there are limited experiences with BTX-B in the bladder, assessment of duration of response would be valuable”.  Chancellor was surprised how short the duration of effectiveness attained by BTX-B was.  Moreover, it is unclear how useful BTX-B will be in urology since there are suggestions that BTX-B has a more systemic effect that Botox.

In a multi-center, randomized, placebo-controlled trial (n = 86), Gallien, et al., (2005) assessed the safety and effectiveness of Botox in the treatment of detrusor sphincter dyssynergia in patients with multiple sclerosis (MS).  Individuals with chronic urinary retention were included if they had post-voiding residual urine volume between 100 and 500 ml.  They received a single transperineal injection of either Botox (100 U) or placebo in the sphincter and also 5 mg slow release alfuzosin twice daily over 4 months.  Main endpoint was post-voiding residual urine volume assessed 1 month after injection.  Follow-up duration was 4 months.  The study was stopped after the 4th analysis (placebo = 41, Botox = 45).  At inclusion, there was no significant difference between groups whichever variable was considered.  Mean (standard deviation) post-voiding residual urine volume was 217 (96) and 220 (99) ml in placebo and Botox groups, respectively.  One month later, post-voiding residual urine volume was 206 (145) and 186 (158) ml (p = 0.45) in placebo and Botox groups, respectively.  However, compared to placebo, Botox significantly increased voiding volume (+54 %, p = 0.02) and reduced pre-micturition (-29 %, p = 0.02) and maximal (-21 %, p = 0.02) detrusor pressures.  Other secondary urodynamic endpoints and tolerance were similar in the two groups.  These investigators concluded that in MS patients with detrusor sphincter dyssynergia, a single injection of Botox (100 U) does not decrease post-voiding residual urine volume.  Also, De Laet and Wyndaele (2005) noted that generalized side effects after Botox injection for voiding disorders are rare but they can be very disabling for patients with spinal cord injury.  Although no long-term side effects are reported so far, urologists should be aware that these effects of Botox injections are unknown.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) reported that botulinum neurotoxin is safe and effective for the treatment of neurogenic detrusor overactivity in adults.  On the other hand, data on the use of botulinum neurotoxin for detrusor-sphincter dyssynergia (DSD) are conflicting.  Botulinum neurotoxin is probably safe and effective for the treatment of DSD in patients with spinal cord injury and should be considered for use in these patients.  However, it does not provide significant benefit for the treatment of DSD in patients with multiple sclerosis.

The role of botulinum toxin in the treatment of lower urinary tract dysfunctions has yet to be established.  Sahai, et al., (2005) stated that application of botulinum toxin in the lower urinary tract has produced promising results in treating lower urinary tract dysfunction, which needs further evaluation with randomized, placebo-controlled trials.  This is in agreement with the observations of Schurch and Corcos (2005) as well as Grise, et al., (2005).  Schurch and Corcos noted that Botox appears to be a reasonable alternative to surgery in the management of intractable OAB in children.  However, studies of the delivery method, site of injection, dose and long-term follow-up are needed to confirm the good safety profile/clinical benefit of this new, minimally invasive approach.  In a review on the use and mechanism of botulinum toxin in the treatment of OAB, Grise and colleagues stated that further studies remain necessary regarding the dosage of Botox, selection of patients, combination with anti-cholinergic treatment, as well as effects of repeated injections.

Chuang et al (2003) stated that botulinum toxin (BTX)-A treatment inhibits afferent-nerve-mediated bladder contraction.  This analgesic effect may expand the application of BTX in the localized genitourinary tract pain syndrome, such as interstitial cystitis and prostatodynia.  The authors concluded that application of BTX is a promising treatment for lower urinary tract dysfunction with profound basic and clinical implications.  Chancellor and Yoshimura (2004) noted that among the potentially effective new treatment modalities for interstitial cystitis currently under investigation are suplatast tosilate, resiniferatoxin, BTX, and gene therapy to modulate the pain response.

