Atlas of Pain Medicine Procedures 1st Edition

SECTION I

BASIC APPLICATIONS

CHAPTER 8

Botulinum Toxins

Charles E. Argoff and Howard Smith

BACKGROUND

Botulinum toxins are neurotoxins produced by the gram-positive, spore-forming, anaerobic bacteria, Clostridium botulinum, as well as C butyricum, C baratii, and C argentinense.1,2 These toxins are the most deadly human neurotoxins known. Clinically, botulism can occur following ingestion of contaminated food or from a wound infection. The clinical signs of botulism include limb paralysis, facial weakness, ophthalmoplegia, dysarthria, dysphagia, dyspnea progressing to respiratory arrest, constipation progressing to ileus, and urinary retention.3 C botulinum produces 7 antigenically (immunologically) distinct neurotoxins: A, B, C1, D, E, F, and G.

  • Varied mechanisms of action of botulinum neurotoxin (BoNT) subtype are believed to be due to its ability to inhibit multiple neurotransmitters from presynaptic vesicles. Specific proteins involved in this process are affected by different toxins and thus different strains of toxin do not necessarily work via the same mechanism.
  • Only types A and B toxin are currently routinely used in clinical practice.
  • Currently, there are 3 types of botulinum toxin type A commercially available in the United States including onabotulinum toxin A (Botox), abobotulinum toxin A (Dysport), and incobotulinum toxin A (Xeomin).
  • Rimabotulinum toxin B (Myobloc) is the only botulinum toxin type B currently available in the United States.
  • Each toxin has been developed with different dosing units and they are not interchangeable—this is clinically important to remember. Synaptosomal-associated protein (SNAP 25) is inactivated by botulinum toxin type A and vesicle associated membrane protein (VAMP) is inactivated by botulinum toxin type B.
  • Its effect on motor function through inhibition of release of acetylcholine has been well documented. Cleavage of either one of these proteins results in inhibition of acetylcholine release, disruption of neuromuscular transmission, and paralysis of the muscle.
  • Most important recent scientific discovery is of SNAP 25 on motor and sensory neurons.
  • Several animal studies demonstrating the toxin’s inhibition of substance P, calcitonin-gene related peptide (CGRP), glutamate, bradykinin, ATP, and purinergic receptors.
  • Additional animal studies have suggested a clinically relevant central analgesic effect of type A toxin as well.

The only FDA-approved specific pain indication for any current commercially available botulinum toxin is chronic migraine for onabotulinum toxin A (Botox).4 The “off-label” use of botulinum toxin for the treatment of other chronic painful conditions has been reported for cervical dystonia–associated neck pain, chronic low back pain, and chronic lateral epicondylitis. Jabbari and Machado have recently published a review of the use of botulinum toxin for refractory pain based on the evidence according to the AAN evidence rating approach. The reader can review these references for additional information regarding the use of botulinum toxins for chronic pain.

BOTULINUM TOXIN FOR THE TREATMENT OF CHRONIC MIGRAINE

The most evidence for treatment with botulinum toxin is for the specific condition, chronic migraine. The importance of defining this group has become vital for proper patient selection. The FDA has approved the use of onabotulinum toxin A (Botox) for the treatment of chronic migraine only, and not tension type or episodic migraine.

Chronic migraine has been defined as:

  • A headache syndrome for more than 3 months
  • At least 15 or more headache days per month
  • The headache experienced for at least 4 hours
  • The headache experienced for at least 8 months

A randomized placebo controlled study examined the use of 100 units of onabotulinum toxin in fixed injection sites including the glabella, frontalis, temporalis, trapezius, and suboccipital regions in 41 patients with chronic migraine. Onabotulinum toxin A resulted in fewer migraine episodes 4 weeks after injection with both reduced headache days and a reduced headache index (composite measure of both headache frequency and intensity) at 16 weeks. Two much larger studies, PREEMPT 1 and PREEMPT 2 each evaluating approximately 700 patients consisted of a 24-week blinded period followed by an extended open label arm. In contrast to the smaller study, which excluded chronic headache associated with medication overuse, the PREEMPT trials included these patients. The primary outcome measure for PREEMPT 1, the number of headache episodes, was not met but in PREEMPT 2, the primary outcome measure, the number of headache days, was met. The change in headache days for treated patients in PREEMPT 2 was 9 days vs. 6.7 days for placebo treated patients (p<0.001). PREEMPT 1 did meet its secondary outcomes including number of migraine days. The FDA approved onabotulinum toxin A for the treatment of chronic migraine in October, 2010, noting that it felt that a reduction in headache days was more meaningful than a reduction in absolute number of headaches. The injection paradigm used in the PREEMPT trials is seen in Table 8-1. Many consider the availability of this treatment to be a great advance in the ability to treat chronic migraine. Published studies and our own experience would suggest that other headache syndromes, for example, episodic migraine, or tension-type headache are not clearly responsive to onabotulinum toxin A (Botox) injections.

