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

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

• MED.00032 Treatment of Hyperhidrosis
• MED.00073 Treatment of Tinnitus

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
• Facial nerve (VII) dystonia
• Hereditary spastic paraparesis
• Idiopathic torsion dystonia
• Cerebral palsy
• Multiple sclerosis
• Neuromyelitis optica
• Organic writer's cramp
• Orofacial dyskinesia (i.e., jaw closure dystonia)
• Schilder's disease
• Spastic hemiplegia
• Spasticity related to stroke, or spinal cord injury
• 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)
• 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 patient 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 patients who are unable to tolerate scopolamine. 

The use of botulinum toxin is considered medically necessary as a treatment of incontinence related detrusor overreactivity 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. 

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, including but not limited to tension, migraine or chronic daily headaches.  

Botulinum toxin is considered investigational and not medically necessary as a treatment in all other conditions not addressed above, including, but not limited to, the following indications:

• 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
• Stuttering
• Tics associated with Tourette's Syndrome
• Tourette's Syndrome
• Tremors
• Urinary and anal sphincter dysfunction (except as listed above in the medically necessary section)
• Sphincter of Oddi dysfunction 
• 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 patient 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 patients 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 patients 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 patients (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 patients with achalasia.

Mikaeli and colleagues (2006) randomly assigned newly diagnosed achalasia patients 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 of patients 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%) patients 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. 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 patients 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 patients in the treated group and 3 in the control group had subjective symptomatic relief (P = 0.0007). In patients 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 patients 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 patients 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 patients were in the BT group and 26 were in the BTalpha group. At the one month follow-up, 18 patients 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 patients had subjective symptomatic relief. The storage symptoms were improved more than the voiding symptoms. Additionally, about 50 percent of the patients 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 patients 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 patients in the treatment group reported healing, compared to only 2 in the control group. The 4 patients who still had fissures after 2 months underwent retreatment with botulinum toxin; 2 of these 4 patients 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 patients. 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 patients 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 three randomized controlled trials describing the effectiveness of botulinum toxin therapy for epicondylitis (Keizer, 2002; Wong, 2005; Placzek, 2007). The studies reported by Wong (n=60) and Placzek (n=130) described trials where Botulinum toxin A was compared to saline placebo injections. Neither of these studies reported significant differences in objective measures at 12 and 18 weeks post-treatment, respectively. A third 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. 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 patients. 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

The interest in using botulinum as a treatment for headache stemmed from the observation that patients receiving pericranial injections of botulinum toxin for other reasons reported a decrease in the incidence of migraine. While it may exert its effect by relieving the muscle tension associated with migraine, it may also exert an effect by inhibiting nociceptive mediators such as glutamate, substance P and calcitonin gene related peptide. Botulinum has now been studied in a variety of headache disorders including episodic migraine headache, tension headache, cluster headache or chronic daily headache.

Due to inconsistent results in treating episodic migraine, tension and cluster headaches (Silberstein. 2000; Evers, 2004, Rollnik, 2000; Rollnik, 2004; Schmitt, 2001; Smuts, 1999; Ondo, 2004; Padberg, 2004; Relja, 2004; and Schulte-Mattler, 2004), research has now focused on the treatment of chronic daily headaches, defined as 16 or more headaches per month. The results of two randomized placebo controlled phase II trials have now been published.

Mathew and colleagues (2005) studied 355 patients 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; patients were evaluated every 30 days. The second trial by Silberstein and colleagues (2005) was similarly designed and enrolled 702 patients. The difference in the trials was primarily the doses of botulinum toxin used. The trial reported by Mathew and colleagues (2005) permitted a range of botulinum toxin doses injected into a variable number of injection sites. In contrast, in the trial reported by Silberstein, patients received one of three different doses of botulinum toxin injected into predetermined sites. In both studies, the primary outcome measure was the mean change from baseline in the frequency of headache-free days at day 180 for the placebo nonresponder group. 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. However, the trial design, in which placebo non-responders were randomized separately from placebo responders, is not consistent with the actual clinical use of botulinum toxin.

Anand and colleagues (2006) studied 32 patients receiving pericranial botulinum toxin injections for multiple monthly migraines. They reported 75% of the patients had some relief from migraine pain, but still had migraine associated decreased normal daily functioning.

