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Botulinum Toxin and Headache

Guest Editors: Emily D. Mauser and Noah L. Rosen, MD

 

Emily Mauser is currently an undergraduate student at Hofstra University, majoring in psychology (clinical/health psychology concentrations) and minoring in writing studies and composition. She has spent the past five years clinically observing and performing headache research with Dr. Noah L. Rosen at the Pain and Headache Center of the North Shore-Long Island Jewish Health System. She presented a poster at the 52nd Annual Scientific Meeting of the American Headache Society in Los Angeles, CA (2010) and is currently awaiting the acceptance of her first original research publication to Headache. Emily hopes to obtain her MD and/or PhD and is looking forward to conducting more neurological and psychological research in the future.

Noah L. Rosen, MD is the Director of the Headache Center, Director of the Residency program in Neurology, and an Assistant Professor of Neurology at the Cushing Neuroscience Institute of the Hofstra North Shore-Long Island Jewish Health System. He is board certified in Neurology, Psychiatry and Pain Management by the American Board of Psychiatry and Neurology ( ABPN) and holds subspecialty certification in Headache Medicine by the United Council of Neurologic Subspecialties (UCNS). Dr. Rosen specializes in comorbid neurologic and psychiatric illnesses in headache and the treatment of intractable migraines. Dr. Rosen has been practicing medicine over the last 10 years in academic centers, including patient care, research, and the education of medical students, residents, and fellows. He is also an active member of the American Headache Society and the American Academy of Neurology.

Botulinum Toxin and Headache

 

INTRODUCTION

As one of a small handful of novel neurologic therapeutics developed over the last several decades, botulinum toxin and its uses has garnered much attention. With the relatively recent approval of the use of onabotulinum toxin for the treatment of chronic migraine by the Food and Drug Administration, there has been a significant increase in its use and the use of related toxins throughout neurologic practices. In the interest of those who use these therapeutic agents, this publication is focused on reviewing those research articles which have been published in the journal Headache over the last several decades.

Botulinum toxin type A is a protein and neurotoxin that blocks the reception of neurotransmitter signals (most notably acetylcholine) to neurons and muscles throughout the brain and body. Other effects are also speculated and our understanding of the fate of botulinum toxin in man is still growing.

This virtual issue examines the use of botulinum toxin type A for the treatment of chronic migraine and other headache disorders. The basic interventional procedure is administered as a series of injections into several different muscle groups across the front, sides, and back of the head, as well as down into the neck. This process has varied significantly across the presented studies with different muscles injected, different dosages utilized, and different protocols utilized.

This publication starts with articles that elucidate the biochemical mechanism (basic science) behind botulinum toxin type A, progresses through studies that evaluate the various headache and other neurological conditions that botulinum toxin type A is used to treat, then covers articles that compare botulinum toxin type A to other headache preventive treatments, and finally presents articles that evaluate the efficacy of botulinum toxin type A. This issue provides an overview of the contributions of research published in Headache on this topic and will hopefully stimulate further investigation into this fascinating therapy.

BIOCHEMICAL MECHANISM (BASIC SCIENCE) BEHIND BOTULINUM TOXIN TYPE A

There are many theories about the basic science behind botulinum toxin type A and how this substance works biochemically. Several studies have been conducted which provide some evidence for botulinum toxin type A’s mechanism of action including antinociceptive activity, synaptic transmission inhibition and calcitonin gene-related peptide regulation. Similar work has been published in other journals. However, full elucidation as to why the effect seems to be more effective in the chronic migraine populations is still pending.

Aoki, K. Roger. “Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain Management.” Headache: The Journal of Head and Face Pain. 43 (July 2003): 9-15. Print.

Dolly, Oliver. “Synaptic Transmission: Inhibition of Neurotransmitter Release by Botulinum Toxins.” Headache: The Journal of Head and Face Pain. 43 (July 2003): 16-24. Print.

Smuts, Johan A.; Schultz, Donovan; Barnard, Adri. “Mechanism of Action of Botulinum Toxin Type A in Migraine Prevention: A Pilot Study.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 801-805. Print.

Durham, Paul L.; Cady, Ryan; Cady, Roger. “Regulation of Calcitonin Gene-Related Peptide Secretion from Trigeminal Nerve Cells by Botulinum Toxin Type A: Implications for Migraine Therapy.” Headache: The Journal of Head and Face Pain. 44.1 (January 2004): 35-43. Print

Caputi, Claudio A. “Effectiveness of BoNT-A in the Treatment of Migraine and Its Ability to Repress CGRP Release.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 837-838. Print.


HEADACHE AND RELATED CONDITIONS FOR WHICH BOTULINUM TOXIN TYPE A IS USED.

