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Introduction: Chronic migraine is often complicated by medication-overuse headache (MOH), a headache due to excessive intake of acute medications. Chronic migraine and MOH are serious and disabling disorders. Since chronic migraine derives from the progression of originally episodic migraine, the fundamental therapeutic strategy is prevention. This narrative review describes how to try to prevent the development of MOH and how to manage it once it has appeared., Areas Covered: A PubMed database search (from 1988 to January 2015) and a review of published studies on chronic migraine and MOH were conducted., Expert Opinion: In spite of progress in migraine treatment, the prevalence of chronic headaches and MOH has not changed in the course of time. Today, a large number of migraine patients have turned to numerous expert physicians and experienced all sorts of prophylactic treatments without decisive benefits. Their condition seems to have crystallized even more as chronic and intractable. This means that to prevent chronification and MOH, we need more effective drugs and better strategies to use them. In particular, we must detect disease biomarkers and predictive factors for drug response that allow for personalized treatment when migraine is still episodic and make analgesic overuse pointless.

Introduction: Migraine is a widespread disorder. Migraine patients experience worse health-related quality of life than the general population. The availability of effective and tolerable treatments for this disorder is an important medical need. This narrative review focuses on the clinical pharmacology of topiramate, an antiepileptic drug that was approved for the prophylaxis of migraine where it should act as a neuromodulator., Areas Covered: A PubMed database search (from 2000 to 24 January 2011) and a review of the human studies published on topiramate and migraine was conducted., Expert Opinion: Topiramate is an important option for the prophylaxis of migraine and is of proven efficacy and tolerability. It has also been studied in chronic migraine with encouraging results, even in patients with medication overuse. However, in migraine prevention its efficacy is comparable to the other first-line drugs and there are no published trials with a superiority design which can establish topiramate's role in the available therapeutic armamentarium.

Triptans, selective 5-HT1B/1D receptor agonists, are specific drugs for the acute treatment of migraine that have the same mechanism of action. Here, it is discussed why the differences among kinetic parameters of oral triptans have proved not to be very important in clinical practice. There are three main reasons: (1) the differences among the kinetic parameters of oral triptans are smaller than what appears from their average values; (2) there is a large inter-subject, gender-dependent, and intra-subject (outside/during the attack) variability of kinetic parameters related to the rate and extent of absorption, i.e., those which are considered as critical for the response; (3) no dose-concentration-response curves have been defined and it is, therefore, impossible both to compare the kinetics of triptans, and to verify the objective importance of kinetic differences; (4) the importance of kinetic differences is outweighed by non-kinetic factors of variability of response to triptans. If no oral formulations are found that can allow more predictable pharmacokinetics, the same problems will probably also arise with new classes of drugs for the acute treatment of migraine.

Aims: The aims of this survey were: (i) to examine the pharmacoepidemiology of triptans in a headache centre; (ii) to compare the characteristics of patients who continued to take triptans with those of patients who had discontinued them., Methods: We enrolled all migraine patients according to ICHD-II criteria, ensuring they were over 18 years of age, consecutively examined during a follow-up visit at the Headache Centre of the University Hospital of Modena from October 2008 to March 2009. Only patients who had used or were using a triptan were included. A specific questionnaire about the use and tolerability of triptans was created for the study and administered to every patient., Results: On the whole, 343 patients (migraine without aura: 72%; chronic migraine: 26%; migraine with aura: 2%; mean age 40.4 +/- 10 years) had used or were using triptans. Most patients (72%) continued to use triptans, above all for their efficacy. The minority (28%) discontinuing them were younger and suffered from less severe migraine; 59% of them had discontinued triptans because of adverse effects. Indeed, 92% of these patients versus 57% of patients who were currently using triptans reported adverse effects (p < .0001, Fisher's exact test). The number of patients reporting adverse effects significantly decreased with age (r = -0.230, p < .005, simple linear regression analysis). The triptan discontinued by the highest percentage of patients (84%) was subcutaneous 6 mg sumatriptan. Significantly more patients reported adverse effects with subcutaneous 6 mg (89%) and tablet 100 mg sumatriptan (67%) than with any other triptan., Conclusions: The increase of the tolerability of triptans with age could partly explain why younger patients suffering from less severe migraine tend to discontinue triptans more than older patients suffering from more severe migraine. In the latter, the efficacy and better tolerability (but not necessarily safety) of triptans could foster the overuse of these medications.

