Botulinum Toxin 

  • Author: Divakara Kedlaya, MBBS; Chief Editor: Consuelo T Lorenzo, MD   more...
 
Updated: Apr 25, 2012
 

Overview

Botulinum toxin (abbreviated either as BTX or BoNT) is produced by Clostridium botulinum, a gram-positive anaerobic bacterium. The clinical syndrome of botulism can occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from a wound infection.

BoNT is broken into 7 neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in animals.

The various botulinum toxins possess individual potencies, and care is required to assure proper use and avoid medication errors. Recent changes to the established drug names by the FDA were intended to reinforce these differences and prevent medication errors. The products and their approved indications include the following:

  • OnabotulinumtoxinA (Botox, Botox Cosmetic)
    • Botox - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity
    • Botox Cosmetic - Moderate-to-severe glabellar lines
  • AbobotulinumtoxinA (Dysport) - Cervical dystonia, moderate-to-severe glabellar lines
  • IncobotulinumtoxinA (Xeomin) - Cervical dystonia, blepharospasm
  • Rimabotulinumtoxin B (Myobloc) - Cervical dystonia

The BoNT molecule is synthesized as a single chain (150 kD) and then cleaved to form the dichain molecule with a disulfide bridge (see image below).

Botulinum toxin structure (schematic diagram). Botulinum toxin structure (schematic diagram).

The light chain (~50 kD - amino acids 1-448) acts as a zinc (Zn2+) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end (see image below). The heavy chain (~100 kD - amino acids 449-1280) provides cholinergic specificity and is responsible for binding the toxin to presynaptic receptors; it also promotes light-chain translocation across the endosomal membrane.

Proteolytic activity is located at the N-terminal Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A.

For patient education resources, see the Procedures Center, as well as BOTOX® Injections.

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History

The German physician and poet Justinus Kerner (1786-1862) first developed the idea of a possible therapeutic use of botulinum toxin, which he called "sausage poison."

  • In 1870, Muller (another German physician) coined the name botulism. The Latin form is botulus, which means sausage.
  • In 1895, Professor Emile Van Ermengem, of Belgium, first isolated the bacterium Clostridium botulinum.
  • In 1928, Dr. Herman Sommer, at the University of California, San Francisco, first isolated in purified form botulinum toxin type A (BoNT-A) as a stable acid precipitate.
  • In 1946, Dr. Edward J Schantz succeeded in purifying BoNT-A in crystalline form–cultured Clostridium botulinum and isolated the toxin.
  • In 1949, Dr. Burgen's ASV group discovered that botulinum toxin blocks neuromuscular transmission.
  • In the 1950s, Dr. Vernon Brooks discovered that when BoNT-A is injected into a hyperactive muscle, it blocks the release of acetylcholine from motor nerve endings.
  • In 1973, Dr. Alan B. Scott, of Smith-Kettlewell Eye Research Institute, used BoNT-A in monkey experiments; in 1980, he used BoNT-A for the first time in humans to treat strabismus.
  • In December 1989, BoNT-A (BOTOX®) was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients aged younger than 12 years.
  • On December 21, 2000, BoNT-A received FDA approval for treatment of cervical dystonia.
  • In 2001, the United Kingdom approved BOTOX®, synthesized by Allergan, for axillary hyperhidrosis (excessive sweating). Canada approved BOTOX® for axillary hyperhidrosis, focal muscle spasticity, and cosmetic treatment of wrinkles at the brow line.
  • On April 15, 2002, the FDA announced the approval of BOTOX® Cosmetic to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). On July 21, 2011, the FDA approved incobotulinumtoxinA (Xeomin) for temporary improvement in the appearance of moderate-to-severe glabellar lines, or frown lines between the eyebrows, in adult patients.
  • In July 2004, the FDA approved BOTOX® to treat severe underarm sweating, known as primary axillary hyperhidrosis, that cannot be managed by topical agents, such as prescription antiperspirants.
  • Although it has not been approved by the FDA for any other indications, the acceptance of BoNT-A use for the treatment of spasticity and muscle pain disorders is growing, with approvals pending in many European countries.
  • The clinical use of BoNT-B has been studied, and several products currently are available commercially (eg, MyoBloc, in the United States; NeuroBloc, in Europe). MyoBloc was approved by the FDA on December 8, 2000, for treatment of cervical dystonia, to reduce the severity of abnormal head position and neck pain.
  • Use of BoNT-F also is under investigation in patients who have become immunologically resistant to serotypes A and B.
  • On April 29, 2009, abobotulinumtoxinA (Dysport) was approved by the FDA for the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients.
  • On March 9, 2010, the FDA approved onabotulinumtoxinA (BOTOX®) to treat spasticity in the flexor muscles of the elbow, wrist, and fingers in adults with stroke, traumatic brain injury, or the progression of multiple sclerosis.
  • On August 2, 2010, the FDA announced the approval of incobotulinumtoxinA (Xeomin) for the treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients and for blepharospasm in adults previously treated with BOTOX®.
  • On October 15, 2010, the FDA approved onabotulinumtoxinA (BOTOX®) injection to prevent headaches in adult patients with chronic migraine. Chronic migraine is defined as having a history of migraine and experiencing a headache on most days of the month.
  • On August 24, 2011, the FDA approved onabotulinumtoxinA (BOTOX®) injection for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.
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Mechanism of Action