Kuo (2005) evaluated the clinical effectiveness of sub-urothelial injection of BTX-A in patients with chronic interstitial cystitis (n = 10).  Eight women and 2 men with chronic interstitial cystitis who had failed conventional treatments were enrolled in this study.  In 5 patients, 100 units of BTX-A was injected sub-urothelially into 20 sites, and an additional 100 units was injected into the trigone in the other 5 patients.  Therapeutic outcome including functional bladder capacity, number of daily urinations, bladder pain, and urodynamic changes were compared between baseline and 3 months after treatment.  In 2 patients bladder pain and urinary frequency were improved 3 months after treatment.  Mild difficulty in urination was reported by 7 patients.  Functional bladder capacity recorded in a voiding diary was significantly increased (155 +/- 26.3 versus. 77 +/- 27.1 ml, p < 0.001), and the frequency of daily urinations (18 +/- 7.7 versus. 24.2 +/- 10.3, p = 0.025) and the pain score (2.4 +/- 1.6 versus. 3.2 +/- 1.1, p = 0.003) were mildly but significantly reduced after treatment.  Only the cystometric capacity improved significantly (287 +/- 115 versus. 210 +/- 63.8 ml, p = 0.05) in urodynamic results.  Trigonal injection had no therapeutic effect on symptom or urodynamic improvement.  No adverse effect was reported.  The author concluded that the clinical result of sub-urothelial BTX-A injection was disappointing.  None of the patients was symptom-free and only a limited improvement in bladder capacity and pain score was achieved in 2 patients.

Toft and Nording (2006) reviewed the recently published literature on intravesical therapy strategies in painful bladder syndrome/interstitial cystitis.  Bladder irrigation with different agents has been used during years in an attempt to treat painful bladder syndrome/interstitial cystitis.  The 'traditional' agent for glycosaminoglycan substitution is hyaluronic acid.  Often used are heparin and dimethyl sulfoxide, the actions of which are not quite clear but supposedly on an anti-inflammatory basis.  Other agents for intravesical treatment are Bacillus Calmette-Guerin vaccine and BTX, and some recent studies have pointed to resiniferatoxin and RDP58.  The authors concluded that painful bladder syndrome/interstitial cystitis persists as a challenging syndrome in urology.  Intravesical instillation therapy has basically not changed during the last few years, although some studies have disconfirmed some regimens.  Intensive research may hopefully result in more effective treatments in the future.

Shah et al (2005) described the development of a flexion contracture in a patient with Parkinson's disease after total knee arthroplasty.  This contracture was successfully treated with manipulation under anesthesia and injections of BTX- A into the hamstring and gastrocnemius muscles, in conjunction with a static progressive extension orthosis and rigorous physical therapy.  This was a case study; and the clinical benefit of BTX, if any, is confounded by the multiple therapies used in this patient.

In a prospective, double-blinded study, Stidham et al (2005) assessed the potential benefit BTX-A in the treatment of tinnitus.  A total of 30 patients with tinnitus were randomly placed into 1 of 2 treatment arms.  Patients either received BTX-A (20 to 50 units) or saline injection at the first treatment, and the opposite treatment 4 months later.  Prospective data including tinnitus matching test, tinnitus handicap inventory (THI), tinnitus rating scale (TRS), and patient questionnaires were obtained over a 4-month period after each injection.  Twenty-six patients completed both injections and follow-up and were included in data analysis.  After BTX-A, subjective tinnitus changes included 7 patients improved, 3 worsened, and 16 unchanged.  Following placebo, 2 patients were improved, 7 worsened, and 17 unchanged.  Comparison of the treatment and placebo groups was statistically significant (p < 0.005) when including better, worse, and same effects.  A significant decrease in THI scores between pretreatment and 4 month post-BTX-A injection (p = 0.0422) was recorded.  None of the other comparisons of pre-treatment to 1 month, or pre-treatment to 4 months were significantly different.  This study found improvement in THI scores and patient subjective results after BTX- A injection compared with placebo, suggesting a possible benefit of BTX- A in tinnitus management.  The authors noted that larger studies need to be completed to further evaluate potential benefits of BTX- A in treatment of this difficult problem.