There are a large number of drugs inducing headache as an adverse reaction. Nevertheless, headaches as adverse reactions to drugs have received limited attention. Non-serious adverse reactions, such as headache, are not quantified and described as accurately as serious, life threatening ones. However, non-serious reactions can also be extremely troublesome, above all when they are chronic: they can affect patients' quality of life and contribute to non-compliance. It is absolutely possible that the number of patients with headache as an adverse reaction, which is going to increase, considering the growing use of medications. Physicians should, therefore, be aware of this issue. Indeed, it is difficult to attribute the diagnosis of adverse drug reaction to a condition, headache, which is also a very common symptom in general population.

The 1988 classification by the International Headache Society (IHS) first defined drug-induced headache as a specific disorder, belonging to secondary headaches, subtype 8.2 (headache induced by chronic substance use or exposure). In 2004 ICHD-II, this definition was replaced by medication-overuse headache (MOH). It was established that a definite diagnosis of MOH required the improvement of the disorder after cessation of medication overuse. The specific characteristics of the various subforms were also indicated. Later revisions have first eliminated these headache characteristics and then the diagnosis of probable MOH. The diagnosis of MOH has therefore become more useful to clinical aims. However, the last revision has eliminated the need to prove that the disorder is caused by drugs, that is, the headache improves after cessation of medication overuse. The classification of MOH as a secondary headache has therefore been modified, too. Clinical trials can consequently include in the same group patients with primary headache and drug overuse and patients with MOH. We therefore propose to continue to use the diagnosis of probable MOH to research aims. We also propose to modify the classification of MOH subforms according to the presence or absence of a dependence-producing property of overused drugs. This will allow to better analyze the role of the various medications in inducing chronic headache and the outcomes of treatments.

Background: The marketing of sumatriptan, a selective serotonin (5-HT) 1B/1D agonist, first of the class of triptans, has increased the therapeutic options for the treatment of migraine attacks. However, almost one third of patients in clinical trials fail to have headache relief after oral administration of sumatriptan., Objective: To evaluate whether the interindividual differences in the clinical response following oral administration of sumatriptan are due to differences in its pharmacokinetics., Methods: We compared the pharmacokinetics of sumatriptan after oral (100 mg) and subcutaneous (6 mg) administration in two age- and gender-matched groups: ten subjects (group A) with satisfactory response and ten (group B) with unsatisfactory response to oral sumatriptan. Patients were studied during headache-free intervals. Blood samples were taken serially from baseline to 360 min after oral administration and from baseline to 180 min after subcutaneous injection. Sumatriptan plasma concentrations were determined by high-performance liquid chromatography (HPLC) with an electrochemical detector., Results: Following oral dosing, patients of group A absorbed sumatriptan significantly faster and achieved early plasma levels significantly higher than patients of group B. The systemic exposure to sumatriptan during the first 2 h, which are the most important for rapid onset of action and for antimigraine efficacy, was significantly greater in group A than in group B (P < 0.001, Student's t test for independent data). On the other hand, after subcutaneous injection of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B., Conclusion: The slow rate and low extent of absorption of the drug during the first 2 h after dosing observed in patients of group B could explain their unsatisfactory response to oral sumatriptan.

