Alan M. Rapoport

Transformed Migraine and Medication Overuse in a Tertiary Headache Centre — Clinical Characteristics and Treatment Outcomes

Studies suggest that a substantial proportion of headache sufferers presenting to headache clinics may overuse acute medications. In some cases, overuse may be responsible for the development or maintenance of a chronic daily headache (CDH) syndrome. The objectives of this study are to evaluate patterns of analgesic overuse in patients consulting a headache centre and to compare the outcomes in a group of patients who discontinued medication overuse to those of a group who continued the overuse, in patients with similar age, sex and psychological profile. We reviewed charts of 456 patients with transformed migraine (TM) and acute medication overuse defined by one of the following criteria: 1. Simple analgesic use (> 1000 mg ASA/acetaminophen) > 5 days/week; 2. Combination analgesics use (caffeine and/or butalbital) > 3 tablets a day for > 3 days a week; 3. Opiate use > 1 tablet a day for > 2 days a week; 4. Ergotamine tartrate use: 1 mg PO or 0.5 mg PR for > 2 days a week. For triptans, we empirically considered overuse > 1 tablet per day for > 5 days per week. Patients who were able to undergo detoxification and did not overuse medication (based on the above definition) after one year of follow-up were considered to have successful detoxification (Group 1). Patients who were not able to discontinue offending agents, or returned to a pattern of medication overuse within one year were considered to have unsuccessful detoxification (Group 2). We compared the following outcomes after one year of follow-up: Number of days with headache per month; Intensity of headache; Duration of headache; Headache score (frequency x intensity). The majority of patients overused more than one type of medication. Numbers of tablets taken ranged from 1 to 30 each day (mean of 5.2). Forty-eight (10.5%) subjects took > 10 tablets per day. Considering patients seen in the last 5 years, we found the following overused substances: Butalbital containing combination products, 48%; Acetaminophen, 46.2%; Opioids, 33.3%; ASA, 32.0%; Ergotamine tartrate, 11.8%; Sumatriptan, 10.7%; Nonsteroidal anti-inflammatory medications other than ASA, 9.8%; Zolmitriptan, 4.6%; Rizatriptan, 1.9%; Naratriptan, 0.6%. Total of all triptans, 17.8%. Of 456 patients, 318 (69.7%) were successfully detoxified (Group 1), and 138 (30.3%) were not (Group 2). The comparison between groups 1 and 2 after one year of follow-up showed a decrease in the frequency of headache of 73.7% in group 1 and only 17.2% in group 2 (P < 0.0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and 14.8% in group 2 (P < 0.0001). The headache score after one year was 18.8 in group 1 and 54 in group 2 (P < 0.0001). A total of 225 (70.7%) successfully detoxified subjects in Group 1 returned to an episodic pattern of migraine, compared to 21 (15.3%) in Group 2 (P < 0.001). More rigorous prescribing guidelines for patients with frequent headaches are urgently needed. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications.

Chronic daily headache: identification of factors associated with induction and transformation.

Background.—Chronic daily headache (CDH) is one of the more frequently encountered headache syndromes at major tertiary care centers. The analysis of factors related to the transformation from episodic to chronic migraine (CM) and to the de novo development of new daily persistent headache (NDPH) remain poorly understood.

Mitochondrial dysfunction and migraine: evidence and hypotheses

The molecular basis of migraine is still not completely understood. An impairment of mitochondrial oxidative metabolism might play a role in the pathophysiology of this disease, by influencing neuronal information processing. Biochemical assays of platelets and muscle biopsies performed in migraine sufferers have shown a decreased activity of the respiratory chain enzymes. Studies with phosphorus magnetic resonance spectroscopy (31P-MRS) have demonstrated an impairment of the brain oxidative energy metabolism both during and between migraine attacks. However, molecular genetic studies have not detected specific mitochondrial DNA (mtDNA) mutations in patients with migraine, although other studies suggest that particular genetic markers (i.e. neutral polymorphisms or secondary mtDNA mutations) might be present in some migraine sufferers. Further studies are still needed to clarify if migraine is associated with unidentified mutations on the mtDNA or on nuclear genes that code mitochondrial proteins. In this paper, we review morphological, biochemical, imaging and genetic studies which bear on the hypothesis that migraine may be related to mitochondrial dysfunction at least in some individuals.

