This document addresses the use of both type A and type B botulinum toxin products (e.g., Botox^® [OnabotulinumtoxinA], Myobloc™ [RimabotulinumtoxinB], Dysport^® [AbobotulinumtoxinA] and Xeomin^® [IncobotulinumtoxinA]), for the treatment of all health conditions, with the exception of hyperhidrosis.

Note: Please see the following documents for other uses for botulinum toxin:

• MED.00032 Treatment of Hyperhidrosis.

Medically Necessary: 

The use of botulinum toxin is considered medically necessary for strabismus.

The use of botulinum toxin is considered medically necessary in the treatment of the following disorders if associated with spasticity or dystonia:

• Blepharospasm
• Cerebral palsy
• Facial nerve (VII) dystonia
• Hemifacial spasm
• Hereditary spastic paraparesis
• Idiopathic torsion dystonia
• Multiple sclerosis
• Neuromyelitis optica
• Organic writer's cramp
• Orofacial dyskinesia (i.e., jaw closure dystonia)
• Schilder's disease
• Spasmodic dysphonia or laryngeal dystonia (a disorder of speech due to abnormal control of the laryngeal muscles present only during the specific task of speaking)
• Spastic hemiplegia
• Spasticity related to stroke, spinal cord injury, or traumatic brain injury
• Symptomatic torsion dystonia
• Other forms of upper motor neuron spasticity

The use of botulinum toxin is considered medically necessary in the initial treatment of cervical dystonia (spasmodic torticollis) of moderate or greater severity when all of the following criteria are met:

• History of recurrent clonic or tonic involuntary contractions of one or more of the following muscles: sternocleidomastoid, splenius, trapezius or posterior cervical muscles; and
• Sustained head tilt or abnormal posturing with limited range of motion in the neck; and
• The duration of the condition is greater than 6 months.

Subsequent injections of botulinum toxin for the treatment of cervical dystonia (spasmodic torticollis) of moderate or greater severity are considered medically necessary when:

• There is a response to the initial treatment documented in the medical records; and
• The individual still meets the medically necessary criteria above.

The use of botulinum toxin is considered medically necessary in the treatment of achalasia.

The use of botulinum toxin is considered medically necessary in the treatment of anal fissures. 

The use of botulinum toxin is considered medically necessary in the treatment of significant drooling in individuals who are unable to tolerate scopolamine. 

The use of botulinum toxin is considered medically necessary as a treatment of incontinence related detrusor overactivity and incontinence of neurogenic origin (i.e., spinal cord injury, multiple sclerosis) that is inadequately controlled with anticholinergic therapy.

The use of botulinum toxin is considered medically necessary for bladder detrusor sphincter dyssynergia of neurogenic origin.

An initial 6-month trial of botulinum toxin for prevention of chronic migraine headaches is considered medically necessary when all of the following are met:

• Adult individual diagnosed with chronic migraine headache; and
• Fifteen (15) or more migraine days per month with headache lasting four (4) hours or longer; and
• First episode at least six (6) months ago; and
• Symptoms persist despite trials of at least 1 agent in any 2 of the following classes of medications used to prevent migraines or reduce migraine frequency:

1. Antidepressants (e.g., amitriptyline, nortriptyline, doxepin); or
2. Antihypertensives (e.g., propranolol, timolol); or
3. Antiepileptics (e.g., valproate, topiramate, gabapentin).

Continuing treatment with botulinum toxin injection for ongoing prevention of chronic migraine headaches is considered medically necessary when:

• Migraine headache frequency was reduced by at least 7 days per month (when compared to pre-treatment average) by the end of the initial trial; or  
• Migraine headache duration was reduced by at least 100 total hours per month (when compared to the pre-treatment average) by the end of the initial trial. 

Not Medically Necessary:

The use of botulinum toxin is considered not medically necessary in the treatment of cervical dystonia (spasmodic torticollis) when the criteria above have not been met. 

Cosmetic and Not Medically Necessary:

Botulinum toxin is considered cosmetic and not medically necessary as a treatment of skin wrinkles or other cosmetic indications.

Investigational and Not Medically Necessary: 

Botulinum toxin is considered investigational and not medically necessary for the treatment of headache other than chronic migraine meeting the criteria above, including but not limited to tension, episodic migraine (14 migraine days per month or less), or chronic daily headaches.   

Botulinum toxin is considered investigational and not medically necessary as a treatment for conditions listed above when criteria are not met and for all other conditions not addressed above, including, but not limited to, the following:

• Anismus (pelvic floor dyssynergia)
• Benign prostatic hyperplasia
• Carpal tunnel syndrome
• Chronic motor tic disorder
• Disorders of the esophagus (except as listed above in the medically necessary section)
• Epicondylitis
• Fibromyalgia/fibromyositis
• Gastroparesis
• Low back pain
• Myofascial pain syndrome
• Neck pain not related to conditions mentioned above
• Nystagmus
• Parkinson's disease
• Sphincter of Oddi dysfunction 
• Stuttering
• Tics associated with Tourette's Syndrome
• Tinnitus
• Tourette's Syndrome
• Tremors
• Urinary and anal sphincter dysfunction (except as listed above in the medically necessary section)
• Vaginismus
• Whiplash-related disorders
• Zygomatic fractures

Spasticity and Dystonia 

The use of botulinum toxin therapy is a well-established, safe and effective treatment for a variety of spasticity related disorders and abnormal muscle tone, including muscle over-activity or spasticity related to upper motor neuron (UMN) syndrome caused by cerebral palsy, multiple sclerosis, stroke, spinal cord injury, or neurodegenerative disease. Controlled clinical trials of botulinum toxin injections for focal muscle spasticity have demonstrated prolonged yet reversible clinical improvements in physical function and comfort, as well as improvement in prevention or treatment of musculoskeletal complications. These benefits have been achieved with few side effects.

Botulinum toxin treatment has been demonstrated to be a safe and effective method for decreasing the severity of abnormal head positioning and postures and pain associated with various dystonias such as cervical, spasmodic, and torsion dystonia. Although botulinum toxin therapy has not resulted in complete relief of symptoms for these conditions, clinical trials have demonstrated temporary but significant improvements in the degree of muscle contractility, flexibility, and pain. An added benefit of this treatment is the ability to target specific muscles in a dose-response relationship, allowing a precise amount of muscle weakness to be induced.

Spasticity related to stroke may be a significant functional problem.  Plantar flexion spasticity may impede walking.  Peripheral neurolysis with phenol injections has been used for many years, but recently botulinum toxin injections have been investigated.  Kirazli and colleagues (1998) compared the effects of phenol block and botulinum toxin in a randomized trial of 20 subjects with spastic foot after stroke.  The authors reported both injections were associated with significant improvements, with botulinum toxin outperforming phenol injections after the first month of treatment, with equal treatment effects at 2 and 3 months.  Possible advantage of the botulinum toxin is the relative ease of the procedure (15 to 30 minutes), while phenol injection may take up to 2 hours to target the motor nerve for injection.  Smith and colleagues (2000) investigated the use of botulinum toxin in a trial which randomized 21 individuals with upper limb spasticity related to stroke or head injury.  There was a significant reduction in spasticity in the wrist and fingers in the botulinum group.  The effects were transitory and disappeared at 12 weeks.