Objective: To quantify and characterize the similarities and the differences between chronic migraine (CM) patients with medication overuse and episodic migraine (EM) patients with only occasional analgesic use., Background: Population-level epidemiology, characteristics, mechanisms of chronic daily headache, and medication-overuse headache have been widely studied but patient characteristics have received less attention. Methods.-We compared sociodemographic data, family history, physiological and medical history, health services utilized, drugs taken/prescribed, and outcome of 2 groups of subjects: 150 patients, suffering from CM, complicated by probable medication-overuse headache (CM group), consecutively admitted during 2005 to the inpatients' ward of the Headache Centre of the University Hospital of Modena and Reggio Emilia, Italy, to undergo withdrawal from their overused medications; 100 patients suffering from EM, uncomplicated by medication overuse (EM group), consecutively referred to the outpatients' ward of the Headache Centre during November and December 2005., Results: All sociodemographic characteristics were significantly different between the 2 groups. As a whole, the CM group began to suffer from migraine earlier than the EM group. Drug and/or alcohol abuse was significantly higher among first-degree relatives of CM (19%) than of EM (6%) patients. The most frequent comorbid disorders were psychiatric (67%) and gastrointestinal diseases (43%) in the CM group, and allergies in the EM group (31%). Seventy percent of CM patients and 42% of EM patients were taking daily at least another drug, besides those for headache treatment. Most overused medications in the CM group were triptans (43%); the EM group used above all single NSAIDs (56%). At 3-month follow-up, prophylactic treatments reduced, by at least 50%, the frequency of headache in about three-fourths of patients of both the groups; however, headache remained significantly more frequent in the CM than in EM group: only a minority (15%) of CM patients reverted to a headache frequency comparable to that of the EM group., Conclusions: CM patients present more multiple comorbid disorders, polypharmacy, and social impediments than EM patients. These associated conditions complicate CM clinical management. Even after withdrawal from medication overuse, CM could not be completely reverted by current prophylactic treatments.

The present part II review highlights pharmacokinetic drug-drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug-drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using beta-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., beta-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered.

Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse.

Background: The combination of indomethacin, prochlorperazine and caffeine (IPC) is one of the most utilized formulations for the treatment of migraine attacks in Italy. Several patients suffering from chronic headache overuse this symptomatic medication in the attempt to control their headache., Objective: To verify whether overuse of IPC combination by chronic headache patients is associated with modified disposition of its components., Methods: We studied indomethacin, prochlorperazine, and caffeine disposition in 34 female subjects suffering from primary headaches, subdivided into four groups: eight migraine patients occasionally using IPC combination suppositories-group 1; nine patients with chronic headache and probable medication-overuse headache, daily taking one or more suppositories of the IPC combination-group 2; 11 migraine patients occasionally using "mild" suppositories of the IPC combination-group 3; six migraine patients occasionally taking tablets of the IPC combination-group 4. The IPC combination habitually used was administered to each patient. Blood samples were taken at baseline and at fixed intervals up to 6h after administration. Plasma levels of indomethacin and prochlorperazine were assayed by high-pressure liquid chromatographic (HPLC) method; caffeine levels were assayed by enzyme multiplied immunoassay test (EMIT). Pharmacokinetic parameters were calculated by means of a computer software (P K Solutions 2.0. Summit Research Services, Montrose, CO, USA)., Results: Half-life of indomethacin was longer, and clearance lower, in group 2 than in the other groups; AUC of indomethacin in group 2 was twice that in group 1 (P<0.05, Newman-Keuls' test). Peak concentrations and AUC(0-->infinity) of caffeine were significantly higher in group 2 than in the other groups (P<0.05, Newman-Keuls' test). We could not define prochlorperazine disposition because it was not detectable in the majority of blood samples., Conclusion: Overuse of IPC combination in chronic headache patients is associated with increased plasma levels of indomethacin and caffeine, and with delayed elimination of indomethacin; the high and sustained concentrations of these drugs may cause rebound headache, organ damages, and perpetuate medication-overuse headache.

