Medication overuse and chronic migraine: a critical review according to clinical pharmacology.

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.

Clinical pharmacology of topiramate in migraine prevention.

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.

Why pharmacokinetic differences among oral triptans have little clinical importance: a comment.

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.

Pharmacoepidemiology of triptans in a headache centre.

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.

Focus on headache as an adverse reaction to drugs.

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.

Past, present, and future prospects of medication-overuse headache classification.

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.

Interindividual variability of oral sumatriptan pharmacokinetics and of clinical response in migraine patients.

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.

Similarities and differences between chronic migraine and episodic migraine.

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.

Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

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.

Pharmacokinetics and interactions of headache medications, part II: 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.

Effect of overuse of the antimigraine combination of indomethacin, prochlorperazine and caffeine (IPC) on the disposition of its components in chronic headache patients.

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.

Pharmacokinetics of sumatriptan in non-respondent and in adverse drug reaction reporting migraine patients.

Sumatriptan is a selective agonist of 5HT1 (1B/1D) receptors, which has proved to be effective and safe for the acute treatment of migraine attacks. Nevertheless, its use by migraine sufferers is still limited and some patients consider adverse reactions related to sumatriptan, especially chest symptoms, unacceptable even if not serious. Moreover, in clinical trials, almost one third and one sixth of patients, respectively, fail to experience headache relief either after oral or after subcutaneous sumatriptan administration. Our aim was to verify whether differences in sumatriptan pharmacokinetics could explain non-response and/or adverse drug reactions. Sumatriptan levels were determined by HPLC with electrochemical detection. Pharmacokinetic parameters were calculated using a computer program (PK Solutions 2.0; non compartmental Pharmacokinetics Data Analysis). After oral administration, sumatriptan is rapidly absorbed and sometimes displays multiple peaks of plasma concentration. This "multiple peaking" gives rise to considerable inter-subject variability in the time of reaching maximum plasma concentration. Pharmacokinetic parameters of sumatriptan, both after oral and subcutaneous administration, were similar in the three patient groups. Blood pressure and heart rate did not show any significant differences between groups. Pharmacokinetic parameters and bioavailability of sumatriptan did not seem to be correlated either to the lack of efficacy or the appearance of side effects. These results could depend on the limited number of patients studied.

Adverse reactions related to drugs for headache treatment: clinical impact.

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.

Methadone--metabolism, pharmacokinetics and interactions.

The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong and prolonged in others. Methadone is mostly metabolised in the liver; the main step consists in the N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among individuals, and such variability is the responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2 are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants and antiretroviral drugs, which can cause pharmacokinetic interactions. In particular, antiretrovirals, which are CYP3A4 inducers, can decrease the levels of methadone, so causing withdrawal symptoms. Buprenorphine, too, is metabolised by CYP3A4, and may undergo the same interactions as methadone. Since it is impossible to foresee the time-lapse from the administration of another drug to the appearing of withdrawal symptoms, nor how much the daily dose of methadone should be increased in order to prevent them, patients taking combined drug treatments must be carefully monitored. The so far known pharmacokinetic drug-drug interactions of methadone do not have life-threatening consequences for the patients, but they usually cause a decrease of the concentrations and of the effects of the drug, which in turn can cause symptoms of withdrawal and increase the risk of relapse into heroin abuse.

Effect of sumatriptan in different models of pain in rats.

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.

Long-term methadone maintenance effectiveness: psychosocial and pharmacological variables.

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.