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Botox Is Safe and Effective as Preventive Treatment for Chronic Migraine

David Evans — Thu, 19 Nov 2009 16:30:00 GMT

PHILADELPHIA—Patients with chronic migraine who were treated with onabotulinumtoxin A (Botox) showed significant reduction in frequency of headache days, compared with patients who received placebo, according to data presented at the 14th Congress of the International Headache Society.

Pooled results from the double-blind, randomized, placebo-controlled phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 trials were reported by David Dodick, MD, Professor of Neurology at the Mayo Clinic in Phoenix, and colleagues. “Based on data from a previous phase II trial of onabotulinumtoxin A, the PREEMPT clinical program (PREEMPT 1 and 2) was conducted to evaluate the safety and efficacy of onabotulinumtoxin A in adults with chronic migraine,” said Dr. Dodick.
PREEMPT Design

Participants included men and women ages 18 to 65 (mean age, 41) with history of migraine that met diagnostic criteria listed in the International Classification of Headache Disorders-II, did not use other prophylactic medications four weeks prior to baseline, and did not have previous exposure to any other botulinum toxin serotype. All patients also had 15 or more headache days per month, at least four distinct headache episodes that lasted four hours or more, and at least 50% of baseline headache days that were migraine or probable migraine. “We were very clear about what constituted a headache day,” Dr. Dodick said.

Subjects were randomized to onabotulinumtoxin A (n = 688) or placebo (n = 696), administered as 31 fixed-site, fixed dose IM injections across seven specific head and neck muscle areas, every 12 weeks throughout 24 weeks. “An additional 40 U onabotulinumtoxin A could have been injected among three muscle groups (occipitalis, temporalis, or trapezius; total of eight sites) using a protocol-defined follow-the-pain paradigm,” Dr. Dodick and colleagues stated. The maximum dose was 195 U at 39 sites. Randomization was stratified according to acute headache medication overuse. Change from baseline to 28 days ending with week 24 was the basis for all efficacy analyses. PREEMPT was conducted in 122 centers across North America and Europe. During the four-week baseline phase, patients recorded their headaches and associated symptoms in electronic diaries. The mean baseline patient diary-day compliance rate was 99% and remained high (greater than 93%) in both treatment groups during the 24-week phase.

Pooled Analyses Reveal Positive Findings

Mean frequency of headache days decreased more significantly among patients treated with onabotulinumtoxin A (-8.4) than with placebo (-6.6) at week 24, and at all other time points. Mean change from baseline for frequency of headache episodes also favored onabotulinumtoxin A at all time points, including week 24 (-5.2), compared with placebo (-4.9). Secondary efficacy variables included frequencies of migraine episodes, migraine days, moderate/severe headache days, total cumulative headache hours on headache days, headache episodes, acute medication use, and the proportion of patients with severe (greater than 60) Headache Impact Test (HIT)-6 score. Significant differences favoring onabotulinumtoxin A were found for all secondary variables in all time points, with the exception of acute medication use.

“We have seen that in previous comparative studies,” Dr. Dodick commented. “The only other two randomized controlled studies to be done in this population also failed to show a significant decrease in the consumption of acute headache medications when compared to the placebo group.However, when we went back and looked at the frequency of triptan use, we showed that both in PREEMPT 1 and PREEMPT 2, there was a statistically significant reduction in the consumption of triptans in the onabotulinumtoxin A group, compared to placebo, but not in other analgesics or pain medications.”

Impact on disability in functioning and vitality, psychologic distress, and health-related quality of life were also assessed by mean change in baseline with total HIT-6 score and with the Migraine-Specific Quality of Life Questionnaire, in the restrictive, preventive, and emotional domains. “Patients treated with onabotulinumtoxin A achieved significant improvements in all of these areas, which I think is an important end point in this population,” Dr. Dodick stated.

