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Patient reported efficacy of the use of botulinum toxin a in the treatment of chronic migraine headaches
h [electronic resource] /
by Patrick Whitney.
[Tampa, Fla] :
b University of South Florida,
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Document formatted into pages; contains X pages.
Thesis (M.S.P.H.)--University of South Florida, 2010.
Includes bibliographical references.
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ABSTRACT: Objective: To assess patient reported efficacy of Botulinum toxin type-A for the prophylaxis of migraine headaches in patients with frequent migraine headaches prior to initiation of treatment with Botulinum toxin type-A compared to post treatment. Questions addressed include is there a difference in frequency of migraine headaches following treatment with Botulinum toxin type-A, is there a difference in cost of conventional treatment versus Botulinum toxin type-A and is there a difference in quality of life. Research Plan: Questions addressed patient status prior to the initiation of treatment as well as post treatment. Patient quality of life change, duration and frequency headache improvement are the primary focus. Other considerations included the cost difference between the previous use of other treatment and the periodic treatment with Botulinum toxin type-A. Methodology: A Cross Sectional study utilizing a questionnaire consisting of a modified Migraine Disability Assessment (MIDAS) questionnaire will be given to patients who had received more than one series of injections. Patients who reported chronic migraine headaches and were refractory to previous treatment methods were screened and placed in programs utilizing intramuscular injection of Botulinum toxin type-A at standard points on the face, Temporalis muscle and paracervical muscles. Clinical Relevance: This assessment is relevant to occupational issues due to the increasing number of patients applying for disability due to uncontrolled migraine headaches as well as lost productivity and reduction in functional capacity for activities of daily living. Impact and Significance: Patient's that are debilitated by recurrent chronic migraine headaches suffer loss of productive time at work and home. Treatment with Botulinum toxin type-A may results in significant relief allowing fewer days lost at work and improved quality of life. There may be significant cost saving if treatment results in discontinuation of other medications previously used for treatment of migraine headaches. Findings: According to the patients' responses to this survey, it appears that there was an overall improvement in the patients' ability to do work, for those who were employed, as well as their ability to do activities of daily living post treatment with Botulinum toxin-A. Though there were occasionally conflicting data seen in individual cases regarding responses to some of the answers, there appeared to be an overall statistically significant reduction in the mean of responses to the questions. The general implication is consistent with studies that indicate Botulinum toxin-A may be a useful adjunct in the prophylactic treatment of refractory migraine headaches.
Advisor: Stuart Brooks, M.D.
Key Words: Chronic daily headache
x Environmental and Occupational Health
t USF Electronic Theses and Dissertations.
Patient Reported Efficacy of Botulinum Toxi n Type A in the Treatment of Chronic Migraine Headaches by Patrick F. Whitney A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Public Health Department of Occupational Medicine College of Public Health University of South Florida Major Professor: Stuart Brooks, M.D. Thomas Truncale, D.O. Daisy Chang, Ph.D. Date of Approval: April 5, 2010 Key Words: Chronic daily headache, MIDAS questionnaire, productiv ity, cost, functional capacity copyright 2010, Patrick F. Whitney
Acknowledgments I would like to star t by thanking the members of my thesis committee who provided continual guidance and suppor t throughout this project. Dr. Thomas Truncale who provided the leadership necessary to initiate this venture and guidance on how to proceed through its completion. Dr. Eve Hanna who contributed her expert advise through her perspective and personal experi ence with thesis writing in th is program. Dr. Daisy Chang who gave critical assistance with regards to operation and interpretation of the data collected and analyzed using the SPSS program. A special thanks to Dr. Sally Zachariah at Bay Pines VA Medical Center. Dr. Zachariah was instrumental in obtaining data from patients currently un der treatment for migraine headaches at the neurology outpatient cl inic and encouraging completion of the questionnaires. She also was helpful in explai ning the procedure performed at that clinic and explaining some of the subtle differences in technique. I am very grateful to Dr. Stanley Krolczyk and Dr. Georgia Laliotis at James A. Haley VA Medical Center Department of Neurology Pain Clinic. Dr. Krolczyk was instrumental in stimulating my initial interest in this topic. He directed me to the resources that I originally reviewed when initially researching this topic. He was also the first to explain to me the theory and technique for the procedure. Dr. La liotis was of help in obtaining data for this research project by presenting the questionnai re to her patients for participation.
i Table of Contents List of Tables ii List of Figures iii Abstract iv Background 1 Migraine Mechanism 4 Management 8 Botulinum Neurotoxin Overview 12 Clinical Uses for Botulinum Neurotoxin 17 Supportive Studies 19 Controversy 28 Recent Data 31 MIDAS Questionnaire 33 Study Protocol 37 Data Collection and Analysis 40 Results 43 Paired Sample Tests 47 Wilcoxon Signed Ranks Test 54 Conclusion 69 List of References 70
ii List of Tables Table 1: MIDAS Grading Definitions 42 Table 2: Paired Samples Statistics Pre & Post 1-5 47 Table 3: Paired Samples Correlations Pre & Post 1-5 47 Table 4: Paired Differences Pre & Post 1-5 48 Table 5: Paired Samples Statistics Pre & Post 6-7 48 Table 6: Paired Samples Correlations Pre & Post 6-7 49 Table 7: Paired Differences Pre & Post 6-7 49 Table 8: Medication Paired Samp les Statistics Pre & Post 50 Table 9: Medication Paired Sa mples Correlations Pre & Post 51 Table 10: Medication Paired Differences Pre & Post 52 Table 11: Quality of Life Paired Samples Statistics Pre & Post 53 Table 12: Quality of Life Paired Samples Correlations Pre & Post 53 Table 13: Quality of Life Paired Differences Pre & Post 53 Table 14: Wilcoxon Signed Ranks Test Pre & Post 1-2 54 Table 15: Wilcoxon Signed Ranks Test Pre & Post 3-5 55 Table 16: Wilcoxon Signed Ranks Test Pre & Post 6-7 56 Table 17: Wilcoxon Signed Ranks Te st Pre & Post Tyl Opiate 57 Table 18: Wilcoxon Signed Ranks Test Pre & Post Triptan Other 58 Table 19: Wilcoxon Signed Ranks Test Pre & Post Quality of Life 59
iii List of Figures Figure 1: Pre Post comparison question 1 60 Figure 2: Pre Post comparison question 2 60 Figure 3: Pre Post comparison question 3 61 Figure 4: Pre Post comparison question 4 61 Figure 5: Pre Post comparison question 5 62 Figure 6: Pre Post comparison question 6 62 Figure 7: Pre Post comparison question 7 63 Figure 8: Pre Post comparison Tylenol 63 Figure 9: Pre Post comparison NSAIDs 64 Figure 10: Pre Post comparison Opiates 64 Figure 11: Pre Post comparison Triptans 65 Figure 12: Pre Post comparison Psy 65 Figure 13: Pre Post comparison Other 66 Figure 14: Pre Post comparison Quality of Life 66
iv Patient Reported Efficacy of Botulinum T oxin Type A in the Treatment of Chronic Migraine Headaches Patrick F. Whitney ABSTRACT Objective: To assess patient reported efficacy of Botulinum toxin type-A for the prophylaxis of migraine headaches in patients with frequent migraine headaches prior to initiation of treatment with Botulinum toxi n type-A compared to post treatment. Questions addressed include is there a difference in freque ncy of migraine headaches following treatment with Botulinum toxin ty pe-A, is there a diffe rence in cost of conventional treatment versus Botulinum toxin t ype-A and is there a difference in quality of life. Research Plan: Questions addressed patient status prior to the initiation of treatment as well as post treatment. Patient quality of life change, duration and frequency headache improvement are the primary fo cus. Other considerations included the cost difference between the previous use of other treatment and the periodi c treatment with Botulinum toxin type-A. Methodology : A Cross Sectional study utilizing a que stionnaire consisti ng of a modified Migraine Disability Assessment (MIDAS) que stionnaire will be give n to patients who had received more than one series of injec tions. Patients who reported chronic migraine headaches and were refractory to previous treatment methods were screened and placed
v in programs utilizing intramuscular injecti on of Botulinum toxin type-A at standard points on the face, Temporalis musc le and paracervical muscles. Clinical Relevance: This assessment is relevant to occupational issues due to the increasing number of patient s applying for disability due to uncontrolled migraine headaches as well as lost productivity and re duction in functional capacity for activities of daily living. Impact and Significance: Patients that are debilitated by recurrent chronic migraine headaches suffer loss of productive time at wo rk and home. Treatment with Botulinum toxin type-A may results in significant reli ef allowing fewer days lost at work and improved quality of life. There may be signi ficant cost saving if treatment results in discontinuation of other medications previo usly used for treatment of migraine headaches. Findings: According to the patients responses to this survey, it a ppears that there was an overall improvement in the patients abil ity to do work, for those who were employed, as well as their ability to do activities of da ily living post treatment with Botulinum toxinA. Though there were occasionally conflicting data seen in individual cases regarding responses to some of the answer s, there appeared to be an overall statistically significant reduction in the mean of respons es to the questions. The gene ral implication is consistent with studies that indicate Bo tulinum toxin-A may be a useful adjunct in th e prophylactic treatment of refractory migraine headaches.
1 Background Migraine headaches have become a significant source of lost work in the US. Social Security disability claims arising from migraine headaches have become more increasingly more common in recent years. It is estimated that 30 million Americans suffer occasionally or regularly with migraine headaches. It is estimated that 113 million lost work days are due to migraine s with $13 billion of lost productivity (1). Migraine ranks in the top 20 of the world's most disab ling medical illnesses. Estimates of the US population suffering from migraine head aches vary in range from 2 10% (1,2). The onset of a migraine headache is potentially disab ling in itself, however many sufferers live knowing that at any time the onset of a headache could disrupt th eir ability to work, go to school, care for their families or generally in terfere with activities of daily living. Less than 10% of those with migraine history ar e able to work or function normally during their migraine attacks (1). About 12 million people experience these attacks on an almost daily basis placing them well outside of the av erage rate of once or twice a month for the typical migraine headache sufferer. These ma y be referred to as chronic daily headache (CDH) and are defined as a group of disorders characterized by very frequent headaches occurring 15 days a month and include those headaches associated with medication overuse (3). In the US, women have a higher pr evalence than men at an estimated 18% vs. 6%. Over 30 million people in the United States cause American employers lose more than $13 billion each year as a result of 113 million lost work days due to migraine headaches. In the 2005 European Journal of Neurology, it was estima ted that migraine
2 headaches were the most costly neurologi cal disorder in the European Community costing more than 27 billion per year (15). Annual employer cost of lost productivity due to migraines has been estimated at $3,309 per sufferer. Total medical costs associated with migraines in the United States amount ed to one billion dollars in 1994 and when combined with the cost of lost productivity is estimated at thirteen to seventeen billion dollars per year. In a recent aritcle publ ished in the Journal of Occupational and Environmental Medicine, a study was published evaluating the impact on the workplace of chronic migraine headaches as compared to episodic migraine headaches (65). Estimates of lost productivity time were based on 2005 data derived from American Migriane Prevalence and Prevention (AM PP) study. This was a large study surveying 11,000 individuals with migraine headaches. The survey was done on patients over 18 years of age suffering from at least occasiona l self defined severe headaches. Migraine case definition included establis hed critreia of unilateral or pulsatile pain with nausea, vomiting, phonophobia, photophobia or unusual aura preceeding the headache. The questionairre was initiated in 2004 with a second follow up survey in 2005. The results of the study indicate that i ndividuals with chro nic migraine headaches were 19% less likely to be working as compared to those who experienced headaches at less than or equal to 3 headace days per month. The aver age time lost per week for those with chronic migraine headaches was 4.6 hours as compared to only 1.1 hours per week for those with less frequent headaches. Those in the chronic migraine group accounted for 20.8% of lost productivity time and 35% of overall lost work time when factoring in medical leave and unemployment. The stud y concluded that the impact of chronic
3 migraine headaches as well as episodic migr aine headaches would be underestimated if employment status is not measured (65).