In a randomized, double-blind, placebo-controlled study (n = 60), Wong et al (2005) examined if an injection of BTX is more effective than placebo for reducing pain in adults with lateral epicondylitis (tennis elbow).  The primary outcome was change in subjective pain as measured by a 100-mm visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst pain ever) at 4 weeks and 12 weeks.  All patients completed post-treatment follow-up.  Mean VAS scores for the BTX group at baseline and at 4 weeks were 65.5 mm and 25.3 mm, respectively; respective scores for the placebo group were 66.2 mm and 50.5 mm (between-group difference of changes, 24.4 mm [95 % CI, 13.0 to 35.8 mm]; p < 0.001).  At week 12, mean VAS scores were 23.5 mm for the BTX group and 43.5 mm for the placebo group (between-group difference of changes, 19.3 mm [CI, 5.6 to 32.9 mm]; p = 0.006).  Grip strength was not statistically significantly different between groups at any time.  Mild paresis of the fingers occurred in 4 patients in the BTX group at 4 weeks.  One patient's symptoms persisted until week 12, whereas none of the patients receiving placebo had the same complaint.  At 4 weeks, 10 patients in the BTX group and 6 patients in the placebo group experienced weak finger extension on the same side as the injection site.  The study was small, and most subjects were women.  The blinding protocol may have been ineffective because the 4 participants who experienced paresis of the fingers could have correctly assumed that they received an active treatment.  The authors concluded that BTX injection may improve pain over a 3-month period in some patients with lateral epicondylitis, but injections may be associated with digit paresis and weakness of finger extension.  This positive finding is in contrast to that of Hayton et al (2005) who performed a double-blind, randomized, controlled, pilot trial comparing injections of BTX- A with those of a placebo (normal saline solution) in the treatment of chronic tennis elbow.  A total of 40 patients with a history of chronic tennis elbow for which all conservative treatment measures, including steroid injection, had failed were randomized into two groups: (i) half the patients received 50 units of BTX- A, and (ii) the remainder received normal saline solution.  The intramuscular injections were performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist.  The two solutions used for the injections were identical in appearance and temperature.  The results of a quality-of-life assessment with the Short Form-12 (SF-12), the pain score on a VAS, and the grip strength measured with a validated Jamar dynamometer were recorded before and 3 months after the injection.  Three months following the injections, there was no significant difference between the two groups with regard to grip strength, pain, or quality of life.   The authors reported that with the numbers studied, they failed to find a significant difference between the two groups.  Therefore, they concluded that there is no evidence of a benefit from BTX injection in the treatment of chronic tennis elbow.

Monnier et al (2006) stated that musculoskeletal pain in patients with rheumatic disorders is among the emerging indications for BTX therapy.  Preliminary data have been obtained in patients with cervical or thoracolumbar myofascial pain syndrome, chronic low back pain, piriformis muscle syndrome, tennis elbow, and stiff person syndrome.  At present, the effects of BTX and its use for pain relief remain controversial.  Carefully designed prospective studies are needed to ascertain the safety and effectiveness of BTX in pain disorders.  In a double-blind, randomized, placebo-controlled, parallel clinical trial, Qerama et al (2006) studied the effect of BTX-A on pain from muscle trigger points and on EMG activity at rest and during voluntary contraction.  Thirty patients with trigger points in the infra-spinatus muscles received either 50 units/0.25 mL of BTX-A or 0.25 mL of isotonic saline.  Baseline measures were determined during a run-in period of 1 week.  Outcome measures including local and referred spontaneous pain, pain detection and tolerance thresholds to mechanical pressure, and shoulder movement were assessed at 3 and 28 days after injection.  The interference pattern of the EMG during maximal voluntary effort of infra-spinatus muscle was recorded and a standardized search for spontaneous electrical motor endplate activity at the trigger points was performed before and 28 days after BTX-A or saline injection.  Botulinum injection reduced motor endplate activity and the interference pattern of EMG significantly but had no effect on either pain (spontaneous or referred) or pain thresholds compared with isotonic saline.  The authors concluded that their findings do not support a specific anti-nociceptive and analgesic effect of BTX-A.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of autonomic disorders and pain (Naumann et al, 2008) found that botulinum neurotoxin is possibly effective for the treatment of chronic predominantly unilateral low back pain.  This was based on a single Class II study.  The authors stated that the evaluation and treatment of low back pain is complicated by its diverse potential causes.  In most clinical settings, it is difficult to diagnose the precise origin of pain.  This creates challenges in study design, especially in the selection of homogeneous subject populations.  The assessment also noted that there is insufficient evidence to support the effectiveness of botulinum neurotoxin in hyper-lacrimation.

