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eMedicine - Botulinum Toxin: Overview : Article by

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Introduction
History
Mechanism of Action
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Therapeutic Uses
Botulinum Toxin Use in Dystonia
Botulinum Toxin Use in Spasticity
Pain Management
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AUTHOR AND EDITOR INFORMATION

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Author: Divakara Kedlaya, MBBS, Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine

Divakara Kedlaya 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

Editors: Martin K Childers, DO, PhD, Associate Professor, Department of Neurology, Wake Forest University Health Services; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael T Andary, MD, MS, Residency Program Director, Professor, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine; Kelly L Allen, MD, Consulting Staff, Department of Physical Medicine and Rehabilitation, Lourdes Regional Rehabilitation Center, Our Lady of Lourdes Medical Center; Consuelo T Lorenzo, MD, Consulting Staff, Department of Physical Medicine and Rehabilitation, Alegent Health Care, Immanuel Rehabilitation Center

Author and Editor Disclosure

Synonyms and related keywords: BOTOX®, BTX, BoNT, Dysport, CS-BOT, NeuroBloc, MyoBloc, BotB, BOTOX® injection, botulinum toxin injection, Clostridium botulinum, C botulinum

INTRODUCTION

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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 BoNT molecule is synthesized as a single chain (150 kD) and then cleaved to form the dichain molecule with a disulfide bridge (see Image 1). 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. 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.

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article BOTOX® Injections.

Related eMedicine topics:
BOTOX® Injections
Botulinum Toxin


HISTORY

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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).
  • 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.

Related eMedicine topics:
BOTOX® Injections to Improve Facial Aesthetics
Botulinum Toxin (BOTOX®): Dystonia Treatment
Botulinum Toxin in Pain Management


MECHANISM OF ACTION

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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

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



PREPARATIONS

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The preparations of BoNT-A marketed in the United States (BOTOX®, by Allergan; Irvine, Calif), the United Kingdom and Europe (Dysport, by Speywood-Vaccine and Research Laboratory-Porton Down; Salisbury, UK), and Japan (CS-BOT) 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 is approximately equivalent to 3 U of Dysport.
  • 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.


THERAPEUTIC USES

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Therapeutic uses of botulinum toxin injection

  • Focal dystonias - Involuntary, sustained, or spasmodic patterned muscle activity
    • Cervical dystonia (spasmodic torticollis)2, 3
    • Blepharospasm (eyelid closure)
    • Laryngeal dystonia (spasmodic dysphonia)
    • Limb dystonia (writer's cramp)
    • Oromandibular dystonia
    • Orolingual dystonia
    • Truncal dystonia
  • 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
  • Strabismus (disorder of conjugate eye movement) and nystagmus
  • Disorders of localized muscle spasms and pain
    • Chronic low back pain
    • Myofascial pain syndrome
    • Temporomandibular joint disorders associated with increased muscle activity
    • Tension headache
    • Migraine headache
    • Cervicogenic headache
  • Smooth muscle hyperactive disorders
    • Detrusor-sphincter dyssynergia
    • Benign prostatic hypertrophy
    • Achalasia cardia
    • Hirschsprung disease
    • Sphincter of Oddi dysfunctions
    • Following hemorrhoidectomy
    • Chronic anal fissures5
  • Cosmetic use
    • Hyperkinetic facial lines (glabellar frown lines, crow's feet)
    • Hypertrophic platysma muscle bands
  • Sweating disorders
    • Axillary and palmar hyperhidrosis
    • Frey syndrome, also known as auriculotemporal syndrome (gustatory sweating of the cheek after parotid surgery)

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BOTULINUM TOXIN USE IN DYSTONIA

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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).2, 3 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.6 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).7

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.8 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.9 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.10 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.