Evers (2006) reviewed randomized double-blind, placebo-controlled trials and noted no sufficient evidence supporting the use of botulinum toxin for the treatment of tension and migraine headache. Evers specifically noted an increasing number of studies on botulinum toxin A in the treatment of idiopathic and symptomatic headache; however, he felt many of the studies were difficult to compare because of different end points and trial designs. Evers noted: "For the prophylactic treatment of tension-type headache and migraine, no sufficient positive evidence for a treatment with botulinum toxin A is obtained from randomized, double-blind, and placebo-controlled trials to date." He further stated: "For the treatment of chronic daily headache (including medication-overuse headache), there is inconsistent positive evidence for subgroups (e.g., patients without other prophylactic treatment). This means that most of the double-blind and placebo-controlled studies do not confirm the assumption that botulinum toxin A is efficacious in the treatment of idiopathic headache disorders; however, it is possible that some subgroups of patients with chronic migraine benefit from a long-term treatment for > or = 6 months." Further trials are needed to make this last determination.

In 2008, the American Academy of Neurology published an assessment on the use of botulinum toxin for the treatment of autonomic disorders and pain (Naumann, 2008). In this document the relevant studies addressing chronic daily headache, episodic migraines, and tension-type headaches are discussed. The AAN concludes that the evidence for the treatment of chronic daily headache is currently insufficient to support or refute a benefit of treatment with BoNT (botulinum toxin). For treatment of episodic migraines and tension-type headaches the AAN states that the use of botulinum toxin is "probably ineffective" for these conditions. The final AAN recommendation regarding the treatment of headaches is as follows:
"BoNT injections should not be considered in patients with episodic migraine and chronic tension-type headaches."

Low Back Pain

Foster et al. (2001) report a randomized, double-blind study of botulinum toxin A in 31 consecutive patients 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. Patients 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 patients 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. Patients 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 patients and 25% of placebo showed a response on VAS scores (p=0.012). This difference in VAS scores remained significant at 8 weeks with 60% of treated patients and 12.5% of placebo patients still responding (p=0.009). The OLBPQ assessment at 8 weeks showed that 66.7% of treated patients and 18.8% of placebo patients were responders (p=0.011). These results show clinically significant and statistically significant improvements in treated patients 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. Patients 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 patients 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 patients randomized to high-dose botulinum toxin or placebo. A crossover study of only 6 patients (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 patients (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 patients (Fishman, 2002) found that the patient 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 patients with acquired nystagmus with prominent vertical or torsional component. Each patient 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 patients for about two to three months. The patient who received 25 units developed complete external ophthalmoplegia and blepharoptosis. The other two patients retained some voluntary movements but developed diplopia. In one patient, visual acuity improved from Jaeger 5 to Jaeger 1. In a second patient, 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 patient with predominantly torsional nystagmus, visual acuity was unchanged at Jaeger 2. No patient 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 patients (nine eyes) with acquired nystagmus. The patients received retrobulbar injection of 25 to 30 U of botulinum neurotoxin A. Patients were followed up for changes in their visual function for at least 6 months following the last injection. Each patient 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 patients 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 patients 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 patients with tremors unrelated to dystonias. One randomized study by Pahwa (1995) reported on 10 patients with essential head tremor. Patients were randomized to receive either botulinum injections into the sternocleidomastoid or splenius capitus muscle. Five patients improved in the treatment group compared to 3 in the control 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 patients, 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 patients who had undergone cholecystectomy and had manometrically confirmed type III sphincter of Oddi (SOD) dysfunction. All patients received an endoscopic injection of 100 mouse units of botulinum toxin into the papilla of Vater. With the exception of one patient with mild pancreatitis (4.5%), no side effects were observed. Six weeks after botulinum toxin A injection, 12 SOD patients (55%) were symptom-free, and ten patients (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 patients became free of complaints again after endoscopic sphincterotomy during a median follow-up of a further 15 months.

The second study (2000) involved 15 patients 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 patients remained asymptomatic (80% primary response). Only one out of three patients without symptomatic benefit showed continued elevated pancreatic sphincter pressure at manometry and only this patient benefited from pancreatic sphincterotomy later on. Eleven of the 12 patients initially responding to botulinum toxin injection developed a symptomatic relapse 6 +/- 2 months after botulinum toxin treatment. These patients 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 patients 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 on botulinum therapy in 59 patients 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. Patients 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 patients 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 patients 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.

Chen and Kuo (2004) showed positive results with botulinum toxin when comparing Botox and no treatment in patients with urinary problems due to intracranial lesions or cerebrovascular accidents. Patients 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<0.05). No adverse effects or withdrawals were reported.

