Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial.

AIM: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. METHODS: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. RESULTS: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, -0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. CONCLUSIONS: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.Trial Registration: ClinicalTrials.gov (NCT03716505).

Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1).

OBJECTIVE: To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of episodic migraine. METHODS: The PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy-1 (PROMISE-1) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with episodic migraine were randomized to eptinezumab 30 mg, 100 mg, 300 mg, or placebo for up to four intravenous (IV) doses administered every 12 weeks. The primary endpoint was change from baseline in monthly migraine days (MMDs) over weeks 1-12. RESULTS: A total of 888 patients received treatment across 84 study sites. Mean MMDs at baseline was ∼8.6 across treatment groups. Eptinezumab 100 mg and 300 mg met the primary endpoint, significantly reducing MMDs across weeks 1-12 compared with placebo (30 mg, -4.0; 100 mg, -3.9, p = 0.0182; 300 mg, -4.3; placebo, -3.2, p = 0.0001). Treatment-emergent adverse events were reported by 58.4% (30 mg), 63.2% (100 mg), 57.6% (300 mg), and 59.5% (placebo) of patients. Treatment-emergent adverse events reported by ≥2% of eptinezumab-treated patients at an incidence greater than placebo included: upper respiratory tract infection (30 mg, 11.4%; 100 mg, 9.9%; 300 mg, 10.3%; placebo, 7.2%), and fatigue (30 mg, 2.3%; 100 mg, 3.6%; 300 mg, 3.6%; placebo, <1%). CONCLUSION: Eptinezumab (100 mg or 300 mg) significantly reduced migraine frequency, was well tolerated, and had an acceptable safety profile when used for the preventive treatment of migraine in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.

Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study.

Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here. Methods Patients aged 18-65 years with episodic migraine were evaluated in this multicenter, double-blind, randomized study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks, followed by a post-treatment off-drug period lasting 12 weeks. Results Treatment-emergent adverse events (TEAEs) were primarily rated as mild to moderate. Serious adverse events reported in galcanezumab dose groups were appendicitis, Crohn's disease, suicidal ideation, and congenital ankyloglossia in an infant of a paternal pregnancy; each of these were reported by one patient. Adverse events leading to discontinuation with galcanezumab treatment were abdominal pain, visual impairment, and upper limb fracture, each reported by one patient. Treatment-emergent injection-site reactions were reported significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with placebo (5.8%). Injection-site pain was the most common injection-site reaction (galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection (galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%; placebo 2.2%) also occurred more frequently with galcanezumab treatment. Potential hypersensitivity events were reported at similar frequencies in galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent anti-drug antibodies in galcanezumab dose groups (4.6% of patients during treatment period) did not appear to have any meaningful effects on safety, the pharmacokinetics of galcanezumab, or its ability to bind to the target ligand. Conclusion The results from this 3-month Phase 2b study support the initiation of larger Phase 3 trials of longer duration.

Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. BACKGROUND: Migraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. METHODS: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. RESULTS: Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9 ± 0.6 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI = -0.9 to -4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. CONCLUSION: The TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study.

OBJECTIVE: To evaluate non-invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment. BACKGROUND: Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments. METHODS: One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. RESULTS: The intent-to-treat population comprised 133 subjects: 60 nVNS-treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. CONCLUSIONS: In one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well-tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360(®) as acute treatment for chronic migraine.

