Editorial

By: Stephen D. Silberstein, MD, Professor of Neurology and Director of the Jefferson Headache Center, Jefferson Medical College, Philadelphia, Pennsylvania

Patients complain of headache more than any other type of pain, with headache accounting for over 10 million physician visits annually (Lipton R, Stewart W, von Korf M. Neurology, 1997;48(Suppl 3):S4-S9; National Center for Health Statistics. D.H.E.W., PHS Publication No. 53. Advance data. Hyattsville, Maryland. National Center for Health Statistics, 1979). Migraine sufferers are often the most dissatisfied patients; half of them stop seeking care for their headaches, often because they are unhappy with the therapy they receive (Lipton R, Stewart W, Simon D. Headache, 1998;38:87-96). Migraine has major implications for the patient's job and for his or her family and social life (Hu H, Markson L, Lipton R, Stewart W, Berger M. Arch Int Med, 1999;159:813-818; Von Korf M, Stewart W, Simon D, Lipton R. Neurology, 1998;50:1741-1745). Migraine sufferers experience significant disability, lost workdays, and diminished quality of life, accounting for over $13 billion a year because of missed workdays (Hu H, Markson L, Lipton R, Stewart W, Berger M. Arch Int Med, 1999;159:813-818).

An estimated 18 percent of women and 6 percent of men suffer from migraine, but many more go undiagnosed (Stewart W, Lipton R, Celentano D, Reed M. JAMA, 1992;267:64-69). There have been a number of advances in the diagnosis and treatment of migraine and great strides in understanding its pathogenesis. In the service of education and patient care, the American Academy of Neurology has led the multidisciplinary US Headache Consortium to develop an evidence-based practice parameter on migraine. Seven organizations participated in the Consortium: the American Academy of Family Physicians, the American Academy of Neurology, the American Headache Society, the American College of Emergency Physicians, the American College of Physicians, the American Osteopathic Association, and the National Headache Foundation. The practice parameter contains five parts: Overview of Program Description and Methodology, Neuroimaging in Patients with Nonacute Headache, Pharmacological Management of Acute Attacks, Behavioral and Physical Treatments, and Pharmacological Management for Prevention of Migraine. (Practice Parameter for Migraine, http://www.aan.com) The goals of the practice parameter are to reduce attacks, improve the response to medication, and restore a patient's ability to function. The sections describe strategies for: 1) preventing migraine, 2) understanding its causes, 3) involving the patient in the treatment plan, 4) following progress, and 5) measuring success. The practice parameters also help physicians select patients who are likely to benefit from the prevention and treatment strategies by providing information about organized pharmacological and non-pharmacological approaches.

Two parts of the evidence-based practice parameter for the migraine patient are reported in this issue (Behavioral and Physical Treatments and Pharmacological Management for Prevention of Migraine). This effort, one of the first, and certainly the most extensive, cooperative projects to develop practice parameters across disciplines, reflects the concern for the migraine patient of the physician-members of the organizations, as evidenced by their willingness to collaborate on this rigorous project. The guidelines are intended to improve care and outcomes for all migraine sufferers.

Introduction

By: Ninan T. Mathew, MD, FRCP(C), Clinical Professor of Neurology, University of Texas Medical School, and Director, Houston Headache Clinic; Houston, Texas

The last decade has witnessed tremendous advancement in our understanding of migraine pathophysiology. There has been a revolution in the treatment of acute attacks of migraine with the introduction of the triptans, antimigraine agents with very specific effects on serotonin 1B, 1D, and 1F receptors. Preventive treatment of migraine is still far from satisfactory. Many drugs are available but their effectiveness has not always been proven and many have unwanted side effects. Their mode of action in migraine is not fully understood. The central neuronal hyperexcitability in migraine is probably reduced by many of the prophylactic drugs, including the beta adrenergic blocking agents, calcium channel blocking agents, tricyclic antidepressants, 5-HT2 antagonists (methysergide), and the anticonvulsants.

Anticonvulsants have a wide variety of clinical effects in addition to their antiseizure effects. They have antinociceptive effects, mood-stabilizing effects (valproate [Depacon®], topiramate [Topamax®], and gabapentin [Neurontin®]), and are used to treat neuropathic pain (gabapentin and carbamazepine [Tegretol®]). Valproate has an approved indication for the treatment of mania. Essential tremor, comorbid with migraine, may be controlled with topiramate.

The clinical benefit of anticonvulsants as a class is attributed to their various mechanisms of action. Their multiple mechanisms of action include inhibition of sodium and calcium channels, NMDA receptors, potentiation of GABA receptors, and carbonic anhydrase inhibition. This broad spectrum of activity may account for their broad clinical benefits.