Patki and colleagues (2006) studied 37 patients in the treatment of drug-resistant urinary incontinence due to acquired spinal cord injury. All patients 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 patients and neurogenic detrusor overactivity was stopped in 76%. In all, 86% of patients 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 patients 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 patients 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 MS patients as reflected in urodynamic measurements and in high patient satisfaction. However, it was also noted patients 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 patients with chronic neck pain (WAD-II chronic). One-half of the patients (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 < 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 < 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 patients with chronic whiplash syndrome (whiplash associated disorders grade 1 and 2) were randomly assigned to receive botulinum toxin (maximum 100 units) or placebo (saline) in muscles with increased tenderness. 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 patients' 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 patients 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 patients who achieved 50% or more of reduction in intensity at 24 weeks (50% vs. 0%, P>0.05 and 70% vs. 11%, P>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.

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, 3 preparations of botulinum are available, produced by 2 different strains of bacteria: type A (Botox^® [OnabotulinumtoxinA] and Dysport^® [AbobotulinumtoxinA]) 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 patients 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 adult patients ≤ 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 patient's response to treatment.

It must be noted that in there are several FDA-approved warning for the package inserts for Botox, Dysport, and Myobloc regarding potential complications. The first warning addressed potential problems when these drugs are used by patients 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 a patient'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

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 patient'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 patient'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 a patient'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

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.  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 are also Medically Necessary:

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above, with the following diagnoses for spasmodic torticollis or cervical dystonia, or drooling:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met. 

When services are Cosmetic and Not Medically Necessary:
For the procedure 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 procedure codes listed above, 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:

