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

BACKGROUND: Recent studies evaluated short-term efficacy and safety of peripheral nerve stimulation (PNS) of the occipital nerves for managing chronic migraine. We present 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial. METHODS: In this institutional review board-approved, randomized, multicenter, double-blinded study, patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, migraine disability assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction and adverse events. Statistical tests assessed change from baseline to 52 weeks using paired t-tests. Intent-to-treat (ITT) analyses of all patients (N = 157) and analyses of only patients who met criteria for intractable chronic migraine (ICM; N = 125) were performed. RESULTS: Headache days were significantly reduced by 6.7 (±8.4) days in the ITT population (p < 0.001) and by 7.7 (±8.7) days in the ICM population (p < 0.001). The percentages of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity were 59.5% and 47.8%, respectively. MIDAS and Zung PAD scores were significantly reduced for both populations. Excellent or good headache relief was reported by 65.4% of the ITT population and 67.9% of the ICM population. More than half the patients in both cohorts were satisfied with the headache relief provided by the device. A total of 183 device/procedure-related adverse events occurred during the study, of which 18 (8.6%) required hospitalization and 85 (40.7%) required surgical intervention; 70% of patients experienced an adverse event. CONCLUSION: Our results support the 12-month efficacy of PNS of the occipital nerves for headache pain and disability associated with chronic migraine. More emphasis on adverse event mitigation is needed in future research. TRIAL REGISTRATION: Clinical trials.gov (NCT00615342).

Results of a multicenter, double-blind, randomized, parallel-group, placebo-controlled, single-dose study comparing the fixed combination of acetaminophen, acetylsalicylic acid, and caffeine with ibuprofen for acute treatment of patients with severe migraine.

INTRODUCTION: In a multicenter, double-blind, randomized, parallel-group, placebo-controlled, single-dose study (n = 1555), a fixed combination of acetaminophen 500 mg, acetylsalicylic acid 500 mg, and caffeine 130 mg (AAC) was compared with ibuprofen 400 mg (IB) and placebo (PLA) for acute treatment of migraine. SUBJECTS AND METHODS: An exploratory post-hoc analysis compared AAC with IB and PLA in the subset of patients with severe pain at baseline (n = 660). RESULTS: At most time points, AAC and IB relieved the pain and associated symptoms of severe migraine significantly better than PLA (p ≤ 0.05). AAC was significantly superior to IB for pain relief at 45 minutes and at one, two, three, and four hours postdose (p < 0.04); pain intensity difference from one hour through three hours (p < 0.05); headache response at two hours (p = 0.04); functional disability reduced to little or none at three hours (p = 0.013); freedom from phonophobia at three hours (p = 0.04) and photophobia at 15 minutes postdose (p = 0.03); and use of rescue medication (p = 0.018). AAC patients also reported meaningful pain relief 16 minutes faster than IB patients (132 minutes vs 148 minutes, p = 0.026). CONCLUSIONS: In patients with severe baseline migraine pain, AAC and IB are significantly more effective than PLA, and AAC provides significantly faster and more effective pain relief than IB.

Sumatriptan/naproxen sodium for the acute treatment of probable migraine without aura: a randomized study.

OBJECTIVE: Probable migraine is a common, disabling migraine subtype fulfilling all but one of the diagnostic criteria for migraine. This study was conducted to evaluate the efficacy and tolerability of sumatriptan/naproxen sodium for the acute treatment of probable migraine without aura. METHODS: Patients treated a headache of probable migraine without aura when pain was moderate or severe with sumatriptan/naproxen sodium ( N = 222 intent-to-treat (ITT)) or placebo ( N = 221 ITT/complete case analysis (a) ) in this randomized, double-blind, parallel-group study. RESULTS: Sumatriptan/naproxen sodium was more effective than placebo with respect to the co-primary efficacy endpoints two-hour pain-free response (29% sumatriptan/naproxen sodium vs 11% placebo, P < 0.001) and two- to 24-hour sustained pain-free response (24% sumatriptan/naproxen sodium vs 9% placebo, P < 0.001). Sumatriptan/naproxen sodium was significantly more effective than placebo with respect to the secondary efficacy endpoints of pain-free response four hours postdose ( P < 0.001), pain-free response maintained one to two hours postdose ( P = 0.034) and two to four hours postdose ( P < 0.001), headache relief four hours postdose ( P < 0.001), headache relief maintained two to four hours postdose ( P = 0.015), sustained headache relief two through 24 hours postdose ( P = 0.002), and rescue medication use ( P < 0.001); but not productivity scores. The most common adverse events were dizziness (4% sumatriptan/naproxen sodium,<1% placebo), dry mouth (2% sumatriptan/naproxen sodium, <1% placebo), and nausea (2% sumatriptan/naproxen sodium, <1% placebo). CONCLUSION: Sumatriptan/naproxen sodium is effective in the acute treatment of probable migraine as demonstrated by higher rates of freedom from pain and restoration of function.