Achalasia

Achalasia is a primary esophageal motor disorder characterized by abnormal lower esophageal sphincter relaxation. The available literature addressing the use of botulinum toxin for achalasia is currently limited to a few studies, including a single case report (Perez-Arroyo, 1997), a retrospective case series of 5 subjects (Ahsan, 2000), and several small prospective case series studies (Miller, 1996; Annese, 1998; Alberty, 2000; Storr, 2001).  These small studies show some benefit. Data from two small randomized controlled trials are available for individuals with achalasia. 

Mikaeli and colleagues (2006) randomly assigned newly diagnosed individuals with achalasia to receive botulinum toxin 1 month before pneumatic dilatation (n=27) or to undergo pneumatic dilatation alone (n=27). At one-year, the remission rate in the botulinum toxin-pneumatic dilatation group was 77% compared with 62% in pneumatic dilatation group (P = 0.1). In the pneumatic dilatation group, the esophageal barium volume significantly (P < 0.001) decreased at 1 month, but this reduction did not persist over 1-year follow-up. The botulinum toxin-pneumatic dilatation group showed a significant (P < 0.001) reduction in barium volume at the various time intervals post-treatment. In the botulinum toxin-pneumatic dilatation group, 10/11 (91%) subjects over 40 were in remission at 1 year, comparing with only five of nine (55%) cases in pneumatic dilatation group (P = 0.07).   

Benign Prostatic Hyperplasia (BPH) 

Botulinum toxin has been investigated for the treatment of urinary symptoms of benign prostatic hyperplasia (BPH).  At this time the peer-reviewed published literature for this treatment method is limited.  One study by Maria and colleagues (2003) involved 30 consecutive male individuals with BPH enrolled in a randomized controlled trial.  Each participant received 4 mL of either saline solution or 200 U of botulinum toxin A injected into the prostate gland.  After 2 months, 13 participants in the treated group and 3 in the control group had subjective symptomatic relief (P = 0.0007).  In individuals who received botulinum toxin, the symptom score was reduced by 65% compared with baseline values and the serum prostate-specific antigen concentration by 51% from baseline.  In subjects who received saline, the symptom score and serum prostate-specific antigen concentration were not significantly changed compared with the baseline values and 1-month values.  Follow-up averaged 19.6 +/- 3.8 months.  Another study by Park et al. (2006) included 52 individuals with symptomatic BPH who received either transperineal intraprostatic injection with botulinum toxin A (BT group) or botulinum toxin A with additional alpha-adrenergic antagonist therapy (BTalpha group).  Twenty-six individuals were in the BT group and 26 were in the BTalpha group.  At the one month follow-up, 18 subjects in the BT group and 21 in the BTalpha group had subjective symptomatic relief (p = 0.337).  Only international prostate symptom score 5 (weak stream) was significantly different between the BT group and BTalpha group (p = 0.034).  At the three month follow-up, 39 participants had subjective symptomatic relief.  The storage symptoms were improved more than the voiding symptoms.  Additionally, about 50 percent of the subjects whose voiding symptom improved expressed improved erectile function.  BTA injection seems to be an alternative treatment for BPH.  The differences after the one month evaluation between the BT and the BTalpha groups might suggest that the adrenergic influence could be relatively reinforced by the anticholinergic effect of BTA. 

At this time the current data does not allow for a sufficient evaluation of botulinum toxin for the treatment of BPH.

Anal Fissure 

An anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the internal anal sphincter. It is treated surgically with an internal sphincterotomy. Since the anal sphincter contraction could be characterized as a dystonia, botulinum toxin represented a logical medical approach. Maria and colleagues (1998) reported on a randomized study of 30 individuals with chronic anal fissure to receive either 2 injections of 20 units of botulinum toxin, on either side of the fissure, or 2 injections of saline. After 2 months, 11 subjects in the treatment group reported healing, compared to only 2 in the control group. The 4 participants who still had fissures after 2 months underwent retreatment with botulinum toxin; 2 of these 4 individuals reported healing scars and symptomatic relief. These results are consistent with earlier case series that reported a healing rate of 80% (Jost, 1997). Nitroglycerin ointment has also been used to successfully treat anal fissure. Brisinda and colleagues (1999) compared the results of nitroglycerin ointment and botulinum toxin in a randomized trial of 50 subjects. After 2 months, 96% of the fissures were healed in the botulinum group compared with 60% in the nitroglycerin group. 

Significant Drooling 

Botulinum toxin has been investigated as a treatment of significant drooling, primarily in participants with Parkinson's disease or cerebral palsy.  Several randomized controlled trials have demonstrated botulinum toxin can decrease the volume of saliva compared to placebo, as evidenced by a change in the number of bibs required each day (Ondo, 2004; Mancini, 2003; and Lipp, 2003).  However, oral scopolamine is an effective technique of reducing salivary flow.  One study randomized 45 children with cerebral palsy to receive either scopolamine therapy or injections of botulinum toxin (Jongerius, 2004).  No significant differences in reduction in saliva volume were noted between the two groups, although those receiving scopolamine had greater side effects.  The results of this study suggest that botulinum injection is a reasonable alternative for those who cannot tolerate scopolamine.  

Epicondylitis 

At this time there are several randomized controlled trials describing the effectiveness of botulinum toxin therapy for epicondylitis (Espandar, 2010; Hayton, 2005; Keizer, 2002; Wong, 2005; Placzek, 2007).  The studies reported by Hayton (n=40), Wong (n=60) and Placzek (n=130) described trials where Botulinum toxin A was compared to saline placebo injections.  None of these studies reported significant differences in objective measures at 12 and 18 weeks post-treatment, respectively.  Espandar and colleagues also compared botulinum toxin to saline placebo injections in 48 subjects with epicondylitis, but found significant decrease in pain at rest during the follow-up period. No other measures were found to be significantly different between groups. The trial by Keizer (n=40) compared botulinum toxin A injection to surgery.  The authors reported that when analyzed with an overall scoring system, no differences were found between the two forms of treatment after 3, 6, 12, and 24 months.  A meta-analysis by Kalichman and others combined and analyzed data from the Espandar, Hayton, Placzek and Wong studies (2011).  The authors report that the summary data "showed a moderate effect for pain favoring botulinum toxin". However, no p-value is provided for this data, so it is unclear whether or not this effect was statistically significant.  Data from larger randomized trials are needed to confirm these findings.

Gastroparesis 

Botulinum toxin has been researched as a treatment of gastroparesis. Through upper endoscopy, botulinum toxin has been injected into the pylorus to relax the muscle and speed emptying of gastric contents. The literature consists of several case series ranging in size from 3 to 20 individuals. Although the results show some positive effect after treatment with botulinum toxin, larger controlled trials are needed to determine the efficacy of this treatment method for gastroparesis (Friedenberg, 2004). 