1. Ahsan SF, Meleca RJ, Dworkin JP. Botulinum toxin injection of the cricopharyngeus muscle for the treatment of dysphagia. Otolaryngol Head Neck Surg. 2000; 122:691-695.
2. Alberty J, Oelerich M, Ludwig K. Efficacy of botulinum toxin A for treatment of upper esophageal sphincter dysfunction. Laryngoscope. 2000; 110:1151-1156.
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. 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.
6. 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.
7. 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.
8. 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
9. 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.
10. 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.
11. 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.
12. Cheshire WP, Abashian SW, Mann JD. Botulinum toxin in the treatment of myofascial pain syndrome. Pain. 1994; 59(1):65-69.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Evers S. Status on the use of botulinum toxin for headache disorders. Curr Opin Neurol. 2006; 19(3):310-315.
19. Evers S.  Investigating prophylactic botulinum toxin type A for chronic headache disorders. Expert Opin Investig Drugs. 2006; 15(10):1161-1166. 
20. 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.
21. Fishman LM, Anderson C, Rosner B. BOTOX and physical therapy in the treatment of piriformis syndrome. Am J Phys Med Rehabi. 2002; 81(12):936-942.
22. Foster L, Clapp L, Erickson M, et al. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology. 2001; 56(10):1290-1293.
23. Friedenberg F, Gollamudi S, Parkman HP. The use of botulinum toxin for the treatment of gastrointestinal motility disorders. Digestive Diseases and Sciences. 2004; 49:165-175.
24. Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol. 2004; 104(5 Pt 1):922-925..
25. 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.
26. 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.
27. 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; 114:620-627.
28. 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.
29. Kayikcioglu A, Erk Y, Mavili E. Botulinum toxin in the treatment of zygomatic fractures. Plast Reconstr Surg. 2003; 111:341-346.
30. Keizer SB, Rutten HP, Pilot P, et al: Botulinum toxin injection versus surgical treatment for tennis elbow. Clin Orthop Relat Res. 2002; 401:125-131.
31. Kirazli Y, On AY, Kismali B, et al. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. Mathew NT, Frishberg BM, Gawel M, et al.  Botulinum toxin type A for the prophylactic treatment of chronic daily headache: A randomized double blind, placebo-controlled trial.  Headache. 2005:293-307.
37. Mikaeli J, Bishehsari F, Montazeri G, et al. Injection of botulinum toxin before pneumatic dilatation in achalasia treatment: a randomized-controlled trial.Aliment Pharmacol Ther. 2006; 24(6):983-989.
38. Miller LS, Parkman HP, Schiano TD: Treatment of symptomatic nonachalasia esophageal motor disorders with botulinum toxin injection at the lower esophageal sphincter. Dig Dis Sci. 1996; 41:2025-2031.
39. Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease. Neurology. 2004; 62(1):37-40.
40. Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia. 2004; 24(1):60-65.
41. Padberg M, de Bruijn, de Haan RJ, et al. Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial. Cephalalgia. 2004; 24(8):675-680.
42. Padberg M, de Bruijn SF, Tavy DL. Neck pain in chronic whiplash syndrome treated with botulinum toxin. A double-blind, placebo-controlled clinical trial. J Neurol. 2007; 254(3):290-295.
43. Pahwa R, Busenbark K, Swanson-Hyland EF, et al. Botulinum toxin treatment of essential head tremor. Neurology. 1995; 45(4):822-824.
44. 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.
45. Pasricha PJ, Miskovsky EP, Kalloo AN. Intrasphincteric injection of botulinum toxin for suspected sphincter of Oddi dysfunction. Gut. 1994; 35:1319-1321.
46. Patki PS, Hamid R, Arumugam K, et al.. Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int. 2006; 98(1):77-82.
47. Placzek R, Drescher W, Deuretzbacher G, et al. Treatment of chronic radial epicondylitis with botulinum toxin A. A double-blind, placebo-controlled, randomized multicenter study. :J Bone Joint Surg Am. 2007; 89(2):255-260. 
48. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain. 2000; 85(1-2):101-105.
49. Price AE, Ditaranto P, Yaylali I, et al.  Botulinum toxin type A as an adjunct to the surgical treatment of the medial rotation deformity of the shoulder in birth injuries of the brachial plexus. J Bone Joint Surg Br. 2007; 89(3):327-329.
50. Reid SM, Johnstone BR, Westbury C, et al. Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders. Dev Med Child Neurol. 2008; 50(2):123-128. 
51. Relja M, Poole AC, Schoenen J, et al. European BoNTA Headache Study Group.A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007; 27(6):492-503.
52. Relja M, Telarovic S. Botulinum toxin in tension-type headache. J Neuro.l 2004; 251(suppl):112-114.
53. Repka MX, Savino PJ, Reinecke RD. Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol. 1994; 112:1320-1324.
54. Rollnik JD, Karst M, Fink M, et al. Botulinum toxin type A and EMG: a key to the understanding of chronic tension-type headaches? Headache. 2001; 41(10):985-989.
55. Rollnik JD, Tanneberger O, Schubert M, et al. Treatment of tension-type headache with botulinum toxin type A: a double-blind placebo-controlled study. Headache .2000; 40(4):300-305.
56. Rollnik JD, Hierner R, Schubert M, et al. Botulinum toxin treatment of cocontractions after birth-related brachial plexus lesions. Neurology. 2000; 55(1):112-114.
57. Saper JR, Mathew NT, Loder EW,  et al. BoNTA-009 Study Group. A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine. Pain Med. 2007; 8(6):478-485.
58. Saper, JR. Mathew NT, Loder EW, et al. Botulinum toxin A in the prophylactic treatment of migraine--a randomized, double-blind, placebo-controlled study. Pain Med 2007; 8:478-485. 
59. Schmitt WJ, Slowey E, Fravi N, et al. Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial. Headache. 2001; 41(7):658-664.