Adverse events occurred in 62.4% of the onabotulinumtoxin A group, compared with 51.7% in the placebo group. “Most adverse events reported by patients were mild or moderate in severity, and adverse events resolved without sequelae,” Dr. Dodick and investigators stated. Discontinuation occurred in 2.8% of participants in the onabotulinumtoxin A group, and 0.7% of those in the placebo group. In the onabotulinumtoxin A group, 8.7% of patients experienced neck pain. In the placebo group, 5.3% of patients experienced upper respiratory tract infection. These were the only adverse events to occur at a rate greater than 5%. “Treatment-related adverse events were consistent with the known tolerability profile of onabotulinumtoxin A, and no newly emerged safety findings were observed,” Dr. Dodick’s group noted.

PREEMPT 1 Versus PREEMPT 2

Although pooled analyses from the two studies showed overall positive results, the findings differed regarding primary end points between PREEMPT 1 and PREEMPT 2.

In PREEMPT 1, onabotulinumtoxin A was not more effective than placebo regarding change from baseline frequency of headache episodes to headache frequency at week 24. There was a significant imbalance at baseline in the frequency of headache episodes between the onabotulinumtoxin A and placebo groups. In a post-hoc analysis of headache episode frequency during the first 14 days of baseline, no significant between-group differences were shown. When this baseline was used, significant between-group differences favoring onabotulinumtoxin A were observed at weeks four, eight, 20, and 24. At week 24, statistically significant mean improvements were also observed for frequencies of headache days (-7.8, onabotulinumtoxin A; -6.4, placebo) and migraine days (-7.6, onabotulinumtoxin A; -6.1, placebo).

PREEMPT 1 included 341 patients randomized to onabotulinumtoxin A, and 338 to placebo. A total of 18 (5.3%) of patients receiving onabotulinumtoxin A reported serious adverse events, compared with eight (2.4%) receiving placebo. Neck pain (8.2%) and muscular weakness (5.9%) were reported by patients receiving onabotulinumtoxin A, while upper respiratory tract infection and sinusitis were experienced by 6.0% and 5.1%, respectively, of the placebo group.

For PREEMPT 2, however, Dr. Dodick and colleagues found that onabotulinumtoxin A was significantly more effective than placebo (n = 358) in achieving its primary end point—reduction in frequency of headache days. Patients who received onabotulinumtoxin A (n = 347) also had significant improvement compared with those who received placebo regarding all secondary end points, including frequency of migraine days, frequency of moderate/severe headache days, monthly cumulative headache hours on headache days, proportion of patients with severe HIT-6 score, and frequency of headache episodes.

Overall, 15 (4.3%) of onabotulinumtoxin A patients in PREEMPT 2 reported serious adverse events, compared with eight (2.2%) placebo patients. Neck pain and muscular weakness were reported by 9.8% and 5.2%, respectively, of patients using onabotulinumtoxin A.

The Future of Migraine Treatment?

“Onabotulinumtoxin A is shown to be an effective, safe, and well-tolerated treatment for the prophylaxis of chronic migraine,” Dr. Dodick said. In addition, multiple IM treatments of onabotulinumtoxin A, from 155 U to 195 U per treatment cycle, were safe and well tolerated. “Pooled analyses from the PREEMPT 1 and 2 trials demonstrate that treatment with onabotulinumtoxin A resulted in highly significant improvements in onabotulinumtoxin A–treated patients versus placebo-treated patients in frequency of headache days in patients suffering from chronic migraine,” Dr. Dodick’s group reported.”

—Laura Sassano

Suggested Reading
Lima MM, Padula NA. Santos LC, et al. Critical analysis of the international classification of headache disorders diagnostic criteria (ICHD I-1988) and (ICHD II-2004), for migraine in children and adolescents. Cephalalgia. 2005;25(11): 1042-1047.

Petri S, Tölle T, Straube A, et al. Botulinum toxin as preventive treatment for migraine: a randomized double-blind study. Eur Neurol. 2009;62(4):204-211.

Sidebar: Patients Treated With Botox Have Reduced MIDAS Scores

PHILADELPHIA—Sustained reduction in migraine-related disability, headache days, and acute medication use were observed in patients treated with onabotulinumtoxin A, according to data presented at the 14th Congress of the International Headache Society.