The findings from Qerama et al (2006) are in agreement with that of Ojala et al (2006) who, in a double-blind, randomized, controlled cross-over study (n = 31) found that there was no difference between the effect of small doses of BTX-A and those of physiological saline in the treatment of myofascial pain syndrome as well as that of Ferrante et al (2005) who, in randomized, double-blind, placebo-controlled study (n = 132) reported that injection of BTX-A directly into trigger points did not improve cervico-thoracic myofascial pain.

In a controlled placebo pilot study with a 6-month follow-up period, Guarda-Nardini and associates (2008) examined the effectiveness BTX in treating myofascial pain in bruxers.  A total of 20 patients (10 males, 10 females; age range of  25 to 45 years) with a clinical diagnosis of bruxism and myofascial pain of the masticatory muscles were randomly assigned to either a treatment group (10 subjects treated with BTX injections- BTX-A) or a control group (10 subjects treated with saline placebo injections).  A number of objective and subjective clinical parameters (pain at rest and during chewing; mastication efficiency; maximum nonassisted and assisted mouth opening, protrusive and laterotrusive movements; functional limitation during usual jaw movements; subjective efficacy of the treatment; tolerance of the treatment) were assessed at baseline time and at 1 week, 1 month, and 6 months follow-up appointments.  Descriptive analysis showed that improvements in both objective (range of mandibular movements) and subjective (pain at rest; pain during chewing) clinical outcome variables were higher in the BTX-treated group than in the placebo-treated subjects.  Patients treated with BTX-A had a higher subjective improvement in their perception of treatment efficacy than the placebo subjects.  Differences were not significant in some cases due to the small sample size.  Results from the present study supported the efficacy of BTX-A to reduce myofascial pain symptoms in bruxers, and provided pilot data which need to be confirmed by further research using larger samples.

In a double-blind, randomized, placebo- controlled trial (n = 60), Abbott et al (2006) examined if BTX-A is more effective than placebo at reducing pain and pelvic floor pressure in women with chronic pelvic pain and pelvic floor muscle spasm.  Subjects had chronic pelvic pain of more than 2 years duration and evidence of pelvic floor muscle spasm.  Thirty women had 80 units of BTX-A injected into the pelvic floor muscles, and 30 women received saline.  Dysmenorrhea, dyspareunia, dyschezia, and non-menstrual pelvic pain were assessed by VAS at baseline and then monthly for 6 months.  Pelvic floor pressures were measured by vaginal manometry.  There was significant change from baseline in the BTX- A group for dyspareunia (VAS score 66 versus 12; chi2 = 25.78, p < 0.001) and non-menstrual pelvic pain (VAS score 51 versus 22; chi2 = 16.98, p = 0.009).  In the placebo group only dyspareunia was significantly reduced from baseline (64 versus 27; chi2 = 2.98, p = 0.043).  There was a significant reduction in pelvic floor pressure (centimeters of water) in the BTX- A group from baseline (49 versus 32; chi2 = 39.53, p < 0.001), with the placebo group also having lower pelvic floor muscle pressures (44 versus 39; chi2 = 19.85, p = 0.003). The authors concluded that objective reduction of pelvic floor spasm reduces some types of pelvic pain. Injection of BTX- A reduces pressure in the pelvic floor muscles more than placebo; it may be a useful agent in women with pelvic floor muscle spasm and chronic pelvic pain who do not respond to conservative physical therapy.  There were no significant inter-group differences reported in this study between BTX-A and placebo for pain scores.  These investigators noted that more research in this area is essential to further define this tool in the treatment of chronic pelvic pain.