TABLE 8-1. Onabotulinumtoxin A Dosing for Chronic Migraine by Muscle Using the PREEMPT Injection Paradigm

BASIC CONCERNS AND CONTRAINDICATIONS

Preprocedure Considerations

  • Informed consent and appropriate explanation of the procedure including the potential benefits as well as risks.
  • We have performed with procedure safely in individuals on antiplatelet or anticoagulant therapy only after checking with the physician prescribing such treatment.
  • The patient can be seated during the procedure.
  • This procedure is contraindicated with a known allergy or hypersensitivity to onabotulinum toxin A (Botox).
  • Fluoroscopy is not required nor recommended for this procedure.

Equipment

  • Onabotulinum toxin A (Botox) is supplied in single-use 100 units or 200 units per vial.
  • Four 1 cc syringes
  • Two 3 cc syringes
  • 20 gauge 1.5 in needle for reconstitution
  • 30 gauge ½ -1 needle for injection

Botox must be reconstituted before using as toxin in the vial is vacuum dried.

The manufacturer of Botox recommends reconstituting the toxin with sterile, preservative free 0.9% sodium chloride USP; however, some injectors have described successfully reconstitution with 1% preservative free lidocaine. The dilution instructions for Botox vials are seen in Table 8-2. After drawing up the appropriate amount of diluent into the correct size syringe, it should be slowly injected into the vial and then gently mixed by gentle rotation of the vial. The Botox should be administered within 24 hours after constitution and it can be stored after reconstitution in a refrigerator during this 24-hour period (2°-8°C).

TABLE 8-2. General Considerations for Treatment

  1. Currently, none of the available botulinum toxins is FDA-approved for a specific painful state except for onabotulinum toxin A (Botox) for chronic migraine; therefore, use otherwise for chronic pain is in an off-labeled manner. Patients should be informed of this prior to treatment.
  2. Significant side effects are uncommon. Pain, muscle weakness, and flu-like symptoms have been reported. Spread of toxin has been noted with weakness, sometimes involving muscles that were not directly injected. Autonomic side effects appear to be more commonly seen with type B toxin.
  3. Contraindications to treatment with botulinum toxin include pregnancy (category C), the concurrent use of aminoglycoside antibiotics, myasthenia gravis, Eaton-Lambert syndrome, or known sensitivity to the toxins.
  4. Treating more frequently than the recommended interval of 12 wk may lead to the development of antibodies to the toxin, which may also be associated with the development of clinical resistance.
  5. There is no valid way to reliably and consistently convert doses of different type A toxin to other type A toxins nor to doses of type B toxin at present.
  6. The use of botulinum toxin for pain management is part of a comprehensive treatment program that has been developed based on an accurate diagnosis.
  7. Be aware of current storage and handling recommendations for each of the toxins.
  8. Whenever possible, use an injection technique, including needle size, that is the least likely to cause additional pain.
  9. Guidance techniques such as EMG, CT, or fluoroscopy should be used at the discretion of the injector.
  10. Prolonged observation following the injections is generally not warranted.
  11. Follow-up should be arranged for 4-6 wk following injections.
  12. More than 1 series of injections may be required to achieve maximal analgesic response.

Technical Considerations

  • For chronic migraine, the recommended dilution is 50 U/mL (final concentration of 5 units/0.1 mL).
  • The FDA approved dose for treating chronic migraine is 155 units administered intramuscularly.
  • Each site is injected with 5 units via a sterile 30 gauge 0.5 in needle.
  • For some people a 1-in needle may be needed in the cervical region.
  • Only the procerus is injected unilaterally. All other injections are bilateral and symmetrical.
  • The recommended interval between injection sessions is 12 weeks.
  • Care must be taken to avoid over injection so that clinically significant muscle weakness will not occur.

Postprocedure Follow-Up

  • We recommend initial follow-up at 6 weeks after the first injection.
  • Thereafter, every 12 weeks follow-up at the time of injection sessions unless otherwise requested by the patient.
  • It is important to remind the patient that it may take up to 3 to 5 sessions to maximize outcome.
  • Local bruising or soreness at the injection sites is common and patients should be advised to apply cold packs if it occurs.

Potential Complications and Pitfalls

  • Muscle weakness.
  • Spread of toxin and the development of swallowing difficulties.
  • Infection is uncommon if the procedure is done aseptically.
  • Excessive bleeding is uncommon.

