Emilio Sternieri

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.

Serum time course of naltrexone and 6β-naltrexol levels during long term treatment in drug addicts

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.

Headaches Associated With Chronic Use of Analgesics: A Therapeutic Approach

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 bar‐biturate‐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).

Need for analgesics/drugs of abuse: a comparison between headache patients and addicts by the Leeds Dependence Questionnaire (LDQ)

Our aim was to compare the need for analgesics/drugs of abuse between headache patients—chronic and episodic headache sufferers—and addicts, by the Leeds Dependence Questionnaire (LDQ). This is a self-completion 10-item instrument to measure dependence upon a variety of substances. We administered the LDQ questionnaire to 122 chronic daily headache (CDH) sufferers who had been taking one dose of analgesic drug every day for at least 1 year; 71 subjects suffering from episodic headache (EH) using analgesics only occasionally; 115 consecutive drug addicts (DA) with a diagnosis of substance dependence. The mean LDQ total score was similar in the CDH (11.58 ± 6.35) and DA (10.37 ± 6.51) groups, and for both it was significantly higher than the score in the EH (5.61 ± 3.00) group (P < 0.001). The CDH group had the highest scores, and higher scores than the DA group (Z = −8.18, P < 0.001) in item 8, assessing the primacy of effect over the kind of analgesic used, and in item 10 (Z = −5.03, P < 0.001), asking if it is difficult to live without the analgesic; the DA group had the highest scores, and higher scores than the CDH group, in item 9 (Z = −5.07, P < 0.001) addressing the need for the continued administration of the drug to maintain well-being, and in item 3 (Z =−2.39, P < 0.05), exploring compulsion to start the use of the drug. The EH group had lower scores in all items (P < 0.05) except for item 9, where there was no difference from CDH group; the EH group had also lower scores (P < 0.001) than the DA group, except for item 8, where, instead, the score was higher than in the DA group (Z = −5.33, P < 0.001). A strong link develops between chronic headache patients and the analgesics they use. This sort of ‘dependence’ appears to be a consequence of headache, originating from the necessity for the analgesic to cope with everyday life.

Headache treatment before and after the consultation of a specialized centre: a pharmacoepidemiology study

Our aim was to study and compare pharmacoepidemiology of headache treatment in two different settings: inside and outside a specialized Centre. We analysed the differences in headache treatment between 612 subjects admitted for the first visit (‘naive’) (F/M: 2.41; mean age = 37.31 ± 14.09 years) and 620 subjects admitted for a control visit (F/M: 3.18; mean age = 44.30 ± 15.37 years) to the Headache Centre of the University of Modena and Reggio Emilia. Most patients suffered from migraine. As acute treatment, on the first visit, 49.4% of them were taking drugs prescribed by a doctor; 41.5% were taking over-the-counter analgesics (OTCAs); 9.1% were not taking any drug. On the control visit, 81.3% of patients were taking prescription drugs; 15.8% OTCAs; 2.9% were not taking drugs (overall chi-square = 139.229, P < 0.001). Non-selective analgesics were the most-used drugs. Triptans were used by 9.1% of ‘naive’ patients and by 31.8% of patients attending for the control visit (Fishers Z = 7.655, P < 0.001). Nimesulide was the most-used drug. A prophylactic treatment was made by 16.8% of ‘naive’ patients, and by 58.2% of patients admitted to the control visit (Fishers Z = 12.135, P < 0.001). Antidepressants were the class of drugs most used for prophylaxis. Amitriptyline was the drug for prophylaxis most frequently used by patients attending the control visit, while flunarizine was the most frequently used by ‘naive’ patients. Before being examined in a specialized centre, few patients take prescription drugs, triptans, or prophylactic drugs; specialized care increases the proportion of patients taking prophylactic drugs, and changes the type of acute treatment used into disease-specific medication for headache.

Effect of liver cirrhosis on the systemic availability of naltrexone in humans

BACKGROUND/AIMS Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. METHODS A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis. RESULTS In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. CONCLUSIONS Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

Emerging problems in the pharmacology of migraine: interactions between triptans and drugs for prophylaxis.

Patients suffering from migraine take drugs for many years in order either to relieve or to prevent recurrent migraine attacks. When two or more drugs are co-administered, there is always the possibility of drug-drug interaction. Interactions can be either kinetic or dynamic. The former are the most frequent ones. Mechanisms of kinetic interaction can be different, but the most common are represented by the induction or inhibition of enzymes of the cytochromes p450 (CYP) system. This system plays an important role in the disposition of a large number of drugs, including those used for migraine. This review examines the interactions between triptans-the most effective drugs for the therapy of migraine attacks-and drugs for migraine prophylactic treatment.

Determination of naltrexone and 6β-naltrexol in plasma by high-performance liquid chromatography with coulometric detection

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.

Analgesic Drug Taking: Beliefs and Behavior Among Headache Patients

Objective. —To explore beliefs and behavior with respect to analgesic drug taking in headache patients. To compare episodic headache to chronic headache sufferers.

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.