4 Migraine Mechanism Migraine attacks often include features that occur in sequence beginning with the prodrome stage. This stage is marked by a change in mood that begins hours or days before the headache. Symptoms of pr odrome include depression, sleepiness, talkativeness, restlessness, or other alterations (6). Next is the Aura phase characterized by visual abnormalities, including flashes, sh immering, and other hallucinations. Finally the headache phase occurs. The headache itse lf is typically one sided but may also present as bilateral. It is usually gradual in onset with moderate to severe in pain intensity. Throbbing and worse pain occurs with physical exertion. The headache can last anywhere from 2 hours to 2 days in children and 4 hours to 3 days in adults (6). The frequency of migraine attacks is difficult to predict. The headache stage is often accompanied by decreased appetite, nausea, vomiting, sensitivity to light and sound, blurred vision, tenderness of the scalp or neck, lightheadedness, sweating, and pallor (6). The cause of migraine headaches appears to be multifaceted consequently no single treatment protocol has been uni formly successful leaving migr aine patients dissatisfied with treatment results. Numerous theories as to the origin and mechanism of migraine headaches have been proposed over the years. One of the first theories to explain migraines was the classic theo ry of vasoconstriction/vasod ilatation. According to this theory, migraine headaches are caused by th e constriction of blood vessels in the brain which is followed by vasodilatation (7). During the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed
5 that intracranial vasoconstricti on is responsible for the aura of migraine and that the subsequent rebound vasodilatation with activat ion of perivascular nociceptive nerves resulted in headache. This theory was based on the observations that extracranial vessels become distended and pulsatile during a migrai ne attack and stimula tion of intracranial vessels in an awak e person induces headache. He also noted that va soconstrictors such as ergotamine improve the headache, whereas vaso dilators such as n itroglycerin provoke an attack. However, this theory has been challenged recently for several reasons. Brain studies during migraine have shown that bloo d flow to the brain is in fact abnormal, which likely contributes to the symptoms. The current view is that a complex series of neural and vascular events in itiates migraine. This view is now called the neurovascular theory (11). Key features of the neurovascular theory include the following. At baseline, a migraineur who is not having any headache ha s a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex (12). This finding has been demonstrated in studies of transcranial ma gnetic stimulation and with functional MRI. This observation explains the special suscepti bility of the migrainous brain to headaches (13). There is speculation that there is a pa rallel with the patient with epilepsy who similarly has interictal neurona l irritability. The theory of hyperexcitability expands on the theory of vasoconstriction/vasodi latation. According to the theory of hyperexcitability, the brai ns of migraine sufferers are more sensitive to normal triggers, such as stress. The frequency of migraine s depends on the level of excitability. An external trigger may stimulat e sudden constriction of the blood vessels in the brain resulting in the onset of a migraine headache. It is theorized that the cause of this excitability is due to abnormal brain chemis try, specifically in the relationship between
6 calcium and magnesium. Calcium flows from th e extracellular fluid to the intracellular space during periods of nerve excitability resulting in vasoconstriction. In theory anything that blocks the flow of calcium or restores the balance of magnesium to calcium would be helpful in mitigating migraine. Some studies have shown that calcium channel blockers can successfully prevent migraine a ttacks due to blocking the flow of calcium into cells (8). Another theory proposes that there is a derangement of serotonin metabolism and an excess of neurotransmitters. During migraine, serotonin levels are depressed in the brain. Triptans selectively stimulate certain serotonin receptors and have been shown to reduce the symptoms of migraine (9). This theory is supported by the fact that melatonin, secreted by the pineal gland along with sero tonin, is also reduced during migraine. This suggests that the pineal gland is depressed in migraine patients (10). High levels of steroid hormones, primarily estroge n, can interact with the serotonin transport system. This further compromises the availability of serotonin. Other parts of the nervous system are also implicated in migraines. Th e sympathetic nervous system is responsible for many functions including increasing the cont ractility of smooth muscle and increasing the heart rate. Many of the reported factors that trigger migraine, such as stress and hormonal changes, also act on th e sympathetic nervous system (9). Similarly, drugs that mimic or enhance norepinephrine may alleviate migraine (9). Some evidence implicates steroid hormonal imbalances in migraine. Reports by women note that their migraine attacks occur in connection w ith their menses. Abnormal hormone levels have been suspected as closely associated with migrai ne headaches. As pr eviously discussed, occasionally a small percentage of migraine sufferers will fall into the category of chronic daily headaches. Current diagnostic cr iteria used to define CDH were published
7 by the International Headache Society in 2004 According to these criteria, primary chronic daily headache (CDH) is defined as daily or almost daily migrainous headache that occurs for more than 15 days a mont h, for greater than 3 months, and has no structural or infectious causes. Associ ated symptoms of nausea, vomiting, photophobia, and phonophobia may be less frequent in ch ronic migraineur. The pathogenesis of chronic daily headache is not well understood, a nd some believe that it is due to a central mechanism involving an altera tion in serotonergic and monoa minergic pathways to the brainstem and hypothalamus (14). Chronic daily headaches have been associated with an increased frequency of primarily psychiatric comorbid conditions su ch as depression, anxiety, bipolar disorders, panic attacks, oromandibular dysfunction, stress, and drug overuse.
8 Management Acute treatment of migraine headaches invo lves the use of medications intended to relieve the symptoms of attacks when they o ccur. Migraine headache preventative efforts involve the use medications taken daily to reduce the number of a ttacks and lessen the intensity of pain. Some patients may respond to alternative treatmen t such as lifestyle changes, relaxation techniques, acupunctu re, exercise, proper rest and dietary modification. Typically these are referred to as complementary treatment and may help avoid the triggering of attacks. Me dication overuse, commonly known as rebound headache, can have a significant influence on initiation of mi graine headaches (4). Standard medical approach to managing mi graine headaches include preventative or prophylactic measures, trigger management, ab ortive measures and pain management of the headache once it occurs. Typically preven tative measures have relied on the use of medications that were never intended to trea t headaches. These include beta blockers, calcium channel blockers, Methylsergide or Divalproex Sodium. Beta-blockers, primarily Propranolol, are one of the most commonly prescribed pr ophylactic treatments for Migraine and are considered to be an effective preventive treatment. Calcium channel blockers are thought to play a role in migraine prevention by affecting blood vessel constriction as previous ly discussed. Methysergide is thought to block the inflammatory and vessel-constricting effects of serotonin. Because of potential sideeffects, Methysergide is generally used only on select patients. Some of the known potential side effects include retroperit oneal fibrosis which may be severe but
9 uncommon. Other severe but uncommon side effects include pleural fibrosis and subendocardial fibrosis as well as an in creased risk of left-sided cardiac valve dysfunction (5). Because of the potential severity of these side effects, Methysergide requires a four to six week drug hiatus every six months Divalproex Sodium was originally developed for Epilepsy. It is typi cally prescribed in sm aller doses to treat migraine headaches to reduce the potential side effects. Management of migraine triggers are effective if the trigger is known and can reasonably be avoided. Triggers are different from person to person. Some exampl es of reported triggers include changes in weather or air-pressure, brig ht sunlight, glare, fluorescent lights, chemical fumes, menstrual cycles, and certain foods such as processed meats, red wine, beer, dried fish, broad beans, fermented cheeses, aspartame, and MSG. Once the prodromal phase of the migraine occurs and the headache is immine nt, abortive measures may be initiated. Abortive medications are used to relieve the severity, duration and associated symptoms of the migraine headache. They are recommen ded to taken as early as possible in an attack. Cerebral vasoconstrictor abortive agents were formulated specifically for migraine headaches. They may be administ ered by subcutaneous oral, rectal, or intramuscular means. Some of the common me dications include ergot amine tartrate or Dihydroergotamine, Sumatriptan, Naratripta n, Rizatriptan, Zolmitripan, Electriptan, Frovatriptan and Isometheptene mucate. The nonvasoconstrictive abortive agent Butorphanol tartrate may be administered by injection or na sal spray. Emergency departments commonly use narcotic injections in combination with Promenthazine or Hydroxyzine for nausea. These can offer an option if other measures fail or are not appropriate for comorbid conditions such as he art disease or other me dical condition that
10 would contraindicate their use. Once the headache starts, pain management may include narcotic analgesics. These ac t on the nervous system rece ptors and alter the patient's perception of pain. These drugs may relieve pain, however they may be addictive and such usage should be done in an appropriate manner. Common narcotic medications include Butalbital with Codeine, Code ine, Acetaminophen and Oxycodone hydrochloride, Meperidine hydrochloride, acetaminophen and codeine, Hydrocodone bitartrate and acetaminophen or methadone. Though normally ineffective for relief of migraine headaches, NSAIDs (non-steroidal anti-inflammatory drugs) act by inhibiting blood vessel inflammation. These medicat ions include Naproxen, Ibuprofen and Ketorolac. Most are readily available ove r the counter in non prescription doses which makes them accessible to the general public. Many migraine headache sufferers take these OTC medications in inappropriate doses in a desperate attempt to relieve a debilitating painful condition. Some migraine urs attempt to manage mild to moderate attacks at home by using a variety of tec hniques which include using a cold compress to the area of pain, resting with pillows comfor tably supporting the head or neck in a room with little or no sensory s timulation (light, sound, odors), avoiding stressful surroundings, sleeping or consuming a moderate amount of c affeine. Other alternative treatments include but are not limited to acupuncture biofeedback, manipulation, massage and nutritional (herbs, vitamins, minerals). Life style and home remedies, as described by the Mayo Clinic staff on their web page regard ing migraines, mayoclinic.com, can include muscle relaxation exercises, proper rest and keeping a headache diary to help learn more about what triggers the migraines and what treatment is most eff ective. They also indicate that Botulinum toxi n type A is sometimes used for treatment of chronic
11 migraines. They state that studies have had mi xed results with respect to effectiveness but that some headache specialists believe that it can be helpful for some people. Injections are made in muscles of the forehead and n eck. When this is effective, the treatment typically needs to be rep eated every three months.