Ira M. Turner, MD, of the Center for Headache Care and Research at Island Neurological Associates, PC, in Plainview, New York, and colleagues, retrospectively reviewed 40 patients treated with onabotulinumtoxin A for chronic migraine (15 or more headache days per month) or high frequency migraine (eight to 14 headache days per month) in three consecutive monthly treatment cycles. The primary end point was a reduction in Migraine Disability Assessment (MIDAS) scores. Reduced headache days and acute medication use were secondary end points.

“The average MIDAS score at baseline was 62.8,” Dr. Turner and investigators stated. “Over the next three cycles, these scores were reduced to 29.2, 31.1, and 24.8.” A reduction in headache days was also seen. “These were reduced from a baseline of 20.7 headache days to 11.6, 9.8, and 9.6 days over successive cycles.” A similar sustained decrease for acute medication intake was also noted, from a baseline average of 51.5 doses per month to 27.9, 24.4, and 21.4 monthly doses.

“This retrospective data review of our community-based experience with chronic migraine and high frequency migraine suggests a sustained response to regular onabotulinumtoxin A treatments at roughly three-month intervals in regard to migraine-related disability,” Dr. Turner’s group concluded. A concomitant persisting decrease in headache days and acute medication usage was also shown. “In combination, these have resulted in much less time lost from work and social and family activities, as well as pharmaco-economic savings in terms of reduced acute medication, primarily triptan, usage.”

—Laura Sassano

Suggested Reading

Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

19-Nov-09 10:30 AM

Texas Neurology Doctors Chosen Among the Best in Dallas-Fort Worth

David Evans — Thu, 22 Oct 2009 18:00:00 GMT

Texas Neurology Doctors Chosen Among the Best in Dallas-Fort Worth

In its October 2009 issue, D Magazine published the results of a survey conducted among 4,800 local doctors who were invited to cast their votes for the Best Doctors in Dallas. In the confidential poll, doctors were asked to name two physicians they would send their parents or loved ones to in 40 specialties.

Only those with a valid Texas medical license were eligible. An outside firm tallied the results, and a panel of esteemed local physicians reviewed the list prior to publication. The list was designed with the patient in mind; therefore, under the guidance of the panel, the list did not include specialties in which the patient has little or no say, such as anesthesiology or pathology. They also excluded pediatrics which is vast enough to warrant its own special feature.

The doctors selected from Texas Neurology include:

Dr. Waleed El-Feky; Dr. Steven Herzog; Dr. Bruce Jenevein; Dr. Alan Martin; and Dr. Gary Tunell.

22-Oct-09 1:00 PM

Texas Neurology. P.A. Newsletter 23-Feb-09

David Evans — Tue, 24 Feb 2009 03:00:00 GMT

Hello [firstname],

Welcome to the Texas Neurology. P.A. newsletter of upcoming events, articles, jobs and more from our membership.

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Articles for 25-Dec-08 to 23-Feb-09

Texas Neurology Presents Staff Service Awards

Author: David Evans

Release Date: Friday 13-Feb-09 8:00 AM

Texas Neurology would like to acknowledge the following employees' service to our organization: 5 Years: LaKyshia Ervin Margaret Hastings 10 Years: LeeAnn Mott Shirley O'Leary
Posted by: David Evans

Releases for 24-Jan-09 to 23-Feb-09

Dr. Herzog is interviewed by Ch. 33 to discuss a link between migraines and mood disorders

Author: David Evans

Release Date: Thursday 29-Jan-09 10:45 AM

Steven Herzog, M.D., Medical Director of the Headache Institute at Texas Neurology, was featured in a news story last night about Migraine... [More Info]
Posted by: David Evans

Jobs for 24-Jan-09 to 23-Feb-09

Nurse Practitioner or Physician Assistant

Company: Texas Neurology

Date Activated: Wednesday 28-Jan-09 0:00 AM

Texas Neurology, P.A, located in the Lakewood area of Dallas, Texas is currently recruiting Nurse Practitioners and/or Physician... [More Info]
Posted by: David Evans

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23-Feb-09 9:00 PM

Texas Neurology Presents Staff Service Awards

David Evans — Fri, 13 Feb 2009 14:00:00 GMT

Texas Neurology would like to acknowledge the following employees' service to our organization:

5 Years:

LaKyshia Ervin

Margaret Hastings

10 Years:

LeeAnn Mott

Shirley O'Leary

13-Feb-09 8:00 AM

Multiple Sclerosis Clinical Research Opportunities at Texas Neurology

David Evans — Thu, 11 Dec 2008 18:00:00 GMT

Texas Neurology is currently conducting several MS research protocols for patients with Relapsing MS and Secondary Progressive MS. If you would like additional information about any of these protocols, please contact Janey Phillips at 214.827.3610 ext 258.