Objective: To assess the clinical impact of adverse reactions related to drugs for primary headache treatment., Methods: We examined the adverse reactions to 360 medications prescribed by the specialists of the Headache Centre of the University of Modena and Reggio Emilia to 256 consecutive outpatients (214 female, 42 male; mean age: 38.88 +/- 14.06 years; range 10-72 years). Adverse reactions were reported by patients during scheduled follow-up visits, classified by specialists and reassessed by a clinical pharmacologist., Results: Adverse reactions with a causal relationship classified as definite/probable/possible were 202 (56%): 62% (80/129) were due to acute treatments and 53% (122/231) to prophylactic treatments (chi2 test, P = 0.115 ns). More than 90% of the adverse reactions were of limited intensity [mild (58%) or moderate (36%)]. Only 5% were severe, and two reactions (1%) were serious. The most affected apparatus was the nervous system (41%). Of these adverse reactions, 43% caused the discontinuance of the treatment, especially of prophylaxis (54%). Patients evaluated 70% of the medications as effective, but, at the same time, they considered most of the adverse reactions (69%) unacceptable., Conclusion: Adverse reactions related to headache medications have a strong impact on patients' management, even if their real intensity and severity are usually very limited. Drugs for headache treatment are still far from being ideal drugs. To prevent the discontinuance of effective medications, the physician, prior to prescribing, should assess, together with the patient, the acceptability of the more common adverse drug reactions.

The effect of sumatriptan in two standard algesimetric tests and in a model of cephalalgia was evaluated in rats. The pain threshold was measured by the hot-plate and the writhing tests; cephalalgia was produced by injecting bradykinin (10 microg in a volume of 10 microl) into a common carotid artery. Sumatriptan was subcutaneously (s.c.) injected at the doses of 4, 8, 24 or 42 mg/kg; morphine (5 or 10 mg/kg s.c.) and indomethacin (5 or 10 mg/kg s.c) were used as standard analgesic drugs. Sumatriptan had no analgesic activity either in the hot-plate test or in the writhing test. On the other hand, at 24 and 42 mg/kg it dose-dependently reduced the response to the intracarotid injection of bradykinin (vocalization and tachypnea), this effect being prevented by the 5-HT(1B) receptor antagonist, isamoltane. The 5-HT(1D) receptor antagonist BRL15572 prevented the effect of sumatriptan on bradykinin-induced tachypnea, but not the effect of sumatriptan on bradykinin-induced vocalization. These data demonstrate that sumatriptan is significantly effective in a reliable animal model of cephalalgia, while having no systemic analgesic activity.

Data were collected from 265 heroin-dependent patients in long-term methadone maintenance treatment for methadone dosage, administration method, illicit drug and problematic alcohol use, psychiatric diagnoses, quality of interpersonal relationships, employment, legal problems, health, and cravings. Patients receiving higher methadone doses (more than 80 mg) were more likely to respond to methadone treatment than patients receiving lower doses. Superior outcome was also related to good quality of interpersonal relationships, stable employment, and lower craving scores. Comorbid psychiatric disorders did not appear to influence methadone effectiveness, but psychopharmacological treatment associated with methadone was associated with a lower rate of urine samples positive for drug use. Administration of methadone weekly or twice weekly ("home methadone") was less effective than daily administration. Although our results were obtained through a descriptive study, which does not permit a prospective evaluation, they suggest the need for higher methadone doses. Job and family relationships appear to be associated, together with psychopharmacological treatment, with a more effective outcome.

The ISO 9000 series has been adopted as a reference standard and operating system for a Quality Assurance project involving all the units of the Polyclinic of Modena, within which the Headache Centre operates, to guarantee a clearly-defined standard of service to the client and the promotion of continuous quality improvement. The implementation of the quality system, which necessitated analysis and description of the process of headache diagnosis and treatment currently being applied, highlighted those aspects that did not conform with the quality objective, primarily, the long waiting list for admission. Since ready accessibility is a basic requisite for the quality of health care services, a new organisational set-up was introduced, and is still in place, with the aim of enabling patients who are really in need to be admitted to the Headache Centre without undue delay.