Side effects, such as weight gain, tremor, hair loss, and the development of polycystic ovarian syndrome (in epileptics), have been the main limitation to use of valproate, which is approved for the prophylactic treatment of migraine. Recent small, double-blind, placebo-controlled studies have indicated potential benefit of topiramate in migraine prophylaxis (Edwards K, Glantz M, Shea P, Norton J. 18th Annual Meeting of the American Pain Society, October 21-24, 1999; Fort Lauderdale Florida, Abstract 215; Potter D, Hart D, Calder C, Storey J. Neurology, 2000; 54(Supp 3):A15, Abstract S07-004). Larger randomized, double-blind, placebo-controlled studies are awaited. The report, which follows this introduction, deals with some of the details of the mechanisms and clinical use of anticonvulsants in migraine prophylaxis.

Disability and quality of life measurements are important in assessing the treatment needs of patients with chronic recurrent migraine. The MIDAS scale (Migraine Disability Assessment) developed by Lipton et al. is an easily applicable, simple measure of disability in migraine patients (Stewart W, Lipton R, Kolodner K et al. Cephalgia, 1999;19:107-14). Chronic daily headache patients have very high MIDAS scores and would be likely to require preventive medications. It has been shown that improvement in the MIDAS score is a reasonable predictor of prophylactic treatment success in patients with chronic migraine.

Migraine remains a challenge because a number of patients remain intractable in spite of intense prophylactic therapy, even when combined with behavioral therapy. In those who are totally intractable, long-term opioid use is reasonable. The results of long-term opioid therapy have been rather disappointing. Saper et al. found that only 25 percent of patients on long-term opioid treatment obtained reasonable benefits. Long-term opioid therapy is challenging and needs careful supervision and a good doctor/patient relationship.

As we come to a better understanding of the basic pathophysiology of migraine, we expect better and more effective preventive treatment. Until newer and better drugs are available, we should look for the most effective combinations of therapy, which would undoubtedly include anticonvulsants, along with treatment of comorbidities that are part of the migraine condition.

The following are summaries of proceedings from the American Headache Society as reported by Andrew Wilner, MD

Office-Based Therapy of Chronic Daily Headache

This session was funded by Glaxo Wellcome, Inc.

Summary report of the oral presentation by: Robert G. Kaniecki, MD, Associate Professor of Neurology, and Director of the Headache Center at the University of Pittsburgh, Pittsburgh, Pennsylvania

Although population surveys estimate a prevalence of only four percent in the United States, patients with chronic daily headache represent a significant proportion of the cases headache specialists see (Wolff I. Headache and Other Head Pain (7th ed). Silberstein S, Lipton R, Dalessio D [eds]. Oxford University Press, in press). Dr. Kaniecki proposed three steps for the care of these patients:

1. Categorize

Differentiate between patients whose headaches last longer than four hours and those whose headaches last less than four hours. Headaches that last less than four hours are likely to be chronic cluster headache, chronic paroxysmal hemicrania, hypnic headache, sudden unilateral, neuralgic, conjunctival, tearing (SUNCT), or idiopathic stabbing headache. Headaches that last longer than four hours include transformed migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache.

2. Analyze

Evaluate the patient for any comorbid medical or psychiatric disease that may influence therapy. As many as 70 percent of patients presenting with daily headache have an Axis I level diagnosis from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Mood, anxiety, and somatoform disorders are common. Patients should be assessed for analgesic dependence. Up to 80 percent of patients presenting to headache clinics with chronic daily headache use analgesics daily or almost daily. When taking a drug history, it is important to be aware that many patients fail to report nonprescription drug use.

3. Customize

Begin with an educational program for patients to engage them as partners in managing their headaches. Address three commonly asked questions:

a. What kind of headache do I have? b. Why do I get my headaches? c. What can I do to fix my headache?

Establish a protocol to break analgesic dependence. In an office practice there are four options:

a. Abrupt outpatient discontinuation (simple analgesics, triptans) b. Outpatient taper (caffeine-containing, butalbital/barbiturates) c. Inpatient program (narcotics, ergots) d. Referral to tertiary centers (complicated cases)

Patients should also regulate sleep, meals, and exercise, and reduce caffeine and nicotine consumption. Some patients will benefit from biofeedback/relaxation training. Prophylaxis with antidepressants or anticonvulsants should be considered.

Dr. Kaniecki found this approach to be efficient in a 45-minute office visit. In his practice, 52 percent of his patients had better than 50 percent improvement.

Headache Center-Based Therapy of Chronic Daily Headache

This session was funded by Glaxo Wellcome, Inc.

Summary report of the oral presentation by: Joel R. Saper, MD, FACP, FAAN, Clinical Professor of Neurology, Michigan State University, East Lansing, Michigan and Director of the Michigan Head Pain and Neurological Institute, Ann Arbor, Michigan

Dr. Saper reported in a plenary session that the typical patient with chronic daily headache who presents to a tertiary center has been unresponsive to standard care, has comorbid psychiatric and/or medical impairment, and suffers from significant drug toxicity or rebound. Patients often demonstrate depression, sleep disturbance, panic/anxiety, epilepsy, bipolar disease, and narcissistic or borderline personality disorder. They may consume drugs in such large quantities that they suffer from starch, talc, or dye toxicity. These refractory patients consume more time, staff, and testing, and cost more than other patients.

