Daily scheduled opioids for intractable head pain: long-term observations of a treatment program.

BACKGROUND: Daily scheduled opioids (DSO) have been employed in some instances to remediate intractable headache. However, long-term studies of effectiveness, sequelae over several years, predictors of long-term benefit, comparisons of pain-related outcome measures, and prevalence of problematic drug behavior are not available. METHODS: The authors evaluated the results of a treatment program at their institution designed to treat and monitor intractable headache patients administered DSO. Of 160 sequential patients participating in the program, 70 who remained on DSO for at least 3 years qualified for inclusion in an efficacy analysis. Patients completed structured questionnaires at each medical visit as part of routine clinical care. The authors assessed medical records during treatment, and during the 2 years before starting DSO. The primary clinical efficacy variable was percentage improvement in the severe headache index (frequency x severity of severe headaches/week). RESULTS: Analysis of the medical records found 41 (26%) of the original 160 patients with >50% improvement. Patients reported larger improvements on a visual analog scale (mean improvement = 70%) than shown by the medical record (mean improvement = 46%), p < 0.00001. Problem drug behavior (dose violations, lost prescriptions, multisourcing) occurred in 50% of patients, usually involving dose violations. CONCLUSIONS: For a select group of intractable headache patients, DSO can offer significant benefit. However, 74% of those treated either failed to show significant improvement or were discontinued from the program for clinical reasons. The relatively low percentage of patients with demonstrated efficacy and unexpectedly high prevalence of misuse have clinical relevance.

Why headache treatment fails.

Management of headache disorders, a leading reason for neurologic outpatient visits, is often difficult. In this article, the authors summarize and categorize the common reasons for treatment failure leading to referral to subspecialty headache centers. They have grouped these treatment failures into five broad categories: 1) the diagnosis is incomplete or incorrect; 2) important exacerbating factors have been missed; 3) pharmacotherapy has been inadequate; 4) nonpharmacologic treatment has been inadequate; 5) other factors, including unrealistic expectations and comorbidity, exist. The authors present an orderly approach to treatment failure to assist neurologists in managing difficult patients. Most refractory headache patients have a biologically determined problem and can be helped by accurate diagnosis or effective treatment. Persistence in treating these patients can be very rewarding. The authors provide a checklist intended to facilitate the management of refractory patients.

Nefazodone for chronic daily headache prophylaxis: an open-label study.

OBJECTIVE: To assess effectiveness, tolerability, and safety of nefazodone as a prophylactic agent for chronic daily headache. BACKGROUND: Nefazodone is a potent, selective 5-HT2 antagonist with a distinct and atypical mechanism of action. The evolution of intermittent migraine to chronic daily headache has been linked to up-regulation of 5-HT2 receptors as well as other factors. Other effective migraine prophylactic medications are also 5-HT2 antagonists. Although research has shown nefazodone to be an effective antidepressant with a good tolerability and safety profile, its potential role in headache prophylaxis has not been tested. DESIGN: This was a two-center, open-label study with a 4-week baseline, followed by 12 weeks of treatment with nefazodone at a median dose of 300 mg (mean, 303.66 +/- 65.57 mg; range, 100 to 450 mg depending on tolerability). Potential patients were required to report more than 15 days of headache per month for at least 3 months prior to screening. Only patients with at least 15 days of recorded headache during baseline were included in the final sample (N=52). Most patients (n=48) had a history of migraine based on International Headache Society criteria; 4 had primarily chronic tension-type headache, but with more migrainous features than permitted by International Headache Society criteria for a primary chronic tension-type headache diagnosis. RESULTS: Significant improvement was demonstrated for all headache diary measures, with significance levels ranging from P<.00001 for average intensity, duration, headache index (intensity x duration), peak intensity, headache days per week, and peak impairment, to P<.0033 for severe headache days per week, and P<.0051 for rescue medication days. During the last month of treatment, 71% of the patients completing the study showed at least a 50% reduction in headache index compared to baseline, and 59% had at least a 75% improvement. Visual analog scales completed at 4-week intervals showed significant improvement in patient ratings of overall headache status, quality of life, sleep, mood (P<.00001), and sexual function (P<.00053). Significant improvements were also observed in the Pain Disability Index (P<.00007), Beck Depression Inventory-II (P<.00001), Hamilton Rating Scale for Depression (P<.0008), and Hamilton Psychiatric Rating Scale for Anxiety (P<.00007). Headache indices for patients in the top quartile on the depression and anxiety scales (clinical depression/anxiety) did not differ from the other patients during baseline. However, patients who were depressed or anxious showed significantly more improvement over the course of 12 weeks of treatment (P<.0006 or less for the depression scales, P<.026 for anxiety). Common mild to moderate adverse events reported by 10% or more of the patients included fatigue, nausea, dry mouth, dizziness, sleep disturbance, blurred vision, irritability/nervousness, and sedation. Only 5 of the 52 patients discontinued the study due to adverse events: headache (2 patients), and nausea, sleep disturbance, and a drugged feeling (1 patient each). CONCLUSIONS: These results provide preliminary support for the efficacy of nefazodone in the prophylaxis of chronic daily headache. In this sample, nefazodone was safe and generally well tolerated. Patient ratings of sexual function improved over the course of treatment, in contrast to what is generally observed with most antidepressants. Nefazodone may be particularly beneficial for patients with chronic daily headache and comorbid depression. Further research is indicated.