Headaches 

Numerous studies regarding the treatment of migraine, tension and cluster headaches have been published (Evers, 2004; Freitag, 2008; Ondo, 2004; Padberg, 2004; Petri 2009; Relja, 2004; Rollnik, 2000; Rollnik, 2004; Saper, 2007; Schmitt, 2001; Schulte-Mattler, 2004; Silberstein. 2000;  Smuts, 1999).  Silberstein (2005) published a large randomized, double blind, placebo-controlled study addressing the use of botulinum toxin for chronic migraine headaches involved 702 subjects.  This study compared placebo to three different concentrations of botulinum toxin.  Mathew and colleagues (2005) studied 355 participants with chronic daily headache who were categorized as placebo responders or non-responders based on an initial single blind trial of placebo.  Both placebo responders and non-responders were then randomized to receive either placebo or botulinum toxin every 90 days for 9 months; individuals were evaluated every 30 days.  In both studies, there was no statistically significant difference in the primary outcome, although there were several statistically significant differences in some of the secondary outcomes.  Anand and colleagues (2006) studied 32 individuals receiving pericranial botulinum toxin injections for multiple monthly migraines.  They reported 75% of the subjects had some relief from migraine pain, but still had migraine associated decreased normal daily functioning.  Relja and colleagues published the findings of a large double-blind, placebo-controlled study which involved 495 participants (2007).  The study evaluated the efficacy of three concentrations of botulinum toxin compared to placebo for the treatment of chronic migraine headaches.  The authors reported no significant differences between any of the experimental groups and placebo for the primary efficacy end-point, which was the mean reduction from baseline in the frequency of migraine episodes at day 180 in the placebo non-responder stratum.  These publications demonstrate the challenges in studying interventions to treat chronic migraine and the inconsistent and often conflicting results were not sufficient to convincingly demonstrate medical benefit of botulinum toxin in migraine.

However, more recently, Dodick and colleagues reported the pooled results of two large randomized, double blind, controlled trials addressing the use of botulinum toxin for the treatment of chronic migraine headaches (2010).  These studies from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program involved a 24-week randomized, double-blind phase followed by a 32-week open-label phase (Aurora, 2010; Diener, 2010).  Subjects were randomized (1:1) to onabotulinumtoxinA or placebo injections every 12 weeks.  A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696).  Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (-8.4 vs -6.6; p less than .001) and at all other time points.  Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, including frequency of headache days, cumulative headache hours, and the proportion of subjects with severe headaches.  No significant difference was noted in the frequency of acute headache pain medication taken.  There were a significantly greater proportion of experimental group subjects that had a greater that 50% decrease from baseline in headache days.  Adverse events occurred in 62.4% of experimental group subjects and 51.7% of placebo subjects, with a greater than 5% incidence of neck pain and muscular weakness in the experimental group. 

Based in part on the Dodick study, in October 2010 the U.S. FDA approved the use of onabotulinumtoxinA (Botox) for the prophylaxis of headaches in adults with chronic migraine as defined as greater than or equal to15 days per month with headache lasting 4 hours a day or longer.  This approval appears to recognize that taken in aggregate, the published peer reviewed evidence supports that the use of botulinum toxin demonstrates material improvements in net health outcomes, in particular a reduction in migraine frequency in carefully selected individuals. 

A report by Lipton and colleagues looks further into these results, with an analysis of combined data from both the PREEMPT-1 and PREEMPT-2 trials.  This report, which looked at 688 subjects who received treatment with Botox vs. 696 who received saline placebo injections, showed that while both groups demonstrated significant improvement, the Botox group had significantly better overall HIT-6 scores at all time periods during the double-blind phase of the trials (p≤0.014).  Additionally, HIT-6 measures of headache impact scores showed significant benefit for the Botox group at 24 weeks of treatment (p<0.001).  Finally, there was a significant benefit shown for the Botox group compared to placebo with regard to the proportion of subjects who received clinically meaningful reduction in the number of headache days at all time points in the double blind study periods (p≤0.025).  These results further support the findings of the individual PREEMPT studies, and demonstrate a significant benefit from Botox treatment for chronic migraine headache sufferers.

The diagnosis and classification of headaches can be challenging. The International Headache Society published the International Classification of Headache Disorders, Second Edition (ICHD-II) in 2004.  This document, used primarily for research purposes, provides specific criteria for the identification and classification of chronic migraine headache.  The criteria for chronic migraine headache are:

1. Headache (tension-type and/or migraine) on ≥15 days per month for at least 3 months*
2. Occurring in a patient who has had at least five attacks fulfilling criteria for "Migraine without aura" as follows:
   1. At least 5 attacks fulfilling criteria b-d.
   2. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) and occurring on greater than 15 days/month.
   3. Headache has at least two of the following characteristics:
      1. Unilateral location
      2. Pulsating quality
      3. Moderate or severe pain intensity
      4. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs)
   4. During headache at least two of the following:
      1. Nausea
      2. Vomiting
      3. Photophobia
      4. Phonophobia
      5. Osmophobia
   5. Not attributed to another disorder
3. On greater than or equal to 8 days per month for at least 3 months headache has fulfilled C1 and/or C2 below, that is, has fulfilled criteria for pain and associated symptoms of migraine without aura
   1. Has at least two of a–d below:
      1. Unilateral location
      2. Pulsating quality
      3. Moderate or severe pain intensity
      4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) and at least one of e or f below:
      5. Nausea and/or vomiting
      6. Photophobia and phonophobia
   2. Treated and relieved by triptan(s) or ergot before the expected development of C1 above
4. No medication overuse† and not attributed to another causative disorder‡

* Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms day-by-day for at least 1 month. Sample diaries are available at http://www.ihs-headache.org
† Medication overuse as defined under 8.2 Medication-overuse headache.
‡ History and physical and neurological examinations do not suggest any of the disorders listed in groups 5–12, or history and/or physical and/or neurological examinations do suggest such a disorder but it is ruled out by appropriate investigations, or such disorder is present but headache does not develop in close temporal relation to the disorder

Low Back Pain 

Foster et al. (2001) report a randomized, double-blind study of botulinum toxin A in 31 consecutive subjects with chronic low back pain. Study selection criteria included low back pain of at least 6 months' duration with more predominant pain on one side.  Subjects were excluded if there was a systemic inflammatory disorder, acute pathology on MRI, or involvement in worker's compensation or litigation among other criteria.

The outcome measures used in this study were a visual analogue scale (VAS) for pain, measured at baseline, 3 weeks and 8 weeks, and a 50% reduction was considered a response.  The Oswestry Low Back Pain Questionnaire (OLBPQ) was used to measure functional ability at baseline and at 8 weeks. This measure has 10 different subscales (pain, personal care, lifting, walking, sitting, standing, sleeping, sex, social life, and traveling) each rated 0 to 5. Responders were required to show a 2-point reduction on the pain subscore and at least 1 of other subscales. Three subjects withdrew or were lost to follow-up over the course of the 8-week study, and these subjects were included in the intent-to-treat analysis as nonresponders. Subjects were injected with 40 units of Botox (Allergan, Inc.) at 5 lumbosacral locations for a total of 200 U (treated group) or saline placebo (placebo group). Injections were made on one side of the back only, depending on predominance of pain.

At baseline, pain scores on the VAS in the treated group ranged from 6 to 10, with an average of 7.5; in the placebo group, scores ranged from 5 to 10, with an average of 7. At 3 weeks, 73.3% of treated subjects and 25% of the placebo group showed a response on VAS scores (p=0.012). This difference in VAS scores remained significant at 8 weeks with 60% of treated subjects and 12.5% of placebo subjects still responding (p=0.009). The OLBPQ assessment at 8 weeks showed that 66.7% of treated subjects and 18.8% of placebo subjects were responders (p=0.011). These results show clinically significant and statistically significant improvements in treated subjects as compared with placebo on all 3 outcome assessments.