The first step in treating the refractory patient is to eliminate the possibility of secondary headache due to other illness and medication overuse. Medication treatment may consist of monotherapy or polypharmacy. Invasive procedures such as a diagnostic block with an anesthetic agent may be appropriate for some patients. Dr. Saper said that opioids should be reserved for patients with contraindications to other drugs or for whom all other treatments fail.

Hospitalization is appropriate in the following situations:

• Severe symptoms refractory to outpatient care • Severe neuropsychiatric or behavioral comorbidity • Confounding medical illness that prevents adequate outpatient pain treatment • Patient requires urgent treatment

In the hospital, patients can receive urine and blood drug screening, neuroimaging, endocrinological studies, intravenous (IV) protocols, aggressive behavioral treatment, detoxification, and consultation with pain anesthesiologists as required. Dr. Saper stressed that it is essential to interrupt the pain cycle and develop preventive and abortive programs to continue treatment when the patient is discharged from the hospital.

Non-Pharmacologic Therapy of Chronic Daily Headache

This session was funded by Glaxo Wellcome, Inc.

Summary report of the oral presentation by: Alvin E. Lake III, PhD, Division Director, Psychology and Associate Program Director, Head Pain Treatment Unit, Ann Arbor, Michigan

In a plenary session, Dr. Lake presented that although there is no International Headache Society classification for chronic daily headache (CDH), Silberstein et al. proposed a working definition: more than 15 headache days per month for at least six months (Silberstein S, Lipton R, Sliwinski M. Neurology, 1996;47:871-875). Chronic tension-type headache comprises 50-70 percent of those with CDH, but CDH also includes transformed migraine, new onset daily persistent headache, and chronic post-traumatic headache. The prevalence of CDH is approximately four to five percent. Only about 37 percent of patients with CDH (1.5 percent of the general population) actually have headache every day.

Dr. Lake noted that behavioral issues are "more prevalent or severe in CDH than in episodic headache," particularly analgesic overuse and abuse. Analgesic abuse may be defined as a "pattern of repetitious behavior" with at least some of the following:

• Noncompliance with prescription guidelines • Problems with prescription medications that generate additional refills for a variety of reasons, including lost, spilled, or stolen medicine • Multisourcing, including prescriptions from emergency room physicians • Drug-seeking behavior, including an overwhelming focus on analgesics to the impediment of addressing other headache-relevant issues • Use despite harm or in dangerous situations (e.g., driving while impaired) • Use for nonacute pain • Recurrent bouts of analgesic rebound • Pattern of failure to fulfill major role obligations due to analgesic-related impairment • Analgesic use that creates recurrent social and medical problems

Approximately 30 percent of patients with CDH overuse prescription and over-the-counter analgesics. Analgesic overuse, which is common (50-58 percent) in patients at tertiary headache centers, predicts poor outcome. In addition, 90 percent of patients with CDH have one or more comorbid psychiatric disorders. Investigators found anxiety and mood disorders (45 percent), major depression (39 percent), and chronic low back pain (18 percent). Fifty-seven percent of patients found that stress aggravated their headaches. Conversely, more frequent and severe headaches increased patients' susceptibility to stress (Wolff I. Headache and Other Head Pain (7th ed). Silberstein S, Lipton R, Dalessio D [eds]. Oxford University Press, in press).

Because patients with CDH often have underlying behavioral and psychiatric problems, behavioral treatment, including biofeedback, cognitive behavioral therapy, and stress management, can be helpful. However, patients with daily or nearly continuous pain do more poorly with cognitive behavioral treatment or biofeedback. Drug prophylaxis can enhance the benefits of biofeedback.

Improvement in Headache-Related Disability in Chronic Daily Headache-Treatment Outcome Assessed by MIDAS

Summary report of the oral presentation by: Ninan T. Mathew, MD, FRCP(C), Clinical Professor, University of Texas Medical School and Director, Houston Headache Clinic, Houston, Texas, along with Drs. S. Villarreal, and J. Kailasam, Houston Headache Clinic, Houston, Texas

According to the presenters, The Migraine Disability Assessment (MIDAS) questionnaire demonstrates high accuracy, face validity, internal consistency, and test-retest reliability, and corresponds to physicians' judgements of illness severity and medical need (Stewart W, Lipton R, Kolodner K et al. Cephalgia, 1999;19:107-14). The questionnaire includes five questions that are scored, and two additional questions:

1. On how many days in the last three months did you miss work or school because of your headaches? 2. On how many days in the last three months was your productivity at work or school reduced by half or more because of your headaches? (Do not include days you counted in question one where you missed work or school.) 3. On how many days in the last three months did you not do household work because of your headaches? 4. On how many days in the last three months was your productivity in household work reduced by half or more because of your headaches? (Do not include days you counted in question three where you did not do household work.) 5. On how many days in the last three months did you miss family, social, or leisure activities because of your headaches? A. On how many days in the last three months did you have a headache? (If a headache lasted more than one day, count each day.) B. On a scale of 0-10, on average how painful were these headaches? (0 = no pain at all, 10 = worst pain possible)

The MIDAS score correlates with degree of disability, as follows:

Grade I-little or no disability-score 0-5 Grade II-mild disability-score 6-10 Grade III-moderate disability-score 11-20 Grade IV-severe disability-score 21 or greater

Although well-established, MIDAS has not been thoroughly assessed for use in chronic daily headache (CDH). Dr. Ninan Mathew and colleagues evaluated MIDAS in 66 patients with CDH, 50 with transformed migraine, and 16 with chronic tension-type headache. Patients completed the MIDAS questionnaire at the initial visit and again four months after comprehensive headache treatment. Patients received in-hospital analgesic detoxification, repetitive intravenous dihydroergotamine, prophylactic pharmacotherapy, behavioral counseling, biofeedback, dietary counseling, and physical therapy. Outpatient therapy consisted of biofeedback, dietary changes, exercise, and prophylactic medications.

Patients initially had a mean elevated MIDAS score of 61.71. Dr. Mathew noted that anxiety and depression increased along with MIDAS scores. Headache frequency was the best predictor of MIDAS scores, however he also found that age was inversely related to MIDAS scores.

The researchers noted that headache-related disability as measured by MIDAS was very high in patients with CDH, but that appropriate treatment reduced headache days, depression, and anxiety and improved disability. Dr. Mathew concluded, "MIDAS appears to be a good predictor as a measure of treatment outcome in chronic daily headache."

Non-Pharmacologic Guidelines

Summary report of the oral presentation by: Donald B. Penzien, PhD, Director, Head Pain Center, University of Mississippi Medical Center, Jackson, Mississippi

Drugs are the principal treatment for headache, both for preventive and acute therapy. However, Dr. Donald Penzien noted, "There is no cure for headache, [and] our medications stop short of giving cures."

Behavioral treatments for migraine prevention are classified into three groups:

1. Relaxation training 2. Biofeedback 3. Cognitive-behavioral (stress management)

Physical treatments for migraine include acupuncture, transcutaneous electrical nerve stimulation (TENS), occlusal adjustment, cervical manipulation, and hyperbaric oxygen.

Patients likely to benefit from behavioral and physical treatments have one or more of the following characteristics:

• Patient preference for nonpharmacological interventions • Poor tolerance for specific pharmacological treatments • Medical contraindications for specific pharmacological treatments • Insufficient or no response to pharmacological treatments • Pregnancy, planned pregnancy, or nursing • History of long-term, frequent, or excessive use of analgesic or acute medications that can aggravate headache problems (or lead to decreased responsiveness to other pharmacotherapies) • Significant life stress or deficient stress-coping skills

Behavioral and physical migraine treatments are usually employed as prophylaxis, rather than acute therapy. Treatment goals are:

• Reduced frequency and severity of headache • Reduced headache-related disability • Reduced reliance on poorly tolerated or unwanted pharmacotherapies • Enhanced personal control of migraine • Reduced headache-related distress and psychological symptoms

The US Headache Consortium developed evidence-based guidelines of behavioral and physical treatments for migraine headaches based on the review of 355 articles, including 70 controlled trials, 39 of which met inclusion criteria for the Agency for Health Care Policy and Research (AHCPR) Technical Review. Only these last studies were considered for the guidelines. (Practice parameter for migraine. http://www.aan.com)

The group analyzed the results of ten trials of relaxation training, five trials of temperature biofeedback, ten trials of temperature biofeedback plus relaxation, five trials of EMG biofeedback, seven trials of cognitive behavioral therapy, two trials of hypnosis, and five trials of cognitive behavioral therapy plus thermal biofeedback. In addition, they evaluated 12 prospective, randomized, controlled trials of physical treatments; seven trials of acupuncture, two of TENS, one of occlusal adjustment, one of cervical manipulation, and one of hyperbaric oxygen.

Based on the analysis of the above data, the group reached the following conclusions:

1. Relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy are all somewhat effective. They should be considered as treatment options. Preventive drug therapy such as propranolol (Inderal®) or amitriptyline (Elavil®, Etrafon®, Limbitrol®) may provide additional clinical improvement. 2. Current evidence is too limited to permit recommendations regarding acupuncture, cervical manipulation, hyperbaric oxygen, hypnosis, occlusal adjustment, or TENS.

Dr. Penzien recommended that future studies include patients from primary care settings rather than tertiary headache clinics in order to provide more relevant results for practicing physicians. Additional studies are needed to clarify which patient characteristics predict response to pharmacologic, physical, or behavioral treatment modalities.