Botulinum toxin acts by binding presynaptically to high-affinity recognition sites on the cholinergic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect. This mechanism laid the foundation for the development of the toxin as a therapeutic tool.

Recovery occurs through proximal axonal sprouting and muscle re-innervation by formation of a new neuromuscular junction. De Paiva and colleagues suggest that eventually the original neuromuscular junction regenerates.[1]

  • BoNT-A and BoNT-E cleave synaptosome-associated protein (SNAP-25), a presynaptic membrane protein required for fusion of neurotransmitter-containing vesicles.
  • BoNT-B, BoNT-D, and BoNT-F cleave a vesicle-associated membrane protein (VAMP), also known as synaptobrevin.
  • BoNT-C acts by cleaving syntaxin, a target membrane protein.

Table 1. Botulinum Toxin Types, Target Sites, Discoverers, and Year Discovered (Open Table in a new window)

TypeTargetDiscovererYear
ASNAP-25Landman1904
BVAMPErmengem1897
C1SyntaxinBengston and Seldon1922
DVAMPRobinson1929
ESNAP-25Gunnison1936
FVAMPMoller and Scheibel1960
GVAMPGimenez and Ciccarelli1970
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Preparations

The different preparations of BoNT-A, onabotulinumtoxinA (BOTOX®; Allergan; Irvine, Calif), abobotulinumtoxinA (Dysport; Ipsen; Paris, France), incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Frankfurt, Germany) and CS-BOT (Chiba Serum Institute; Chiba, Japan), differ in potency.