An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache.

OBJECTIVE: To assess effectiveness and safety of tizanidine hydrochloride tablets for the prophylaxis of chronic daily headache. BACKGROUND: Tizanidine hydrochloride is an alpha2-adrenergic agonist that inhibits the release and effectiveness of norepinephrine at both central sites (eg, the locus ceruleus) and the spinal cord. It acts as a central muscle relaxant and has antinociceptive effects. Preliminary research and retrospective analyses have suggested efficacy in treatment of both chronic tension-type headache and chronic daily headache with migrainous features. DESIGN: Thirty-nine patients with more than 15 headache days per month (33 with migraine, 5 migrainous, 1 chronic tension-type) completed a 4-week baseline, with 31 completing a planned 12 weeks of treatment with tizanidine. Dosing was titrated from 2 mg at bedtime to a median daily dose of 14 mg (mean, 13.5; SD, 4.3; range, 4 to 20, divided over three doses per day) by treatment week 4. RESULTS: The overall headache index through week 12 (headache frequency x average intensity x duration) declined significantly (P<.00000002), with a corresponding increase in mean percentage improvement from 49% for weeks 1 through 4, to 65% for weeks 5 through 8, and 64% for weeks 9 through 12 (P<.0182). During weeks 9 through 12, 67% had improved more than 50% compared to baseline. Overall headache frequency declined from 22.83 to 15.83 days per month (P<.00001), with frequency of severe headaches dropping from 7.52 to 3.58 days per month (P<.000035). Average headache intensity dropped from 1.83 to 1.07 (1-to-5 scale), peak intensity declined from 2.37 to 1.40, and mean duration was reduced from 6.96 to 4.00 hours per headache (P<.00001). Improvement also occurred on visual analog scales of overall headache status, mood, sleep, quality of life (P<.00001), and sexual function (P<.0075); as well as the Beck Depression Inventory-II (P<.00073). Mild-to-moderate adverse events reported by more than 10% of the patients included somnolence, asthenia, and dry mouth. Only 3 patients discontinued treatment due to adverse events: somnolence and dry mouth alone (n = 1), or in combination with either hyperkinesis (n = 1) or constipation (n = 1). One patient had elevated liver enzymes that returned to normal after the drug was discontinued. CONCLUSIONS: The results provide preliminary support for the efficacy, safety, and tolerability of tizanidine in the prophylaxis of chronic daily headache.

Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine.

OBJECTIVE: To compare the safety and efficacy of isometheptene mucate, dichloralphenazone with acetaminophen to sumatriptan succinate for the treatment of mild-to-moderate migraine, with or without aura, when taken at the first sign of an attack. BACKGROUND: The Food and Drug Administration approved sumatriptan succinate and the combination of isometheptene mucate, dichloralphenazone with acetaminophen for the treatment of migraine. As part of the stratified treatment of migraine, those patients whose headaches are mild or moderate may benefit from nontriptan medications. Additionally, early treatment of acute migraine before the headache has become moderate or severe may improve response to treatment. METHODS: This was a multicenter, double-blind, randomized, parallel-group study to assess the safety and efficacy of the combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the early stages of a single migraine attack. Patients diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria were enrolled. RESULTS: One hundred thirty-seven patients were enrolled in the study. Data for efficacy were available for 126 patients; safety data were available for 128 patients. No statistically significant difference between the two active agents in the patient's response to treatment was demonstrated. Headache recurrence was not significantly different over the 24-hour evaluation period for those patients responding in the first 4 hours. In those with headache recurrence, it was statistically significantly more severe in those patients treated with sumatriptan succinate. Improvement in functional disability was, in general, better among those treated with isometheptene mucate, dichloralphenazone with acetaminophen. Global analysis of efficacy was similar in the two active groups. Patients treated with sumatriptan succinate were somewhat more likely to have adverse effects than the isometheptene mucate, dichloralphenazone with acetaminophen group. CONCLUSIONS: Both isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate are safe and effective when used early in the treatment of an acute migraine. Several parameters suggest that isometheptene mucate, dichloralphenazone with acetaminophen may have a slight advantage compared with sumatriptan succinate in the early treatment of mild-to-moderate migraine.

