Opioid use and dependence among persons with migraine: results of the AMPP study.

OBJECTIVE: To assess the frequency of opioid use for acute migraine treatment and characterize use groups by sociodemographics, health-care resource utilization (HRU), comorbidities and probable dependence within a large, US population-based sample of persons with migraine. BACKGROUND: Opioids are used in the acute treatment of migraine. However, their use is controversial. METHODS: Data from the 2009 American Migraine Prevalence and Prevention (AMPP) study were used to categorize persons with migraine into 4 groups based on reported opioid use: nonusers (between 2005 and 2009), previous users (history of use between 2005 and 2008 but no-use in 2009), and current opioid users (those reporting use of opioids in the 3 months preceding the 2009 American Migraine Prevalence and Prevention survey). Current opioid users were divided into nondependent and probable dependence users according to criteria for dependence adapted for inclusion in the survey from the Diagnostic and Statistical Manual of Mental Disorders-4th edition. All opioid-use groups were contrasted by sociodemographics, headache characteristics, medical and psychiatric comorbidities (depression [measured by the Patient Health Questionnaire-9], anxiety [measured by the Primary Care Evaluation of Mental Health Disorders, PRIME-MD], and cardiovascular events and risk factors), and headache-related HRU. RESULTS: In a sample of 5796 migraineurs, 4076 (70.3%) were opioid nonusers, 798 (13.8%) were previous users, and 922 (15.9%) were current opioid users. Among current opioid users, 153 (16.6%) met criteria for probable dependence and 769 (83.4%) did not. Headache-related disability (Migraine Disability Assessment sum scores) increased across groups as follows: nonusers: 7.8, previous users: 13.3, current nondependent users: 19.1, and current probable dependence users: 44.4, as did monthly headache frequency: nonusers: 3.2 days/month, previous users: 4.3 days/month, current nondependent users: 5.6 days/month, and current probable dependence users: 8.6 days/month. The prevalence of depression and anxiety was highest among current users with probable dependence. Rates of headache-related HRU were higher for all opioid-use groups for emergency department/urgent care, primary care, and specialty care visits compared to nonusers. CONCLUSIONS: Opioid use for migraine is associated with more severe headache-related disability, symptomology, comorbidities (depression, anxiety, and cardiovascular disease and events), and greater HRU for headache. Longitudinal studies are needed to further assess the directionality and causality between opioid use and the outcomes we examined.

Defining the pharmacologically intractable headache for clinical trials and clinical practice.

The terms refractory headache and intractable headache have been used interchangeably to describe persistent headache that is difficult to treat or fails to respond to standard and/or aggressive treatment modalities. A variety of definitions of intractability have been published, but as yet, an accepted/established definition is not available. To advance clinical and basic research in this population of patients, a universal and graded classification scheme of intractability is needed, and must include a definition of failure, to which and how many treatments the patient has failed, the level of headache-related disability, and finally, the intended intervention (clinical or research) and intensity of the intervention. This paper addresses each of these variables with the intent of providing a graded classification scheme that can be used in defining intractability for clinical practice interventions and clinical research initiatives.

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.

Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine.

Migraine is a disabling, painful primary headache disorder that is associated with various combinations of neurological, gastrointestinal, autonomic and pain symptoms. Gastrointestinal disturbances associated with migraine, including nausea and vomiting, affect a majority of migraineurs and often result in a delay in taking or avoidance of pharmacological intervention. Gastric stasis and vomiting may lead to delayed or inconsistent absorption of orally administered medications. Many migraineurs awake early in the morning with their attack progressing and already associated with nausea and vomiting. As a result, there is a need for a novel, non-invasive, non-oral delivery system for fast and effective acute treatment of migraine. There are two non-oral delivery systems currently available in the US for the acute treatment of migraine: three nasal sprays and two injectable formulations. Although nasal sprays depend partially on nasal mucosal absorption, a significant amount of drug is swallowed, transits the stomach and is absorbed in the small intestine, which is not as rapid or effective a route of delivery for those migraineurs with gastric stasis. Sumatriptan is rapidly absorbed by subcutaneous injection with or without a needle, but the invasiveness and discomfort of the delivery, the high incidence of adverse events and the high recurrence rate all limit its use for many patients. Iontophoretic delivery of medication is a non-invasive transdermal approach that uses small amounts of electrical current to promote rapid movement of the ionized drug through the skin and into the systemic circulation. This delivery bypasses hepatic first-pass metabolism and also avoids gastric transit delay and slowing of small intestinal absorption associated with gastrointestinal stasis in migraineurs. Two pharmacokinetic studies have demonstrated that iontophoretic transdermal delivery of sumatriptan results in rapid and consistent achievement of therapeutic plasma concentrations. These studies also suggest that, by avoiding patient exposure to a rapid rise in and high plasma concentrations of sumatriptan as seen with injectable sumatriptan, transdermal delivery using iontophoresis may significantly reduce typical triptan-related adverse events. A large, randomized, double-blind, placebo-controlled, multicentre clinical trial showed statistically significant efficacy, good tolerability and virtually no triptan-related adverse events. Iontophoretic delivery of sumatriptan, with a novel transdermal patch device, offers patients a migraine-specific medication that is non-invasive and non-oral. Clinically, transdermal delivery provides rapid and effective relief of migraine while bypassing the gastrointestinal tract, with minimal classic triptan-related adverse effects. This unique approach facilitates the rapid absorption of this migraine-specific triptan, which should improve the chances of consistently achieving a therapeutic plasma concentration of sumatriptan, resulting in effective migraine relief.