  • BoNT-A is prepared by laboratory fermentation of C botulinum cultures. Crude botulinum toxin is a protein with a molecular weight of about 190,000 Daltons. After purification, the toxin is diluted with human serum albumin, bottled in vials, lyophilized (freeze-dried), and sealed.
  • Each freeze-dried vial containing 100 units (U) of BoNT-A is reconstituted with preservative-free normal saline (1-5 mL) just before use. The manufacturer recommends that the toxin be used within 4 hours of reconstitution.
  • The potency of BoNT-A is measured in mouse units (MU). One MU of BoNT-A is equivalent to the amount of toxin that kills 50% of a group of 20 g Swiss-Webster mice within 3 days of intraperitoneal injection (LD50).
  • According to one report, 1 nanogram of toxin contains approximately 20 U of BOTOX® (ie, 1 U of BOTOX® is equal to approximately 0.05 nanogram of the toxin).
  • According to another report comparing the 3 different preparations of BoNT-A, 1 nanogram of Dysport contains approximately 40 MU, whereas 1 nanogram of the BOTOX® contains approximately 4 MU, and 1 nanogram of CS-BOT contains approximately 15.2 MU.
  • LD50 of BoNT-A for a 70-kg adult male has been calculated to be 2500-3000 U (35-40 U/kg).
  • Minimum lethal dose of BoNT-B in monkeys is 2400 U/kg.
  • Clinically, 1 U of BoNT-A (BOTOX®) is approximately equivalent to 3 U of Dysport.[2]
  • Standardization efforts are underway using measurements of the toxin's pharmacologically relevant actions (eg, median paralysis unit).
  • BoNT-B is marketed in the United States as MyoBloc. This preparation is a ready-to-use solution that does not require reconstitution; it is available in 3 vial sizes (ie, 2500 U, 5000 U, and 10,000 U) and is stable for up to 21 months in refrigerator storage.
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Therapeutic Uses

Therapeutic uses of botulinum toxin injection

  • Focal dystonias - Involuntary, sustained, or spasmodic patterned muscle activity
    • Cervical dystonia (spasmodic torticollis)[3, 4]
    • Blepharospasm (eyelid closure)
    • Laryngeal dystonia (spasmodic dysphonia)
    • Limb dystonia (writer's cramp)
    • Oromandibular dystonia
    • Orolingual dystonia
    • Truncal dystonia
  • Spasticity - Velocity-dependent increase in muscle tone
  • Nondystonic disorders of involuntary muscle activity
    • Hemifacial spasm
    • Tremor
    • Tics
    • Myokymia and synkinesis
    • Myoclonus (tensor veli palatini muscle [middle ear], causing tinnitus)
    • Hereditary muscle cramps
    • Nocturnal bruxism[7]
    • Trismus[8]
    • Anismus[9]
  • Strabismus (disorder of conjugate eye movement) and nystagmus
  • Chronic pain and disorders of localized muscle spasms
  • Smooth muscle hyperactive disorders
  • Cosmetic use
    • Hyperkinetic facial lines (glabellar frown lines, crow's feet)
    • Hypertrophic platysma muscle bands
  • Sweating, salivary, and allergy disorders
    • Axillary and palmar hyperhidrosis
    • Frey syndrome, also known as auriculotemporal syndrome (gustatory sweating of the cheek after parotid surgery)
    • Drooling in cerebral palsy and other neurological disorders[38, 39, 40, 41]
    • Nasal allergy[42]
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Botulinum Toxin Use in Dystonia

Use of BoNT-A in different types of focal dystonias has been well studied and has proven to be very effective. Botulinum toxin injection is the treatment of choice for cervical dystonia (spasmodic torticollis).[3, 4, 43] This injection benefits the highest percentage of patients in the shortest time and has been proven effective in many double-blind, placebo-controlled trials. Botulinum toxin injection has fewer side effects than do other pharmacologic treatments.

In a double-blind, placebo-controlled trial by Greene and colleagues, 55 patients who previously had failed to find relief in 2 trials of medication received either BoNT or placebo in a double-blinded fashion and were tracked for 12 weeks.[44] Four weeks of open phase then followed when all patients received BoNT. By 6 weeks, 61% of patients showed improvement in head posture, and 39.5% reported reduction of pain. Both measures significantly improved (P < .05) compared to controls. During the open phase, patients who previously received placebo exhibited a similar response. Overall, 74% of patients improved by the end of the study.