Awaard (1999) reported that the combination of baclofen/botulinum toxin type A are very effective, safe, and reliable in the treatment of tics/Tourette's syndrome.  It is worthwhile considering this treatment approach in patients with tics/Tourette's syndrome in order to reduce or avoid the side effects of other medications.  Moreover, the author concluded that further studies are needed.

Marras et al (2001) discussed the use of botulinum toxin for simple motor tics (n = 18).  The authors concluded that botulinum toxin reduced treated tic frequency and the urge associated with the treated tic.  Despite these changes, patients did not report an overall benefit from the treatment.

The American Academy of Neurology's assessment on the use of botulinum neurotoxin in the treatment of movement disorders (Simpson et al, 2008b) stated that botulinum neurotoxin is possibly effective for the treatment of motor tics (based on one Class II study).  On the other hand, there is insufficient data to ascertain the effectiveness of botulinum neurotoxin in patients with phonic tics.

Botulinum toxin is the only known treatment for painful dystonia accompanying rare corticobasilar degeneration (CBD). Dystonia, often accompanied by painful rigidity and fixed contractures, is one of the most disabling features of CBD. Vanek and Janovic (2001) found that dystonia is a common manifestation of CBD; of 66 patients with CBD, 39 (59.0%) had dystonia. The investigators noted that there is no effective treatment for this relentless disorder, except for temporary relief of dystonia and pain, with local botulinum toxin injections.

Botulinum toxin has also been studied for its use in treating brachial plexus injury and restless leg syndrome.  However, there is currently insufficient evidence to support it use for these indications.

Heise et al (2005) reported their preliminary experience with the use of BTX-A for the treatment of biceps-triceps muscle co-contraction.  A total of 8 children were treated with 2 to 3 U/Kg of BTX injected in the triceps (4 patients) and biceps (4 patients) muscle, divided in 2 or 3 sites.  All patients submitted to triceps injections showed a long-lasting improvement of active elbow flexion and none required new injections, after a follow-up of 3 to 18 months.  Three of the patients submitted to biceps injections showed some improvement of elbow extension, but none developed anti-gravitational strength for elbow extension and the effect lasted only 3 to 5 months.  One patient showed no response to triceps injections.  The authors stated that their findings suggested that BTX can be useful in some children that have persistent disability secondary to obstetrical brachial plexopathy.

DeMatteo et al (2006) noted that following obstetrical brachial plexus injury, infants are unable to learn specific patterns of movement due to the disruption of neural pathways.  Even with successful re-innervation (spontaneously or post-surgical reconstruction), function can be suboptimal due to over-activity in antagonist muscles preventing movement of re-innervated muscles.  Botulinum toxin type A was used to temporarily weaken antagonistic muscles early in the re-innervation process following brachial plexus injury, with the aim of facilitating functional improvement.  These researchers reported a case series of 8 children (5 females, 3 males; mean age of 12.5 months [SD 6.43]; range of 5 to 22 months) with significant muscle imbalances but evidence of re-innervation who were given BTX-A injections into the triceps, pectoralis major, and/or latissimus dorsi muscles.  After a single injection, all parents reported improvement in function.  Active Movement Scale total score changed significantly between pre BTX-A and 1 month (p = 0.014), and 4 months (p = 0.022) post BTX-A injection.  The authors proposed that BTX-A facilitated motor learning through improved voluntary relaxation of antagonist muscles while allowing increased activity in re-innervated muscles.