11-Dec-08 12:00 PM

Optimizing Quality of Life in Multiple Sclerosis Patients

Sat, 18 Aug 2007 16:00:00 GMT

Shirley A. O'Leary, RN, MSCN; J. Theodore Phillips, MD, Ph.D

Introduction

The varying diversity and severity of multiple sclerosis (MS) that affects the quality of life in young, child-rearing, and career-developing persons presents significant challenges to the healthcare professional. Neurologists, nurses, physical and occupational therapists, urologists, and primary care physicians are only a few among the vast interdisciplinary team who endeavor to not only evaluate but also strive to positively affect the quality of life in MS patients. As recent years have provided us with disease-modifying agents and improved options for symptom management, this previously elusive goal has become increasingly more tangible.

The Impact of Disease-Modifying Therapies

Optimization is the "act, process, or methodology of making something as fully perfect, functional, or effective as possible".^[1] Prior to the advent of FDA-approved disease-modifying agents a mere 14 years ago (eg, interferon betas, glatiramer acetate, mitoxantrone, and natalizumab), optimization was not a term used in the discussion of MS. Now a paradigm shift is taking place.

Over the years, much attention has been devoted to the development of various tools with which to measure the quality of life in MS patients. One such tool, the Multiple Sclerosis Quality of Life Inventory (MSQLI), is a questionnaire that offers healthcare professionals a construct in which to view individual areas of concern as well as areas of stability. The MSQLI is a health-related quality-of-life assessment particular to MS and contains not only generic but also disease-specific components.^[2] To truly optimize the quality of life in persons with MS, it is imperative that healthcare professionals grasp the impact that these disease-specific components have in the lives of persons with MS, especially concerning those individuals without adequate coping strategies. Clearly, understanding each person's individual level of satisfaction with his or her perceived quality of life should translate to productive interventions.

Along with innovative symptom management, truly life-altering disease-modifying therapies have created an environment of a supportive, self-efficacious, and wellness-focused MS population. Acknowledging that persons with MS have a fairly close to normal life expectancy and that the optimal goal of the currently available disease-modifying therapies is to slow the accumulation of disability over the disease course, rather than to cure, reiterates the importance of their impact on quality of life.^[3] Our role here, as healthcare partners, is to not only assist in treatment selection but to also provide education on realistic expectations, injection strategies (if applicable), and side-effect management.^[4] For instance, we^[5] and others have found that utilization of various prophylactic medications for interferon therapy-related side effects and injection-site management strategies, as well as dose titration consideration and timing, are necessary to insure successful treatment adherence and optimal outcomes. Ortega and colleagues^[6] recently reported significantly reduced injection-site reactions after the application of warm compresses prior to injection of glatiramer acetate. Failure to partner, support, and problem-solve with patients in important arenas such as these will most assuredly lead to patient dissatisfaction, perceived treatment intolerability, and discontinuation of therapy, thus potentiating a negative impact on quality of life.

Challenges Beyond Disease-Modifying Therapies

Additionally, challenges to the healthcare professional to optimize the quality of life go far beyond the disease-modifying therapies. MS is a disease that comprises a complex variety of symptoms that, while possessing some commonalities, often vary widely in their presentation from person to person. Concerns such as bowel/bladder dysfunction, fatigue, cognitive deficits, spasticity, tremor, sexual dysfunction, and sensation disturbance are among some of the quality-of-life detractors that persons with MS may deal with throughout their lifetime. The remainder of this discussion will focus on potentially beneficial interventions relating to some of these problems.