A study by Brans and colleagues showed that in 64 patients with cervical dystonia, 84% reported long-term benefits in terms of impairment, disability, handicap, and quality of life (QOL).[45]

Procedure

Treatment dosages of BoNT-A in the United States have been reported to range from 100-300 U per patient. In a double-blind, placebo-controlled study, Poewe and colleagues demonstrated that magnitude and duration of improvement were greatest after injections of 1000 U of Dysport, but the injections caused significantly more adverse effects.[46] The researchers recommended a lower starting dose of 500 U of Dysport (1 U of BoNT-A = 3 U of Dysport). One hundred U of toxin per mL of preservative-free normal saline are commonly used.

Injections are performed with a Teflon-coated, 24-gauge needle connected to an electromyographic (EMG) machine. Those muscles with highest clinical and EMG activity are injected. Usually, 2-4 separate muscles are injected in 1 session and, in larger muscles, 2-4 sites per muscle are injected.

No general consensus exists among users of BoNT regarding the need for EMG guidance while injecting the compound for cervical dystonia. EMG guidance, however, is helpful, particularly in obese patients whose neck muscles cannot adequately be palpated.

Identifying the specific muscles involved in cervical dystonia prior to the injection is important. Those most commonly injected are the sternocleidomastoid, trapezius, splenius capitis, and levator scapulae muscles. An EMG study of 100 patients found that 2 or 3 muscles commonly are abnormal. Eighty-nine percent of patients with rotating torticollis had involvement of the ipsilateral splenius capitis and contralateral sternocleidomastoid with or without the additional involvement of the contralateral splenius capitis. Patients with laterocollis had ipsilateral sternocleidomastoid, splenius capitis, and trapezius involvement, while retrocollis was produced by bilateral splenius capitis activity.

Beneficial effect from toxin injection usually is apparent in 7-10 days. Maximum response from the toxin is reached in approximately 4-6 weeks and lasts for an average of 12 weeks. Injections usually are repeated every 3-4 months.

Complications

Neck weakness, dysphagia, and local pain at the injection site are the most commonly reported side effects. Other adverse effects (eg, local hematoma, generalized fatigue, lethargy, dizziness, dry mouth, dysphonia, flulike syndrome, pain in neighboring muscles) also have been reported.

Most studies have reported side effects in 20-30% of patients per treatment cycle. The incidence of adverse effects varies based on the dosage used (ie, the higher the dose, the more frequent the adverse effects); however, Jankovic and Schwartz reported that incidence of complications was not related to the total dose of BoNT used.[47] Women and patients who received injections into the sternocleidomastoid muscles had significantly higher rates of complications.

Dysphagia has been the most prevalent significant complication and most probably is related to diffusion of the toxin into nearby pharyngeal muscles. In the study by Comella and colleagues, 33% of patients receiving their first dose of botulinum toxin experienced dysphagia.[48] This complication most commonly occurs with injections of the sternocleidomastoid and can be reduced significantly when the dose of toxin administered is 100 U or less.

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Botulinum Toxin Use in Spasticity

Spasticity is defined as a velocity-dependent increase in muscle tone. Intramuscular injections of BoNT have been studied and found to be useful in the treatment of spasticity in multiple sclerosis (MS), cerebral palsy (CP), stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). Different studies have shown the effectiveness of BoNT-A injection in the management of spasticity.[5]

Table 2. Studies of Botulinum Toxin in the Treatment of Spasticity in Different Disorders (Open Table in a new window)

Clinical DiagnosisAuthorStudy Design
Multiple SclerosisBenecke



Borg-Stein et al[49]



Snow et al[50]



Hyman et al[51]



Open-label



Open-label



Double-blind, placebo-controlled, randomized, crossover



Double-blind, placebo-controlled, randomized, dose-ranging



Spinal Cord InjuryBohlega et al



Takenaga et al



Open-label



Open-label



Cerebral PalsyKoman et al[52] Koman et al[53]



Cosgrove et al[54]



Chutorian and Root



Chutorian, Root, and the BTA study group



Corry et al[55]



Fehlings et al[56]



Wissel et al[57]



Baker et al[58]