Geriatric headache. How to make the diagnosis and manage the pain.

Approximately 10% of women and 5% of men at age 70 experience severe recurrent or constant headaches. Severe headache presenting for the first time in a patient over age 50 is unusual and requires a thorough medical and neurologic examination. Primary headache etiologies in older patients include migraine, tension-type, cluster, and the rare hypnic headache. For all of these, effective pain control includes pharmacologic and nonpharmacologic interventions. Secondary etiologies include temporal arteritis, medication-induced headache, cerebrovascular or cardiac ischemia, and intracranial hemorrhage or tumors. Head pain may also be cervicogenic or related to glaucoma or sleep apnea. In secondary cases, pain management is specific to treatment of the underlying structural or systemic disease.

Intranasal civamide for the acute treatment of migraine headache.

The objective of this study was to investigate the safety and efficacy of intranasal civamide for the acute treatment of migraine headache with or without aura. Civamide is a vanilloid receptor agonist and neuronal calcium channel blocker that inhibits the neuronal release of excitatory neurotransmitters (e.g. calcitonin gene-related peptide (CGRP) and substance P (SP)) and depletes the neurones of the trigeminal plexus of their neurotransmitter content. Applied intranasally, the release of neurotransmitters to meningeal and dural blood vessels should be decreased, along with the resultant vasodilatation, plasma extravasation, and histamine/serotonin release. Subsequent migraine headache pain may also be diminished. Thirty-four patients were enrolled into a double-blind study of intranasal civamide, and randomized to receive a single dose of either 20 microg or 150 microg of civamide, for the treatment of a single migraine headache, with or without aura, of moderate to severe pain. At 2 h post-dose, 55.6% of patients treated with either dose had a decrease in pain severity, with 22.2% of patients being pain-free. At 4 h post-dose, 72.7% of patients treated with either dose had a decrease in pain severity, with 33.0% of patients being pain-free. Adverse events were similar for both dosages, with 91.2% of patients experiencing nasal burning and 44.1% of patients experiencing lacrimation. No systemic side-effects were observed. Based upon the results of this study, intranasal civamide may be effective in the acute treatment of migraine headache. Given civamide's proposed mechanism of action, intranasal civamide should be substantially more effective for prophylaxis than acute treatment of migraine. A study evaluating its efficacy in prophylaxis of migraine is currently planned.

The use of rizatriptan in the treatment of acute, multiple migraine attacks.

Therapy for migraine can be classified as preventive or acute. Preventive therapy is intended to reduce the frequency of headache, whereas the goal of acute migraine therapy is to optimize the patient's ability to function by reversing, aborting, or reducing pain and migraine-associated symptoms. Rizatriptan is a new, selective 5-HT1B/1D receptor agonist that is effective for treatment of migraine. Clinical studies of this drug have demonstrated its efficacy, safety, and tolerability when used as therapy for acute attacks on multiple occasions.

Behavioral self-management in an inpatient headache treatment unit: increasing adherence and relationship to changes in affective distress.

OBJECTIVE: To evaluate prospectively the contribution of a psychological self-management program to the amelioration of headache-related distress of patients with intractable migraine treated in a comprehensive, multidisciplinary, inpatient program. BACKGROUND: Previous research has shown the effectiveness of this overall inpatient program but did not examine the relationships between the use of relaxation and other headache-related behavioral factors. METHODS: Data from 221 admissions to a Commission on Accreditation of Rehabilitation Facilities-accredited, nationally recognized, inpatient treatment unit were analyzed for the current study. On admission and on discharge (average length of stay, 12.9 days), subjects completed a 7-day retrospective, self-report questionnaire assessing health behavior compliance and emotional factors. The intervention consisted of intensive medical therapy in addition to cognitive-behavioral treatment delivered in a group setting. RESULTS: Adherence increased significantly for relaxation practice and life-style modifications of diet, exercise, and sleep regulation for headache prevention (P<.00001). Beck Depression Inventory scores decreased significantly (P<.00001), and a greater decrease in depression by the end of the program was reported by subjects who practiced relaxation most compared with those who practiced relaxation least. CONCLUSIONS: Low baseline adherence rates for health behavior increased significantly during the final week of inpatient treatment. Behavioral self-management variables, not headache reduction, were significantly associated with patients' reduction in affective distress.