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).

Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system.

OBJECTIVE: To assess the long-term tolerability and efficacy of NP101, a novel transdermal sumatriptan patch being developed for the acute treatment of migraine. BACKGROUND: Nausea (with or without vomiting) and gastroparesis have been characterized as being among the most problematic challenges affecting migraine care today. Migraine-associated nausea can cause patients to delay or avoid taking oral medication with a resultant loss or reduction of therapeutic efficacy. Migraine-associated gastroparesis can impair absorption and reduce bioavailability of oral migraine medications and thereby reduce and delay therapeutic efficacy. The non-oral triptan formulations that have been used to overcome these challenges are associated with other shortcomings that can limit their use. Designed to overcome these shortcomings and treatment limitations imposed by gastrointestinal signs and symptoms, the NP101 patch avoids the need for oral administration, does not depend upon gastrointestinal absorption, and provides more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan and a lower maximum plasma concentration than sumatriptan injection. METHODS: Patients diagnosed with migraine who had participated in a randomized, double-blind, Phase III study of the NP101 patch were given the option to use NP101 to treat migraine episodes with moderate or severe headache pain for up to 12 months in this open-label trial. RESULTS: One hundred eighty-three patients applied 2089 study patches. The most common adverse events involved the patch application site (45% of patients). The only non-application-site adverse events reported in >2% of patients were nausea (n=6, 3.3%), upper respiratory tract infection (n=6, 3.3%), and nasopharyngitis (n=4, 2.2%). The incidence of triptan-associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12-month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief,78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. No evidence of waning tolerability or efficacy was observed over the 12-month study period. CONCLUSION: NP101, a transdermal sumatriptan formulation in development for the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.

A sumatriptan iontophoretic transdermal system for the acute treatment of migraine.

OBJECTIVE: Gastrointestinal symptoms, such as nausea and vomiting, occur almost universally at one time or another in patients during a migraine attack. One third of patients who experience migraine-related nausea report that this symptom interferes with their ability to take oral medications. The sumatriptan iontophoretic transdermal system (NuPathe Inc., Conshohocken, PA, USA) uses proprietary technology to circumvent the gastrointestinal tract while delivering triptan therapy. This phase III randomized, double-blind, placebo-controlled trial evaluated the efficacy and tolerability of this system for the acute treatment of migraine. METHODS: Patients were randomized to treat a single moderate-to-severe migraine attack with the sumatriptan iontophoretic transdermal system or placebo. The primary end point was the proportion of patients who were headache pain-free 2 hours after patch activation. Other end points included the proportions of patients who reported headache pain relief, and freedom from nausea, photophobia, and phonophobia; rescue medication use; and tolerability. RESULTS: Four hundred sixty-nine patients were treated. Significantly more patients treated with the sumatriptan iontophoretic transdermal system compared with placebo experienced freedom from headache pain, nausea, photophobia, and phonophobia 2 hours after patch activation, experienced rapid and sustained headache pain relief, and used less rescue medication. Treatment-emergent adverse events were reported by 50% and 44% of patients treated with the sumatriptan iontophoretic transdermal system and placebo, respectively. Most events were transient mild-to-moderate application-site reactions. CONCLUSIONS: The sumatriptan iontophoretic transdermal system is effective and well tolerated, and may be particularly useful in patients with migraine-related gastrointestinal symptoms such as nausea.

A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the treatment of migraine.

BACKGROUND: Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack. Some attacks require high-end therapy, while other attacks have treatment needs that are less immediate. While triptans are considered the "gold standard" of migraine therapy, they do have limitations and many patients are seeking other therapeutic alternatives. In 2005, an open-label study of feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase of the attack. METHODS/MATERIALS: In this multi-center pilot study, 60 patients treated 221 attacks of migraine with sublingual feverfew/ginger or placebo. All subjects met International Headache Society criteria for migraine with or without aura, experiencing 2-6 attacks of migraine per month within the previous 3 months. Subjects had <15 headache days per month and were not experiencing medication overuse headache. Inclusion required that subjects were able to identify a period of mild headache in at least 75% of attacks. Subjects were required to be able to distinguish migraine from non-migraine headache. Subjects were randomized 3:1 to receive either sublingual feverfew/ginger or a matching placebo and were instructed but not required to treat with study medication at the earliest recognition of migraine. RESULTS: Sixty subjects treated 208 evaluable attacks of migraine over a 1-month period; 45 subjects treated 163 attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo preparation. Evaluable diaries were completed for 151 attacks of migraine in the population using feverfew/ginger and 57 attacks for those attacks treated with placebo. At 2 hours, 32% of subjects receiving active medication and 16% of subjects receiving placebo were pain-free (P= .02). At 2 hours, 63% of subjects receiving feverfew/ginger found pain relief (pain-free or mild headache) vs 39% for placebo (P= .002). Pain level differences on a 4-point pain scale for those receiving feverfew/ginger vs placebo were -0.24 vs -0.04 respectively (P= .006). Feverfew/ginger was generally well tolerated with oral numbness and nausea being the most frequently occurring adverse event. CONCLUSION: Sublingual feverfew/ginger appears safe and effective as a first-line abortive treatment for a population of migraineurs who frequently experience mild headache prior to the onset of moderate to severe headache.