OBJECTIVE: To determine if repetitive sphenopalatine ganglion (SPG) blocks with 0.5% bupivacaine delivered through the Tx360(®) are superior in reducing pain associated with chronic migraine (CM) compared with saline. BACKGROUND: The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa (PPF) in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. From an anatomical and physiological perspective, SPG blockade may be an effective acute and preventative treatment for CM. METHOD: This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition. They were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5% bupivacaine or saline, respectively. The primary end-point was to compare numeric rating scale scores at pretreatment baseline vs 15 minutes, 30 minutes, and 24 hours postprocedure for all 12 treatments. SPG blockade was accomplished with the Tx360(®) , which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space. A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG. The procedure is performed similarly in each nostril. The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5% bupivacaine or saline provided 2 times per week for 6 weeks. Subjects were re-evaluated at 1 and 6 months postfinal procedure. RESULTS: The final dataset included 38 subjects, 26 in the bupivacaine group and 12 in the saline group. A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M=3.78 vs M=3.18, P=.10), 15 minutes (M=3.51 vs M=2.53, P<.001), 30 minutes (M=3.45 vs M=2.41, P<.001), and 24 hours after treatment (M=4.20 vs M=2.85, P<.001), respectively. Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = -4.52, P=.005), whereas no significant change was seen in the saline group (Mdiff = -1.50, P=.13). CONCLUSION: SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360(®) device demonstrates promise as an acute treatment of headache in some subjects with CM. Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline. The Tx360(®) device was simple to use and not associated with any significant or lasting adverse events. Further research on sphenopalatine ganglion blockade is warranted.

Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine.

BACKGROUND: This study aims to determine if repetitive sphenopalatine ganglion (SPG) blockades with 0.5% bupivacaine delivered with the Tx360 device results in long-term improvement in chronic migraine (CM). The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. In a previous article, these authors reported repetitive SPG blockades with 0.5% bupivacaine delivered by the Tx360 device, which was an effective and well-tolerated intervention to incrementally decrease baseline headache intensity of subjects with CM. METHODS: This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. A total of 41 subjects were enrolled at two headache specialty clinics in the USA. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by International Classification of Headache Disorders-II definition. Subjects were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists 2:1 to receive 0.3 cc of 0.5% bupivacaine or saline, respectively, delivered with the Tx360 twice a week for 6 weeks. Secondary end-points reported in this manuscript include post-treatment measures including number of headache days and quality of life measures. RESULTS: The final data set included 38 subjects: 26 in the bupivacaine group and 12 in the saline group. Our primary end-point for the study, difference in numeric pain rating scale scores, was met and reported in a previous article. The supplemental secondary end-points reported in this manuscript did not reach statistical significance. When looking collectively at these end-points, trends were noticed and worthy of reporting. Subjects receiving bupivacaine reported a decrease in the number of headache days 1 month post-treatment (Mdiff = -5.71), whereas those receiving saline only saw a slight improvement (Mdiff = -1.93). Headache Impact Test 6 scores were decreased in the bupivacaine group at 1 month (Mdiff = -5.13) and 6 months (Mdiff = -4.78) post-treatment, but only a modest reduction was seen for those receiving saline at 1 and 6 months, respectively (Mdiff = -2.08, Mdiff = -1.58). Furthermore, subjects receiving bupivacaine reported a reduction in acute medication usage and improved quality of life measures (average pain in the previous 24 hours, mood, normal work, and general activity) up to 6 months post-treatment. The changes in these measures for the saline group were minimal. CONCLUSIONS: Data from this exploratory pilot study suggest that there may be long-term clinical benefits with the use of repetitive SPG blockades with bupivacaine delivered with the simple to use Tx360 device. These include a sustained reduction of headache days and improvement in several important quality of life assessments. The SPG blockades were not associated with any significant or lasting adverse events. Further research on SPG blockade is warranted.

Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study.

BACKGROUND: Chronic migraine (CM) is a debilitating neurological disorder with few treatment options. Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients. METHODS: In this randomized, controlled multicenter study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation. The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a ≥50% reduction in mean daily visual analog scale scores) in each group at 12 weeks. RESULTS: There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of -0.06; p = 0.55). However, there was a significant difference in the percentage of patients that achieved a 30% reduction (p = 0.01). Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001). The most common adverse event was persistent implant site pain. CONCLUSION: Although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability. Additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need. TRIAL REGISTRATION: Clinical trials.gov (NCT00615342).

Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study.