Open-label



Double-blind, placebo-controlled



Open-label



Open-label



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled



Single-blind, randomized, controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



StrokeDas and Park Memin et al



Grazko et al



Dengler et al



Jabbari et al



Simpson et al



Bhaktha et al



Smith et al[59]



Childers et al[60]



Pittock et al[61]



Brashear et al[62]



Bakheit et al[63]



Open-label



Open-label



Double-blind, placebo-controlled, crossover



Open-label



Double-blind, placebo-controlled, crossover



Double-blind, placebo-controlled



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Traumatic Brain InjuryYablon et al[64]



Pavesi et al[65]



Open-label



Open-label



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Pain Management

Use of BoNT-A in the management of different pain disorders is being studied. At this time, indications for the use of BoNT in managing muscle pain disorders still are controversial. The exact mechanism of action behind BoNT's analgesic effect is not known; however, a study by Purkiss and colleagues showed that BoNT inhibits calcium-dependent release of substance P in embryonic dorsal root ganglia.[66] Hence, BoNT may, by blocking the release of substance P, produce an analgesic effect through peripheral inhibition of C and A delta fibers. In a double-blind, randomized, placebo-controlled study, Foster and colleagues showed the efficacy of 200 U of BoNT-A injection, employing 40 U per site at 5 lumbar paravertebral levels on the side of maximum discomfort in chronic low back pain patients.[67] Different studies on the use of BoNT in the management of different pain disorders are listed in Table 3.

Table 3. Studies on the Use of Botulinum Toxin in Pain Management (Open Table in a new window)

Author(s) (Year)Clinical ConditionStudy TypeNResults
Zwart et al (1994)[68] Tension headacheOpen-label6Unilateral temporal injection not effective
Sherman et al (1995)[69] Chronic pancreatitisOpen-label7Not effective
Paulson et al (1996)[70] FibromyalgiaRandomized, controlled5Not effective
Wheeler et al (1998)[71] Myofascial pain[72] Randomized, double-blind, controlled33No significant difference, second injection effective?
Wheeler (1998)[73] Tension headacheOpen-label4Effective in 4 patients
Schulte-Mattler et al (1999)[74] Tension headacheOpen-label9Effective in 8 of 9 patients
Freund et al (1999)[75] Temporomandibular disordersOpen-label15Effective
Freund et al (2000)[76] Temporomandibular disordersOpen-label46Effective
Silberstein et al (2000)[77] Migraine headacheDouble-blind, vehicle-controlled123Effective prophylaxis
Rollnik et al (2000)[78] Tension headacheDouble-blind, placebo-controlled21Not effective
Freund et al (2000)[79] Cervicogenic HeadacheRandomized, double-blind, placebo-controlled26Effective
Freund et al (2000)[80] Whiplash associated with neck painRandomized, double-blind, placebo-controlled26Effective
Barwood et al (2000)[81] Severe postoperative pain and spasm in cerebral palsyRandomized, double-blind, placebo-controlled16Effective prophylaxis
Porta (2000)[82] Chronic myofascial pain syndromeRandomized, controlled, comparative40BOTOX® better than methylprednisolone

For more information, see Medscape Reference article Botulinum Toxin in Pain Management.

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Contributor Information and Disclosures
Author

Divakara Kedlaya, MBBS  Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine; Medical Director, Physical Medicine and Rehabilitation and Pain Management, St Mary Corwin Medical Center

Divakara Kedlaya, MBBS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, and Colorado Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Martin K Childers, DO, PhD  Professor, Department of Neurology, Wake Forest University School of Medicine; Professor, Rehabilitation Program, Institute for Regenerative Medicine, Wake Forest Baptist Medical Center

Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Osteopathic Association, Christian Medical & Dental Society, and Federation of American Societies for Experimental Biology

Disclosure: Allergan pharma Consulting fee Consulting

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Michael T Andary, MD, MS  Professor, Residency Program Director, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine

Michael T Andary, MD, MS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists

Disclosure: Allergan Honoraria Speaking and teaching

Kelly L Allen, MD  Medical Director, Medevals

Disclosure: Nothing to disclose.