12 Botulinum Neurotoxin Overview Botulinum toxin is a neur otoxic protein produced by the bacterium Clostridium botulinum, and is held to be the mo st toxic substance known to mankind (16) with an LD50 of roughly 0.0050.05 g/kg. Th e flaccid muscular paralysi s can be fatal in cases of botulism. Ironically, this property is inte ntionally used as an advantage in medical treatments. The toxins are injected into the muscles at diffe rent sites on the body resulting in temporary paralysis with effects lasting from 3 to 9 months. The toxin is a microbial product synthesized by the anaerobic gram-positive, spore forming bacteria ubiquitously found in the soil. Historically Botulinum toxin has been considered a byproduct of the bacteria re sulting in spoiled food. Th e Botulinum toxin's most significant adverse health effect is its prev ention of neurotransmi ssion causing paralysis. Death occurs from Botulism primarily as a result of paralysis of the respiratory muscles leading to respiratory failure (19). German physician Justin us Kerner (1786-1862) first developed the idea of a possible therapeutic use of Botulinum toxin which he called "sausage poison. In 1928, Dr. Herman Somm er, at the University of California, San Francisco, first isolated in purified form Bo tulinum toxin type A (BoNT-A) as a stable acid precipitate. In the 1950s, Dr. Vernon Br ooks discovered that when BoNT-A is injected into a hyperactive muscle, it blocks the release of acetylcholine from motor nerve endings. Work with Botulinum toxin type A as a therapeutic agent to treat human disease began in the late 1960s through the co llaboration of Alan B. Scott, MD, of the Smith-Kettlewell Eye Research Foundation and Edwa rd J. Schantz, PhD, director of food
13 microbiology and toxicology at the University of Wisconsin. This is when Botulinum toxin type A was first consider ed as a powerful therapeutic agent to treat symptoms of neurological disorders rather than an agent of human sic kness and disease. In 1980, Dr. Alan B. Scott, of Smith-Kettlewell Eye Research Institute, used Botulinum neurotoxin-A for the first time in humans to treat st rabismus. In December 1989, BTX-A (BOTOX) was approved by the FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old. Alt hough the effect had been observed by a number of independent groups, the cosmetic effect of BoNT-A was initially described by ophthalmologist Jean Carruthers and dermatol ogist Alastair Carruthers working in Vancouver, Canada. The FDA announced the approval of BOTOX Cosmetic on April 15, 2002 as a treatment to temporarily improve the appearance of moderate to severe frown lines between the eyebrows referred to as glabellar lines. BoNT is broken into 7 neurotoxins labeled types A, B, C [C1, C2], D, E, F, and G. They are all antigenically and serologically distinct but structurally similar. Human botulism is primarily caused by types A, B, E, and F. Types C and D are onl y toxic in animals. The toxin is a zinc dependent protease that cleaves one or more of the fusion protei ns by which neuronal vesicles release acetylcholine (A ch) into the neuromus cular junction. It acts preferentially on peripheral cholinergic nerve endings to block Ach release (18). The details of BoNT mechanism are described by Takamizawa K, Iw amori M and Kozaki S, et al. The BoNT molecule is synthesized as a single chain and then cleaved to form the dichain molecule with a disulfide bridge. The light chain acts as a zinc endopeptidase similar to tetanus toxin with proteolytic activity located at th e N-terminal end. The heavy chain provides cholinergic specificity and is responsible for bi nding the toxin to presynaptic receptors. It
14 also promotes light chain translocation acr oss the endosomal membrane. Botulinum toxin acts by binding presynaptically to high affin ity recognition sites on the cholinergic nerve terminals. This results in decreased the release of acetylcholine causing a neuromuscular blocking effect. Specifically, Botulinum t oxin cleaves SNARE proteins which are involved with fusing synaptic vesicles to the plasma membrane. Cleaving of SNARE proteins inhibits the release of acetylcholin e at the neuromuscular junction leading to inhibition of neurotransmission. Cleaving SNARE proteins creates a nonfunctional SNARE complex disrupting calcium influx a nd fusion is disrupted. Increasing the calcium concentration in the synaptic termin al may diminish the effects of Botulinum toxin. According to de Paiva A, Meunier FA Molg J, et al, recovery occurs through proximal axonal sprouting and muscle reinnervation by formation of a new neuromuscular junction. BoNT-A and BoNT-E cleave synaptosome associated protein (SNAP-25), a presynaptic membrane protein required for fusion of neurotransmittercontaining vesicles (17). When BoNT-A is injected into a striate muscle, paresis occurs after two to five days and lasts from two to three months before it gradually starts to wear off. When Botulinum Toxin is injected into a target tissue it is almost completely bound to the axon terminal (20). However, when BoNT-A is a pplied to treat cer vical dystonia, small fractions of the applied Botulinum toxi n are distributed systemically and can be detected by increase of neuromuscula r jitter in non injected muscles (21). When Botulinum Toxin-B is applied to treat cervical dystoni a substantial systemic anticholinergic side effects can be clinically detected (18). Despite its systemic dist ribution, direct Botulinum Toxin effects on the CNS have not been repor ted. This is because Botulinum neurotoxin with its size of 150 KiloDalton does not pene trate the blood brain barrier. Apart from
15 systemic penetration Botulinum toxin could theoretically reach the CNS by retrograde axonal transport. Such retrogr ade axonal transport has been detected for Botulinum toxin with radioactively labeled Botulinum neurotoxin (22). The Botulinum toxin was likely inactivated before it reached the CNS since the retrograde axonal tr ansport was so slow. Transsynaptic transport was not observed. Botulinum Toxin action upon Renshaw cells was only demonstrated after intraspinal injection (23). Effects of Botulinum Toxin on the neuromuscular synapse and on the muscle sp indle organs can produc e various indirect effects on the CNS. On the spinal level Botulinum Toxin produces reflex inhibition of alpha motoneurons by gamma mo toneuron blockade and subse quent Ia/II afferent input suppression1(24,25). Botulinum toxin may normalize alte red reciprocal inhibition between flexor and extensor muscles in patients with upper limb dystonia (26). A similar effect was also demonstrated in patients with essential tremor (27). EMG changes of the contralateral ocular muscles after injection of Botulinum toxin into the lateral rectus muscle also suggest central effects (28). Botulinum toxin may also normalize altered intracortical inhibition at the supraspinal level (29) as well as altered somatosensory evoked potentials (30). Although Botulinum toxin can enhance some aspects of cortical activation it fails to improve the impaired activation of the primary motor cortex as seen in writer's cramp (31). When Botulinum Toxin is used to treat painful muscle hyperactivity disorders frequently substantial pa in relief is reported. Pain relief is usually attributed to the reduction of the muscle hyperactivity. Ho wever, formalin-induced pain in animals can be reduced by Botulin um toxin direct analgesic effect (32). Substance-P is a neuropeptide involved in pain perception, vasodilatation an d neurogenic inflammation. It has been shown to be bloc ked by Botulinum toxin togeth er with acetylcholine in the
16 iris muscles of rabbits (33) as well as in cultured dorsal root ganglia neurons (34). Direct Botulinum toxin effect is suggested due to th is association of inhi bition with a decrease of SNAP 25. Botulinum Toxin induced su ppression of substance-P has also be demonstrated in embryonic rat dorsal root ganglia neurons (35). When different Botulinum toxin serotypes were tested, Botulinum Toxin-A produced the strongest substance-P suppression (35). Botulinum Toxin has also been shown to suppress the release of glutamate, another neurotransmitter involved in nociception, in the periphery and in the dorsal horn (36). This confirmed earlier findi ngs of Botulinum toxin induced inhibition of glutamate release fr om cerebrocortical synaptosomes (37). The release of noradrenalin in PC12 cells (38), used as a model system for neuronal differentiation, and calcitonin gene related peptide in autonomic vascular nerve terminals (39) could also be reduced by Botulinum Toxin suggesting addi tional possible mechanisms for Botulinum Toxin effects on pain transmission (40).
17 Clinical uses for Botulinum Neurotoxin According to the FDA website, www.fda.gov information regarding approved preparations of Botulinum toxin products is limited to 3 preparations of Botulinum neurotoxin type A. They are marketed by 2 companies under the labels Botox, Botox Cosmetic and Dysport. The only listed indications for use according to the FDA site are for cervical dystonia, severe pr imary axillary hyperhidrosis, strabismus, blepharospasm, and temporary improvement in the appearance of moderate to severe glabellar lines. Considerations for hea lth care professionals se ction states that a boxed warning has been added to the prescribing information to highl ight that Botulinum t oxin may spread from the area of injection to produce symptoms cons istent with botulism. Symptoms such as unexpected loss of strength or muscle weakne ss, hoarseness or dysphonia, dysarthria, loss of bladder control, trouble breathing, troub le swallowing, double visi on, blurred vision and drooping eyelids may occur. Swallowi ng and breathing difficulties can be life threatening and there have been reports of d eaths related to the effects of spread of Botulinum toxin. It also states that clinical doses expressed in units are not comparable from one Botulinum toxin product to the next Units of one product cannot be converted into units of another produc t thus Botulinum toxin product s differ from one another in dose units, names, and dosing and are not in terchangeable. In November 2001, Health Canada approved Botox injections to reduce sp asticity that can occur after a stroke. Allison Brashear, MD, professor and chair of the Neurology department at Wake Forest University Baptist Medical Center in Winston Salem, N. C., directed the first major study
18 in 2002 on the use of Botox for post stroke muscle spasticity (41). The results were published in the New England Journal of Medicine In that multi-center study, half of the 126 patients received Botox and the other ha lf took a placebo. 62% of the Botox group reported improvement in the area they desi red as opposed to just 27% of the placebo group. In that study, patients received just one injection. In 2005 at the annual meeting of the American Association of Physical Medici ne in Philadelphia, Dr. Brashear presented the findings of the first long-term study of the repeated use of Botulinum toxin type-A for the treatment of post stroke spasticity. The study focused on 279 patients at 35 rehabilitation centers in Indi ana over a 1 year period. Th e research was funded by the company that manufactures Botox, Allergen In c. The participants in the study had hand, wrist or elbow spasticity. Up to five doses were given to targeted muscles in the wrist, elbows and fingers. Six weeks into the study researchers discovered a notable improvement in patients muscle tone from the onset of treatment. Improvement was graded in four areas consisti ng of pain, hygiene, dressing an d limb posture. At least half the participants by the end of the study reported that they had improved by one point in the area they deemed most significant. De spite these results, treatment for muscle spasticity remains an off label use. Several other off label uses of Botulinum toxin-A has been and are currently used in practices of various subspecialties. Some of the more common off label uses include low back pai n, dystonia, laryngeal spasm, hemifacial spasm and migraine headaches. Since the na ture of this study involves treatment using Botulinum toxin-A for migraine headaches, I will focus on information to that use.