Primary chronic daily headache and its subtypes in adolescents and adults

Objectives: To determine the relative frequency of chronic daily headache (CDH) subtypes in adolescents and to compare the distribution of CDH subtypes in adolescents and adults of various ages. Methods: Adolescents (13 to 17 years, n = 170) and adults (18 or older, n = 638) were recruited during the same time frame. CDH subtypes were classified according the criteria proposed by Silberstein and Lipton (1996) as transformed migraine (TM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC). Results: Among adolescents and adults there were substantial differences in the distribution of CDH subtypes. The relative frequency of TM was lower in adolescents (68.8% vs 87.4%, p < 0.001), while NDPH (21.1% vs 10.8%, p < 0.001) and CTTH (10.1% vs 0.9%, p < 0.0001) were more common. HC (0 vs 0.9%, NS) was equally rare. The lower relative frequency of TM in adolescents was accounted for by TM with medication overuse (TM+), much more common in adults (28.2% vs 62.5%, p < 0.001). In fact, TM without medication overuse (TM−) was more common in adolescents (40.5% vs 24.9%, p < 0.001). The relative frequency of TM+ increased until the age of 50 years (p < 0.001). Conclusions: In adolescents with CDH, TM usually develops without medication overuse. Adolescents with the early onset form of TM may develop the disorder in the absence of medication overuse because they are at increased biologic risk.

Tolosa–Hunt syndrome: critical literature review based on IHS 2004 criteria

In 2004, the International Headache Society (IHS) re-defined the diagnostic criteria of Tolosa–Hunt syndrome (THS) specifying that granuloma, demonstrated by magnetic resonance imaging (MRI) or biopsy, is required for diagnosis. We reviewed the literature on THS published from 1988 (year of publication of first IHS criteria) to 2002, analysing individual cases in relation to the new IHS criteria. One hundred and twenty-four cases were identified. As far as it was possible to discern, clinical presentation was similar in all, but 44 (35±) were reported to have inflammation on MRI or bioptic evidence of granuloma, 41/124 (33±) had normal neuroimaging findings and 39 (31±) had a specific lesion, so the THS was secondary. These data confirm that clinical criteria for THS are common to several conditions and their application alone does not guarantee a correct diagnosis. The requirement for inflammation on MRI will result in better classification of painful ophthalmoplegias; nevertheless, an MRI protocol that best defines inflammation should be specified. The status of cases which fulfil the clinical criteria but have normal MRI remains to be clarified.

The triptan formulations : how to match patients and products.

The 5-HT1b/1d receptor agonists (the ‘triptans’) are migraine-specific agents that have revolutionised the treatment of migraine. They are usually the drugs of choice to treat a migraine attack in progress. Different triptans are available in various strengths and formulations, including oral tablets, orally disintegrating tablets, nasal sprays and subcutaneous injections. In Europe, sumatriptan is also available as a suppository.Specific differences among the triptans exist, as evidenced by different pharmacological profiles including half-life, time to peak plasma concentrations, peak plasma concentrations, area under the concentration-time curve, metabolism and drug-drug interaction profiles. How or whether these differences translate to clinical efficacy and tolerability advantages for one agent over another is not well differentiated. However, delivery systems may play an important role in onset of action.Given that the clinical distinctions among these agents are subtle, identification of the most appropriate triptan for an individual patient requires consideration of the specific characteristics of the patient and knowledge of patient preference, an accurate history of the efficacy of previous acute-care medications and individual features of the drug being considered. The selection of an acute antimigraine drug also depends upon the stratification of the patient’s migraine attack by peak intensity, time to peak intensity, level of associated symptoms such as nausea and vomiting, time to associated symptoms, comorbid diseases and concomitant treatments that might cause drug-drug interactions.Individual patient response to the triptans seems to be idiosyncratic and possibly genetically determined. Therefore, a set of specific questions can be used to determine whether a currently used triptan is optimally effective, whether the dose needs to be increased or whether another triptan should be tried.The clinician has in his/her armamentarium an ever-expanding variety of triptans, available in multiple formulations and dosages, which have good safety and tolerability profiles. Continued clinical use will yield familiarity with the various triptans, and it should become possible for the interested physician to match individual patient needs with the specific characteristics of a triptan to optimise therapeutic benefit. Use of the methods outlined in this review in choosing a triptan for an individual patient is probably more likely to lead to migraine relief than making an educated guess as to which triptan is most appropriate.

The International Classification of Headache Disorders revised criteria for chronic migraine—field testing in a headache specialty clinic