Preventive Guidelines

Summary report of the oral presentation by: Stephen D. Silberstein, MD, FACP, Professor of Neurology, Jefferson Medical College of Thomas Jefferson University and Director, Jefferson Headache Clinic at Thomas Jefferson University, Philadelphia, Pennsylvania

Stephen D. Silberstein, MD, FACP, reviewed evidence-based guidelines for migraine headache developed by the US Headache Consortium in a plenary session. Comprised of the American Academy of Family Physicians, American Academy of Neurology, American Headache Society, American College of Emergency Physicians, American College of Physicians, American Society of Internal Medicine, American Osteopathic Association, and National Headache Foundation, the US Headache Consortium has produced four evidence-based guidelines that cover behavioral and physical treatments, pharmacologic management of acute attacks, neuroimaging in patients with nonacute headache, and pharmacologic management for the prevention of migraine (http://www.aan.com).

Dr. Silberstein outlined general principles of migraine management:

1. Establish a diagnosis. 2. Educate patients about their condition. 3. Establish realistic expectations. 4. Involve patients in their management (calendars). 5. Choose treatment based on attack frequency, severity, disability, and associated symptoms, such as nausea and vomiting. 6. Individualize management plans.

Goals of prevention include reducing attack frequency, severity, and duration, improving responsiveness to treatment, improving function, and reducing disability. Dr. Silberstein noted that "medication should not have an adverse effect that [is] worse [than the headache]."

Behavioral treatments such as relaxation therapy, biofeedback, cognitive behavioral therapy, and physical treatments can also be combined with pharmacologic treatment.

Dr. Silberstein suggested the following guidelines for preventive medication use: 1. Use the most effective medication with the fewest adverse events. 2. Take coexisting conditions into account: a) select a drug that will treat all conditions, if possible, b) be sure that coexistent disease is not a contraindication to the migraine treatment, c) ensure that treatments used for coexistent conditions do not exacerbate migraine, and d) be aware of drug interactions. 3. Start low and increase dose slowly until clinical benefits are achieved in absence of, or until limited by, adverse events. 4. Give selected drug an adequate trial at adequate doses (two to three months). 5. Avoid interfering medications (overuse of acute medications). 6. A long-acting formulation may improve compliance. 7. Monitor the patient's headache with a diary. 8. Re-evaluate therapy; if controlled at six months, consider tapering or discontinuing treatment.

Many medications, including beta-blockers, calcium channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, and others are used for migraine prophylaxis. The US Headache Consortium has classified these drugs into five categories, depending on quality of evidence, scientific effect, clinical impression, and adverse events. Group 1 drugs, those with medium to high efficacy, good evidence, and mild to moderate adverse events, include amitriptyline (Elavil®), divalproex sodium (Depakote®), propranolol (Inderal®), and timolol (Blocadren®) (http://www.aan.com). Dr. Silberstein commented that many commonly used drugs have not yet been scientifically proven to be effective, such as doxepin (Sinequan®), sertraline (Zoloft®), nortriptyline (Pamelor®, Aventyl®), diltiazem (Cardizem®), and others. (See chart on the inside back cover for approved indications.)

Dr. Silberstein concluded that the US Headache Consortium guidelines are the first and most extensive collaborative project for evidence-based practice guidelines intended to "improve care and outcome for all migraine sufferers." They reflect high physician concern for migraine patients and the need for improving care across disciplines.

Sustained Opioid Therapy for Intractable Headache: Five Year Study

The ACHE Lecture

This session was funded by Ortho-McNeil Pharmaceutical, Inc.

Summary report of the oral presentation by: Joel R. Saper, MD, FACP, FAAN, Clinical Professor of Neurology, Michigan State University, East Lansing, Michigan, and Director, Michigan Head Pain and Neurological Institute, Ann Arbor, Michigan

"In the last 10 years, we have witnessed a dramatic increase in public awareness of pain, and the need, as well as demand, for better treatment," Dr. Saper said. "[There is a] growing expectation that physicians will use more and more opioids."

In his own practice, he has seen "increasing referrals of young and otherwise healthy headache patients, as well as others, who have been placed on high-at times toxic-amounts of opioids, far too early in the course of their pain history, and, oftentimes, well before more appropriate and creative treatments had been administered."

In order to assess the role of sustained opioid treatment for intractable headache, Dr. Saper performed a prospective, unfunded, five-year study, which is still underway. He included patients who had daily severe head pain of at least six hours' duration who failed to improve on other treatments or for whom standard treatments were contraindicated. The study included monthly and bimonthly medical and psychological visits, a gradual increase in opioid dose, rescue medications as needed, aggressive treatment of side effects (including methylphenidate [Ritalin®] for drowsiness), and alternate opioids if the initial choice proved ineffective. Opioids included oxycodone sustained action, morphine sustained action, methadone, fentanyl patch, and short-acting opioids.