19 Supportive Studies Chronic daily headaches (CDH) are a he terogeneous group of headache disorders occurring on at least 15 days per month that, according to population studies, affects 4% to 5% of the general population worldwide (42-45). Chronic migraine is in the subset of the CDH disorders. Chronic migraine was first characterized by Silberst ein and Lipton. By definition it includes head pain occurri ng on 15 or more days per month, headache duration of 4 or more hours and increasing headache frequency with decreasing symptom severity over a 3-month period (46-47). The two most common forms of primary, long duration CDH disorders are chronic (trans formed) migraine and chronic tension headaches, with most subclassif ied as transformed migraine (48-50). While most CDH patients are categorized as having transformed migraine others may have chronic tension type headache (51-52). Transformed migraine may also be associated with medication overuse headache (53,54). As indicated previously, the current standard treatment for migraine headaches includes primarily medi cations designed to abort an imminent headache or manage the pain associated w ith the headache once it starts. Chronic migraine is often both common and resist ant to treatment even with prophylactic medications known to be effective in pati ents with episodic migraine headaches (55). Medications used to treat chronic migraine s include simple analgesics as well as prophylactic medications that were originally designed to treat other conditions such as depression, hypertension, and seizures. Pract itioners often struggle with decisions on how to best manage patients who present with persistent migraine headaches that have
20 shown little lasting response to standard medication regimens and are either utilizing excessive amounts of prescription medications or showing poor response to medications prescribed with no other explanation as to wh y their headaches persist. The disability and impact associated with this disorder is substantial and touches al most every aspect of the patient's life. These patients experience si gnificantly diminished health-related quality of life. Mental health as well as physical social, and occupational functioning may also be impaired (56). Many alternative methods of manageme nt as previously listed also have had mixed results. Interest in the use of botulinum toxin-A was first generated following an observation by practitioners using the co mmercial preparation for cosmetic purposes following the initial approval by the FDA. Wh en doing procedures involving injections to remove glabellar lines, patients who had previously experienced frequent migraine headaches reported a reduction in the frequency and intensity of headaches. Since 1992, Botulinum toxin-A had been used in purified an d diluted form to temporarily paralyze the Corrugator and Procerus muscles that bring th e eye brows together to eliminate wrinkles in this region. The practic e of injecting the area with Botulinum toxin-A in the upper third of the face for treatment of cosmetic frown lines in patients who coincidentally suffered from Migraines, resulted in the re ported unexpected benifi t of migraine relief (57). During the November 2-5, 2000 American Society of Dermatologic Surgery meeting Richard Glogau, MD, University Of Californi a, San Francisco professor of dermatology presented a study that he performed at UCSF. He reported that 75 % of patients in his case study experienced four to six months of Migraine relief following injections of Botulinum toxin-A into muscles of the face and head. Glogau's small study of 24 patients added weight to previous reports that Bo tulinum toxin-A can relieve Migraines.
21 Following this opportune discovery, Dr. Glogau and other researchers began to evaluate injection points and dosages that could al leviate Migraines. Dr. Glogau's results indicated that Botulinum toxin-A injected into the muscles of the brow, eyes, forehead, side of the head and back of the head near the neck provoked sometimes immediate migraine relief and provided benefit for up to six months. The dosage of Botulinum toxin-A in his case studies averaged 80 units per patient (57). Unfortunately most of the data at that time consisted of case reports and meeting abstracts. There were no published randomized double-blind trials that demonstrated safety and efficacy of Botulinum toxinA for treatment of migraines. There we re only two previous studies which were presented at the 1999 meeting of the Ameri can Association for the Study of Headache (currently the American Headache Society) The first study was reported by researchers at the Michigan Head Pain and Neurological Institute in Ann Arbor and Michigan State University. The study involved a procedur e using a one time dose of 25 units of Botulinum toxin A injected into the muscles of the brow, forehead and side of the head. The results of this study reflected a reduction in the frequency of Migraines, the severity of pain, vomiting, and the use of pain medications for up to three months. Treatment with 75-units resulted in migraine relief but also elicited undesirable side effects like eyelid drooping. In the second study, reported by res earchers at the University of California, Los Angeles, 51% of 96 patients reported co mplete improvement of their Migraine pain (57). Other researchers developed an interest and proceeded to set up their own studies following these reports of migr aine relief using Botulinum toxin-A. In 2004, Stafford Conway, M.D. et al, undertook an open label st udy to evaluate the safety and utility of Botulinum toxin type-A injection therapy for patients with ch ronic migraine who
22 previously had failed to respond to at least three prophylactic medica tions. The study at the University of South Alabama Headache Cent er in Mobile, Al. i nvolved a total of 59 patients. An inclusion criterion was that the patient had previously failed at least three adequate trials of prophylact ic medications known to be effective in treating episodic migraine. All participating patients were asked to complete a Migraine Disability Assessment (MIDAS) questionnaire and to keep a headache diary for the month preceding Botulinum toxin type-A administra tion. All patients received 25 units of Botulinum toxin type-A per the fixed front al-temporal site protocol published by Silberstein et al (58). Participating patients were asked to return for follow-up 6 weeks after Botulinum toxin type-A treatment and present their headache diary including any perceived side effects. Their report included only a descriptiv e analysis of the results. A positive response was defined to be a 50% or greater reduction in headache days per month over the last 30 days of the followup period relative to the patients baseline status. Other outcome variables analyzed in cluded subjective res ponse (much better, somewhat better, same, or worse) a nd functionally incapacita ting headache days per month over the last 30 days of the fo llow-up period relative to the 30 days pretreatment. Their results showed a 41% positive response rate however their conclusion stated that Based on our obser vations and results from other published reports, we offer for speculation the possibility that the current uncertainty regarding the efficacy of BoNT-A for prevention or suppression of migraine may reflect a type II error; that is, even the large-scale studies perfor med to date have involved too few patients overall and included too many s ubjects predestined to fail. One of the most frequently referenced studies was a multicenter trial f unded by Allergan Inc., the makers of Botox
23 (BoNT-A ) which was used in the study. Th is was one of the first randomized, doubleblind, placebo-controlled study of Botulinum toxin type-A in patients with diagnostic criteria of CDH and was c onducted from July 6, 2001, through November 7, 2003, at 28 North American study centers. The study was headed by Stephe n D. Silberstein, M.D. in cooperation with the Bonta-039 Study Group. The study was a randomized, doubleblind, placebo-controlled, para llel group clinical study of 3 fixed-dose treatments of Botulinum toxin type-A compared with placebo in the tr eatment of patients with CDH. Inclusion criteria for the study included men and wo men aged 18 to 65 years who experienced headaches on more than 15 days during a 30-day baselin e screening period. Headaches could include any combination of migraines with or without aura, migrainous headache, probable migraine, an d/or episodic or chronic tension-type headaches. Included were long-term prophyl actic headache medications however they had to be stable with no change in dose or dosing regimen for at least 3 months immediately before the baseline period. Patients were exclude d from the study if they had any medical condition such as neuromuscular disorders or used any agent that might expose them to risk if they received Botulinum toxin type-A had an infection or skin problem at any of the injection sites, had a known allergy or se nsitivity to the study medication or to its components as well as other ex clusions listed in the study (60). This was a double-blind study and neither the investigator nor the pa tient knew which treatment was given at day 0, day 90, and day 180. Among 1200 screened patients, 702 (mean age 43.4 years with 82.9% female) were enrolled, entered into the placebo run-in period, and subsequently randomized to active treatment or placebo at day 0. At the end of the placebo run-in period, of 702 patients, 538 were classified as placebo nonresponders and 164 as placebo
24 responders. Subsequently, patients within each group were randomized to receive Botulinum toxin type-A at 225 U (n=182), 150 U (n=168), 75 U (n=174), or placebo (n=178). The primary efficacy end point was the mean change from baseline in the frequency of headache-free days for the 30day period ending on day 180 for the placebo nonresponder group. A secondary efficacy end point was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period at day 180 for the placebo nonresponder group. Other variables evaluated per 30day period included the frequency of any type of headaches, the proportion of patients with a decrease from baseline of 50% or more headaches, the frequency of migraine headaches of any severity, the proportion of patients with a decrease from baseline of 50% or more in migraine headaches, the pr oportion of patients with a decrease from baseline of 2 or more migraine headaches, and the frequency of moderate to severe migraine headaches. Although the primary efficacy end point was not met, Botulinum toxin type-A treatment in this trial showed a signi ficant difference from placebo in some analyses. At day 240, the decrease in headach e frequency was significantly greater for the Botulinum toxin type-A 225 U and 150 U groups compar ed with placebo. The placebo response was higher than expected but a greater percentage of patients in the placebo group used pain medications for acute headache throughout the study, thereby confounding the results (60). A later study was published in Headache April 2005 by Mathew NT, Frishberg BM, Gawel M, Dimitr ova R, Gibson J, Turkel C; BOTOX CDH Study Group. This was an 11-month, randomi zed double-blind, placebo-controlled study of Botulinum toxin type-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducte d at 13 North American study centers. The
25 primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy m easure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches per 30-day period, th e proportion of patient s with a decrease from baseline of 50% or greater in the fr equency of headaches per 30-day period, acute medication use, and adverse events were also assessed. 355 patients, with a mean age of 43.5 years and 84.5% female, were enrolled and randomized (59). At day 180, placebo nonresponders treated with Botulinum toxin t ype-A had an improved mean change from baseline of 6.7 headache-free days per 30 day period compared to a mean change from baseline of 5.2 headache-free days for pl acebo-treated patients. The between group difference was not statistically significant but revealed 1.5 headache-free days in favor of Botulinum toxin type-A treatment. There was a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of Botulinum toxin type-A patient s had a decrease from baseline of 50% or greater in the frequency of headache da ys per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). The mean change from base line in the frequency of headaches per 30 day period at day 180 was -6.1 for Botulinum toxin type-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 Botulinum toxin type-A patients (2.3%) discontinued the study due to adverse events (59). From the data collected in this study, the researchers concluded that Botulinum t oxin type-A treatment resulted in patients having, on average, approximately seven more headache free days compared to baseline.