Price et al (2007) retrospectively reviewed 26 patients who underwent reconstruction of the shoulder for a medial rotation contracture after birth injury of the brachial plexus.  Of these, 13 patients with a mean age of 5.8 years (2.8 to 12.9) received an injection of BTX-A into the pectoralis major as a surgical adjunct.  They were matched with 13 patients with a mean age of 4.0 years (1.9 to 7.2) who underwent an identical operation before the introduction of BTX therapy to these investigators' unit.  Pre-operatively, there was no significant difference (p = 0.093) in the modified Gilbert shoulder scores for the 2 gropus.  Post-operatively, patients who received the BTX had significantly better Gilbert shoulder scores (p = 0.012) at a mean follow-up of 3 years (1.5 to 9.8).  It appears that BTX-A produces benefits which are sustained beyond the period for which the toxin is recognised to be active.  The authors suggested that by temporarily weakening some of the power of medial rotation, afferent signals to the brain are reduced and cortical recruitment for the injured nerves is improve.

In a double-blind, placebo-controlled, pilot trial (n = 6),  Nahab and colleagues (2008) examined the effects of botulinum toxin A in the treatment of patients with restless legs syndrome (RLS).  Patients, aged 18 or older, had a diagnosis of primary RLS based on International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria,1 had a minimum score of 11 (at least moderate severity) on the IRLSSG rating scale (IRLS), and were stable on medications for greater than 6 weeks prior to enrollment.  Patient assessment included a medical history, neurological examination, and baseline ratings.  Eligible patients were evaluated by a second investigator who documented symptom location.  A standard set of muscles were selected as potential targets: quadriceps femoris (QF), tibialis anterior (TA), gastrocnemius (GCS), and soleus (SOL).  After baseline ratings, patients were randomized to receive BTX-A or saline.  The maximum dose was 90 mU per leg, distributed in the following sites (number of injections): QF-40mU (4); TA-20mU (2); GCS-20mU (2); SOL-10mU (1).  At week 12, patients received the alternate compound with continued monitoring.

These researchers used the IRLS and the Clinical Global Improvement scale (CGI) to assess efficacy.  To monitor adverse effects (AE), patients were asked to rate from 0 (no symptoms) to 10 (severe symptoms) the presence of weakness, pain, swelling, and redness based on the preceding 2 weeks.  Ratings were completed at baseline (weeks 0 and 12), and 2 and 4 weeks post-injections. The primary outcome measure was mean change in IRLS from baseline at 4 weeks post-injection.  Secondary outcomes included mean IRLS change from baseline at 2 weeks post-injection, mean CGI scores at weeks 2 and 4, and reported AEs.  A power analysis using standard treatment and placebo response rates reported for pramipexole was performed.  These investigators estimated a mean difference from baseline between placebo and BTX-A of 10 points ± 3 (SD) on the IRLS.  They therefore required a sample size of 3 patients per group (power = 0.80, a = 0.05).