However, this is only one suggestive study that included 31 subjects, and replication of these findings would be desirable. The population with chronic low back pain is a heterogeneous population, and results in this small group of selected subjects cannot be used to generalize results for the whole population with chronic low back pain. Furthermore, studies should examine the long-term effectiveness of using repeated courses of botulinum toxin to determine the durability of repeated treatments.

Myofascial Pain

Painful muscles with increased tone and stiffness containing trigger points characterize myofascial pain syndrome. Subjects are often treated with injections of the trigger points with saline, dilute anesthetics, or dry needling. These trigger point injections, while considered established therapy, have been controversial since it is unclear whether any treatment effect is due to the injection, dry needling of the trigger point, or a placebo effect. Among 3 studies on cervicothoracic myofascial pain syndrome, Wheeler and colleagues (1998) conducted a randomized trial of 33 subjects randomized into 3 groups; 1 group receiving 50 units of botulinum toxin, 1 group receiving 100 units of botulinum toxin, and 1 group receiving normal saline. All 3 groups showed similarly significant treatment effects, based on the Neck Pain and Disability Visual Analogue Scale. These same authors (Wheeler, 2001) later found no differences among 50 subjects randomized to high-dose botulinum toxin or placebo. A crossover study of only 6 subjects (Cheshire, 1994) found significantly better results for botulinum toxin over placebo at 2 and 4 weeks for 4 of 5 pain outcomes. Together, these 3 studies are insufficient to permit conclusions about the effects of botulinum toxin on cervicothoracic myofascial pain syndrome.

Three studies addressed another form of myofascial pain, piriformis syndrome, characterized by buttock tenderness and sciatica. One very small study of 9 subjects (Childers, 2002) compared botulinum toxin with placebo, finding postinjection pain scores were significantly improved in the treatment group for only 1 of 4 pain domains, while none improved in the placebo group.  Unfortunately the small sample size and lack of control group significantly limits the usefulness of these findings.  Another study of 36 subjects (Fishman, 2002) found that the group given botulinum toxin had a 50% or greater reduction in pain on each of the last 2 follow-up visits, compared with lidocaine and steroid injections.  This study had a significantly high loss to follow-up (35.6%), with statistically significant difference in the proportion of participants dropping out in each group.  These small and flawed studies do not establish the effects of botulinum toxin exceed those of placebo.  A third study (Porta, 2000) comparing botulinum toxin with methylprednisolone found better results for the former, but placebo effects were not considered.  The evidence for piriformis myofascial pain syndrome does not support conclusions about the effects of botulinum toxin. 

Nystagmus 

The available evidence addressing the use of botulinum toxin for the treatment of nystagmus is limited to two small case series studies.  Tomsak and colleagues (1995) report on three subjects with acquired nystagmus with prominent vertical or torsional component.  Each subject received a different concentration of botulinum toxin A (10, 12.5, or 25 units) via retrobulbar injection.  The authors report that botulinum toxin abolished or reduced all components of the nystagmus in the treated eye in all three subjects for about two to three months.  The subject who received 25 units developed complete external ophthalmoplegia and blepharoptosis.  The other two subjects retained some voluntary movements but developed diplopia.  In one subject, visual acuity improved from Jaeger 5 to Jaeger 1.  In a second subject, filamentary keratitis developed, and visual acuity declined from Jaeger 2 to Jaeger 7; keratitis was a recurrent problem one year after the botulinum toxin injection.  In the third subject with predominantly torsional nystagmus, visual acuity was unchanged at Jaeger 2.  No subject was pleased with the results, because of blepharoptosis, diplopia, or discomfort (from keratitis), and none elected to repeat the procedure.

The other study by Repka et al. (1994) was a prospective study of 6 subjects (nine eyes) with acquired nystagmus.  The subjects received retrobulbar injection of 25 to 30 U of botulinum neurotoxin A.  Subjects were followed up for changes in their visual function for at least 6 months following the last injection.  Each subject had subjective and objective improvement in distance visual acuity following the injection.  A reduction in the amplitude of the nystagmus was seen following each of the injections, but the frequency of the nystagmus was generally unchanged.  Visual improvement usually lasted no more than 8 weeks.  However, improvement persisted for 6 months after injection in two subjects with oculopalatal myoclonus. 

These two studies are insufficient to establish the efficacy and safety of the use of botulinum toxin for the treatment of nystagmus. 

Tremor 

Tremor may be defined as alternate or synchronous contractions of antagonistic muscles. Some subjects may be disabled by severe or task-specific tremors.  Tremors are also a frequent component of dystonias, and successful treatment of dystonias resulted in an improvement in tremors.  Botulinum toxin has been investigated in subjects with tremors unrelated to dystonias.  One randomized study by Pahwa (1995) reported on 10 subjects with essential head tremor.  Subjects were randomized to receive either botulinum injections into the sternocleidomastoid (SCM) or splenius capitus (SC) muscle. Five subjects improved in the SCM group compared to 3 in the SC group. The lack of statistical significance may be related to the small size of the study. Two randomized, placebo-controlled studies addressed essential hand tremors, enrolling 133 and 25 subjects, respectively (Brin, 2001; Jankovic, 1996).  In both studies, significant advantages for botulinum toxin found on tremor symptom scales were inconsistent, and none were shown on functional outcomes.  Thus, the clinical significance of these findings is unclear.

Sphincter of Oddi dysfunction

To date, only two studies have investigated the use of botulinum toxin for the treatment of sphincter of Oddi dysfunction.  Both case series studies are by the same group of authors, Wehrmann and colleagues.  The first study (1998) involved 22 subjects who had undergone cholecystectomy and had manometrically confirmed type III sphincter of Oddi (SOD) dysfunction.  All subjects received an endoscopic injection of 100 mouse units of botulinum toxin into the papilla of Vater.  With the exception of one subject with mild pancreatitis (4.5%), no side effects were observed.  Six weeks after botulinum toxin A injection, 12 SOD subjects (55%) were symptom-free, and ten subjects (45%) were not.  Recurrent symptoms appeared in 11 of the 12 responders after a median period of six months and manometry revealed sphincter hypertension in all 11 cases; all subjects became free of complaints again after endoscopic sphincterotomy during a median follow-up of a further 15 months.

The second study (2000) involved 15 subjects with pancreatic sphincter of Oddi dysfunction with frequent attacks of acute pancreatitis within 6 months, and manometrically proven pancreatic sphincter of Oddi dysfunction. All underwent endoscopic injection of 100 units of botulinum toxin into the major papilla.  Within 3 months after treatment, 12 out of 15 subjects remained asymptomatic (80% primary response).  Only one out of three subjects without symptomatic benefit showed continued elevated pancreatic sphincter pressure at manometry and only this subject benefited from pancreatic sphincterotomy later on.  Eleven of the 12 subjects initially responding to botulinum toxin injection developed a symptomatic relapse 6 +/- 2 months after botulinum toxin treatment.  These subjects then achieved long-term clinical remission from pancreatic or combined (biliary and pancreatic, n=5) sphincterotomy (median follow-up, 15 months).

Further evidence is required for a full evaluation of the efficacy of botulinum toxin therapy for sphincter of Oddi dysfunction. 

Vaginismus

At this time there are only two peer-reviewed published studies that address the efficacy or safety of botulinum toxin therapy for the treatment of vaginismus (Shafik, 2000; Ghazizadeh, 2004).  Both these studies have small numbers of participants and short-term follow-up.  Until the time when such data is available, the use of this therapy is not considered the standard of care for this condition.