26 Although at the primary time point the Botulinum toxin type-A treatment resulted in a 1.5 between-group difference compared to placebo and the difference was determined to be not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days in addition to st atistically significant re ductions in headache frequency. A follow up study using a subgr oup analysis of th e 11month, randomized double-blind, placebo-controlled study of Botulinum toxin type-A was later published in April of 2005. The objective of this study was to assess the efficacy and safety of Botulinum toxin type A for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications. This investigation involved data for pa tients who were not receiving simultaneous prophylactic headache medication and who cons tituted 64% of the full study population. This placebo-controlled study consisted of a 30 day baseline period during which headache frequency was monitored along with a 30 day single blind placebo run in period during which response to placebo was determ ined and a 9 month double blind treatment period during which patients received three tr eatment cycles (Botulinum toxin type-A or placebo) separated by 90 days (56). 228 patients from the original study group were not taking prophylactic medication and were included in this analysis. 117 patients received Botulinum toxin type-A and 111 patients rece ived placebo injections. Mean age was 42.4 10.90 years with a mean frequency of headaches per 30 days at baseline of 14.1 for the Botulinum toxin type-A group and 12.9 for the placebo group ( P = .205). After two injection sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the Botulinum toxin type-A group compared with only -4.5 in the placebo
27 group ( P = .032). There was a statistically si gnificant between group difference of 3.3 headaches. The between group difference favor ing Botulinum toxin type-A treatment continued to improve to 4.2 headaches after a third injection session ( P = .023). Botulinum toxin type-A treatment at least halv ed the frequency of baseline headaches in over 50% of patients after three injection sess ions compared to baseline. Statistically significant differences between Botulinum toxi n type-A and placebo were evident for the change from baseline in headache frequency an d headache severity for most time points from day 180 through day 270. Only 5 patients (4 patients receiving Botulinum toxin type-A treatment; 1 patient receiving placebo) discontinue d the study due to adverse events and most treatment related events were transient and mild to moderate in severity. The researchers concluded that Botulinum toxin type-A is an effective and well-tolerated prophylactic treatment in migraine patie nts with CDH who are not using other prophylactic medications (56).
28 Controversy Although there have been well done studies th at have indicated that BoNT has shown promise in cases of refractory migraine headache treatment and prophylaxis, not everyone is convinced that th e evidence is worthy of FDA a pproval for routine use. The primary issue with acceptance of research results showing efficacy of Botulinum toxin type-A in the treatment of mi graine headaches is that the largest studies were funded by Allergan, the company that produces BoNT. "Official Disability Guidelines" and "ODG" are trademarks of Work Loss Data Institute The Official Disability Guidelines uses a comprehensive annual update process based on scientific medical literature review, survey data analysis, and expert pane l validation to determine strength of recommendation regarding medical procedures It was designed for use by providers, employers, insurance claims professionals, and state workers compensation authorities. The large claims review centers use the ODG as a guide to authorize or deny requests for authorization of procedures on enrolled worker s. According to the ODG, the evidence is mixed for migraine headaches. This RCT found that both Botu linum toxin type-A (BoNT-A) and Divalproex sodium (DVPX) si gnificantly reduced disability associated with migraine, and Botulinum toxin type-A ha d a favorable tolerabi lity profile compared with DVPX. (Blumenfeld, 2008 ). In this RCT of episodic migraine patients, low-dose injections of BoNT-A into the frontal, tempor al, and/or glabellar mu scle regions were not more effective than placebo (Saper, 2007 ). Botulinum neurotoxin is probably ineffective in episodic migraine and chronic tension-type headache. (Naumann, 2008 ). In the
29 referenced study by Blumenfel d, comparative evaluation of the efficacy and safety of Botulinum toxin type A and Divalproex sodium as prophylaxis in re ducing disability and impact associated with migraine was done This was a randomized, double-blind, singlecenter prospective study. Fiftynine patients received either Botulinum toxin type-A 100 U/placebo-DVPX bid or placeboBotulin um toxin type-A /DVPX 250 mg bid. Botulinum toxin type-A /placebo injections we re given at Day 0 and at Month 3. Patients were evaluated at Months 1, 3, 6, and 9. Both trea tments showed significant improvements in migraine disability scor es and reductions in headache days and headache index. A trend of decreased headache severity was observed with Botulinum toxin type-A. A greater percen tage of DVPX patients report ed adverse events possibly related to treatment (DVPX 75.8% vs. Botu linum toxin type-A 50%, P = .04) and discontinued because of adverse events ( DVPX 27.6% vs Botulinum toxin type-A 3.3%, P = .012) (61). The second referenced study was done by Saper et al in 2007. This was a randomized, double-blind, placebo-controlled stu dy of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four Botu linum toxin type-A groups that received injections into different muscle regions in th e frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U). For 3 months following a single treatment, patients recorded migraine-related variables in a daily diary. Their results indicated that Botulinum toxin type-A and placebo produced co mparable decreases from baseline in the frequency of migraines (P > or = 0.411). In gene ral, no statistically significant differences were observed for any efficacy variable. The ov erall rates of adverse events or treatment related adverse events were similar among the groups. Th ey concluded that low dose
30 injections of Botulinum toxin type-A into th e frontal, temporal, and/ or glabellar muscle regions were not more effective than placebo (62). The third referenced study was done by Naumann et al in 2008. A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to Botulinum toxin type-A and the selected indications. They concluded by thei r research that Botuli num toxin type-A is probably ineffective in episodic migr aine and chronic tensiontype headache. There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of Botulinum toxin type-A in C DH mainly transformed migraine (63).
31 Recent Data In September 2008, Allergan announced that it had completed anal yzing data of two Phase III clinical trials designed to evaluate the use of botulinum toxin type-A for the prophylactic treatment of headach e in adults suffering from chronic migraine as defined by the criteria of chronic daily headaches. In the two Phase III clinical trials, patients were randomly assigned for treatment with bot ulinum toxin type-A or placebo injections every 12 weeks. The primary analysis was performed at week 24 following 2 treatment cycles. The two major efficacy measures eval uated in the trials were change from baseline in the number of headache episodes and number of headache days occurring in the 28 day period preceding the week 24 time point. In the first Phase III clinical trial, Allergan prospectively select ed number of headache episode s as the primary endpoint for evaluation. Number of headache days was se lected as the major secondary endpoint. Results from the first Phase III clinical tr ial indicated that alt hough both the botulinum toxin type-A and placebo treatment groups show ed a statistically significant improvement from baseline. There was no significant difference in the reduc tion of number of headache episodes between patien ts receiving botulinum toxi n type-A and placebo. As in previous study outcomes, the study did show a decrease in number of headache days which is the FDA's preferred efficacy measure. This was significantly greater in patients receiving botulinum toxin type-A as compar ed to patients receiving placebo (p=0.006). The decrease in number of migraine or pr obable migraine days was also found to be significantly greater in patients treated with botulinum toxin type-A as compared to
32 patients receiving placebo (p=0.002). Based on the data from the first Phase III clinical trial, the primary endpoint for the second Ph ase III study was prospectively changed to number of headache days, w ith number of headache episodes changed to a secondary endpoint, before the data were unmasked. In the second Phase III study, the primary endpoint and key secondary endpoints showed statistically significant benefit of botulinum toxin type-A treatment over placeb o injections. The patients treated with botulinum toxin type-A demonstrated a signif icantly greater decrea se in both number of headache days (p<0.001) and number of headac he episodes (p=0.003). As in the first Phase III trial, the second study also show ed a decrease in num ber of migraine or probable migraine days that wa s significantly greater in pati ents treated with botulinum toxin type-A as compared to placebo (p<0.0 01). In both Phase III clinical trials, botulinum toxin type-A treatments were well tolerated in patients suffering from chronic migraine. Both studies used quality of life evaluation us ing the validated Headache Impact Test which is a migraine management tool to help identify the severity and frequency of migraine headaches. Patients receiving botulinum toxi n type-A treatments scored statistically significantl y higher improvement in quality of life when compared to patients receiving placebo injecti ons (p<0.001 in both studies). Allergan is in the process of gaining approval from the FDA to add the use of botulinum toxin-A for treatment of chronic migraine headaches based on this new data. Other recent smaller studies sponsored by Allergan produced similar results (64).