60. Schulte-Baukloh H, Schobert J, Stolze T, et al. Efficacy of botulinum-A toxin bladder injections for the treatment of neurogenic detrusor overactivity in multiple sclerosis patients: an objective and subjective analysis. Neurourol Urodyn. 2006; 25(2):110-105. 
61. Schulte-Mattler WJ, Krack P. Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study. Pain. 2004; 109(1-2):110-104.
62. Schulte-Mattlera  WJ, Martinez-Castrillob JC. Botulinum toxin therapy of migraine and tension-type headache: comparing different botulinum toxin preparations.  Eur J Neurol. 2006; 13 Suppl 1:51-54. 
63. Schurch B, de Seze M, Denys P, et al. Botulinum toxin type A is a safe and effective treatment of neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol. 2005; 174(1):196-200.
64. Shafik A, El-Sibai O. Vaginismus: results of treatment with botulinum toxin. J Obstet Gynaecol. 2000; 20(3):300-302. 
65. Silberstein SD, Stark SR, Lucas SM, et al.  Botulium toxin type A for the prophylactic treatment of chronic daily headache: A randomized double blind, placebo controlled trial.  Mayo Clin Proceedings. 2005; 80:1126-1137.
66. Silberstein S, Mathew N, Saper J, et al. Botulinum toxin type A as a migraine preventive treatment. Headache. 2000; 40(6):445-450.
67. Simpson DM, Gracies JM, Yablon SA, et al. BoNT/TZD Study Team. Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study. J Neurol Neurosurg Psychiatry. 2009; 80(4):380-385
68. Smith SJ, Ellis E, White S, et al. A double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injury. Clin Rehabil. 2000; 14(1):5-13.
69. Smuts JA, Baker MK, Smuts HM, et al. Prophylactic treatment of chronic tension-type headache using botulinum toxin type A. Eur J Neurol. 1999; 6(suppl 4):S99-102.
70. Stidham KR, Solomon PH, Roberson JB. Evaluation of botulinum toxin A in the treatment of tinnitus, Otolaryngol Head and Neck Surg. 2005; 132(6):883-889.
71. Storr M, Allescher HD, Rosch T, et al. Treatment of symptomatic diffuse esophageal spasm by endoscopic injection of botulinum toxin: a prospective study with long term follow-up. Gastrointest Endosc. 2001; 54:754-759.
72. Straube A, Empl M, Ceballos-Baumann A, et al. Dysport Tension-Type Headache Study Group. Pericranial injection of botulinum toxin type A (Dysport) for tension-type headache - a multicentre, double-blind, randomized, placebo-controlled study. Eur J Neurol. 2008; 15(3):205-213. 
73. Tomsak RL, Remler BF, Averbuch-Heller L, et al. Unsatisfactory treatment of acquired nystagmus with retrobulbar injection of botulinum toxin. Am J Ophthalmol. 1995; 119:489-496.
74. Vaezi MF, Richter JE, Wilcox CM, et al. Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial. Gut. 1999; 44(2):231-239.
75. Wehrmann T, Schmitt TH, Arndt, A et al. Endoscopic injection of botulinum toxin in patients with recurrent acute pancreatitis due to pancreatic sphincter of Oddi dysfunction. Aliment Pharmacol Ther. 2000; 14:1469-1477.
76. Wehrmann T, Seifert H, Seipp M, et al. Endoscopic injection of botulinum toxin for biliary sphincter of Oddi dysfunction. Endoscopy. 1998; 30:702- 707.
77. Werner M, Schmid DM, Schussler B. Efficacy of botulinum-A in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol. 2005; 192(5):1735-1740.
78. Wheeler AH, Goolkasian P, Gretz SS. A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal myofascial pain syndrome. Spine. 1998; 23(15):1662-1667.
79. Wheeler AH, Goolkasian P, Gretz SS. Botulinum toxin A for the treatment of chronic neck pain. Pain. 2001; 94(3):255-260.
80. Wong SM, Hui AC, Tong PY, et al. Treatment of lateral epicondylitis with botulinum toxin: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2005;143(11):838-839.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. Al-Muharraqi MA, Fedorowicz Z, Al Bareeq J, Al Bareeq R, Nasser M. Botulinum toxin for masseter hypertrophy. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007510.
2. Blue Cross Blue Shield Assoc. 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: June 22, 2009.
4. Botulinum Toxin Monography. June 2008. American Hospital Formulary Service (AHFS). Available at: http://www.ashp.org.  Accessed on June 22, 2009.
5. Costa J, Espírito-Santo C, Borges A, Ferreira JJ, Coelho M, Moore P, Sampaio C. 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, Ferreira JJ, Coelho M, Moore P, Sampaio C. Botulinum toxin type A therapy for hemifacial spasm. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD004899.
7. Duthie J, Wilson DI, Herbison GP, Wilson D. Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD005493.
8. Hayes Medical Technology Directory. Botulinum Toxin Treatment for Spasticity Following Stroke. Winifred S. Hayes, Inc., Lansdale PA. December 22, 2008.
9. Hayes Medical Technology Directory. Botulinum Toxin Treatment for Spasticity Due to Cerebral Palsy. Winifred S. Hayes, Inc., Lansdale PA. November 25, 2008.
10. Hayes Medical Technology Directory. Botulinum toxin treatment for dystonias. Winifred S. Hayes, Inc., Lansdale PA. February, 2006. Search updated March 30, 2008..
11. 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.
12. MyoBlock. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com  Accessed on: June 22, 2009.
13. Nelson R. Non surgical therapy for anal fissure. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003431.
14. Naumann M, So Y, Argoff CE, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008; 70(19):1707-1714.   
15. Peloso P, Gross A, Haines T, Trinh K, Goldsmith CH, Aker P, Cervical Overview Group. Medicinal and Injection therapies for mechanical neck disorders. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD000319.
16. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD006499.
17. Simpson DM, Blitzer A, Brashear A, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008a; 70(19):1699-1706.   
18. Simpson DM, Gracies JM, Graham HK, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008b; 70(19):1691-1698.
19. 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 August 4, 2009.

1. Dystonia Medical Research Foundation. Available at:  http://www.dystonia-foundation.org. Accessed on June 22, 2009.
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 June 22, 2009.

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

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.