Chief Editor

Consuelo T Lorenzo, MD  Physiatrist, Department of Physical Medicine and Rehabilitation, Alegent Health Immanuel Rehabilitation Center

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

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Botulinum toxin structure (schematic diagram).
Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A.
Table 1. Botulinum Toxin Types, Target Sites, Discoverers, and Year Discovered
TypeTargetDiscovererYear
ASNAP-25Landman1904
BVAMPErmengem1897
C1SyntaxinBengston and Seldon1922
DVAMPRobinson1929
ESNAP-25Gunnison1936
FVAMPMoller and Scheibel1960
GVAMPGimenez and Ciccarelli1970
Table 2. Studies of Botulinum Toxin in the Treatment of Spasticity in Different Disorders
Clinical DiagnosisAuthorStudy Design
Multiple SclerosisBenecke



Borg-Stein et al[49]



Snow et al[50]



Hyman et al[51]



Open-label



Open-label



Double-blind, placebo-controlled, randomized, crossover



Double-blind, placebo-controlled, randomized, dose-ranging



Spinal Cord InjuryBohlega et al



Takenaga et al



Open-label



Open-label



Cerebral PalsyKoman et al[52] Koman et al[53]



Cosgrove et al[54]



Chutorian and Root



Chutorian, Root, and the BTA study group



Corry et al[55]



Fehlings et al[56]



Wissel et al[57]



Baker et al[58]



Open-label



Double-blind, placebo-controlled



Open-label



Open-label



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled



Single-blind, randomized, controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



StrokeDas and Park Memin et al



Grazko et al



Dengler et al



Jabbari et al



Simpson et al



Bhaktha et al



Smith et al[59]



Childers et al[60]



Pittock et al[61]



Brashear et al[62]



Bakheit et al[63]



Open-label



Open-label



Double-blind, placebo-controlled, crossover



Open-label



Double-blind, placebo-controlled, crossover



Double-blind, placebo-controlled



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Traumatic Brain InjuryYablon et al[64]



Pavesi et al[65]



Open-label



Open-label



Table 3. Studies on the Use of Botulinum Toxin in Pain Management
Author(s) (Year)Clinical ConditionStudy TypeNResults
Zwart et al (1994)[68] Tension headacheOpen-label6Unilateral temporal injection not effective
Sherman et al (1995)[69] Chronic pancreatitisOpen-label7Not effective
Paulson et al (1996)[70] FibromyalgiaRandomized, controlled5Not effective
Wheeler et al (1998)[71] Myofascial pain[72] Randomized, double-blind, controlled33No significant difference, second injection effective?
Wheeler (1998)[73] Tension headacheOpen-label4Effective in 4 patients
Schulte-Mattler et al (1999)[74] Tension headacheOpen-label9Effective in 8 of 9 patients
Freund et al (1999)[75] Temporomandibular disordersOpen-label15Effective
Freund et al (2000)[76] Temporomandibular disordersOpen-label46Effective
Silberstein et al (2000)[77] Migraine headacheDouble-blind, vehicle-controlled123Effective prophylaxis
Rollnik et al (2000)[78] Tension headacheDouble-blind, placebo-controlled21Not effective
Freund et al (2000)[79] Cervicogenic HeadacheRandomized, double-blind, placebo-controlled26Effective
Freund et al (2000)[80] Whiplash associated with neck painRandomized, double-blind, placebo-controlled26Effective
Barwood et al (2000)[81] Severe postoperative pain and spasm in cerebral palsyRandomized, double-blind, placebo-controlled16Effective prophylaxis
Porta (2000)[82] Chronic myofascial pain syndromeRandomized, controlled, comparative40BOTOX® better than methylprednisolone
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