33 MIDAS Questinnaire Despite the lack of support by the FDA, nu merous practitioners as including those in some VA hospitals perform botulinum toxinA injections for prophy lactic treatment of refractory chronic megraine headaches. Bo th the Neurology Department at Bay Pines Hospital in St. Petersburg, Fl and the Neurol ogy Departments Pain Management Clinic at James A Haley VA Hospital in Tampa, Fl pr ovide this service. From observation and evaluation of the patients undergoing the proced ure, it appeared that there was a general positive response to the treatment and overall patient satisfaction. Unfortunately there was no documentation to quantitat e the effect on the patients improvement in lost work days, ability to perform activities of daily li ving, increase or decr ease in medication use as well as cost difference pre and post treatm ent and effect on activities of daily living. One of the tools for evaluation of the severity of a patients disability due to the effects of migraine headaches is the Migraine Disabili ty Assesment (MIDAS) questionairre. The MIDAS questionnaire was put together to help measure the impact migraine headaches have on the patients life over the 3 mont hs prior to the inte rview by the physician administering it. The primary intent was to assess headache-related disability with the aim of improving migraine care. Headache sufferers answer five questions scoring the number of days in the past 3 months related to activity limitations due to migraine. The internal consistency, testretest reliability, and validity of the questionnaire were assessed in separate population based studies of migraine sufferers. The face validity, ease of use, and clinical utility of the questionnaire were evaluated in a group of 49 physicians who
34 independently rated disease seve rity and need for care in a diverse sample of migraine case histories. The testretest Pearson correlation coefficient for the total MIDAS score was approximately 0.8. The MIDAS scor e was valid when compared with a reference diary based measure of disabi lity. The overall correlation between MIDAS and the diary based measure was 0.63. The MIDAS score was also correlated with physicians assessments of need for medical care ( r = 0.69). From studies completed to date, the MIDAS Questionnaire has been shown to be internally consistent, highly reliable, valid, and correlates with physicians clinical judgment. These featur es support its suitability for use in clinical practice. Use of the MIDAS Questionnaire may improve physician patient communication about headache related disability and may favorably influence health care delivery for migraine patients (66). Though the questionnaire ha s been validated by the American Academy of Neurology, it only gives information regarding the severity of the patients disability prior to care by the phys ician giving it. The questionnaire does not address other issues such as di rect or indirect cost of tr eating migraine headaches. In a 2005 study done by Goldberg, migraine headache s were estimated to result in annual costs totaling as much as $17 billion in the United States (67). Most of the direct costs are for outpatient services such as medications, office visits, emergency department visits, laboratory/diagnostic services a nd management of treatment si de effects. Indirect costs from lost productivity in the workplace, as previously discussed, add substantially to the total. The Triptan class of drugs, used for abortive treatment, acc ount for the greatest portion of medication costs. Rese arch suggests that a stratifi ed care strategy, with initial therapy based on the patients score on the MIDAS scale, is both clinically advantageous and more cost effective than stepped care strate gies. It should be noted that the Triptans
35 are not interchangeable and costs as well as clinical outcomes may vary with different agents in this class. Migraine prophylaxis is aimed at preventing frequent attacks and the development of a long term condition that ofte n incurs heavy costs for abortive treatment, diagnostic services, and medical care. Agents approved for migraine prophylaxis include those listed in the above prev ious discussion. As with abortiv e therapy, costs vary widely among these prophylactic agents. Of the total annu al cost associated w ith migraine and its treatment, roughly $1.5 billion goes to medica tion with Triptans accounting for $1.18 billion with a mean cost per prescription of $160 (68). Focusing specifically on migraine headaches, another study found that the annua l cost to employers exceeded $14.5 billion, of which $7.9 billion was due to absenteeism, $5.4 billion to diminished productivity, and $1.2 billion to medical costs (69). A small open label trial of Botulinum toxin was conducted in 5 patients with migraine headaches that were unresponsive to conventional antimigraine medications. Evaluation was done after 1 year of injections at 3 month intervals. The use of other migraine medi cations, as measured by the change in annual costs for other medications, had decreased from pretreatment levels. When the cost of the Botulinum toxin-A treatment itself was incl uded, the total change in annual medication cost ranged from an increase of $648 to a de crease of $2717. All of the patients showed substantial clinical improveme nt with no reported adverse events. Migraine symptoms typically decreased within a few days after each injection and maximal effects were noted over the 2 months after treatment (70). A budgetary model prov ided a theoretical basis for predicting the cost outcome of selecting a given approach to migraine management. This model focused on the use of Botulinum t oxin-A for prophylaxis in chronic migraine patients enrolled in a commercial managed care plan. The goal was to assess the impact
36 of a decision to allow the use of Botulinum toxi n, in terms of cost eff ect for the plan as a whole. In calculating the cost of prophylax is with Botulinum toxin, treatment at a standard interval of 3 months means that patients would receive 4 treatments per year. With the cost of each treatment given as $521.25, the yearly cost per patient is $2085, and the total yearly cost for 240 patient s was $500,400. The model did not account for a decrease in emergency department visits and hospitalization as a result of effective migraine prophylaxis which would be expected to augment the savings. Offsetting these costs would be a reduction in the amount of headache medication used for abortive treatment (70). The final cost difference according to the study by Goldberg is that in a plan with 1 million members, the savings as sociated with migraine prophylaxis using Botulinum toxin represents a change of less than 1 cent in overall cost per member per month ($76 360 divided by 12 m illion member months is a reduction of approximately $0.006 per member per month). The point, howeve r, is not the insignificant change in cost, but that superior clinical outcomes in migraine management can be obtained with no increase in cost (67). According to the results of his study, headache related visits to the office and emergency department were re duced by 32% and 49% respectively. These reductions in headache related visits result ed in a net savings of $18,757. The greatest clinical improvements were seen in patient s whose conditions were most severe at baseline (72).
37 Study Protocol Having an interest in the patients respons e to treatment with Botulinum toxin-A for migraine headache prophylaxis, this study utilized the questions in the MIDAS questionnaire with a slight modification to assess the patients post treatment response. In addition to the original 7 questions on the questionnaire, additional information regarding medication usage pre and post treatm ent as well as assessment of functional ability pre and post and number of treatments. The study is designed as a cross sectional survey of patients currently undergoing the procedure at James A. Haley VA Medical Center Department of Neurology Pain Clinic and Bay Pines VA Hospital Department of Neurology outpatient clinic. Inclusion cr iteria were patients age 21 65 who had received at least 2 treatmen ts. The patients currently undergoing the treatment with Botulinum toxin-A were pre screened by each de partment, on initial evaluation when first presenting to each clinic, to fit the criteria of chronic daily headaches as previously referenced and demonstrated a history of failu re to other standard treatment protocols. Since the standard time between each treatment is typically 3-4 months, the questionnaire was to be administered ove r a 60 day period once initiate d to prevent duplication of patient responses. No personal health info rmation was required on the questionnaire and exemption was granted for informed cons ent and HIPPA requirements. The study objective is to assess patient reported effi cacy of Botulinum toxin-A for the prophylaxis of Migraine headaches in patients with freque nt Migraine headaches prior to initiation of treatment with Botulinum toxin-A compared to post treatment. The research plan as
38 previously discussed is to pr esent questions addre ssing the patient status prior to the initiation of treatment as well as post treatment. Patient quality of life change, duration and frequency headache improvement are th e primary focus. Other considerations included the cost difference between the previo us use of other treatment and the periodic treatment with botulinum toxin-A. Methodol ogy is a cross sectional study utilizing a questionnaire consisting of a modified Migraine Disability Assessment (MIDAS) questions were given to patien ts by the principle investigator or a significant member of the study who has undergone the required privac y training. Qualifie d patients are those who had received at least tw o series of injections. Ne w patients who have not yet received treatment are excluded. The patien ts are currently under treatment at both Bay Pines VA neurology in St Petersburg, Fl and Ja mes A Haley VA pain clinic in Tampa, Fl. Patients who reported chronic Migraine head aches and were refractory to previous treatment methods were screened and placed in programs utilizing intramuscular injection of Botulinum toxin-A at standard points on the face, Temporalis muscle and paracervical muscles. The st udys anticipated impact and signi ficance relate to the fact that p atients that are debilitated by recurrent chronic migraine headaches suffer loss of productive time at work and home. Treatme nt with Botulinum toxin-A may results in significant relief allowing fewer days lost at work and improved quality of life. There may be significant cost saving if treatment re sults in discontinuation of other medications previously used for treatment of migraine headaches or decreased use of hospital and emergency department facilities. This study utilizes a questionnaire consisting of a modified Migraine Disability Assessment (M IDAS) questions will be given to patients who had received more than one series of inje ctions. Included in the study are Male or
39 Female veterans age 21 65 currently under treatment with Botulinum toxin-A for migraine headache prophylaxis. Exclusion crit eria consist of patients less than 21 years of age, initial treatment, over 65 years of ag e or physician clinical judgment for exclusion. Questionnaire filled out by the pa tient or by one of the attending physicians with proper privacy training with no pers onal health information on the form and voluntary participation as outlined on the cove r sheet. Statistical analysis through patient response to a standardized ques tionnaire with weighted responses. Classification is based on existing patients currently undergoing ca re at the 2 neurology clinics who have already been screened to qualify for the pr ocedure by the respective departments. The study is designed to extend no longer than 60 days following the start of initiating the questionnaire to prevent dupli cation of responses. This is assured since the patient treatment is no more frequent than every 90 120 days.
40 Data Collection and Analysis Patients at both James A Haley VA Department of Neurology Pain Clinic and Bay Pines Neurology Clinic who were currently undergoi ng treatment for migraine headaches with Botulinum toxin-A were randomly presented with the survey. The patients were screened per protocol to meet the criteria for the study. Since the patients were already undergoing treatment with Botulinum toxinA for persistent refractory migraine headaches, they were already presumed to fit the definition of chronic daily headaches. Due to unplanned inconsistency in offering the questionnaire to the patients, the qualified respondents were randomly chosen and answered the survey. A total of 46 patients were surveyed at both Bay Pines VA and James A Ha ley VA. 19 patients were being treated at Bay Pines VA Neurology Clinic and 27 we re under care at James A Haley VA Department of Neurology Pain Clinic. Of th e 46 total patients surveyed, 10 were female and 36 were male. Due to IRB concerns at Bay Pines VA, the age variable was not recorded on surveys that were filled out in the Neurology Department there. Gender was recorded at both facilities as previously not ed. The questions were graded according to responses to days affected by headache for 3 months prior to initiation of treatment and compared to responses of the same question mo dified to reflect the patients condition for 3 months following at least one treatment. The first questio n of the questionnaire relates to the affect of migraine headaches on the patients work. The second question relates lost work productivity. Question three asks about the ability of the patient to do housework during their migraine episodes. Simi larly question four rela tes to interference
41 and decreased ability to eff ectively do housework, but not pr event it, due to migraine episodes. The fifth question asks about how the headache would interfere with family or social events. The 2 following questions labeled A and B on the MIDAS questionnaire were designated as 6 and 7 on the study pre and post questionnaire. They request the patients assessment of frequency of headaches in days over the previous three months and severity of headaches as graded on a scale of 1 10. The MIDAS grading system contains a scale from I IV. For simplic ity purposes and data analysis, these are designated as 1 4 when inte rpreting the responses on the questionnaire (Table 1). Responses to questions 1 5 are converted fr om number of days reported to appropriate MIDAS grading scores. Since cost of treatme nt is a component of this study, section 8 asks additional questions regarding use of medications for treatment of migraine headaches pre and post Botulinum toxin-A. Question 9 asks the patient to assess the quality of life prior to and after treatment with Botulinum toxin-A. The final question on the post treatment questionnaire refers to the total number of treatments that the patient has had.