Urologic Applications 

Botulinum toxin is currently being studied for the management of individuals with lower urinary tract dysfunctions including detrusor-sphincter dyssynergia and detrusor overactivity. Botulinum toxin is injected into the external urethral sphincter to treat detrusor sphincter dyssynergia, while intra-detrusal injection of botulinum toxin is employed in treating detrusor overactivity and symptoms of the overactive bladder (OAB).  Schurch and colleagues (2005) performed a single treatment, randomized, placebo-controlled study of botulinum therapy in 59 subjects with incontinence related to detrusor overactivity secondary to spinal cord injury (n=53) or multiple sclerosis (n=6) that was inadequately controlled with anticholinergic therapy.  Subjects were randomized to receive either botulinum toxin or placebo injection into the detrusor muscle.  The study demonstrated a statistically significant decrease (approximately 50%) in daily incontinence episodes in subjects treated with botulinum toxin over the duration of the 24 week trial.  Although the study is small, the results showed significant improvement to confirm the efficacy of botulinum toxin as a treatment of neurogenic incontinence.

In a study performed by De Seze and colleagues (2002), 13 subjects with chronic urinary retention due to detrusor sphincter dyssynergia from spinal cord injury were randomized to receive perineal botulinum toxin or lidocaine injections into the external urethral sphincter.  In the botulinum group, there was a significant decrease in the post-void residual volume (one of the endpoints) compared to no change in the control group receiving a lidocaine injection.  Improvements were also seen in the satisfaction scores and other urodynamic outcomes.

Cruz and others described the results of a double-blind, placebo-controlled trial comparing two different doses of Botox to saline placebo injection in a population with neurogenic detrusor overactivity (2011).  Individuals with both multiple sclerosis (MS) and spinal cord injury (SCI) were included in the study.  Experimental group subjects received either 200 units (n=92) or 300 units (n=91) of Botox.  All injections avoided the trigone region.  At six weeks, both experimental groups had significantly improved urinary incontinence episodes (p>0.01), maximum cystometric capacity, maximum detrusor pressure during the first voluntary detrusor contraction, and incontinence quality of life (p<0.001 for all three measures).  There were no differences noted between subjects with MS or SCI with regard to these benefits.  No significant difference was found between dose groups.

Chen and Kuo (2004) showed positive results with botulinum toxin when comparing Botox and no treatment in subjects with urinary problems due to intracranial lesions or cerebrovascular accidents.  Subjects who received a urethral injection of Botox showed improved voiding pressure and increased maximum urine flow rates (+3.1 mL/sec) compared to baseline (p less than 0.05).  No adverse effects or withdrawals were reported.

Patki and colleagues (2006) studied 37 subjects in the treatment of drug-resistant urinary incontinence due to acquired spinal cord injury.  All subjects received botulinum toxin-type A injected cystoscopically into the detrusor muscle.  At a mean follow-up of 7 months, maximum cystometric capacity increased from a mean of 259 to 522 mL and maximum detrusor pressure fell from 54 to 24 cm H₂0.  Incontinence was abolished in 82% of subjects and neurogenic detrusor overactivity was stopped in 76%.  In all, 86% of subjects were able to stop or reduce anticholinergics and a similar proportion showed an increase in quality-of-life scores.  The mean duration of symptomatic improvement was 9 months, and 12 subjects had a mean of 14 months of improvement.  Although the study is nonrandomized, the results showed significant improvement to confirm the efficacy of botulinum toxin as a treatment of drug-resistant urinary incontinence due to acquired spinal cord injury.

Other 2006 case series tend to support the use of botulinum toxin in drug-resistant urinary incontinence as well.  In a prospective uncontrolled case series performed by Schulte-Baukloh et al (2006), 16 subjects with neurogenic detrusor overactivity due to multiple sclerosis (MS) with drug-refractory overactive bladder (OAB) symptoms were given botulinum toxin injections into the bladder.  They concluded botulinum toxin detrusor injections are very effective in the treatment of drug-resistant OAB symptoms in individuals with MS as reflected in urodynamic measurements and in high treatment satisfaction.  However, it was also noted subjects need to be warned of the potential for increased residual volume that may require temporary self-catheterization.

Whiplash-related disorder

Botulinum toxin therapy has been proposed as a treatment for whiplash-related disorders.  There are only three small controlled trials for this treatment available in the peer-reviewed published literature. 

Freund and colleagues (2000) conducted a randomized, double blind, placebo controlled study with 26 subjects with chronic neck pain (WAD-II chronic).  One-half of the subjects (n=14) received 100 units botulinum toxin A diluted in 1 ml saline, while the other half received a total of 1 ml of saline alone (n=12).  Five trigger points were targeted and received 0.2 ml each of injectant via a 30 gauge needle.  At 4 weeks post-injection the treatment group was significantly improved from preinjection levels (p  less than 0.01).  The placebo group showed no statistically significant changes at any post-treatment time.  The authors stated that botulinum toxin treatment of subjects with chronic WAD II neck pain resulted in a significant (p less than 0.01) improvement in range of motion (ROM).

A randomized, placebo-controlled clinical trial to prove efficacy of botulinum toxin for neck pain in chronic whiplash syndrome was reported by Padberg et al. (2007).  Forty subjects with chronic whiplash syndrome (whiplash associated disorders grade 1 and 2) were randomly assigned to receive botulinum toxin (maximum 100 units) or placebo (saline) in muscles with increased tenderness.  After 12 weeks there was no significant difference between the two treatment groups in decrease of neck pain intensity, mean number of neck pain days, neck pain hours per day, days on which symptomatic treatment was taken , number of analgesics taken per day, and total cervical range of motion.  There also was no significant difference in subjects' assessment of improvement after week 4, 8 and 12.  The authors concluded that botulinum toxin was not proven effective in treatment of neck pain in chronic whiplash syndrome.

The most recent published article by Braker and others (2008) enrolled 20 subjects with cervical myofascial pain due to whiplash injury in a randomized controlled trial.  All participants were randomly assigned to receive either 200 U of botulinum toxin A or placebo at 4 trigger points and were seen during the follow-ups 3, 6, 9, 12, and 24 weeks after the injections.  The authors reported a time-dependent improvement in all the parameters in both groups, which was consistently larger in the botulinum toxin A-treated group, but mostly not at a significant level.  Significant differences between the groups were found only in the percentages of subjects who achieved 50% or more of reduction in intensity at 24 weeks (50% vs. 0%, p greater than 0.05 and 70% vs. 11%, p greater than >0.05, respectively).  Systemic adverse effects tended to be more common in the botulinum toxin A -treated group (40% vs. 0%, P=0.07).

Wrinkles 

The use of botulinum toxin for the treatment of facial or other wrinkles does not provide any proven medical benefit.  Any improvement in physical appearance is considered cosmetic regarding facial and other wrinkles.

Zygomatic fractures

At this time there are no peer-reviewed published studies that demonstrate the efficacy or safety of botulinum toxin therapy for the treatment of zygomatic fractures.  Until the time when such data is available, the use of this therapy is not considered the standard of care for this condition.