BOTULINUM TOXIN USE IN SPASTICITY

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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.4

Table 2. Studies of Botulinum Toxin in the Treatment of Spasticity in Different Disorders

Clinical DiagnosisAuthor Study Design
Multiple Sclerosis

Benecke
Borg-Stein et al11
Snow et al12
Hyman et al13

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 al14
Koman et al15
Cosgrove et al16
Chutorian and Root
Chutorian, Root, and the BTA study group
Corry et al17
Fehlings et al18
Wissel et al19
Baker et al20
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
Stroke

Das and Park Memin et al
Grazko et al
Dengler et al
Jabbari et al
Simpson et al
Bhaktha et al
Smith et al21
Childers et al22
Pittock et al23
Brashear et al24
Bakheit et al25

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 al26
Pavesi et al27		Open-label
Open-label



PAIN MANAGEMENT

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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.28 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.29 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

Author(s) (Year)Clinical ConditionStudy TypeNResults
Zwart et al (1994)30Tension headacheOpen-label6Unilateral temporal injection not effective
Sherman et al (1995)31Chronic pancreatitisOpen-label7Not effective
Paulson et al (1996)32FibromyalgiaRandomized, controlled5Not effective
Wheeler et al (1998)33Myofascial pain34Randomized, double-blind, controlled33No significant difference, second injection effective?
Wheeler (1998)35Tension headacheOpen-label4Effective in 4 patients
Schulte-Mattler et al (1999)36Tension headacheOpen-label9Effective in 8 of 9 patients
Freund et al (1999)37Temporomandibular disordersOpen-label15Effective
Freund et al (2000)38Temporomandibular disordersOpen-label46Effective
Silberstein et al (2000)39Migraine headacheDouble-blind, vehicle-controlled123Effective prophylaxis
Rollnik et al (2000)40Tension headacheDouble-blind, placebo-controlled21Not effective
Freund et al (2000)41Cervicogenic HeadacheRandomized, double-blind, placebo-controlled26Effective
Freund et al (2000)42Whiplash associated with neck painRandomized, double-blind, placebo-controlled26Effective
Barwood et al (2000)43Severe postoperative pain and spasm in cerebral palsyRandomized, double-blind, placebo-controlled16Effective prophylaxis
Porta (2000)44Chronic myofascial pain syndromeRandomized, controlled, comparative40BOTOX® better than methylprednisolone


Related eMedicine topic:
Botulinum Toxin in Pain Management


MULTIMEDIA

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Media file 1:  Botulinum toxin structure (schematic diagram).
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Media type:  Image

Media file 2:  Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A.
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Media type:  Image