Migraine

The diagnosis of migraine is given to patients that meet the conditions outlined in the ICHD-II criteria. That includes the repetitive nature, time requirements, lack of other organic causation and headaches that are unilateral, worsen with movement, moderate to severe in intensity, pounding or throbbing in quality, associated with nausea (and/or vomiting), photophobia and phonophobia, and may be associated with aura or not.

Early articles showed promise for the use of botulinum toxin in episodic migraines, but later, larger placebo controlled studies failed to meet efficacy endpoints. Research looking at the duration of migraine as a predictor of response may have led to later research focusing on the chronic migraine phenotype.

Silberstein, Stephen; Mathew, Ninan; Saper, Joel; Jenkins, Stephen. “Botulinum Toxin Type A as a Migraine Preventive Treatment.” Headache: The Journal of Head and Face Pain. 40.6 (June 2000): 445-450. Print.

Dodick, David W. “Botulinum Neurotoxin for the Treatment of Migraine and Other Primary Headache Disorders: From Bench to Bedside.” Headache: The Journal of Head and Face Pain. 43 (July 2003): 25-33. Print.

Eross, Eric J.; Gladstone, Jonathan P; Lewis, Susan; Rogers, Robert; Dodick, David W. “Duration of Migraine is a Predictor for Response to Botulinum Toxin Type A.” Headache: The Journal of Head and Face Pain. 45.4 (April 2005): 308-314. Print.

Aurora, Sheena K.; Gawel, Marek; Brandes, Jan L.; Pokta, Suriani; VanDenburgh, Amanda M. “Botulinum Toxin Type A Prophylactic Treatment of Episodic Migraine: A Randomized, Double-Blind, Placebo-Controlled Exploratory Study.” Headache: The Journal of Head and Face Pain. 47.4 (April 2007): 486-499. Print.

Chronic Migraine

Before the term “chronic migraine” was established as an official ICHD diagnosis, the term “transformed migraine” and many other terms were used to describe the increase in frequency of patients’ migraines from an episodic to chronic pattern. Chronic daily headache was and remains a mixed bag of headache disorders which can be broken down into headaches that occur more than 4 hours at a time or less than 4 hours.
Now the diagnosis of chronic migraine is used to describe headaches that occur 15 days or more per month, of which at least 8 days meet ICHD criteria for migraine, and which may occur with or without medication overuse. The need to study this condition led key researchers to reexamine the existent definition and modify it based upon best scientific knowledge. The PREEMPT studies are the most recent research on botulinum toxin type A for headache prophylaxis; these studies provided evidence that aided in the FDA granting approval of botulinum toxin type A for the treatment of chronic migraine. The original two PREEMPT studies were published in the journal Cephalalgia, not Headache, but the pooled results and analyses studies were published in Headache, and are therefore included in this virtual publication.

Conway, Stafford; Delplanche, Curtis; Crowder, Jessica; Rothrock, John. “Botox Therapy for Refractory Chronic Migraine.” Headache: The Journal of Head and Face Pain. 45.4 (April 2005): 355-357. Print.

Freitag, Frederick G.; Diamond, Seymour; Diamond, Merie; Urban, George. “Botulinum Toxin Type A in the Treatment of Chronic Migraine without Medication Overuse.” Headache: The Journal of Head and Face Pain. 48.2 (February 2008): 201-209. Print.

Lake III, Alvin E.; Lipton, Richard B.; Hanton, Alexandra; Siegel, Sherry; Levin, Morris; Goadsby, Peter J.; Markley, Herbert G. “Defining Refractory Migraine: Results of the RHSIS Survey of American Headache Society Members.” Headache: The Journal of Head and Face Pain. 49.4 (April 2009): 509-518. Print.

Manack, Aubrey; Turkel, Catherine; Silberstein, Stephen. “The Evolution of Chronic Migraine: Classification and Nomenclature.” Headache: The Journal of Head and Face Pain. 49.8 (September 2009): 1206-1213. Print.

Dodick, David W.; Turkel, Catherine C.; DeGryse, Ronald E.; Aurora, Sheena K.; Silberstein, Stephen D.; Lipton, Richard B; Diener, Hans-Christoph; and Brin, Mitchell F. “OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double-Blind, Randomized, Placebo-Controlled Phases of the PREEMPT Clinical Program.” Headache: The Journal of Head and Face Pain. 50.6 (June 2010): 921-936. Print.