Tinnitus

It has been postulated that the blockage of autonomic pathways with botulinum toxin might have a favorable impact on the perception of tinnitus. In a randomized, double-blind study, Stidham and colleagues (2005) explored the use of botulinum toxin A injections for the treatment of tinnitus in thirty subjects with unilateral or bilateral non-pulsatile tinnitus with no evidence of middle ear disease for greater than two months. The subjects ranged in age from 31 to 73 years, with duration of symptoms from five months to 30 years, with a median duration of 72 months. Subjects were recruited from an existing population under care at a single treatment center for a variety of conditions including primary tinnitus, hearing loss, and Ménierè's disease. Subjects were randomized to receive three subcutaneous injections of botulinum toxin A near the ear followed by placebo injections four months later; a second group received placebo injections first followed by botulinum toxin A four months later. Included in the data analysis were twenty-six subjects who completed both injections.

After treatment, subjects' responses to treatment were recorded at one month and again at four months. Following treatment with botulinum toxin A, subjective tinnitus improved in seven subjects, worsened in three, and 16 were unchanged. Following placebo, two subjects were improved, seven worsened, and 17 were unchanged. Comparison of subjective responses in the treatment and placebo groups was statistically significant (p less than 0.005). However, using the standardized THI scale to judge response to treatment, there was no difference at one month between active and placebo treatments. A THI marginal statistical difference was reached only in the comparison of pre-botulinum toxin A to 4 months post treatment (p=0.042). However, no other significant differences were noted when comparing the two treatments at one and four months after injections. This study is limited by its small numbers, lack of intent to treat analysis, as well as differing etiologies and lengths of tinnitus. The authors concluded a larger study is needed before drawing conclusions regarding the potential benefit of botulinum toxin A in the treatment of tinnitus.

Botulinum is a family of toxins produced by the anaerobic organism Clostridia botulinum. There are 7 distinct serotypes designated as type A, B, C-1, D, E, F, and G. In this country, 4 preparations of botulinum are available, produced by 2 different strains of bacteria: type A (Botox^® [onabotulinumtoxinA], Dysport^® [abobotulinumtoxinA], and Xeomin^®  [incobotulinumtoxinA]) and type B (Myobloc™ [rimabotulinumtoxinB]). When administered intramuscularly, all botulinum toxins reduce muscle tone by interfering with the release of acetylcholine from nerve endings.  However, it should be noted that these drugs are not interchangeable and the potency ratios for dosing cannot be converted.  Careful adherence to the specific instructions for dosing in the package insert is recommended.

The U.S. Food and Drug Administration (FDA)-approved label for Botox states it is indicated for the treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain, primary axillary hyperhidrosis that is inadequately managed with topical agents, and strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or facial nerve (VII nerve) disorders in individuals older than 12 years, and for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults less than or equal to 65 years of age.  The use of botulinum toxin for the treatment of primary axillary hyperhidrosis is addressed in MED.00032 Treatment of Hyperhidrosis.  The FDA- approved label for Myobloc states it is indicated for the treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain.  The FDA-approved label for Dysport specifies that it is indicated for the treatment of cervical dystonia in adults to reduce the severity of abnormal head position and neck pain, and the temporary improvement in the appearance of moderate to severe glabellar lines in adults younger than 65 years of age.

Dystonia is a general term describing a state of abnormal or disordered tonicity of muscle. As an example, achalasia is a dystonia of the lower esophageal sphincter, while cervical dystonia is also known as torticollis. Spasticity is a subset of dystonia, describing a velocity-dependent increase in tonic-stretch reflexes with exaggerated tendon jerks. Spasticity typically is associated with injuries to the central nervous system. Spasticity is a common feature of cerebral palsy. Since its FDA approval in 1991, Botox has been used for a wide variety of off-label indications; all associated with dystonia, ranging from achalasia, spasticity after strokes, cerebral palsy, and anal fissures. In addition to widening indications, Botox has also been used in children under 12, particularly for the treatment of cerebral palsy.

The use of botulinum toxin for the treatment of cervical dystonia and spasmodic torticollis may be assessed using specific rating scales such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scale, which can aid in judging the individual's response to treatment.

It must be noted that there are several FDA-approved warnings in the package inserts for Botox, Dysport, Myobloc, and Xeomin regarding potential complications.  The first warning addressed potential problems when these drugs are used by individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome); "Patients with neuromuscular disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of either of these drugs".  The second warning addresses potential complications related to spread from the initial injection site.  The following was released by the FDA to health care professionals:

• Be aware that a Boxed Warning has been added to the prescribing information to highlight that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism. Symptoms such as unexpected loss of strength or muscle weakness, hoarseness or trouble talking (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids may occur.
• Understand that swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effects of spread of botulinum toxin.
• Be aware that children treated for spasticity are at greatest risk for these symptoms, but symptoms can also occur in adults treated for spasticity and other conditions.
• Be aware that cases of toxin spread have occurred at botulinum toxin doses comparable to those used to treat cervical dystonia and at lower doses.
• Be aware that no definitive serious adverse event reports of distant spread of toxin effect have been associated with dermatologic use of Botox/Botox Cosmetic at approved doses.
• Be aware that no definitive serious adverse event reports of distant spread of toxin effect have been associated with Botox for blepharospasm or for strabismus at approved doses.

Achalasia: A condition involving the esophagus and the muscle that separates the esophagus from the stomach. In this condition the esophagus is less able to move food toward the stomach and the valve from the esophagus to the stomach does not relax adequately during swallowing to allow the passage of food.

Benign Prostatic Hyperplasia: A condition characterized by non-cancerous overgrowth of the prostate gland leading to urinary dysfunction and other problems. 

Blepharospasm: A condition characterized by abnormal, involuntary blinking or spasm of the eyelids. 

Botulinum Toxin: A powerful drug that can be used to paralyze the nerves that motivate muscle movement.

Cervical Dystonia: A nervous system-related movement disorder characterized by neck muscles contracting involuntarily, causing abnormal movements and postures of the head and neck.

Detrusor Sphincteric Dyssynergia: A disturbance of the normal relationship between bladder (detrusor) contraction and sphincter relaxation during voluntary or involuntary voiding efforts.

Dystonia: A nervous system related movement disorder characterized by sustained muscle contractions.

Epicondylitis: A condition due to inflammation of the epicondyle (a part of the end of the humerus bone) or of the tissues adjoining the epicondyle of the humerus.  Also known as tennis elbow. 

Facial Nerve VII Disorders (also known as hemifacial spasm): A condition where the face muscles on one side of an individual's face contract involuntarily.

Hereditary Spastic Paraparesis (also known as familial spastic paralysis or parapalegia): A group of genetic disorders that are characterized by progressive weakness and spasticity (stiffness) of the legs.  Symptoms may occur alone in combination with a number of other neurological symptoms.

Idiopathic Torsion Dystonia (also known as primary dystonia): A group of genetic diseases of the nervous system, which cause involuntary abnormal twisting movements of the body. 

Infantile Cerebral Palsy: A group of disorders characterized by loss of movement or loss of other nerve functions; these disorders are caused by injuries to the brain that occur during fetal development or near the time of birth.

Migraine Day: One calendar day consisting of 4 hours or more of continuous migraine headache.

Multiple Sclerosis: A disorder of the brain and spinal cord caused by progressive damage to the outer covering of nerve cells.  This results in decreased nerve function leading to a variety of symptoms including muscle spasticity, atrophy, weakness, paralysis, or tremor of the limbs.