A total of 7 patients were screened, with 1 excluded due to leukocytosis on laboratory testing.  All remaining patients completed the study.  Five patients were on stable doses of a dopamine agonist, and 1 patient was on a stable dose of clonazepam.  No patient had received prior BTX treatment.  Group demographics were as follows: 57.7 ± 8.8 years of age, equal male-female ratio, 33.5 ± 14.4 years disease duration, and an IRLS score of 27 ± 4.8.  All patients received the maximum BTX dose of 90 mU/leg with the exception of 1 patient who had no symptoms in the proximal legs and did not receive injections into his QF.  At week 2, placebo-treated patients noted a 5.0 ± 5.1 point improvement on the IRLS versus a 1.0 ± 3.5 point improvement in the BTX-arm (p = 0.06).  At week 4, placebo-treated patients maintained only a 2.7 ± 5.9 point improvement from baseline, whereas BTX-treated patients showed a 5.0 ± 6.0 point improvement (p = 0.24).  The CGI showed similar findings for the BTX-arm with scores of 4.3 ± 0.8 at week 2 (p = 0.01) and 3.7 ± 1.4 at week 4 (p = 0.74), compared to placebo-arm scores of 2.8 ± 1.2 at week 2 and 3.8 ± 1.7 at week 4.  These researchers compared baseline scores at week 0 and week 12 to assess for any carry-over effect in the BTX-arm and found no differences (p = 0.55).  Reported AEs were similar between groups, with mean placebo AE scores of 1.5 ± 2.5 at baseline, 3.2 ± 5.4 at week 2, and 5 ± 7.4 at week 4, while BTX-A scores were 1.8 ± 3.3 at baseline, 6.3 ± 7.1 at week 2, and 4.5 ± 5.6 at week 4.  Two patients reported mild weakness following both placebo and BTX-A injections.  This study showed no significant improvement in IRLS and CGI at week 4 for BTX-A.  A statistically significant benefit was noted on the CGI secondary endpoint for the placebo group at week 2.  Adverse events were similar between the groups.  Any future studies should be powered to account for the significant placebo response while exploring higher doses without unmasking controls.

Testing for Neutralizing Antibodies to Botulinum Toxin:

Patients who respond to BTX injections initially but lose the response on subsequent injections may have developed neutralizing antibodies.  According to the prescribing information for BTX-A, the potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.  In uncontrolled studies, there are individuals who continue to respond to treatment despite the presence of neutralizing antibodies.  Not all patients who became non-responsive to BTX after an initial period of clinical responsiveness had neutralizing antibodies.

According to Hauser and Wahba (2205), an estimated 5 to15% of patients injected serially with 79-11 BOTOX developed secondary non-responsiveness from the production of neutralizing antibodies.  Risk factors associated with the development of neutralizing antibodies include injection of more than 200 units per session and repeat or booster injections given within 1 month of treatment.  The new BCB 2024 BOTOX may have a lower potential for neutralizing antibody production because of its decreased protein load, but this is not known.

Some patients injected for cosmetic purposes develop neutralizing antibodies.  When a patient loses his or her response, serum can be tested for neutralizing antibodies, although this rarely is performed outside research settings.  Alternatively, a patient's physiological response can be evaluated with a single injection of 15 units into the frontalis on one side.

Limited information is available as to whether neutralizing antibodies resolve over time and, consequently, whether attempts at re-injection should be made after a prolonged period.  An investigation is underway to determine whether injections of BTX-B are useful in patients with neutralizing antibodies to BTX-A.  Using the lowest dose of toxin necessary to achieve the desired clinical effect and avoiding re-injection within 1 month appear prudent in an effort to keep antibody formation as low and unlikely as possible.

Dressler and Hallett (2006) stated that in some patients treated with BTX, antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the BT preparation used.  Therapeutic BTX preparations are comprised of botulinum neurotoxin, non-toxic proteins and excipients.  Antibodies formed against botulinum neurotoxin can block BTX's biological activity.  The antigenicity of a BTX preparation depends on the amount of botulinum neurotoxin presented to the immune system.  This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation.  For Botox the specific biological activity is 60 MU-EV/ng neurotoxin, for Dysport 100 MU-EV/ng neurotoxin and for Myobloc/NeuroBloc 5 MU-EV/ng neurotoxin.  For Myobloc/NeuroBloc this translates into an antibody-induced therapy failure rate of 44% in patients treated for cervical dystonia, whereas for BTX-A preparations this figure is approximately 5%.  No obvious differences in antigenicity of BTX- A preparations have been detected thus far.  For the current formulation of Botox, the rate of antibody-induced therapy failure is reportedly less than 1%.  The authors concluded that to determine the antigenicity of different BTX preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific BTX antibody tests are needed.