The protocol also included a contract, participation of a significant other, performance and function evaluation, and compliance checks. Dr. Saper measured results with a headache index calculation, visual analog scale, and pain disability index.

Dr. Saper noted that approximately 50 percent of the patients dropped out of the study due to intolerance or failure of opioid therapy. Of 160 patients enrolled for three or more years, only 23 percent improved. He found that "the more severe intractable patient, with four to five days of severe pain, appears to respond to this treatment better than the less severe patient who also has daily persistent pain."

Of the patients who remained on opioids, 80 percent reported improving more than 50 percent on the visual analog scale. There was a 63 percent mean percentage improvement. An additional benefit of opioid therapy was a reduction in hospitalization and emergency care episodes.

Seventy-three percent of patients used the same opioid for three to five years, but 50 percent of the patients required an increase in dose. Twenty percent succeeded in reducing their dose. However, patients continued their abortive and preventive medications.

Despite frequent office visits, one pharmacy, one physician, psychological intervention, and a contract, 41 percent of the patients had at least one noncompliant behavior in the first year. Dr. Saper noted that "substantial noncompliance and addictive behavior" must be reckoned with in this population.

He also commented that opioid therapy should not be used as first-line therapy except in pregnancy, when other drugs may not be used or when profound comorbid disease prohibits traditional treatment. Primary care physicians should not use opioids before referral to pain specialists and tertiary care centers. He expressed concern that the long-term central nervous system consequences of sustained opioid therapy are not yet known.

Contraindications to sustained opioid therapy include severe DSM-IV Axis I disease or such syndromes as borderline, narcissistic, histrionic, or antisocial personality disorders.

Research goals include developing more refined predictors for success, correlating clinical and physiological parameters with opioid responsiveness, and determining reversibility after long term use. Dr. Saper concluded by noting, "Of the 23 percent of the total group who did well, many did remarkably well, and it truly changed the course of their lives."

Topiramate for Migraine Prophylaxis: A Double-Blind,Randomized, Placebo-Controlled Study

Summary report of the oral presentation by: Keith R. Edwards, MD, Western New England Headache Clinic and Neurological Research Center, Bennington, Vermont

Topiramate (Topamax®) is a novel compound indicated for adjunctive therapy of partial onset and primary generalized tonic-clonic seizures in adult and pediatric patients ages two and over. Topiramate has multiple mechanisms of action, including: • State-dependent blockade of voltage-gated sodium channels • Inhibition of high-voltage-activated calcium channels • Enhancement of action at GABA (A) receptors • Blockade of AMPA/kainate subtype of glutamate receptors • Carbonic anhydrase inhibition

Dr. Keith Edwards and colleagues performed a double-blind, randomized, placebo-controlled study of topiramate for migraine prophylaxis. The majority of the study patients had attended Dr. Edwards' migraine clinic for many years and had failed at least two other prophylactic medications.

Subjects were men and women 18-65 years of age with migraine with or without aura (International Headache Society criteria). Patients had to have migraines for at least one year, averaging two or more per month. During a prospective baseline, patients had to have two to eight migraines per four weeks, with or without concomitant prophylactic therapy. The protocol excluded patients who used abortive therapy three or more days per week or had tension-type headaches more than 12 days per month.

The baseline period lasted four weeks, the titration phase six weeks, and the maintenance phase 12 weeks. Thirty patients were enrolled. Researchers initiated topiramate at a dosage of 25 mg/day, titrated in 25 mg increments per week to a target maintenance dose of 100 mg BID.

The primary efficacy variable was a comparison of a 28-day migraine frequency during the 18-week, double-blind phase. The three secondary efficacy variables were:

1. Comparison of mean reduction in a 28-day migraine frequency during the entire double-blind phase 2. Comparison of the mean percentage reduction in a 28-day migraine frequency from baseline to the double-blind phase 3. Comparison of the number of patients experiencing a reduction in migraine headaches of 50 percent or more over the double-blind phase

Fifteen patients took topiramate and 15 took placebo. All of the patients were female except for one placebo-treated patient. The average ages of the topiramate and placebo patients were 45.8 and 43.9 respectively. Four topiramate patients and three placebo patients took concomitant prophylactic medications. The mean dose of topiramate was 173 mg/day. Eleven of the 15 patients achieved the target dose of 200 mg/day.

Baseline 28-day headache rates were comparable between the two treatment groups (4.2 topiramate vs. 4.1 placebo). The primary efficacy variable was the mean 28-day migraine frequency during the entire double-blind phase in the intent-to-treat population. There was a trend toward greater benefit in this measure for topiramate-treated patients compared with placebo-treated patients (3.0 topiramate vs. 3.8 placebo, p = 0.09).