BACKGROUND: Medically intractable chronic migraine (CM) is a disabling illness characterized by headache ≥15 days per month. METHODS: A multicenter, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM. Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups. RESULTS: Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66. A responder was defined as a subject who achieved a 50% or greater reduction in number of headache days per month or a three-point or greater reduction in average overall pain intensity compared with baseline. Three-month responder rates were 39% for AS, 6% for PS and 0% for MM. No unanticipated adverse device events occurred. Lead migration occurred in 12 of 51 (24%) subjects. CONCLUSION: The results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.

Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT).

OBJECTIVE: This study assessed the efficacy of diclofenac potassium for oral solution, a novel water-soluble buffered powder formulation, versus placebo for the acute treatment of migraine. Diclofenac potassium for oral solution has a time to maximum plasma concentration (Tmax) of 15 minutes, suggesting the potential for a rapid onset of therapeutic effects. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study conducted in 23 US centers. Adult sufferers with an established migraine diagnosis according to the International Classification of Headache Disorders, second edition (ICHD-II), treated one moderate or severe attack with 50 mg diclofenac potassium for oral solution (dissolved in approximately 2 ounces of water; N=343) or matching placebo (N=347). Four co-primary endpoints included the percentage of subjects who at two hours post-treatment reported no headache pain, no nausea, no photophobia and/or no phonophobia. RESULTS: Significantly more subjects treated with diclofenac potassium for oral solution (N=343) achieved a two-hour pain-free response (25% vs. 10%, p<.001), no nausea (65% vs. 53%; p=.002), no photophobia (41% vs. 27%; p<.001) and no phonophobia (44% vs. 27%; p<.001) compared to placebo. Pain intensity differences between treatments were significantly lower in the diclofenac potassium oral solution group, starting at 30 minutes post-treatment (p=.013) with significant differences at all time points thereafter (p<.001). Twenty-four-hour sustained pain-free response favored diclofenac potassium oral solution treatment versus placebo (19% vs. 7%, p<.0001). The most common adverse event considered to be treatment related was nausea (diclofenac potassium for oral solution [4.6%]; placebo [4.3%]). CONCLUSIONS: This study shows that this formulation of diclofenac potassium for oral solution is effective in reducing pain intensity within 30 minutes, which may be related to the 15-minute T(max) associated with this formulation. The rapid-onset benefits were sustained through 24 hours post-treatment.

Randomized, controlled trial of telcagepant over four migraine attacks.

METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as ≥ 3 successes, and lack of consistent efficacy was defined as ≥ 2 failures, in treatment response. A total of 1677 patients treated ≥ 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence ≥ 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704).

A practice guide for continuous opioid therapy for refractory daily headache: patient selection, physician requirements, and treatment monitoring.

OBJECTIVES: To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience. BACKGROUND: There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring. METHODS: A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society. RESULTS: The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders. CONCLUSIONS: Only a select and very limited group (estimate of 10-20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.

Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs.