The pharmacokinetics of naltrexone have been scarcely explored in patients during chronic treatment despite the observation that the pharmacological effect of the drug is related to its plasma concentrations. In this study we investigated the time course of serum levels of naltrexone and its active metabolite, 6 beta-naltrexol, in 13 heroin addicts (3 F, 10 M; age 22-32 years) in the 24 h after 100 mg of naltrexone orally. Six patients were studied once, at different times during chronic treatment, whereas in seven patients the study was done at the beginning and after 1 month of naltrexone treatment. Four of these patients also repeated the study after 3 months of naltrexone treatment. Serum naltrexone and 6 beta-naltrexol were assayed by GLC with a nitrogen-phosphorus detector. Our results showed large differences among patients in serum naltrexone and 6 beta-naltrexol levels. On the other hand, there were no differences in serum time course of both substances in the same patient over 3 months. Peak levels and AUCs of naltrexone were lower than those of 6 beta-naltrexol in ten addicts and higher than those of the metabolite in three patients. No significant differences in the apparent half-lives of the two drugs were detected among groups. These data are consistent with the occurrence of a decreased first-pass metabolism of naltrexone in three patients leading to a larger availability of an oral dose. The increased bioavailability of the drug is not very important for opioid receptor antagonist activity but may play a role in naltrexone treatment safety.

Objective: To explore beliefs and behavior with respect to analgesic drug taking in headache patients. To compare episodic headache to chronic headache sufferers., Methods: A consecutive series of 280 headache patients, newly admitted to the Headache Center of the University of Modena, all referred by their general practitioner, were asked to fill out a brief questionnaire, specially compiled for this survey. The questionnaire invited patients to indicate how they themselves thought they should best cope with their headache, and how they actually did so in practice., Results: The majority of our patients had a positive attitude towards the over-the-counter analgesics, which they believed to be more adequate than prescription drugs for acute treatment of their headache. They handled analgesics very carefully, believing it correct to take the drug only when the pain became unbearable, if it was not possible for them to stop work. Chronic headache patients tended to consume more prescription drugs than episodic headache sufferers. Furthermore, the majority of chronic sufferers, as opposed to episodic sufferers, took the analgesic even when not at work., Conclusions: The use of over-the-counter drugs is considered the best way to treat acute headache even by subjects suffering from severe idiopathic headache and seeking professional care in specialized clinics. Prescribed analgesics are underused by patients with serious episodic headache, which is precisely the group for which they are principally intended.

We evaluated 102 patients attending the Headache Study Center of the University of Modena who were suffering from chronic daily headache with daily drug intake. Patients underwent either day hospital treatment followed by a standard prophylactic therapy or they started prophylactic therapy immediately. After 30 and 120 days, both the Headache index and the daily drug intake had significantly improved (P < 0.001), and there were no differences in reduction of mean values of the Headache index or daily drug intake with respect to the two treatments, nor with regard to the prophylactic therapy chosen. Twenty-eight percent of patients reverted to daily drug intake after a 4-month follow-up; these patients took barbiturate-containing mixtures in a higher percentage than other drugs, and within the group of relapsing patients the outpatients relapsed to analgesic intake more than the day hospital-treated patients (P < 0.05).

It has been found that acute ethanol (EtOH) intoxication to rats caused approximately 40% depletion of mitochondrial reduced glutathione (GSH). A GSH reduction of similar extent was also observed after the administration to rats of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis. The combined treatment of EtOH plus BSO induced a further mitochondrial GSH decrease up to 70% with respect to control. The presence of lipid hydroperoxides in the mitochondrial membrane was observed whenever an additional oxidative stress was associated to a condition of GSH depletion as in the case of EtOH or EtOH plus BSO. Under these conditions a severe derangement in mitochondrial oxidative functions occurred.