Secondary outcomes included the mean percentage reduction in 28-day migraine frequency and the percentage of patients achieving a 50 percent reduction in headaches. There was a statistically significant difference in mean percentage reduction in 28-day migraine frequency during the entire double-blind phase (topiramate 37.2 percent and placebo 11.9 percent, p = 0.034).

Likewise, the percentage of patients achieving a 50 percent reduction in migraine frequency was 46.7 percent on topiramate and only 6.7 percent for placebo, statistically significant at p = 0.035.

Adverse events in ten percent or more of the patients included paresthesias, diarrhea, altered taste, somnolence, dry mouth, and memory impairment. Paresthesias typically occurred during titration but did not result in any patient discontinuing the drug. Twenty-two percent of the patients lost more than ten percent of their body weight. Two patients in both the topiramate and placebo groups reported memory loss.

Overall, 13 patients dropped out of the study, seven on topiramate and six on placebo. Four topiramate patients discontinued because of adverse events, one for lack of efficacy, one for noncompliance, and one for unspecified reasons. Three placebo patients discontinued because of continued headaches and three for unspecified reasons.

Based on his experience during this trial, Dr. Edwards felt that a lower topiramate dose would be better tolerated. "I would start with 15 or 25 mg per day, and not even titrate for a couple of weeks." He observed that headache patients may not tolerate side effects as well as epilepsy patients, and may require more gradual anticonvulsant titration. Dr. Edwards noted that his results of topiramate in migraine prophylaxis were similar to a study by Potter et al., suggesting that topiramate may be effective for headache treatment (Potter D, Hart D, Calder C, Storey J. Neurology, 2000; 54(Supp 3):A15, Abstract S07-004).

Differentiating the Pediatric/Adolescent Headache

This session was funded by Glaxo Wellcome, Inc.

Summary report of the oral presentation by: A. David Rothner, MD, Director Emeritus, Section of Child Neurology and Director of the Pediatric/Adolescent Clinic, Cleveland Clinic Foundation, Cleveland, Ohio

Headaches are a common complaint in children and adolescents as well as in adults. Although the International Headache Society published a new headache classification in 1988, Dr. Rothner finds that approaching childhood headaches based on their temporal pattern provides pragmatic information that more effectively guides diagnosis and treatment (Rothner D. Cephalgia, 1988;1(Supp 7)). He described five patterns: acute, acute-recurrent, chronic and progressive, chronic and nonprogressive, and mixed.

Dr. Rothner included a list of questions that establish a "Headache Database" (See TABLE). The answers to these 21 questions facilitate the accurate classification of the headache and direct the correct diagnostic tests and treatment. Although most headache patients have a normal physical and neurologic examination, practitioners should pay close attention to vital signs, skin, head circumference, and also auscultate for intracranial bruits when examining children and adolescents with headache.

Acute and Subacute Headaches

An acute headache is the patient's first headache in this population. The most common cause of acute and subacute headache is a febrile illness, especially a systemic viral disease.

Sinusitis, traumatic, and post-traumatic headaches may also be responsible. If the patient is severely ill, the physician should consider meningitis, aseptic meningitis, and encephalitis. Hypertension, pseudotumor cerebri, and medication and substance abuse may also present as acute headaches. Unless the patient has an abnormal eye exam, ocular disease is rarely responsible.

Acute-Recurrent Headache

Migraine is the most common cause of acute-recurrent headache in this population. Migraine attacks begin before age 20 in 50 percent of patients. Seventy percent of patients have a positive family history, and the disorder appears to be autosomal dominant.

Children and adolescents usually have migraine without aura. There are many triggers, including anxiety, diet, excitement, exercise, fatigue, head trauma, illness, medication, stress, and travel. Attacks typically last two to six hours and occur once or twice a month. Pain is throbbing and severe, unilateral or bilateral, frontal or temporal. Anorexia, abdominal pain, nausea, vomiting, phonophobia, photophobia, and the need to sleep are common accompaniments. Migraine never occurs daily, and another etiology should be sought for patients with daily headaches.

Complex migraine, such as hemiplegic migraine, occurs more commonly in adolescents than adults. Certain other migraine variants, such as acute confusional migraine, paroxysmal vertigo, and the periodic syndrome of cyclic vomiting are also less common in adults.

Chronic Progressive Headache

Patients who suffer headaches that increase in frequency and severity, particularly when accompanied by an abnormal neurologic examination, are likely to harbor an intracranial abnormality. Etiologies include brain abcess, brain tumor, cerebrovascular disease, hydrocephalus, pseudotumor cerebri, and subdural hematoma. The best diagnostic test for these patients is usually magnetic resonance imaging.

Chronic Nonprogressive Headache

Adolescents are more likely to suffer chronic nonprogressive headache than any other headache type. Conversion headaches, depressive equivalents, headaches related to malingering, muscle contraction headaches, post-traumatic headaches, and tension headaches are often responsible. Symptoms are usually vague and non-specific and may be accompanied by blurred vision, dizziness, fatigue, and syncope. Frequent school absences may result.