42 Table 1 Grade Definition Days Grade 1 Minimal or Inf requent Disability 0-5 Grade 2 Mild or Infrequent Disability 6-10 Grade 3 Moderate Disability 11-20 Grade 4 Severe Disability 21+
43 Results The mean age of the patients surveyed was confined to responses from James A Haley VA only due to the previously mentioned issu es with Bay Pines VA IRB. Among those surveyed, the mean age was 51.8 with a range fro m 30 to 65 years of age. The ratio of males to females surveyed at both facilities was 3.6:1. Comparisons of responses to questions 19 were analyzed using paired Ttest, with the patients pre-treatment status as the control, and Wilcoxon Signed Ranks Test. In Table 2 we see the results of paired samples statistics for questions 1 5. In response to question 1 regarding disability relating to the frequency of lost work days, the mean level of disa bility as indicated by the MIDAS score is reduced overall for the 46 respondents from a score of Grade 2 to Grade 1 with a mean reduction of .957 (Table 4). 95% confidence interval was .626 to 1.288 with a T-score of 5.82. When evalua ting the results by Wilcoxon Signed Ranks Test, the number of patients who indicated a reduction in overall disability days is equal to those who indicated no change (Table 13). In analyzing the effect on interference with productivity at work, response to questi on 2 resulted in an overall mean reduction from Grade 3 to Grade 1. There was a m ean reduction of 1.391 with a 95% confidence interval of 1.051 to 1.731 a nd a T-score of 8.244. Wilcoxon Signed Ranks Test revealed 32 respondents indicated a reduction in disab ility with 14 respondents indicating no change. In order to evaluate the effect that migraine headaches have on activities of daily living, question 3 asks how often the patie nt was prevented from performing daily housework. Assessment of the responses re veals a reduction overall from Grade 3 to
44 Grade 1 with a mean reduction of 1.28 at a 95% confidence interval of .947 to 1.618 and a t-score of 7.707 (Table4). Wilcoxon Signed Ra nks Test analysis indicated that there were 31 respondents that reported a reduction in disability days and 15 that indicated no change (Table 13). Overall days where produc tivity was diminished regarding activities of daily living were addressed in question 4. The response indicate d that there was an overall reduction from Grade 3 to Grad e 1with a mean reduction of 1.457 at a 95% confidence interval of 1.088 to 1.825 with a t score of 7.954. Wilcoxon Signed Ranks Test analysis indicated 32 respondents had a reduction in MIDAS score while 13 had no change and 1 patient reported an actual increa se in MIDAS score. The effect on social life and family activities is another area of concern which is addressed in question 5. According to the respondents there was a redu ction in disability score from Grade 3 to Grade 1 with a mean reduction of 1.174 at 95% confidence interval of .829 to 1.519 with a T-score of 6.860. Wilcoxon Signed Ranks Test analysis reveals 28 respondents with a reduction in MIDAS score and 18 with no change in social or family activities. Question 6 asks the patient to record how many head aches they had in the 3 months prior to initiation of treatment and 3 months prior to the questionnaire po st botulinum toxin-A treatment. Analysis of the responses demonstrates that there is a mean reduction of 41.957 headache days with a 95% confidence interval of 32.936 to 50.977 and a T-score of 9.368(Table 7). Wilcoxon Signed Ranks Test an alysis reveals 42 pa tients reporting a reduction in frequency of headaches and 4 repo rting no change (Table 16). Patients were asked to rate the severity of their headaches in question 7 based upon a standard scale of 0 10 with 0 being no pain and 10 being pain as bad as it could be. Analysis of the responses shows that there is an overall reduction of pain scores from a mean of 8.85
45 prior to treatment to 5.09 post treatment (Table 5) giving a mean reduction of 3.76 at a 95% confidence interval of 3.03 to 4.49 with a T-score of 10.368 (Table 5-7) Wilcoxon Signed Ranks Test analysis reveals 40 patient s reporting a reduction in the severity of their headaches, 1 reporting an increase in severity and 5 indi cating no change in headache severity (Table 16). There is a lot of variability when evaluating medication usage. The type of medication used can va ry greatly in price and frequency of usage. To simplify this, medications were placed on general categories. Weekly acetaminophen usage, as reflected in Tables 8-10, appeared to be reduced post treatment from a mean of 11.74 to 2.20 (Table 8) with a mean reduc tion of 9.04 at a 95% confidence interval between 1.476 to 16.611 and a T-score of 2.407 (T able 10). A breakdown of usage by Wilcoxon Signed Ranks Test analysis reveal s 18 patients repor ting a reduction, 26 patients indicating no change a nd 2 patients indicating an incr ease in usage (Table 17). General use of NSAIDs also showed reduction in use post treatment from a mean of 12.67 to 1.91 with a mean reduction of 10.761 at a 95% confidence interval between 4.518 to 17.004 and a T-score of 3.471. Wilcoxon Si gned Ranks Test analysis indicates 20 patients reported a decrease in use, 1 increa se in usage and 25 with no change in use. Use of opiates showed a decrease from a m ean of 7.80 to 3.39 with a mean reduction of 4.413 at a 95% confidence inte rval between 1.743 to 7.083 and a T-score of 3.329. Wilcoxon Signed Ranks Test analysis shows 19 pa tients with a decrease in weekly use, 2 with an increase and 25 with no change in w eekly use. Weekly Triptan use was reduced from a mean of 1.22 to .52 with a mean reduction of .696 at a 95% confidence interval of 2.24 to 1.168 and a T-score of 2.968. Wilcoxon Si gned Ranks Test anal ysis reveals 14 patients reporting a decrease, 1 reporting an increase and 31 with no change (Table 18).
46 Response to use of psychotropic medications for treatment of migraine headaches showed a mean reduction from 3.54 to 1.24 with a mean reduction of 2.28 at a confidence interval of .528 to 3.983 and a T-score of 2.704. Wilcoxon Signed Ranks Test analysis indicates 11 patients with an increase in weekly use and 35 with no change. Other medications can consist of a wide variet y including Ergotamines and Tramadol. The responses from the 46 patients reveal a m ean reduction in weekly use from 2.54 to 1.70 with a mean reduction of .848 at a 95% c onfidence interval of -1.351 to 3.047 and a Tscore of .776. Wilcoxon Signed Ranks Test analysis shows 9 patients reporting a reduction, 2 with an increase in use and 35 with no change in weekly usage. Overall quality of life showed an increase from a mean score of 3.20 to 7.17 (Table 11) with a mean improvement of 3.978 at a 95% confid ence interval of -4.746 to -3.210 and a Tscore of -10.433 (Table 13). Wilcoxon Signed Ranks Test analysis shows 1 patient indicating a decrease in quali ty of life, 41 indicating an improvement and 4 with no change (Table 19). Of the 46 patients res ponding to the questionna ire, 40 responded to the final question of number of treatments. The mean of those who responded was 10.2. Figures 1 14 graphically represent the pre and post responses of each patient to the questions on the survey.
47 Paired Sample Tests Table 2 Paired Samples Statistics Mean N Std. Deviation Std. Error Mean Pair 1 Pre1 2.20 46 1.222 .180 Post1 1.24 46 .766 .113 Pair 2 Pre2 2.72 46 1.167 .172 Post2 1.33 46 .790 .117 Pair 3 Pre3 2.67 46 1.194 .176 Post3 1.39 46 .930 .137 Pair 4 Pre4 2.72 46 1.223 .180 Post4 1.26 46 .648 .095 Pair 5 Pre5 2.46 46 1.295 .191 Post5 1.28 46 .688 .102 Table 3 Paired Samples Correlations N Correlation Sig. Pair 1 Pre1 & Post1 46.448 .002 Pair 2 Pre2 & Post2 46.367 .012 Pair 3 Pre3 & Post3 46.458 .001 Pair 4 Pre4 & Post4 46.235 .115 Pair 5 Pre5 & Post5 46.450 .002
48 Table 4 Paired Samples Test Paired Differences 95% Confidence Interval of the Difference Mean Std. Deviation Std. Error Mean Lower Upper t df Sig. (2tailed) Pair 1 Pre1 Post1 .957 184.108.40.20661.288 5.820 45 .000 Pair 2 Pre2 Post2 1.391 1.145.1691.0511.731 8.244 45 .000 Pair 3 Pre3 Post3 1.283 220.127.116.1171.6187.707 45 .000 Pair 4 Pre4 Post4 1.457 1.242.1831.0881.8257.954 45 .000 Pair 5 Pre5 Post5 1.174 18.104.22.16891.5196.860 45 .000 Table 5 Paired Samples Statistics Mean N Std. Deviation Std. Error Mean Pair 1 Pre6 62.89 62.894629.411 4.336 Post6 20.93 20.934625.404 3.746 Pair 2 Pre7 8.85 8.85461.095 .161 Post7 5.09 5.09462.439 .360
49 Table 6 Paired Samples Correlations N Correlation Sig. Pair 1 Pre6 & Post6 46.393.007 Pair 2 Pre7 & Post7 46.205.172 Table 7 Paired Samples Test Paired Differences 95% Confidence Interval of the Difference t df Sig. (2tailed) Mean Std. Deviation Std. Error Mean Lower Upper Pair 1 Pre6 Post6 41.957 30.376 4.479 32.936 50.977 9.368 45 .000 Pair 2 Pre7 Post7 3.761 2.460 .363 3.030 4.491 10.368 45 .000
50 Table 8 Paired Samples Statistics Mean N Std. Deviation Std. Error Mean Pair 1 Tyl Pre 11.744624.848 3.664 Tyl Post 2.70466.073 .895 Pair 2 NSAID Pre 12.674621.170 3.121 NSAID Post 1.91464.273 .630 Pair 3 Opiate Pre 7.804611.299 1.666 Opiate Post 3.39468.131 1.199 Pair 4 Triptan Pre 1.22462.021 .298 Triptan Post .5246.752 .111 Pair 5 PSY Pre 3.52466.595 .972 Psy Post 1.24463.484 .514 Pair 6 Other Pre 2.54466.735 .993 Other Post 1.70466.759 .997
51 Table 9 Paired Samples Correlations N Correlation Sig. Pair 1 Tyl Pre & Tyl Post 46.016.914 Pair 2 NSAID Pre & NSAID Post 46.135.371 Pair 3 Opiate Pre & Opiate Post 46.615.000 Pair 4 Triptan Pre & Triptan Post 46.698.000 Pair 5 PSY Pre & Psy Post 46.497.000 Pair 6 Other Pre & Other Post 46.398.006
52 Table 10 Paired Samples Test Paired Differences t df Sig. (2taile d) 95% Confidence Interval of the Difference Mea n Std. Devia tion Std. Error Mean Lower Uppe r Pair 1 Tyl Pre Tyl Post 9.04 3 25.48 3 3.7571.47616.61 1 2.4 07 45 .02 0 Pair 2 NSAID Pre NSAID Post 10.7 61 21.02 4 3.1004.51817.00 4 3.4 71 45 .00 1 Pair 3 Opiate Pre Opiate Post 4.41 3 8.9901.3261.7437.0833.3 29 45 .00 2 Pair 4 Triptan Pre Triptan Post .6961.590.234.2241.1682.9 68 45 .00 5 Pair 5 PSY Pre Psy Post 2.28 3 5.726.844.5823.9832.7 04 45 .01 0 Pair 6 Other Pre Other Post .8487.4061.092-1.3513.047.77 6 45 .44 2