Since plasma reduced glutathione (GSH) seems to reflect liver GSH content, we have assessed plasma GSH in patients using paracetamol daily. In these patients a significant lower plasma GSH concentration was found with respect to controls. After the i.v. administration of GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests that the possible protective effect of GSH administration is due to the availability of plasma thiol compounds that enter the cell rather than GSH itself.

Within the pharmacological treatment of migraine it is possible to distinguish treatment of attacks and prevention therapy. The aim of attack treatment is to stop pain and accompanying symptoms, or at least to make them more tolerable, whereas the aim of prophylaxis is to reduce the frequency and possibly the severity and duration of the residual episodes. The choice to initiate either treatment, or both, is based on quantitative criteria, such as attack frequency (if greater than 2-3 per month, prophylaxis treatment is recommendable) and on qualitative features, like the degree of disability, the response and the tolerance of the patient to attack treatment. Prophylaxis treatment has not achieved any improvement since 1981, when propranolol was first utilized. The knowledge of the mechanisms of action of drugs used in prophylaxis, as well as their results, are at a standstill. Even with the newer calcium channel antagonists and beta-blockers we achieve a 50% reduction of attacks in less than half of subjects treated. On the other hand, we had important news in the treatment of migraine attacks. Sumatriptan, a selective agonist of serotonin receptors, represents a therapeutic novelty due both to the results obtained and to the studies that have been stimulated on the pathogenesis of migraine. New therapeutic perspectives are now opening and hopefully thanks to the cooperation of basic and clinical scientists, they might become a reality in a short time.

A simple and reliable reversed-phase high-performance liquid chromatographic method with coulometric detection is described for the quantitation of naltrexone and its metabolite, 6 beta-naltrexol, in plasma samples of healthy volunteers who received orally 50 mg of naltrexone. The analytes and the internal standard, naloxone, are extracted with an octadecyl solid-phase extraction column before chromatography. The mobile phase is 0.01 M potassium phosphate (pH 3)-acetonitrile (85:15, v/v) and it is pumped at 0.8 ml/min. The coulometric detector is formed by two electrodes set at +0.20 V and +0.70 V, with a palladium reference electrode. The limit of quantitation observed was 5 ng/ml for both naltrexone and 6 beta-naltrexol. This method can be used to investigate pharmacokinetic parameters of different pharmaceutical preparations of this opioid antagonist.

The activity of dapiprazole, clonidine and a placebo were studied to reduce abstinence symptoms and modify the psychological outline during a withdrawal period in heroin addicts. Forty heroin addicts were treated in a double-blind design and, within two weeks, relapse in heroin use was higher in the placebo group (8/10) in comparison with the dapiprazole (1/20) and clonidine (0/10) groups. During treatment clonidine was able to reduce depression and paranoid-ideas scores, whereas dapiprazole reduced depression, anxiety, hostility, phobic anxiety, obsessiveness and psychoticism. Side-effects were mild and it may be concluded that both dapiprazole and clonidine are effective and safe drugs for the treatment of opiate withdrawal syndrome.

This study examined the pharmacokinetics of 300 mg of tiaprofenic acid, a NSAID belonging to the 2-arylpropionic class, as a single oral dose, in 10 migraine patients during and out of migraine attacks. Plasma concentration of tiaprofenic acid was determined by HPLC analysis. Drug absorption appeared to be the same during and out of migraine attacks (absorption half life: during attack, 0.249 +/- 0.122 hr; out of attack, 0.249 +/- 0.105 hr; maximum plasma concentration: during attack, 37.8 +/- 9.8 ug/ml; out of attack, 40.1 +/- 13.2 ug/ml). The other pharmacokinetic parameters evaluated were not affected by headache attacks as well. We conclude that tiaprofenic acid absorption and metabolism are not affected by migraine attacks. Also, our data suggest that tiaprofenic acid might be useful in the treatment of migraine.