Headache disorders.

Head, neck, and facial pain disorders possess characteristic features that, in some ways, distinguish them from other painful disorders. Generally speaking, the headache disorders can be reconciled within the same model of assessment as that of other painful conditions.

Medicolegal issues: headache.

This article addresses headache-related topics in which medicolegal issues have occurred or in which they are likely to occur. Where possible, an actual case has been presented. Most sections of this article are divided into three parts: principle of care, case history, and discussion and recommendations. When appropriate, American Academy of Neurology guidelines have been noted.

Headache level during neuropsychological testing and test performance in patients with chronic posttraumatic headache.

This study addresses (1) the relationship between headache presence/intensity at time of testing and neurocognitive performance, and (2) the probability that testing triggers or intensifies pain. Subjects were 125 patients with chronic posttraumatic headache (mean = 2.67 years post injury) who completed a 4-hour test battery emphasizing memory. Comparisons of 34 individual tests/subtests and the five Wechsler Memory Scale-Revised (WMS-R) indices of relative memory impairment for 73 patients with no headache or mild headache versus 52 patients with moderate to severe pain revealed no significant differences. Testing intensified existing headaches for 55% but triggered headache for only 1 of 20 (5%; P =.00003). Results support the validity of neuropsychological test performance regardless of pain level, although testing can be painful.

Comprehensive/tertiary care for headache: a 6-month outcome study.

OBJECTIVE: To assess programwide (outpatient plus inpatient) outcome using prospective measures for the first 6 months of treatment at a comprehensive headache center. Background.-There is little published data on the overall programwide efficacy of comprehensive, multidisciplinary treatment centers for severe, refractory headache disorders. METHODS: For 1 week each month over a 2-year period, all new patients completed an initial questionnaire noting frequency/severity of headaches and other headache-relevant measures. A follow-up version mailed at 6 months was returned by 218 of 421 patients (response rate 52%). Sixteen percent were treated both in and out of the hospital, with 84% treated as outpatients only. Patients had a mean of 2.50 medical visits after the initial evaluation, and 43% met with a psychologist. RESULTS: Mean headache frequency dropped from 5.30 to 3.45 days per week (P<.00001), with severe headaches declining from 2.31 to 1.33 days per week (P<.00001). Sixty-seven percent of the patients had at least a 50% reduction in headaches, with a mean percentage improvement per patient in severe headaches of 56% (median 67%). Emergent care visits within 6 months dropped from 4.39 to 1.67 (P<.00001). Days with significant headache-related work impairment declined from 2.04 to 0.67 days per week (P<.00001), a net annualized reduction of 71.24 impaired workdays per year per patient. For full-time workers, missed work days in 6 months dropped from 5.46 to 2.68 (P<.00261). The mean percentage improvement for headache-impaired workdays was 67% (median 88%), and for work absence was 63% (median 100%). Total days incapacitated per week dropped from 1.72 to 0.89 (P<.00001), with a mean percentage improvement of 67% (median 91%). Significant treatment satisfaction was reported by 89%. A weighted Goal Attainment Scale based on the percentage of patients showing significant improvement in pain control, functioning, work performance, reliance on emergent care, depression, and satisfaction revealed an overall Goal Attainment score of 72%. CONCLUSIONS: Despite a mean of only 3.50 medical visits in a population of complex patients, significant improvement was demonstrated in several key economically relevant variables within 6 months of referral. If maintained over the long term, the results support the concept that matching intensity of treatment (comprehensive/tertiary care) to severity of illness (complex/refractory cases) is cost-effective.

Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study.

Lanepitant is a high-affinity, selective neurokinin-1 receptor (NK-1) and is effective in the dural inflammation model of acute migraine. Lanepitant 30, 80, and 240 mg given orally was evaluated in a double-blind, placebo-controlled crossover study to determine its effect in reducing migraine pain and severity of associated symptoms. Outpatients treated four migraine headaches of moderate or severe pain intensity with study drug according to a randomization schedule. They recorded their pain intensity and severity of migraine-associated symptoms at 30, 60, 90, and 120 min. Although 53 patients were randomly allocated to a treatment sequence, only 40 patients completed all treatments. There was no statistically significant difference in improvement in migraine pain at any time for any of the treatments. Additionally, there was no change in severity of migraine-associated symptoms associated with lanepitant therapy. No adverse events could be attributed to lanepitant. Lanepitant was ineffective orally in treating acute migraine in this trial. This may be due to poor bioavailability during a migraine attack. Alternatively, the neurogenic inflammation hypothesis may not apply to migraine.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group.

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.