Neuromyelitis Optica (also known as Devic's disease): A rare nerve disorder characterized by inflammation and swelling of the nerves in the eyes and spinal cord.  Affected individuals may also experience loss of visual clarity (acuity), mild paralysis, and loss of bladder and bowel control.

Nystagmus: A condition characterized by an involuntary, rapid, rhythmic movement of the eyeball, which may be horizontal, vertical, rotary or mixed.

Organic Writer's Cramp: A task-specific focal dystonia of the hand; symptoms usually appear when a person is trying to do a task that requires fine motor movements; symptoms may appear only during a particular type of movement, such as writing or playing the piano, but the dystonia may spread to affect many tasks.

Orofacial Dyskinesia (also known as jaw closure dystonia): A condition where a individual's face or mouth are subject to involuntary movements due to muscle contractions.

Schilder's Disease: A rare progressive disease affecting the brain and nerves; symptoms may include dementia, difficulty speaking, seizures, personality changes, poor attention, and tremors.

Spasmodic Dysphonia or Laryngeal Dystonia: A disorder of speech due to abnormal control of the laryngeal muscles present only during the specific task of speaking.

Spastic Hemiplegia: A condition where one half of a individual's body is subject to involuntary muscle contractions leading to paralysis.

Spasmodic Torticollis: A congenital condition that is caused by a chronically contracted muscle on one side of the head that pulls the head (ear) down toward one shoulder as the chin tilts to the opposite side.

Sphincter of Oddi: A muscular structure that controls the flow of secretions from the liver, pancreas, and gallbladder into the duodenum of the small intestine; also known as the hepatopancreatic sphincter or Glisson's sphincter.

Strabismus: A condition where an individual's eyes are misaligned and point in different directions due to involuntary contractions of the muscles controlling the eyes.

Symptomatic Torsion Dystonia: A group of genetic diseases of the nervous system that cause involuntary abnormal twisting movements of the body.

Tinnitus: A perception of sound in the head when no outside sound is present. Typically referred to as "ringing in the ears" or "head noise," but other forms of sound have been described such as hissing, roaring, pulsing, whooshing, chirping, whistling and clicking. 

Vaginismus: A condition characterized by painful spasmodic contraction of the vagina.

Whiplash injury: A musculoskeletal injury due to hyperextension-hyperflexion of the neck.

Zygomatic fractures: A fracture of the zygoma, the portion of the skull that forms part of the floor and lateral wall of the orbit of the eye.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services are Medically Necessary:

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the codes listed above for those indications listed in the Position Statement section as not medically necessary. 

When services are Cosmetic and Not Medically Necessary:
For the procedure and botulinum toxin codes listed above for the following diagnoses, or when the code describes a procedure indicated in the Position Statement section as cosmetic and not medically necessary.

When services are Investigational and Not Medically Necessary:
For the codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

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2. Alberty J, Oelerich M, Ludwig K, et al. Efficacy of botulinum toxin A for treatment of upper esophageal sphincter dysfunction. Laryngoscope. 2000; 110(7):1151-1156.
3. Anand KS, Prasad A, Singh MM, et al. Botulinum toxin type A in prophylactic treatment of migraine. Am J Ther. 2006; 13(3):183-187.
4. Aurora SK, Gawel M, Brandes JL, et al. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007; 47(4):486-499. 
5. Aurora SK, Dodick DW, Turkel CC, et al. Onabotulinumtoxin A for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalgia  2010; 30:793-803.
6. Basciani M, Intiso D.  Botulinum toxin type-A and plaster cast treatment in children with upper brachial plexus palsy. Pediatr Rehabil. 2006; 9(2):165-170.
7. Benecke R. Xeomin in the treatment of cervical dystonia. Eur J Neurol. 2009; 16 Suppl 2:6-10.
8. Blumenfeld AM, Schim JD, Chippendale TJ.  Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache. 2008; 48(2):210-220.
9. Braker C, Yariv S, Adler R, et al.  The analgesic effect of botulinum-toxin A on postwhiplash neck pain. Clin J Pain. 2008; 24(1):5-10.
10. Brant C, Moraes-Filho JP, Siqueira E, et al. Intrasphincteric botulinum toxin injection in the treatment of chagasic achalasia. Dis Esophagus. 2003; 16(1):33-38
11. Brin MF, Lyons KE, Doucette J, et al. A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology. 2001; 56(11):1523-1528.
12. Brisinda G, Maria G, Bentivoglio AR, et al. A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. N Engl J Med. 1999; 341(2):65-69.
13. Cady R, Schreiber C. Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues. Headache. 2008; 48(6):900-913.
14. Chen RS, Lu CS, Tsai CH. Botulinum toxin A injection in the treatment of hemifacial spasm. Acta Neurol Scand. 1996; 94(3):207-211. 
15. Chen YH, Kuo HC. Botulinum A toxin treatment of urethral sphincter pseudodyssynergia in patients with cerebrovascular accidents or intracranial lesions. Urol Int. 2004; 73(2):156-161.
16. Cheshire WP, Abashian SW, Mann JD. Botulinum toxin in the treatment of myofascial pain syndrome. Pain. 1994; 59(1):65-69.
17. Childers MK, Wilson DJ, Gnatz SM, et al. Botulinum toxin type A use in piriformis muscle syndrome: a pilot study. Am J Phys Med Rehabil. 2002; 81(10):751-759.
18. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol. 2011; 60(4):742-750.
19. DeMatteo C, Bain JR, Galea V, Gjertsen D. Botulinum toxin as an adjunct to motor learning therapy and surgery for obstetrical brachial plexus injury. Dev Med Child Neurol. 2006; 48(4):245-252.
20. De Seze M, Petit H, Gallien P, et al. Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol. 2002; 42(1):56-62.
21. Desiato MT, Risina B. The role of botulinum toxin in the neuro-rehabilitation of young patients with brachial plexus birth palsy.  Pediatr Rehabil. 2001; 4(1):29-36.
22. Diener HC, Dodick DW, Aurora SK, et al. Onabotulinumtoxin A for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalgia  2010; 30:804-814.
23. Dodick DW, Mauskop A, Elkind AH, et al.; BOTOX CDH Study Group. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache. 2005; 45(4):315-324.
24. Dodick DW, Turkel CC, Degryse RE, et al. Onabotulinumtoxin A for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREMPT clinical program. Headache. 2010; 50(6):921-936.
25. Dowson C, Sahai A, Watkins J, et al. The safety and efficacy of botulinum toxin-A in the management of bladder oversensitivity: a randomised double-blind placebo-controlled trial. Int J Clin Pract. 2011; 6 5(6):698-704.
26. Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of onabotulinumtoxinA for idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. J Urol. 2010; 184(6):2416-2422. 
27. Dressler D. Routine use of Xeomin in patients previously treated with Botox: long term results. Eur J Neurol. 2009; 16 Suppl 2:2-5.
28. Espandar R, Heidari P, Rasouli MR, et al. Use of anatomic measurement to guide injection of botulinum toxin for the management of chronic lateral epicondylitis: a randomized controlled trial. CMAJ. 2010; 182(8):768-773.
29. Evers S.  Investigating prophylactic botulinum toxin type A for chronic headache disorders. Expert Opin Investig Drugs. 2006; 15(10):1161-1166. 
30. Evers S, Vollmer-Haase J, Schwaag S, et al. Botulinum toxin A in the prophylactic treatment of migraine – a randomized, double-blind, placebo-controlled study. Cephalalgia. 2004; 24(10):838-843.
31. Fishman LM, Anderson C, Rosner B. BOTOX and physical therapy in the treatment of piriformis syndrome. Am J Phys Med Rehabil. 2002; 81(12):936-942.
32. Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology. 2001; 56(10):1290-1293.
33. Freitag FG, Diamond S, Diamond M, Urban G. Botulinum Toxin Type A in the treatment of chronic migraine without medication overuse. Headache. 2008; 48(2):201-209.
34. Friedenberg F, Gollamudi S, Parkman HP. The use of botulinum toxin for the treatment of gastrointestinal motility disorders. Dig Dis Sci. 2004; 49:165-175.
35. Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol. 2004; 104(5 Pt 1):922-925.
36. Guyuron B, Reed D, Kriegler JS, et al. A placebo-controlled surgical trial of the treatment of migraine headaches. Plast Reconstr Surg. 2009; 124(2):461-648.
37. Hayton MJ, Santini AJ, Hughes PJ, et al. Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled, pilot study. J Bone Joint Surg Am. 2005; 87(3):503-507.
38. Heise CO, Goncalves LR, Barbosa ER, Gherpelli JL. Botulinum toxin for treatment of cocontractions related to obstetrical brachial plexopathy. Arq Neuropsiquiatr. 2005; 63(3A):588-591.
39. Jankovic J. Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm. Eur J Neurol. 2009; 16 Suppl 2:14-18.
40. Jankovic J, Comella C, Hanschmann A, Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-a randomized trial. Mov Disord. 2011; 26(8):1521-1528.
41. Jankovic J, Schwartz K, Clemence W, et al. A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord. 1996; 11(3):250-256.
42. Jongerius PH, van den Hoogen FJ, van Limbeek FJ, et al.  Effect of botulinum toxin in the treatment of drooling: a controlled clinical trial.  Pediatrics. 2004; 114(3):620-627.
43. Jost WH. One hundred cases of anal fissure treated with botulinum toxin: early and long-term results. Dis Colon Rectum. 1997; 40(9):1029-1032.
44. Kaňovský P, Slawek J, Denes Z,et al. Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. J Rehabil Med. 2011; 43(6):486-492.
45. Kanovský P, Slawek J, Denes Z, et al. Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol. 2009; 32(5):259-265.
46. Kayikcioglu A, Erk Y, Mavili E, et al. Botulinum toxin in the treatment of zygomatic fractures. Plast Reconstr Surg. 2003; 111(1):341-346.
47. Keizer SB, Rutten HP, Pilot P, et al: Botulinum toxin injection versus surgical treatment for tennis elbow: a randomized pilot study. Clin Orthop Relat Res. 2002; 401:125-131.
48. Kirazli Y, On AY, Kismali B, Aksit R. Comparison of phenol block and botulinus toxin type A in the treatment of spastic foot after stroke: a randomized, double-blind trial. Am J Phys Med Rehabil. 1998; 77(6):510-515.
49. Lipp A, Trottenberg T, Schink T, et al. A randomized trial of botulinum toxin A for treatment of drooling. Neurology. 2003; 61(9):1279-1281.
50. Lipton RB, Varon SF, Grosberg B, et al. OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine. Neurology. 2011 ; 77(15):1465-1472.
51. Mancini F, Zangaglia R, Cristina S, et al. Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in Parkinsonism. Mov Disord. 2003; 18(6):685-688.
52. Maria G, Brisinda G, Civello IM, et al. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology. 2003; 62(2):259-265.
53. Maria G, Cassetta E, Gui D, et al. A comparison of botulinum toxin and saline for the treatment of chronic anal fissure. N Engl J Med. 1998; 338(4):217-220.
54. Mathew NT, Frishberg BM, Gawel M, et al.  Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized double-blind, placebo-controlled trial.  Headache. 2005; 45(4):293-307.
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56. Miller LS, Parkman HP, Schiano TD, et al. Treatment of symptomatic nonachalasia esophageal motor disorders with botulinum toxin injection at the lower esophageal sphincter. Dig Dis Sci. 1996; 41(10):2025-2031.
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62. Park DS, Cho TW, Lee et al. Evaluation of short term clinical effects and presumptive mechanism of botulinum toxin type A as a treatment modality of benign prostatic hyperplasia. Yonsei Med J. 2006; 47(5):706-714.
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Government Agency, Medical Society, and Other Authoritative Publications: 