Psychosocial stress often lies behind chronic nonprogressive headaches. Practitioners should take a detailed social history to look for evidence of abuse, alcoholism, divorce, death, or behavioral problems. Psychological interviews of the patient and parents, IQ and achievement tests, and the Minnesota Multiphasic Personality Inventory for Adolescents, and the Parent Inventory for Children may be helpful. Dr. Rothner has had good treatment results with a combination of biofeedback, counseling, and amitriptyline.

Mixed Headache

Patients may have migraine as well as chronic nonprogressive headaches. Both types of headache must be addressed simultaneously for good results.

Other Headache

Physicians should be aware of less frequent types of headache that may also appear in children, such as cluster headaches, temporomandibular joint dysfunction headaches, occipital neuralgia, and indomethacin-responsive headaches.

TABLE: Headache Database

1. Do you have one type or two types of headache? 2. How did the headache begin? 3. How long has the headache been present? 4. Are the headaches static, intermittent, or progressive? 5. How often does the headache occur? 6. How long does the headache last? 7. Do the headaches occur at any special time or under special circumstances? 8. Are the headaches related to specific foods, medications, or activities? 9. Are there warning symptoms? 10. Where is the pain located? 11. What is the quality of the pain? 12. Are there associated symptoms during the headache? 13. What do you do during the headache? 14. How long does the headache last? 15. What makes the headache better? 16. What makes the headache worse? 17. Do symptoms continue in between the headache? 18. Are you being treated for any other medical problem? 19. Do you take any medication, for any reason, regularly or intermittently? 20. Does anyone else in your family have headache? 21. What do you think is causing your headaches and why do you have them?

(Wolff I. Headache and Other Head Pain (7th ed). Silberstein S, Lipton R, Dalessio D [eds]. Oxford University Press, in press)

Management of Pediatric Headache

This session was funded by Glaxo Wellcome, Inc.

Summary report of the oral presentation by: Paul Winner, DO, FAAN, Clinical Assistant Professor of Neurology, Nova Southeastern University, Ft. Lauderdale, Florida, and Co-director, Palm Beach Headache Center and Premier Research Institute at Palm Beach Neurology, Ft. Lauderdale, Florida

Paul Winner, DO, FAAN, noted in his plenary presentation that 75 percent or more of children experience a headache by age 15 (Winner P. Current Opinion in Neurology, 1999; 12:269-272). Children with headache have more bruxism, occipital and temporomandibular joint tenderness, motion sickness, and family history of headache than controls. Headaches tend to be bifrontal and most often begin in the afternoon (72 percent), compared to the evening (22 percent), or morning (six percent).

In order to improve the International Headache Society (IHS) classification for children and adolescents, researchers have suggested revised criteria for pediatric migraine. These include altering the duration, from four to 72 hours to one to 48 hours, adding bifrontal and bitemporal to the unilateral location, and permitting a choice of phonophobia or photophobia rather than requiring both. These changes increased the sensitivity from 68 percent with the present IHS criteria to 90 percent for patients ages two to 17 years.

Chronic daily headache occurs in 0.5 percent to 0.9 percent of children. Patients with serious underlying pathology may awaken from sleep with headache or have growth or pubertal arrest, amenorrhea, or elevated intracranial pressure. Benign chronic daily headache may be associated with acting-out behaviorally, family problems, "la belle indifference," school phobia, and separation anxiety. Both pharmacologic and non-pharmacologic treatments are necessary.

Children with migraine suffer more psychiatric comorbidity than those with episodic tension-type headaches. For example, 11 percent of migraineurs had anxiety, compared with only two percent with tension-type headaches. Sleep disorders are experienced similarly by 12 percent of migraineurs and 14 percent of those with tension-type headaches. However, patients with chronic tension-type headaches were more likely to have multiple comorbid disorders (57 percent), compared to episodic tension-type headaches (19.4 percent) or migraineurs (21.9 percent).

Pediatricians commonly prescribe tricyclics [amitriptyline (Elavil®)], [nortriptyline (Pamelor®, Aventyl®)]; calcium channel blockers [verapamil (Calan®)]; B-blockers propranolol (Inderal®), nadolol (Corgard®), atenolol (Tenormin®)]; and anticonvulsants [divalproex sodium, (Depakote®)] for preventive headache therapy. Mild to moderate migraine often responds to mild analgesics, combination analgesics, or nonsteroidal anti-inflammatory drugs. In recent studies, approximately 75 percent of patients with moderate to severe migraine responded to serotonin-1 agonists. More data on triptans in children and adolescents will soon be forthcoming from clinical trials.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: Jefferson Medical College; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This educational monograph includes discussion of treatment and indications outside of current approved labeling. This CME monograph was made possible through an unrestricted educational grant from Ortho-McNeil Pharmaceutical, Inc.

(c) 2000 Millennium Medical Communications, Inc.