Blumenfeld, Andrew; Silberstein, Stephen D; Dodick, David W.; Aurora, Sheena K; Turkel, Catherine C.; and Binder, William J. "Method of Injection of OnabotulinumtoxinA for Chronic Migraine: A Safe, Well-Tolerated, and Effective Treatment Paradigm Based on the PREEMPT Clinical Program." Headache: The Journal of Head and Face Pain. 50.9 (October 2010): 1406-1418. Print.

Aurora, Sheena K.; Winner, Paul; Freeman, Marshall C.; Spierings, Egilius L.; Heiring, Jessica O.; DeGryse, Ronald E.; VanDenburgh, Amanda M.; Nolan, Marissa E.; Turkel, Catherine C. “OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Analyses of the 56-Week PREEMPT Clinical Program.” Headache: The Journal of Head and Face Pain.51.9 (October 2011): 1358-1373. Print.

Tension-Type Headache and Chronic Tension-Type Headache

Although migraine remains the most common headache disorder that is seen in physicians' offices, it is not the most common headache. That distinction is owned by tension type headaches. According to the ICHD, tension-type headaches are repeated headaches comprised of bilateral, vice-like or band-like constant pressure of mild to moderate intensity, do not have any of the autonomic/associated features that can be associated with other headache disorders except potentially mild nausea and tend not to worsen with movement. This can occur in episodic form, frequent episodic form on chronic form. Again, the chronic form of this condition refers to occurrence greater than 15 days per month. This type of headache was one of the earliest studied with botulinum toxin denervation. However, results were mixed with no clear efficacy.

Zwart, John-Anker; Bovim, Gunnar; Sand, Trond; Sjaastad, Ottar. “Tension Headache: Botulinum Toxin Paralysis of Temporal Muscles.” Headache: The Journal of Head and Face Pain. 34.8 (September 1994): 458-462. Print.

Blumenfeld, Andrew M.; Binder, William; Silberstein, Stephen D.; Blitzer, Andrew. “Procedures for Administering Botulinum Toxin Type A for Migraine and Tension-type Headache.” Headache: The Journal of Head and Face Pain. 43.8 (September 2003): 884-891. Print.

Rollnik, Jens D.; Tanneberger, Oliver; Schubert, Margot; Schneider, Udo; Dengler, Reinhard. “Treatment of Tension-type Headache With Botulinum Toxin Type A: A Double-Blind, Placebo-Controlled Study.” Headache: The Journal of Head and Face Pain. 40.4 (April 2000): 300-305. Print.

Schmitt, Wolfgang J.; Slowey, Eva; Fravi, Nina; Weber, Sabine; Burgunder, Jean-Marc. “Effect of Botulinum Toxin A Injections in the Treatment of Chronic Tension-type Headache: A Double-Blind, Placebo-Controlled Trial.” Headache: The Journal of Head and Face Pain. 41.7 (July/August 2001): 658-664. Print.

Rollnik, Jens D.; Karst, Matthias; Fink, Matthias; Dengler, Reinhard. “Botulinum Toxin Type A and EMG: A Key to the Understanding of Chronic Tension-type Headaches?” Headache: The Journal of Head and Face Pain. 41.10 (December 2001): 985-989. Print.

Gagnon, Christine M.; Smitherman, Todd A.; Weinland, Stephan R.; Tann, Beverly; Joseph, Petra; Lee, Thomas S.; Houle, Timothy T. “Botulinum Toxin A in the Treatment of Chronic Tension-Type Headache With Cervical Myofascial Trigger Points: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.” Headache: The Journal of Head and Face Pain. 49.5 (May 2009): 732-743. Print.

Chronic Daily Headache Not Otherwise Specified

The overarching diagnosis of chronic daily headache with episodes lasting greater than four hours includes the more specific conditions of chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. The following articles review studies that include patients suffering from a variety of these conditions and/or do not specify which sub-diagnoses with which these patients could be more specifically classified.

Mathew, Ninan T.; Frishberg, Benjamin M.; Gawel, Marek; Dimitrova, Rozalina; Gibson, John; Turkel, Catherine. “Botulinum Toxin Type A (BOTOX) for the Prophylactic Treatment of Chronic Daily Headache: A Randomized, Double-Blind, Placebo-Controlled Trial.” Headache: The Journal of Head and Face Pain. 45.4 (April 2005): 293-307. Print.

Dodick, David W.; Mauskop, Alexander; Elkind, Arthur H.; DeGryse, Ronald; Brin, Mitchell F.; Silberstein, Stephen D. “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: The Journal of Head and Face Pain. 45.4 (April 2005): 315-324. Print.

Mathew, Ninan T.; Kailasam, Jayasree; Meadors, Lori. “Predictors of Response to Botulinum Toxin Type A (BoNTA) in Chronic Daily Headache.” Headache: The Journal of Head and Face Pain. 48.2 (February 2008): 194-200. Print.