1. Al-Muharraqi MA, Fedorowicz Z, Al Bareeq J, et al. Botulinum toxin for masseter hypertrophy. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007510.
2. Blue Cross Blue Shield Association. Botulinum toxin for treatment of primary chronic headache disorders. Technology Evaluation Center. 2004.
3. Botox. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on: April 13, 2012.
4. Botulinum Toxin Monography. June 2008. American Hospital Formulary Service (AHFS). Available at: http://www.ashp.org.  Accessed on: April 13, 2012.
5. Costa J, Espírito-Santo C, Borges A, et al. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD003633.
6. Costa J, Espírito-Santo C, Borges A, et al. Botulinum toxin type A therapy for hemifacial spasm. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD004899.
7. Delgado MR, Hirtz D, Aisen M, et al. Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2010; 74(4):336-343. Available at: http://www.neurology.org/cgi/reprint/74/4/336. Accessed on March 08, 2012.
8. Duthie JB, Vincent M, Herbison GP, et al. Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst Rev. 2011 Dec 7;12:CD005493.
9. Hoare BJ, Wallen MA, Imms C, Villanueva E, et al. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE). Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD003469.
10. International headache Society.  The International Classification of Headache Disorders, Second Edition (ICHD-2). 2004. Criteria for Chronic Migraine. Available at: http://ihs-classification.org/en /.  Accessed on November 18, 2010.
11. Langevin P, Peloso PM, Lowcock J, et al. Botulinum toxin for subacute/chronic neck pain. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD008626.
12. Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005046.
13. MyoBlock. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on: March 21, 2011.
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15. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD006499.
16. Schwartz SR, Cohen SM, Dailey SH, et al.American Academy of Otolaryngology-Head and Neck Surgery Foundation. Clinical practice guideline: hoarseness (dysphonia). Otolaryngol Head Neck Surg. 2009; 141(3 Suppl 2):S1-S31.
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19. Singh JA, Fitzgerald PM. Botulinum toxin for shoulder pain. Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.: CD008271.
20. United States Food and Drug Administration.  Information for Healthcare Professionals: OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc). August, 2009. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm. Accessed on March 12, 2012.
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22. Young CA, Ellis C, Johnson J, et al. Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis. Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD006981.
23. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010; 74(11):924-931. Available at: http://www.neurology.org/cgi/reprint/74/11/924. Accessed on March 12, 2012.

1. Dystonia Medical Research Foundation. Available at:  http://www.dystonia-foundation.org. Accessed on March 12, 2012.
2. Institute of Neurological Disorders and Stroke. Cerebral Palsy Information Page.  Available at: http://www.ninds.nih.gov/health_and_medical/disorders/cerebral_palsy.htm. Accessed March 12, 2012.

AbobotulinumtoxinA
Botox^®
Botulinum Toxin Type A
Botulinum Toxin Type B
Dysport^®
IncobotulinumtoxinA
Myobloc™
OnabotulinumtoxinA
RimabotulinumtoxinB
Xeomin^®   

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.