Multi-center comparison of response to a single tablet of sumatriptan 85 mg and naproxen 500 mg vs usual therapy treating multiple migraine attacks as measured by the completeness of response survey.

OBJECTIVE: To investigate a broad definition of migraine resolution that extends beyond specific migraine-associated diagnostic symptoms as measured by the Completeness of Response Survey. METHODS: Conducted at 8 sites, 135 subjects treated migraines with SumaRT/Nap over 2 months. To measure subjects' experiences with SumaRT/Nap compared to their usual migraine medication, the Headache Impact Test, Revised Patient Perception of Migraine Questionnaire, and Completeness of Response Survey were administered at baseline and at 2 months. RESULTS: The effects of the study medicine compared to the subjects' usual migraine medicine reached statistical significance in decreasing headache severity, lessening of associated symptoms, and attaining complete relief with a single dose (60.04% of attacks resolved at 2 hours post-treatment). CONCLUSION: Compared to a subject's usual treatment, SumaRT/Nap used early and consistently for treatment of acute migraine offers important clinical improvements, including lessening of associated symptoms beyond International Headache Society criteria. CLINICAL TRIAL REGISTRATION NUMBER: NCT00893737.

Breaking the bond between stimulant use and risky sex: a qualitative study.

Stimulant-using men who have sex with men (MSM) are at increased risk for human immunodeficiency virus (HIV) transmission, and are more likely to practice unprotected anal sex than MSM who do not use methamphetamine and/or crack cocaine. In this paper the authors report on interviews with stimulant-using men who have sex with men who have participated in Crystal Meth Anonymous and other 12-step groups, focusing on those who did not have unprotected anal intercourse during a 6-month follow-up period and their reasons for doing so. The authors find 4 common themes cited: a diminished sexual drive; exclusive sex with a primary partner; greater sense of responsibility/commitment to safer sex; and most commonly of the four, an overall healthier sex life. Participants' use of terms such as "healthy," "enjoyable," and "fulfilling" to describe sex not on stimulants, and avoidance of these terms for sex on stimulants, suggests a distinct dimension of sexual experience.

Expanding access to triptans: assessment of clinical outcome.

OBJECTIVE: To evaluate whether access to more liberal quantities of rizatriptan improves clinical outcome in patients with episodic migraine. BACKGROUND: Currently many pharmacy benefit programs limit the number of triptan tablets/injections per month based on perceived cost savings and the belief that too-frequent use of triptans may lead to medication overuse headache and headache chronification. METHODS: This observer-blind, randomized, parallel-group study enrolled 197 subjects with migraine with or without aura. Subjects completed a 3-month baseline period to establish migraine frequency and then were randomly assigned to receive 9 (formulary limit [FL]) or 27 (clinical limit [CL]) tablets of 10 mg rizatriptan orally disintegrating tablet (ODT) per month for 3 months. The primary endpoint was change in the mean number of migraine days from the baseline to treatment period. RESULTS: There was no statistically significant difference between the FL and CL groups in mean number of migraine days (FL-CL LS mean: -0.08 [-0.39, 0.23]; P = .613). Subjects in the CL group treated attacks at lower headache severity. No CL subjects were reported to have developed chronic migraine despite utilization of greater than 10 rizatriptan ODT tablets per month. Rizatriptan was generally well tolerated by both groups. CONCLUSION: Providing a greater quantity of rizatriptan ODT 10 mg did not reduce the number of migraine days compared with providing 9 tablets per month for this population with episodic migraine with a frequency of 3-8 migraines per month. Regardless of quantity provided, rizatriptan was generally well tolerated.

Stimulant use and HIV risk behavior: the influence of peer support group participation.

This study examines 12-step groups for recovery from methamphetamine and cocaine use that are attended by men having sex with men and the impact of attendance on HIV risk behavior. Participants in Crystal Meth Anonymous and other 12-step groups were interviewed up to 3 months since their last substance use. Sixty-two initial interviews, and ethnographic observations, were conducted. With entry into the program, mean reported sexual partners fell from around seven to one per month and the proportion having unprotected anal intercourse declined from 70% to 24%. HIV-positive men were more likely than HIV-negative men to report unprotected anal intercourse when using stimulants but less likely in recovery. Qualitative data suggest a transition from cocaine to methamphetamine in Chicago, and that reduction in partners is due to fear of relapsing in sexual situations rather than program teachings. These programs do however facilitate discussions around drug use and sexual issues.