Other Headache Types

The following articles include patients suffering from other primary headache disorders, such as headaches associated with pericranial muscle tension, refractory headache, cervical-associated headache, and nummular headache. These tend to be smaller, pilot studies. Methodology differs significantly between each.

Wheeler, Anthony H. “Botulinum Toxin A, Adjunctive Therapy for Refractory Headaches Associated With Pericranial Muscle Tension.” Headache: The Journal of Head and Face Pain. 38.6 (June 1998): 468-471. Print.

Freund, Brian J. and Schwartz, Marvin. “Treatment of Chronic Cervical-Associated Headache with Botulinum Toxin A: A Pilot Study.” Headache: The Journal of Head and Face Pain. 40.3 (March 2000): 231-236. Print.

Blumenfeld, Andrew. “Botulinum Toxin Type A as an Effective Prophylactic Treatment in Primary Headache Disorders.” Headache: The Journal of Head and Face Pain. 43.8 (September 2003): 853-860. Print.

Tepper, Stewart J.; Bigal, Marcelo E.; Sheftell, Fred D.; Rapoport, Alan M. “Botulinum Toxin Type A in the Preventive Treatment of Refractory Headache: A Review of 100 Consecutive Cases.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 794-800. Print.

Mathew, Ninan T.; Kailasam, Jayasree; Meadors, Lori. “Botulinum Toxin Type A for the Treatment of Nummular Headache: Four Case Studies.” Headache: The Journal of Head and Face Pain. 48.3 (March 2008): 442-447. Print.

Dusitanond, Petcharat and Young, William. “Botulinum Toxin Type A’s Efficacy in Nummular Headache.” Headache: The Journal of Head and Face Pain. 48.9 (October 2008): 1379. Print.

Silberstein, Stephen D.; Marmura, Michael J.; Shaw, James; Yu, Shengsheng. “Headache Prophylaxis with BoNTA: Patient Characteristics.” Headache: The Journal of Head and Face Pain. 50.1 (January 2010): 63-70. Print.

Other Neurological Conditions Not Otherwise Specified

These articles review other neurological conditions that botulinum toxin type A is also used to treat, such as blepharospasm, myofascial wrinkles, temporomandibular disorders, cervical dystonia, and occipital neuralgia. Many of these cross over into the demesne of the headache specialist. Research into treatment for many secondary headache conditions is limited, and this may provide a fruitful area for use with novel therapeutics such as botulinum toxin.

Johnstone, Sharon J. and Adler, Charles H. “Headache and Facial Pain Responsive to Botulinum Toxin: An Unusual Presentation of Blepharospasm.” Headache: The Journal of Head and Face Pain. 38.5 (May 1998): 366-368. Print.

Carruthers, Alastair; Langtry, James A. A.; Carruthers, Jean; Robinson, Gordon. “Improvement of Tension-type Headache When Treating Wrinkles with Botulinum Toxin A Injections.” Headache: The Journal of Head and Face Pain. 39.9 (October 1999): 662-665. Print.

Freund, Brian J. and Schwartz, Martin. “Relief of Tension-type Headache Symptoms in Subjects with Temporomandibular Disorders Treated with Botulinum Toxin-A.” Headache: The Journal of Head and Face Pain. 42.10 (November 2002): 1033-1037. Print.

Ondo, William G.; Gollomp, Stephen; Galvez-Jimenez, Nestor. “A Pilot Study of Botulinum Toxin A for Headache in Cervical Dystonia.” Headache: The Journal of Head and Face Pain. 45.8 (September 2005): 1073-1077. Print.

Taylor, Martin; Silva, Sachin; Cottrell, Constance. “Botulinum Toxin Type-A (BOTOX) in the Treatment of Occipital Neuralgia: A Pilot Study.” Headache: The Journal of Head and Face Pain. 48.10 (November/December 2008): 1476-1481. Print.


BOTULINUM TOXIN TYPE A COMPARED TO OTHER HEADACHE PREVENTIVE TREATMENTS

The following section reviews articles that compare botulinum toxin type A to other headache preventive treatments; for example, the oral medications of Depakote and Topamax, as well as the alternate form of botulinum toxin type A known as Dysport. This article is the sole evidence looking at headache efficacy of other botulinum toxins besides that of onabotulinum toxin A.

Blumenfeld, Andrew M.; Schim, Jack D.; Chippendale, Thomas J. “Botulinum Toxin Type A and Divalproex Sodium for Prophylactic Treatment of Episodic or Chronic Migraine.” Headache: The Journal of Head and Face Pain. 48.2 (February 2008): 210-220. Print.