OBJECTIVE: The primary objective of this study was to compare the efficacy and tolerability of topiramate and amitriptyline in the prophylaxis of episodic migraine headache. METHODS: This was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority study. Adults with 3 to 12 migraines per month were randomized in a 1:1 ratio to receive an initial dose of 25 mg/d of either topiramate or amitriptyline, subsequently titrated to a maximum of 100 mg/d (or the maximum tolerated dose). The primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. Secondary efficacy variables included changes from the prospective baseline phase to the end of the double-blind phase in the mean monthly (28-day) rate of days with migraine, mean monthly rate of days with headache (migraine and nonmigraine), mean monthly rate of acute abortive medication use, mean monthly migraine duration, and mean monthly migraine severity. Additional secondary efficacy variables included changes in the mean monthly severity of migraine-associated symptoms (photophobia, phonophobia, and nausea), change in the mean monthly frequency f migraine-associated vomiting, and response rates (based on monthly migraine days and total headache days). The Migraine-Specific Quality of Life Questionnaire (MSQ) and the Weight Satisfaction Scale Questionnaire, which measures subjective satisfaction with current weight, were administered. Treatment-emergent adverse events (TEAEs) were monitored through the end of double-blind treatment. RESULTS: The intent-to-treat population included 331 subjects (172 topiramate, 159 amitriptyline; 84.9% female; 84.6% white; mean [SD] age, 38.8 [11.0] years; mean weight, 77.1 [20.1] kg) who provided at least 1 efficacy assessment. The least squares mean (LSM) change from baseline in the mean monthly number of migraine episodes was not significantly different between the topiramate and amitriptyline groups (-2.6 and -2.7, respectively; 95% CI, -0.6 to 0.7). There were no significant differences between treatment groups in any of the prespecified secondary outcome measures. Subjects receiving topiramate had a significantly greater improvement in mean functional disability scores during migraine attacks compared with amitriptyline (LSM change: -0.33 vs -0.19; 95% CI, -0.3 to 0.0; P = 0.040) and in the role function-restrictive, role function-preventive, and emotional function domains of the MSQ (P = 0.012, P = 0.014, and P = 0.029, respectively). Subjects receiving topiramate had a mean weight loss of 2.4 kg, compared with a mean weight gain of 2.4 kg in subjects receiving amitriptyline. Subjects in the topiramate group reported an overall improvement from baseline in weight satisfaction, whereas the amitriptyline group reported an overall deterioration in weight satisfaction (P < 0.001, topiramate vs amitriptyline). TEAEs of mild or moderate severity were reported in 118 subjects (66.7%) in the topiramate group and 112 subjects (66.3%) in the amitriptyline group. Among the most common TEAEs (reported in +/-5% of subjects during the double-blind phase) in the topiramate group were paresthesia (29.9%), fatigue (16.9%), somnolence (11.9%), hypoesthesia (10.7%), and nausea (10.2%). The most commonly reported TEAEs in the amitriptyline group were dry mouth (35.5%), fatigue (24.3%), somnolence (17.8%), weight increase (13.6%), dizziness (10.7%), and sinusitis (10.7%). CONCLUSIONS: In this noninferiority study, topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy end points. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction.

Comprehensive inpatient treatment of refractory chronic daily headache.

OBJECTIVE: (1) To assess outcome at discharge for a consecutive series of admissions to a comprehensive, multidisciplinary inpatient headache unit; (2) To identify outcome predictors. BACKGROUND: An evidence-based assessment (2004) concluded that many refractory headache patients appear to benefit from inpatient treatment, underscoring the need for more research, including outcome predictors. METHODS: The authors completed a retrospective chart review of 283 consecutive admissions over 6 months. The inpatient program (mean length of stay = 13.0 days) included intravenous and oral medication protocols, drug withdrawal when indicated, cognitive-behavior therapy, and other services when needed, including anesthesiological intervention. Patient-reported pain levels and consensus of medical staff determined outcome status. RESULTS: The 267 completers (94%) included 212 women and 55 men (mean age = 40.3 years, range = 13-74) from 43 states and Canada. The modal diagnosis was intractable, chronic daily headache (85%), predominantly migraine. Most (59%) had medication overuse headache (MOH), involving opioids (48%), triptans (16%), or butalbital-containing analgesics (10%). Psychiatric diagnoses included stress-related headache (82%), mood disorders (70%), anxiety disorders (49%), and personality disorders (PD, 26%). More patients with a PD (62%) had opioid-related MOH than those with no PD (38%), P < .005. Of the completers, 78% had moderate to significant pain reduction, with comparable improvement in mood, function, and behavior. Clinical factors predicting moderate-significant headache improvement were limited to MOH (84% vs 69%, P < .007) and presence of a PD (68% vs 81%, P < .03). CONCLUSIONS: Most patients (78%) improved following aggressive, comprehensive inpatient treatment. Maintenance of improvement is likely to depend on multiple post-discharge factors, including continuity of care, compliance, and home or work environment.

Pearls from an inpatient headache unit.