REFERENCES

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  1. de Paiva A, Meunier FA, Molgó J, et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A. Mar 16 1999;96(6):3200-5. [Medline]. [Full Text].
  2. Dowson AJ, Kilminster SG, Salt R. Clinical profile of botulinum toxin A in patients with chronic headaches and cervical dystonia: a prospective, open-label, longitudinal study conducted in a naturalistic clinical practice setting. Drugs R D. 2008;9(3):147-58. [Medline].
  3. Tiple D, Strano S, Colosimo C, et al. Autonomic cardiovascular function and baroreflex sensitivity in patients with cervical dystonia receiving treatment with botulinum toxin type A. J Neurol. May 7 2008;[Medline].
  4. Elovic EP, Brashear A, Kaelin D, et al. Repeated treatments with botulinum toxin type A produce sustained decreases in the limitations associated with focal upper-limb poststroke spasticity for caregivers and patients. Arch Phys Med Rehabil. May 2008;89(5):799-806. [Medline].
  5. Brisinda G, Cadeddu F, Brandara F, et al. Botulinum toxin for recurrent anal fissure following lateral internal sphincterotomy. Br J Surg. Jun 2008;95(6):774-8. [Medline].
  6. Greene P, Kang U, Fahn S, et al. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology. Aug 1990;40(8):1213-8. [Medline].
  7. Brans JW, Lindeboom R, Aramideh M, et al. Long-term effect of botulinum toxin on impairment and functional health in cervical dystonia. Neurology. May 1998;50(5):1461-3. [Medline].
  8. Poewe W, Deuschl G, Nebe A, et al. What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport. German Dystonia Study Group. J Neurol Neurosurg Psychiatry. Jan 1998;64(1):13-7. [Medline]. [Full Text].
  9. Jankovic J, Schwartz KS. Clinical correlates of response to botulinum toxin injections. Arch Neurol. Dec 1991;48(12):1253-6. [Medline].
  10. Comella CL, Tanner CM, DeFoor-Hill L, et al. Dysphagia after botulinum toxin injections for spasmodic torticollis: clinical and radiologic findings. Neurology. Jul 1992;42(7):1307-10. [Medline].
  11. Borg-Stein J, Pine ZM, Miller JR, et al. Botulinum toxin for the treatment of spasticity in multiple sclerosis. New observations. Am J Phys Med Rehabil. Dec 1993;72(6):364-8. [Medline].
  12. Snow BJ, Tsui JK, Bhatt MH, et al. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol. Oct 1990;28(4):512-5. [Medline].
  13. Hyman N, Barnes M, Bhakta B, et al. Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg Psychiatry. Jun 2000;68(6):707-12. [Medline].
  14. Koman LA, Mooney JF 3rd, Smith B, et al. Management of cerebral palsy with botulinum-A toxin: preliminary investigation. J Pediatr Orthop. Jul-Aug 1993;13(4):489-95. [Medline].
  15. Koman LA, Mooney JF 3rd, Smith BP, et al. Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity spasticity in cerebral palsy: a randomized, double-blind, placebo-controlled trial. BOTOX Study Group. J Pediatr Orthop. Jan-Feb 2000;20(1):108-15. [Medline].
  16. Cosgrove AP, Corry IS, Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy. Dev Med Child Neurol. May 1994;36(5):386-96. [Medline].
  17. Corry IS, Cosgrove AP, Duffy CM, et al. Botulinum toxin A compared with stretching casts in the treatment of spastic equinus: a randomised prospective trial. J Pediatr Orthop. May-Jun 1998;18(3):304-11. [Medline].
  18. Fehlings D, Rang M, Glazier J, et al. An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy. J Pediatr. Sep 2000;137(3):331-7. [Medline].
  19. Wissel J, Heinen F, Schenkel A, et al. Botulinum toxin A in the management of spastic gait disorders in children and young adults with cerebral palsy: a randomized, double-blind study of "high-dose" versus "low-dose" treatment. Neuropediatrics. Jun 1999;30(3):120-4. [Medline].
  20. Baker R, Jasinski M, Maciag-Tymecka I, et al. Botulinum toxin treatment of spasticity in diplegic cerebral palsy: a randomized, double-blind, placebo-controlled, dose-ranging study. Dev Med Child Neurol. Oct 2002;44(10):666-75. [Medline].
  21. Smith SJ, Ellis E, White S, Moore AP. A double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injury. Clin Rehabil. Feb 2000;14(1):5-13. [Medline].
  22. Childers MK, Brashear A, Jozefczyk P, et al. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil. Jul 2004;85(7):1063-9. [Medline].
  23. Pittock SJ, Moore AP, Hardiman O, et al. A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke. Cerebrovasc Dis. 2003;15(4):289-300. [Medline].
  24. Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. Aug 8 2002;347(6):395-400. [Medline].
  25. Bakheit AM, Pittock S, Moore AP, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. Eur J Neurol. Nov 2001;8(6):559-65. [Medline].
  26. Yablon SA, Agana BT, Ivanhoe CB, et al. Botulinum toxin in severe upper extremity spasticity among patients with traumatic brain injury: an open-labeled trial. Neurology. Oct 1996;47(4):939-44. [Medline].
  27. Pavesi G, Brianti R, Medici D, et al. Botulinum toxin type A in the treatment of upper limb spasticity among patients with traumatic brain injury. J Neurol Neurosurg Psychiatry. Mar 1998;64(3):419-20. [Medline]. [Full Text].
  28. Purkiss J, Welch M, Doward S, et al. Capsaicin-stimulated release of substance P from cultured dorsal root ganglion neurons: involvement of two distinct mechanisms. Biochem Pharmacol. Jun 1 2000;59(11):1403-6. [Medline].
  29. Foster L, Clapp L, Erickson M, et al. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology. May 22 2001;56(10):1290-3. [Medline].
  30. Zwart JA, Bovim G, Sand T, et al. Tension headache: botulinum toxin paralysis of temporal muscles. Headache. Sep 1994;34(8):458-62. [Medline].
  31. Sherman S, Kopecky KK, Brashear A, et al. Percutaneous celiac plexus block with botulinum toxin A did not help the pain of chronic pancreatitis. J Clin Gastroenterol. Jun 1995;20(4):343-4. [Medline].
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Botulinum Toxin: Overview excerpt

Article Last Updated: Jun 4, 2008