53 Table 11 Paired Samples Statistics Mean N Std. Deviation Std. Error Mean Pair 1 PreQual 3.20461.614.238 PostQual 7.17462.069.305 Table 12 Paired Samples Correlations N CorrelationSig. Pair 1 PreQual & PostQual 46.030.846 Table 13 Paired Samples Test Paired Differences t df Sig. (2tailed) Mean Std. Deviation Std. Error Mean 95% Confidence Interval of the Difference LowerUpper Pair 1 PreQual PostQual 3.978 2.586.381-4.7463.210 10.433 45 .000
54 Wilcoxon Signed Ranks Test Table 14: Ranks N Mean Rank Sum of Ranks Post1 Pre1 Negative Ranks 23a12.00276.00 Positive Ranks 0b.00.00 Ties 23c Total 46 Post2 Pre2 Negative Ranks 32d16.50528.00 Positive Ranks 0e.00.00 Ties 14f Total 46 a. Post1 < Pre1; b. Post1 > Pre1; c. Post1 = Pre1 d. Post2 < Pre2; e. Post2 > Pre2; f. Post2 = Pre2 Test Statisticsb Post1 Pre1 Post2 Pre2 Z -4.256a-5.004a Asymp. Sig. (2-tailed) .000.000 a. Based on positive ranks. b. Wilcoxon Signed Ranks Test
55 Table 15: Ranks N Mean Rank Sum of Ranks Post3 Pre3 Negative Ranks 31a16.00 496.00 Positive Ranks 0b.00 .00 Ties 15c Total 46 Post4 Pre4 Negative Ranks 32d17.36 555.50 Positive Ranks 1e5.50 5.50 Ties 13f Total 46 Post5 Pre5 Negative Ranks 28g14.50 406.00 Positive Ranks 0h.00 .00 Ties 18i Total 46 a. Post3 < Pre3; b. Post3 > Pre3; c. Post3 = Pre3; d. Post4 < Pre4; e. Post4 > Pre4; f. Post4 = Pre4; g. Post5 < Pre5; h. Post5 > Pre5; i. Post5 = Pre5 Test Statistics b Post3 Pre3 Post4 Pre4 Post5 Pre5 Z -4.928a-4.983a -4.687a Asymp. Sig. (2-tailed) .000.000 .000 a. Based on positive ranks. b. Wilcoxon Signed Ranks Test
56 Table 16: Ranks N Mean Rank Sum of Ranks Post6 Pre6 Negative Ranks 42a21.50 903.00 Positive Ranks 0b.00 .00 Ties 4c Total 46 Post7 Pre7 Negative Ranks 40d21.38 855.00 Positive Ranks 1e6.00 6.00 Ties 5f Total 46 a. Post6 < Pre6; b. Post6 > Pre6; c. Post6 = Pre6; d. Post7 < Pre7; e. Post7 > Pre7; f. Post7 = Pre7 Test Statistics b Post6 Pre6 Post7 Pre7 Z -5.647a-5.521a Asymp. Sig. (2-tailed) .000.000 a. Based on positive ranks. b. Wilcoxon Signed Ranks Test
57 Table 17: Ranks N Mean Rank Sum of Ranks Tyl Post Tyl Pre Negative Ranks 18a10.11 182.00 Positive Ranks 2b14.00 28.00 Ties 26c Total 46 NSAID Post NSAID Pre Negative Ranks 20d11.50 230.00 Positive Ranks 1e1.00 1.00 Ties 25f Total 46 Opiate Post Opiate Pre Negative Ranks 19g11.00 209.00 Positive Ranks 2h11.00 22.00 Ties 25i Total 46 a. Tyl Post < Tyl Pre; b. Tyl Post > Tyl Pr e; c. Tyl Post = Tyl Pre; d. NSAID Post < NSAID Pre; e. NSAID Post > NSAID Pre; f. NSAID Post = NSAID Pre; g. Opiate Post < Opiate Pre; h. Opiate Post > Opia te Pre; i. Opiate Post = Opiate Pre. Test Statistics b Tyl Post Tyl Pre NSAID Post NSAID Pre Opiate Post Opiate Pre Z -2.876a-3.982a-3.258a Asymp. Sig. (2-tailed) .004.000.001 a. Based on positive ranks. b. Wilcoxon Signed Ranks Test
58 Table 18: Ranks N Mean Rank Sum of Ranks Triptan Post Triptan Pre Negative Ranks 14a8.32 116.50 Positive Ranks 1b3.50 3.50 Ties 31c Total 46 Psy Post PSY Pre Negative Ranks 11d6.00 66.00 Positive Ranks 0e.00 .00 Ties 35f Total 46 Other Post Other Pre Negative Ranks 9g5.83 52.50 Positive Ranks 2h6.75 13.50 Ties 35i Total 46 a. Triptan Post < Triptan Pre; b. Triptan Post > Triptan Pre; c. Triptan Post = Triptan Pre; d. Psy Post < PSY Pre; e. Psy Post > PSY Pre; f. Psy Post = PSY Pre; g. Other Post < Other Pre; h. Other Post > Ot her Pre; i. Other Post = Other Pre. Test Statistics b Triptan Post Triptan Pre Psy Post Psy Pre Other Post Other Pre Z -3.255a-3.207a -1.746a Asymp. Sig. (2-tailed) .001.001 .081 a. Based on positive ranks. b. Wilcoxon Signed Ranks Test
59 Table 19: Ranks N Mean Rank Sum of Ranks PostQual PreQualNegative Ranks 1a17.50 17.50 Positive Ranks 41b21.60 885.50 Ties 4c Total 46 a. PostQual < PreQual; b. PostQual > PreQual; c. PostQual = PreQual Test Statistics b PostQual PreQual Z -5.444a Asymp. Sig. (2-tailed) .000 a. Based on negative ranks. b. Wilcoxon Signed Ranks Test.
60 Figure 1 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 13579111315171921232527293133353739414345 Pre1 Post1 Figure 2 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 13579111315171921232527293133353739414345 Pre2 Post2
61 Figure 3 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 13579111315171921232527293133353739414345 Pre3 Post3 Figure 4 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 13579111315171921232527293133353739414345 Pre4 Post4
62 Figure 5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 13579111315171921232527293133353739414345 Pre5 Post5 Figure 6 0 10 20 30 40 50 60 70 80 90 100 13579111315171921232527293133353739414345 Pre6 Post6
63 Figure 7 0 2 4 6 8 10 12 13579111315171921232527293133353739414345 Pre7 Post7 Figure 8 0 20 40 60 80 100 120 140 160 13579111315171921232527293133353739414345 Tyl Pre Tyl Post
64 Figure 9 0 20 40 60 80 100 120 13579111315171921232527293133353739414345 NSAID Pre NSAID Post Figure 10 0 5 10 15 20 25 30 35 13579111315171921232527293133353739414345 Opiate Pre Opiate Post
65 Figure 11 0 2 4 6 8 10 12 14 13579111315171921232527293133353739414345 Triptan Pre Triptan Post Figure 12 0 5 10 15 20 25 30 35 40 13579111315171921232527293133353739414345 PSY Pre Psy Post
66 Figure 13 0 5 10 15 20 25 30 35 40 13579111315171921232527293133353739414345 Other Pre Other Post Figure 14 0 2 4 6 8 10 12 13579111315171921232527293133353739414345 PreQual PostQual
67 Conclusion According to the patients response to this survey, it appears that there was an overall improvement in the patients ability to do wo rk, for those who were employed, as well as their ability to do activities of daily living post tr eatment with Botulinum toxin-A. From the patients response there wa s an approximate 67% decrease in the mean frequency of headaches over the surveyed pre and post 3 month periods. The intensity of headaches also demonstrated a mean decrease from approximately 9/10 to 5/10 from pre to post treatment. When estimating the cost of tr eatment, prices for each class of medication were calculated using an estimated average fo r the prescription strength of each class of medication. The estimated cost of Acet aminophen 325mg is about $.17 per capsule. Having a mean reduction in weekly use of appr oximately 9 pills doesnt really amount to a tremendous cost saving and over a 3 month period it would translate to approximately $18.36 saved. Similarly inexpensive are NSAIDs At an average price using the most commonly prescribed/recommended NSAI Ds (Ibuprofen 800mg, Naproxen 500mg, Nabumetone 750mg and Fiorin al 50/325/40), the average pr ice per pill is $1.66. There was a mean reduction of 10.76 pills per week according to the survey responses. This translates to a weekly reduction of $17.87 and a 3 month saving of approximately $214.36. Mean weekly opiate use reduction was 4.413. At and average cost of the most commonly prescribed narcotic analgesics (Hydrocodone, Oxycodone, Meperidine as well as combination with non narcotic analgesics) of $2.41 per pill, the overall savings for the 3 month period would be estimated at $127.62. The most expensive medications of this
68 survey were the Triptans. Using an average per dose price for the most commonly prescribed of this group (Max alt, Imitrex and Zomig), the av erage price per oral dose was approximately $26.53. With a mean reduction of .696 per week at a 3 month time frame, the estimated cost saving would be $221.58. The use of psychotropic medications, such as Trazadone 100mg, Amitryptyline 50mg and Divalproex sodium 250mg, was estimated at an average price of $2.34 pe r pill. Calculatio n of 3 month use was reduced by a mean weekly drop of 2.253 results in a sa ving of $63.26. There are numerous other medications that are used to treat migraine headaches however for simplicity purposes I chose to evaluate Tramadol 50mg and Cafe rgot 1-100. The average price per dose for these two medications is approximately $2.67. With a mean weekly reduction of .848, the 3 month saving would translate to appr oximately $27.17. The cost of each treatment with Botulinum toxin A for the VA facilities participating in this study is about $400.00. There was a reported mean increase in overa ll quality of life from 3.20 to 7.17 on the scale of 0 (non functional) to 10 (excellent). When interviewing the patients the majority of those responding indicated overall satisfactio n with their treatment. The mean number of treatments was 10.2.
69 Discussion When interpreting the results of the respondent s to this survey, a few concerns come to mind. The first thought is that I was unable to evaluate responses from patients who may have had adverse response or stopped treatmen t due to lack of response. There is also some technical difficulty in ensuring that the response only involve s information relating to migraine headache and not other chronic pain conditions that may also coexist. Also when evaluating pain medication usage, lim iting responses only to those medications used for the treatment of migraine headaches proved challenging since some medications were used for other chronic pain conditions concurren tly. It is difficult to get an accurate cost analysis since there is a tendency to have multiple prescription medications and over the counter medications used in efforts to tr eat and prevent chronic migraine headaches. Also the cost of the medications particularly Triptans, will vary greatly according to the route administered. Another cost factor that was occasionally revealed by the respondents is the frequency of visits to th e emergency room for treatment of migraine headaches. Though it was not evaluated by this study, some of the respondents did reveal frequent visits to the emergency room whic h they indicate were reduced or eliminated post treatment. Overall it appears that the use of Botulinum toxin-A in the treatment of migraine headaches does have some clinical va lue and can possibly be used in refractory cases to help increase the patients functiona l capacity and possibly reduce the cost of treatment by reducing multiple prescription medication use and reduce the frequency of visits to emergency rooms.
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