Mathew, Ninan T. and Jaffri, Sayyed Farhan A. “A Double-Blind Comparison of OnabotulinumtoxinA (BOTOX) and Topiramate (TOPAMAX) for the Prophylactic Treatment of Chronic Migraine: A Pilot Study.” Headache: The Journal of Head and Face Pain. 49.10 (November/December 2009): 1466-1478. Print.

Cady, Roger K.; Schreiber, Curtis P.; Porter, John A. H.; Blumenfeld, Andrew M.; and Farmer, Kathleen U. "A Multi-Center Double-Blind Pilot Comparison of OnabotulinumtoxinA and Topiramate for the Prophylactic Treatment of Chronic Migraine." Headache: The Journal of Head and Face Pain. 51.1 (January 2011): 21-32. Print.

Chankrachang, Siwaporn; Arayawichanont, Arkhorn; Poungvarin, Niphon; Nidhinandana, Samart; Boonkongchuen, Pairoj; Towanabut, Somchai; Sithinamsuwan, Pasiri; Kongsaengdao, Subsai. "Prophylactic Botulinum Type A Toxin Complex (Dysport) for Migraine Without Aura." Headache: The Journal of Head and Face Pain. 51.1 (January 2011): 52-63. Print.

Krymchantowski, Abouch V. and Jevoux, Carla C. "Topiramate vs. Divalproex Sodium in the Preventive Treatment of Migraine: A Prospective ‘Real World’ Study." Headache: The Journal of Head and Face Pain. 51.4 (April 2011): 554-558. Print.


EFFICACY AND SIDE EFFECTS OF BOTULINUM TOXIN TYPE A

This final section reviews articles that discuss the efficacy and side effects of botulinum toxin type A, including the effect of single-site/single-file injections, side effects such as hourglass deformity and atrophy of the corrugator supercilli muscle, as well as compliance issues. This section also contains pro vs. con debate articles and a prediction about the influence of the placebo effect on the efficacy of botulinum toxin type A.

Behmand, Ramin A.; Tucker, Tarvez; Guyuron, Bahman. “Single-Site Botulinum Toxin Type A Injection for Elimination of Migraine Trigger Points.” Headache: The Journal of Head and Face Pain. 43.10 (November 2003): 1085-1089. Print.

Guyuron, Bahman; Rose, Kevin; Kriegler, Jennifer S.; Tucker, Tarvez. “Hourglass Deformity After Botulinum Toxin Type A Injection.” Headache: The Journal of Head and Face Pain. 44.3 (March 2004): 262-264. Print.

Blumenfeld, Andrew. “Botulinum Toxin Type A for the Treatment of Headache: Pro.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 825-830. Print.

Welch, K.M.A. “Botulinum Toxin Type A for the Treatment of Headache: Con.” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 831-833. Print.

Blumenfeld, Andrew. “Does Single-File Botox Injection Really Work for Primary Headache?” Headache: The Journal of Head and Face Pain. 44.8 (September 2004): 838-839. Print.

Cady, Roger and Schreiber, Curtis. “Botulinum Toxin Type A as Migraine Preventive Treatment in Patients Previously Failing Oral Prophylactic Treatment Due To Compliance Issues.” Headache: The Journal of Head and Face Pain. 48.6 (June 2008): 900-913. Print.

Solomon, Seymour. “Botulinum Toxin for the Treatment of Chronic Migraine: The Placebo Effect.” Headache: The Journal of Head and Face Pain. 51.6 (June 2011): 980-984. Print.

Zhao, Chong-hao and Stillman, Mark. “Atrophy of Corrugator Supercilii Muscle in a Patient Induced by the Onabotulinum Toxin Injection.” Headache: The Journal of Head and Face Pain. 52.2 (February 2012): 309-311. Print.

CONCLUSION

The recent approval by the Food and Drug Administration for the use of onabotulinum toxin type A for the prevention of chronic migraine has increased patients’ access to this novel interventional therapy. This has provided additional treatment to patients that were previously unsuccessful in relieving their refractory pain and/or headache symptoms via other forms of therapy. Currently, onabotulinum toxin is the only FDA approved treatment for chronic migraine. With further research in the future, we would hope to see more evidence as to the mechanism of effect, subclasses of headache sufferers who are more likely to respond, predictors of response, and potentially individually tailored treatments.

Finkel, Alan G. “Botulinum Toxin and the Treatment of Headache: A Clinical Review.” Headache: The Journal of Head and Face Pain. 51.10 (November/December 2011): 1565-1572. Print.

Virtual Issue compilied 10 July 2012.

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