Randomized, placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe.

OBJECTIVE: To evaluate whether frovatriptan would provide greater relief if given early during a migraine attack. RESEARCH DESIGN AND METHODS: Adults with a history of migraine of at least 1 year, and who had 2-8 headaches in the previous month were recruited from 19 US centres for a prospective, placebo-controlled crossover study over 2 migraine attacks. Dose 1 was taken at the onset of mild migraine headache, Dose 2 was taken at least 2 h later if the headache progressed to moderate/severe. Patients were randomized to receive Dose 1 frovatriptan then Dose 2 placebo or Dose 1 placebo followed by Dose 2 frovatriptan. Treatment order was reversed for the second attack. This schedule enabled a comparison of frovatriptan with placebo and a comparison of early and later treatment with frovatriptan. MAIN OUTCOME MEASURES: Freedom from pain at 2 h for frovatriptan versus placebo as Dose 1; use of Dose 2 and/or rescue medication, pain severity, functional impairment and headache recurrence. RESULTS: In 241 patients who each treated 2 migraine attacks, Dose 1 frovatriptan was more effective than placebo in terms of the proportion of patients who were pain free at 2 h (28% vs 20%, p = 0.04). This benefit was sustained up to 4 h post-dose (p = 0.003). Early use of frovatriptan significantly reduced re-medication (p < 0.001). Twenty-four-hour headache recurrence was low in both early (4%) and later use (6%) groups. Sustained pain-free response occurred in 40% of frovatriptan early use patients compared with 31% of later use patients (p < 0.05). Early use prevented headache progression: 69%-78% had mild/no headache 2-4 h after Dose 1 frovatriptan compared with 54%-63% taking Dose 1 placebo (p < 0.001). Early use reduced pain burden and functional disability (p < or = 0.001). More patients rated early use of frovatriptan as excellent or good (57% vs 46%). CONCLUSIONS: Early use of frovatriptan resulted in a higher, earlier and sustained pain-free response, prevented progression to moderate/severe headache and reduced pain burden and functional disability.

Frovatriptan: a review.

Frovatriptan is a potent 5-HT(1B/1D) receptor agonist and has the highest 5-HT(1B) potency in the triptan class. preclinical pharmacology studies demonstrated that frovatriptan is apparently cerebro-selective. In clinical pharmacology studies, frovatriptan was shown to have a long-terminal elimination half-life of 26 h and to be well-tolerated across a broad dose range of 1-100 mg. Frovatriptan has no inhibiting or inducing effects on cytochrome P450 isoenzymes and is only slightly bound to plasma proteins; thus it has a low potential for drug interactions. No dosage adjustments are necessary based on age or renal or hepatic impairment. Efficacy studies show significantly higher response rates compared with placebo and the lowest reported range of headache recurrence rates in the triptan class. Safety studies show a side effect profile similar to placebo. The combination of cerebro-selectivity, long half-life, reliable efficacy, low recurrence rates and good tolerability make frovatriptan a valuable new choice for acute treatment of migraine. Frovatriptan may be particularly well suited to patients with migraine of long duration, those prone to recurrence and those troubled by "triptan-type" side effects.

Sumatriptan iontophoretic transdermal system: A novel approach to migraine-specific therapy.

The sumatriptan iontophoretic transdermal system (TDS) (Zecuity, NuPathe, Malvern, PA), a novel approach to the acute treatment of migraine, circumvents the gastrointestinal tract by using low-level electrical energy to transport sumatriptan across the skin. In clinical trials, sumatriptan TDS has provided consistent drug delivery; rapid relief of migraine headache pain and migraine-related nausea; and an excellent safety profile, with a low incidence of triptan-sensation adverse events. Ease of use/application of sumatriptan TDS by migraineurs during an attack is rated highly. Sumatriptan TDS will provide a convenient, acute migraine-specific therapeutic option to the significant subset of patients for whom oral formulations are suboptimal, particularly those with migraine-related nausea (MRN).

Abdominal wall haematoma in the obese: a dangerous phenomenon.

We report the case of a 59-year-old obese female who developed an abdominal wall haematoma during administration of prophylactic clexane. Compared with the non-obese, the subcutaneous tissue of the obese is considered dysfunctional and has a different vascular structure and extra-cellular matrix composition. While the development of an abdominal wall haematoma is relatively uncommon, when they occur they can have fatal consequences. The altered subcutaneous tissue environment in the obese attenuates the normal external compression of an abdominal wall haematoma and as a result the obese are at greater risk of haemorrhage.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid ß (Aß)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aß(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aß(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.