One important caveat worthy of mention in any discussion of MS quality-of-life optimization is the likening to the ripple effect of the proverbial pebble cast into the pond which results in an ever-widening, far-reaching cascade. One symptom contributes to another and, sometimes counterintuitively, medication used to improve certain symptoms may contribute to the worsening of other symptoms. For instance, medications that have significant benefits on spasticity, tremor, or sensation disturbance can often lead to exaggeration of fatigue, increased issues with concentration and memory, and even depression. Awareness of these complicated interactions motivates healthcare professionals to look for innovative medication management personally tailored to optimize quality of life, such as combining lower doses of several medications as opposed to high doses of a single medication, in an effort to reduce side effects. In MS rehabilitation therapy, an educational strategy, in the form of energy conservation, is used to facilitate changes in behavior, hopefully minimizing fatigue impact .^[7] However, mediation of fatigue in any one individual is not the same in the next; comorbid conditions such as anemia or thyroid disorders, unrealistic work expectations and schedules with extensive recreational activities, along with a myriad of other psychosocial concerns may be factors to consider for some individuals but not all. Use of open verbal and nonverbal communication skills is necessary to elicit all factors contributing to fatigue.

The Goldman Consensus Group^[8] reported that the rate of major depression is significantly higher in the MS population when compared with the US population at large. Furthermore, this group reported higher rates of depression in MS patients compared with other chronic disease states. This likely comes as no surprise to healthcare providers who interact with MS patients on a daily basis. Nor does it seem surprising that depression is just as likely to be problematic in a newly diagnosed patient with minimal neurologic impairment as in those profoundly affected. As mentioned above, depression, cognitive function, fatigue, and medication side effects often can be interrelated. Of note, depression is not unique to MS; those persons without adequate life coping skills or intact family/community support, or who have low levels of self-esteem or family histories of depression, may be at much higher risk and consequently more likely to succumb to depressive syndromes. Clearly, in order to optimize quality of life for patients, healthcare providers must take the time to identify those at risk for depression and develop interventions, both through counseling and pharmacologic management.

Coping Strategies, Health Behavior, and Psychological Adjustment

A broad discussion of optimizing quality of life would be incomplete without reference to coping strategies, theory of health behavior, and psychological adjustment. These factors and the therapeutic interventions developed in response are of paramount importance to patient outcomes -- and ultimately quality of life.

Health-related behavioral theories comprise the selection of a theory that brings an enlightened perspective to the problem at hand and is developed after thorough assessment of the need. The Health Belief Model is one of several health-related behavioral theories that have been used to both assess and explain health-related behaviors. In the 1950s, this model was developed by the US Public Health Department to evaluate nonadherence to preventative measures for asymptomatic diseases.^[9] There are 4 basic components to this theory: (1) the person's perceived susceptibility to acquiring a condition; (2) the perceived belief in the severity of the condition (consequences); (3) the perceived benefits of treatment or actions to decrease negative effect; and (4) the perceived barriers to treatment, such as cost.^[10] Added to the basic 4 components in subsequent years were cues to action (such as advertisement and physician reminder calls) and self-efficacy. Utilization of this model by healthcare professionals can be quite helpful in the arena of adherence to disease-modifying agents. Through education and partnering, healthcare professionals can concretely communicate the consequences and implications of no therapy (perceived severity), relate evidence-based outcomes of therapy (perceived benefit), and strive to minimize cost concerns, explain risk vs benefit, and involve family members (perceived barriers). Nursing care especially provides substantial impact on cues to action and self-efficacy through a comprehensive plan of care geared toward optimizing quality of life.

For many persons with MS, the unpredictability of exacerbations, extent of recovery, and impact of residual symptoms on daily life can challenge coping mechanisms. McCabe and colleagues^[11] noted that persons who engaged in more emotion-focused coping styles (wishful thinking) were more likely to experience poor psychological adjustment than were those who employed more problem-focused strategies. They demonstrated that women in general, both with and without MS, were more likely to focus on the positive and seek social support than were men, and that levels of fatigue and medication impact were factors in psychological adjustment and coping. There are numerous variables that affect any one individual's ability to psychologically adjust to a lifelong chronic disease. Aside from MS-related variables such as fatigue, cognition, depression, and medication effects, which affect coping strategies, there are factors related to family of origin. Some of these include -- but are not limited to -- cultural, ethnic, spiritual, and socioeconomic backgrounds, as well as family support. All of these factors need to be considered when generating an effective care plan for optimizing quality of life in MS.