Much can be learned from treating over 15,000 headache hospitalized patients over the course of 30 years. By the very need to be admitted, these individuals are complicated, both physiologically and often psychologically. Founded in 1978, the Michigan Head Pain and Neurological Institute and its hospital unit developed a set of criteria for admission and a growing staff of professionals to serve this complex population of patients. Experience has taught us many lessons; several are considered in this review. Among the important topics discussed are: admission criteria to the hospital unit; treatment protocols and other hospital-based strategies; integration of behavioral therapy and therapists into the treatment system; diagnostic testing of patients with intractable headache; identifying the "problem patient" and "medication misuse" early in the course of therapy; approaching the headache patient with cluster B personality disorder; and the use of interventional and anesthesiological treatment for intractable headache. Outcome data and a review of recent publications are presented.

Fifty years of headache care evolution: from a few interested doctors to certified specialists and comprehensive systems.

Headache care has evolved dramatically during the lifetime of the American Headache Society. Dr. Saper charts the most important developments and recognizes those instrumental in influencing current thought and practice.

Continuous opioid therapy (COT) is rarely advisable for refractory chronic daily headache: limited efficacy, risks, and proposed guidelines.

Intractable pain, headache or otherwise, is a devastating and life-controlling experience. The need to effectively and aggressively control pain is a fundamental tenet of clinical care. In the past several years, increasing advocacy for continuous opioid therapy has become an important, if not controversial, theme in the development of treatment guidelines and teaching programs. Ironically, the increasing willingness of physicians to prescribe scheduled opioids for their headache and pain patients has occurred in the absence of compelling data demonstrating efficacy or long-term safety. To the contrary, two meta-analyses on chronic noncancer pain (CNCP) and one long-term uncontrolled study on headache patients demonstrate a relatively small number of patients benefiting from the treatment. Recent neuroscience data on the effects of opioids on the brain raise serious concern for long-term safety and also provide the basis for the mechanism by which chronic opioid use might induce progression of headache frequency and severity. Significant adverse effects, including influence on sexual hormonal balances, physical and psychological dependence, the development of opioid-induced hyperalgesia, and cardiac arrhythmia and sudden death that can be seen with standard dosages of methadone, make a strong argument against widespread use of continuous opioid therapy (COT) in otherwise healthy young and middle-aged headache patients. We believe that COT should be used in rare circumstances for chronic headache patients, and propose initial guidelines for selecting patients and monitoring treatment. The physician should be well versed in the details of opioid prescribing, administration, and monitoring, and should be prepared to discontinue opioids when clinical justification, patient behavior, or failure to achieve therapeutic goals make discontinuance necessary.

Trendelenburg position: a tool to screen for the presence of a low CSF pressure syndrome in daily headache patients.

OBJECTIVE: To test the hypothesis that the Trendelenburg position is an accurate screening investigation for the presence of a low cerebrospinal fluid (CSF) pressure syndrome in patients with daily headache. BACKGROUND: The Trendelenburg position causes a rapid increase in intracranial CSF pressure. In a patient with a known CSF leak who overtime had less improvement in the supine position, being placed in Trendelenburg rapidly alleviated her daily headache. This suggested that the Trendelenburg position might be a good screening tool for low CSF pressure syndromes. METHODS: Case reports. All patients were placed in the Trendelenburg position (10 degrees -20 degrees head-down tilt) for 5 minutes. A patient was considered to have a positive Trendelenburg test if they experienced complete pain freedom or substantial improvement in baseline head pain in the Trendelenburg position. RESULTS: Case patients are presented for 3 clinical scenarios: Scenario 1: Daily headache with or without a positional component with a positive response to the Trendelenburg position and subsequent evidence of an underlying low CSF pressure syndrome. Scenario 2: Daily headache with a strong positional component but no improvement in the Trendelenburg position and a negative evaluation for a low CSF pressure syndrome. Scenario 3: Trendelenburg position proves the existence of a post-lumbar puncture headache in patients with near-daily headaches. CONCLUSION: The Trendelenburg position appears potentially useful as a clinical tool to screen for the presence of a low CSF pressure syndrome in patients with daily headache.