In the absence of a biological marker and expert consensus on the best approach to classify chronic migraine (CM), recent revised criteria for this disease has been proposed by the Headache Classification Committee of the International Headache Society. This revised criteria for CM is now presented in the Appendix. Herein we field test the revised criteria for CM. We included individuals with transformed migraine with or without medication overuse (TM+ and TM-), according to the criteria proposed by Silberstein and Lipton, since this criterion has been largely used before the Second Edition of the International Classification of the Headache Disorders (ICHD-2). We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+), as well as the revised ICHD-2 (ICHD-2R) criteria for CM (≥15 days of headache, ≥8 days of migraine or migraine-specific acute medication use—ergotamine or triptans). We also tested the ICHD-2R vs. three proposals. In proposal 1, CM/CM+ would require at least 15 days of migraine or probable migraine per month. Proposal 2 required ≥15 days of headache per month and at least 50% of these days were migraine or probable migraine. Proposal 3 required ≥15 days of headache and at least 8 days of migraine or probable migraine per month. Of the 158 patients with TM-, just 5.6% met ICHD-2 criteria for CM. According to the ICHD-2R, a total of 92.4% met criteria for CM (P < 0.001 vs. ICHD-2). The ICHD-2R criterion performed better than proposal 1 (47.8% of agreement, P < 0.01) and was not statistically different from proposals 2 (87.9%) and 3 (94.9%). Subjects with TM+ should be classified as medication overuse headache (MOH), and not CM+, according to the ICHD-2R. Nonetheless, we assessed the proportion of them who had ≥8 days of migraine per month. Of the 399 individuals with TM+, just 10.2% could be classified as CM+ in the ICHD-2. However, most (349, 86.9%) had ≥8 days of migraine per month and could be classified as MOH and probable CM in the ICHD-2R (P < 0.001 vs. ICHD-2). We conclude that the ICHD-2R addresses most of the criticism towards the ICHD-2 and should be adopted in clinical practice and research. In the population where use of specific acute migraine medications is less common, the agreement between ICHD-2R CM and TM may be less robust.

Chronic daily headache: Correlation between the 2004 and the 1988 International Headache Society diagnostic criteria

Background.—In a previous study, we compared the 1988 International Headache Society (IHS) criteria and the Silberstein‐Lipton criteria (S‐L) in a subspeciality clinic sample of 638 patients with chronic daily headache (CDH) assessed both clinically and with headache diaries. Both systems allowed for the classification of most patients with CDH. The 1988 IHS classification required multiple diagnoses and was more complex to apply.

Zolmitriptan nasal spray in the acute treatment of cluster headache A double-blind study

Objective: To evaluate the efficacy and tolerability of zolmitriptan 5 mg and 10 mg nasal spray (ZNS) vs placebo in the acute treatment of cluster headache. Design/Methods: We conducted a multicenter, double-blind, randomized, three-period crossover study using ZNS 5 mg, ZNS 10 mg, and placebo. Headache intensity was rated by a 5-point scale: none, mild, moderate, severe, or very severe. The primary efficacy measure was headache response (pain reduced from moderate, severe, or very severe at baseline, to mild or none) at 30 minutes. Logistic regression was used to account for treatment period effect as well as for cluster headache subtype effect. Results: A total of 52 adult patients treated 151 attacks. For the primary endpoint, both doses reached significance at 30 minutes (placebo = 30%, ZNS 5 mg = 50%, ZNS 10 mg = 63.3%). For headache relief, ZNS 10 mg separated from placebo at 10 minutes (24.5% vs 10%). Zolmitriptan 5 mg separated from placebo at 20 minutes (38.5% vs 20%). For pain-free status, ZNS 10 mg was superior to placebo at 15 minutes (22.0% vs 6%). Both doses had higher pain-free rates than placebo at 30 minutes (placebo = 20%, ZNS 5 mg = 38.5%, ZNS 10 mg = 46.9%). Side effects were mild and seen in 16% of those attacks treated with placebo, 25% of attacks treated with ZNS 5 mg, and 32.7% treated with ZNS 10 mg. Conclusions/Relevance: Zolmitriptan nasal spray, at doses of 5 and 10 mg, is effective and tolerable for the acute treatment of cluster headache.

Field testing alternative criteria for chronic migraine.

The criteria for chronic migraine (CM), as proposed by the Second Edition of the International Classification of Headache Disorders (ICHD-2) is very restrictive, excluding most patients that evolve from episodic migraine. In this study we empirically tested three recent proposals for revised criteria for CM. We included individuals with transformed migraine (TM) with or without medication overuse, according to the criteria proposed by Silberstein and Lipton. All individuals had headache calendars for at least three consecutive months. We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+). We also tested three proposals for making the CM criteria more inclusive. In proposal 1, CM/CM+ would require at least 15 days of migraine or probable migraine per month. Proposal 2 suggests that CM/CM+ would be classified in those with ≥15 days of headache per month, where at least 50% of these days are migraine or probable migraine. Proposal 3 suggests that CM/CM+ would be classified in those with chronic daily headache and at least 8 days of migraine or probable migraine per month. Among TM sufferers, 399 (62.5%) had TM with medication overuse, and just 10.2% were classified as CM+ 158 (37.5%) had TM without medication overuse; just nine (5.6%) met current ICHD-2 criteria for CM. Using the alternative criteria, proposal 1 included 48.7% of patients with TM without medication overuse; proposal 2 captured 88%, and proposal 3 classified 94.9% of these patients. For TM with medication overuse, the proportions for proposals 1-3 were, respectively, 37%, 81% and 91%. The differences were statistically significant, favouring proposal 3. Consistently, criteria for CM and CM+ should be revised to require at least 8 days of migraine or probable migraine per month, in individuals with 15 or more days of headache per month.