Conclusion

In summary, everything we do as members of a collaborative interdisciplinary healthcare team is targeted at optimizing the quality of life of those persons living with MS. As strides are made in optimistic pursuit of new treatment modalities and strategies, it is important for healthcare professionals to "pass it on." Pass it on to patients, and their families, friends, coworkers, other healthcare providers, and the community at large. Educate and teach so that MS patients do not cope by wishful thinking but have access to others who can problem-solve with them, who are prepared to "act, process and make something as functional and as effective as possible." It's called optimization; pass it on.

Supported by an independent educational grant from Biogen

References

Merriam-Webster Online Dictionary. Retrieved May 18, 2007 from http://www.merriam-webster.com/dictionary

Fischer J, LaRocca N, Miller D, Ritvo P, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS). Mult Scler. 1999;5:251-259. Abstract

Arnoldus J, Killestein J, Pfennings L, Jelles B, Uitdehaag B, Polman C. Quality of life during the first 6 months of interferon-b treatment in patients with MS. Mult Scler. 2000;6:338-342. Abstract

Denis L, Namey M, Costello K, et al. Long-term treatment optimization in individuals with multiple sclerosis using disease-modifying therapies: a nursing approach. J Neurosci Nurs. 2004;36:10-22. Abstract

Frohman E, Phillips T, Kokel K, et al. Disease-modifying therapy in multiple sclerosis: strategies for optimizing management. Neurologist. 2002;8:227-236. Abstract

Ortega J, Bishop B, Robbins J, et al. Impact of warm compresses on local injection site reactions with self-administered Copaxone. Program and abstracts of the Consortium of Multiple Sclerosis Centers (CMSC) 2006 Annual Meeting; June 1-3, 2006; Scottsdale, Arizona. Poster S60.

Finlayson M, Shevil E, Luo P, Chen H, Mathiowetz V. Effects of cognition on quiz performance, behavior change, and vitality after energy conservation course among people with multiple sclerosis. Int J MS Care. 2007;9:13-21.

Goldman Consensus Group. The Goldman consensus statement on depression in multiple sclerosis. Mult Scler. 2005;11:328-337. Abstract

Lai J, Cheng S. Health beliefs, optimism, and health-related decisions: A study with Hong Kong Chinese. Int J Psychol. 2004;39:179-189.

US Department of Health and Human Services. Theory at a glance: A guide for health promotion practice. 2nd ed. September 2005. NIH Publication No. 05-3896. Available at: http://www.nci.nih.gov/PDF/481f5d53-63df-41bc-bfaf-5aa48ee1da4d/TAAG3.pdf Accessed June 15, 2007.

McCabe M, McKern S, McDonald E. Coping and psychological adjustment among people with multiple sclerosis. J Psychosom Res. 2004;56:355-361. Abstract

J. Theodore Phillips, MD, PhD, Clinical Professor of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas; Director, Multiple Sclerosis Center, Texas Neurology, P.A., Dallas, Texas

Shirley A. O'Leary, RN, MSCN, Multiple Sclerosis Nurse Specialist, Texas Neurology P.A., Dallas, Texas

TEST

18-Aug-07 11:00 AM

Texas Neurology. P.A. Articles RSS Feed

Botox Is Safe and Effective as Preventive Treatment for Chronic Migraine

Texas Neurology Doctors Chosen Among the Best in Dallas-Fort Worth

Texas Neurology Doctors Chosen Among the Best in Dallas-Fort Worth

Texas Neurology. P.A. Newsletter 23-Feb-09

Texas Neurology Presents Staff Service Awards

Multiple Sclerosis Clinical Research Opportunities at Texas Neurology

Optimizing Quality of Life in Multiple Sclerosis Patients

Shirley A. O'Leary, RN, MSCN; J. Theodore Phillips, MD, Ph.D

Medscape Neurology & Neurosurgery. © 2007 Medscape

Introduction

The Impact of Disease-Modifying Therapies

Challenges Beyond Disease-Modifying Therapies

Coping Strategies, Health Behavior, and Psychological Adjustment

Conclusion

References