Transcranial magnetic simulation in the treatment of migraine.

Transcranial magnetic stimulation (TMS) is a diagnostic and therapeutic modality that is being developed as both an acute and preventive treatment for migraine. TMS delivers a fluctuating magnetic field from the scalp surface to induce current in the subjacent cortex. Magnetic pulses are delivered one at a time in single-pulse TMS (sTMS) or as a train of pulses in repetitive TMS (rTMS). For most of its 30-year history, TMS has been delivered in clinical and research settings using large tabletop devices. Based on the theory that sTMS may disrupt cortical spreading depression, sTMS has been studied and shown to be effective as an acute treatment for migraine with aura. Subsequent work in animal models confirms that sTMS disrupts cortical spreading depression. To make outpatient self-treatment possible, a portable device has been developed for acute treatment of migraine with aura. Based on the theory that rTMS alters brain excitability and neurotransmitter activity, rTMS has been studied as a preventive migraine treatment. A small body of evidence suggests that rTMS may have a role, but further studies are needed. In this review, we summarize the data on TMS as a treatment of migraine, and we suggest directions for future research.

Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial.

BACKGROUND: Preliminary work suggests that single-pulse transcranial magnetic stimulation (sTMS) could be effective as a treatment for migraine. We aimed to assess the efficacy and safety of a new portable sTMS device for acute treatment of migraine with aura. METHODS: We undertook a randomised, double-blind, parallel-group, two-phase, sham-controlled study at 18 centres in the USA. 267 adults aged 18-68 years were enrolled into phase one. All individuals had to meet international criteria for migraine with aura, with visual aura preceding at least 30% of migraines followed by moderate or severe headache in more than 90% of those attacks. 66 patients dropped out during phase one. In phase two, 201 individuals were randomly allocated by computer to either sham stimulation (n=99) or sTMS (n=102). We instructed participants to treat up to three attacks over 3 months while experiencing aura. The primary outcome was pain-free response 2 h after the first attack, and co-primary outcomes were non-inferiority at 2 h for nausea, photophobia, and phonophobia. Analyses were modified intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00449540. FINDINGS: 37 patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with sTMS (n=82) or sham stimulation (n=82; modified intention-to-treat analysis set). Pain-free response rates after 2 h were significantly higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95% CI 3-31%; p=0.0179). Sustained pain-free response rates significantly favoured sTMS at 24 h and 48 h post-treatment. Non-inferiority was shown for nausea, photophobia, and phonophobia. No device-related serious adverse events were recorded, and incidence and severity of adverse events were similar between sTMS and sham groups. INTERPRETATION: Early treatment of migraine with aura by sTMS resulted in increased freedom from pain at 2 h compared with sham stimulation, and absence of pain was sustained 24 h and 48 h after treatment. sTMS could be a promising acute treatment for some patients with migraine with aura. FUNDING: Neuralieve.

Pharmacological approaches to managing migraine and associated comorbidities--clinical considerations for monotherapy versus polytherapy.

Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than would be found as a coincidental association in the general population. Conditions that are frequently comorbid with migraine include depression, anxiety, stroke, epilepsy, sleep disorders, and other pain disorders. In addition, many common illnesses occur concomitantly (at the same time) with migraine and influence the treatment choice. Migraine management, and especially migraine prevention, can be challenging when patients have comorbid or concomitant illnesses. The objectives of this initiative are to review the literature on managing patients who have migraine and common comorbidities, present additional clinical approaches for care of these difficult patients, and evaluate the areas in which research is needed to establish evidence-based guidelines for the management of migraine with associated comorbid conditions.

Common headache misdiagnoses.

The authors have a personal philosophy that it is worthwhile for a physician on occasion to be the patient. When this particular physician consults another physician for a medical problem, he is seeking treatment to eradicate that particular problem. It is difficult to afford the appropriate therapy for that problem if the correct diagnosis is not made. It is exactly the same situation with patients that come to us with complaints of headache. If we cannot make the proper diagnosis, it is unlikely we will be able to render the appropriate therapy. We need to keep this in mind when we evaluate patients with these headache problems, many of whom have suffered with an incorrect diagnosis for many years.