CLINICAL PEARLS

  • Be patient—the best results may not occur until after the third treatment. Many patients have described “failing” Botox injection treatment of their chronic migraine because they were incorrectly told by their “injector” that if they did not benefit sufficiently after the first treatment, then there was no reason to continue. This has serious implications because the treatment can be very helpful even for those who have failed to respond adequately to other approaches.
  • Success will be measured in reduced number of headache days as well as reduced intensity of headaches.
  • There are no clear guidelines regarding when to stop treatment even when successful.
  • Openly discuss this subject with your patients and generally those who are in a vulnerable age groupfor chronic migraine who are successfully treated with Botox would prefer to continue with treatment since this becomes their prophylactic regimen and they do not want to risk a severe, potentially disabling exacerbation.
  • Certainly, as a patient’s susceptibility to migraine may change with time, this can be considered with respect to ongoing treatment with Botox.

References

  1. 1. Schantz EJ, Johnson EA. Properties and use of botulinum toxin and other microbial neurotoxins in medicine.Microbiol Rev. 1992;56:80-99.
  2. 2. Johnson EA. Biomedical aspects of botulinum toxin.J Toxicol Toxin Rev. 1999;18:1-15.
  3. 3. Botox, prescribing information,botox.com.
  4. 4. Dysport, prescribing information,dysport.com.
  5. Xeomin, prescribing information,www.xeomin.com.
  6. Myobloc, prescribing information,www.myobloc.com.
  7. Aoki KR. Evidence for antinociceptive activity of botulinum toxin A in pain management.Headache. 2003; 43(suppl 1):S9-S15.
  8. Lawrence GW, Aoki KR, Dolly JO. Excitatory cholinergic and purinergic signaling in bladder are equally susceptible to botulinum neurotoxin A consistent with co-release of transmitters from efferent fibers.J Pharmacol Exp Ther. 2012;334:1080-1086.
  9. Gronseth G, French J. Practice parameters and technology assessments: what are they, what are they not and why you should care.Neurology. 2008;71:1639-1643.
  10. 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. Naumann M, So Y, Argoff CE, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.Neurology. 2008 May 6;70(19):1707-1714.
  11. Jabbari B, Machado D. Treatment of refractory pain with botulinum toxins—an evidence-based review.Pain Med. 2011 Nov;12(11):1594-1606.
  12. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind, placebo controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis.
  13. Troung D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum A toxin (Dysport®) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study.Mov Disorder. 2005;20:783-791.
  14. Troung D, Brodsky M, Lew M, et al. Global Dysport®Cervical Dystonia Study Group. Long-term efficacy and safety of botulinum toxin type A (Dysport®) in cervical dystonia.Parkinsonism Relat Disord. 2010;16:316-323.
  15. Lew MF, Adornato BT, Duane DD, et al. Botulinum toxin type B: a double-blind, placebo controlled safety and efficacy study in cervical dystonia.Neurology. 1997;49:701-707.
  16. Lew MF, Chinnapongse R, Zhang Y, Corliss M. Rima botulinum toxin B effects on pain associated with cervical dystonia: results of placebo and comparator controlled studies.Int J Neurosci. 2010;120:298-300.
  17. Comella CL, Jankovic J, Shannon KM, Tsui J, Swenson M, Leurgans S, Fan W. Dystonia Study Group. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia.Neurology. 2005;65:1423-1429.
  18. Odergren T, Hajaltason H, Kaakola S, et al. A double blind, randomized, parallel group study to investigate the dose equivalence of Dysport and Onabotulinum toxin A in the treatment of cervical dystonia.J Neurol Neurosurg Psychiatry. 1998;64:6-12.
  19. Wong SM, Hui AC, Tong PY, Poon DW, Yu E, Wong LK. Treatment of lateral epicondylitis with botulinum toxin: a randomized, double-blind, placebo-controlled trial.Ann Intern Med. 2005;143(11):793-797.
  20. Hayton MJ, Santini AJ, Hughes PJ, Frostick SP, Trail IA, Stanley JK. Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled pilot study.J Bone Joint Surg Am. 2005;87:503-507.
  21. Aurora SK, Dodick DW, Turkel CC, et al. PREEMPT 1 Chronic Migraine Study Group. Onabotulinumtoxin A for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT I trial.Cephalagia. 2010;30:793-803.
  22. Diener HC, Dodick DW, Aurora SK, et al. PREEMPT 2 Chronic Migraine Study Group. Onabotulinumtoxin A for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.Cephalagia. 2010;30:804-814.

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