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.

Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine in the treatment of episodic tension-type headache: a double-blind, randomized, nimesulide-controlled, parallel group, multicentre trial.

In this double-blind, randomized, parallel group, multicentre study the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine (IndoProCaf) and nimesulide were compared over an 8-h period in the treatment of two consecutive episodes of tension-type headache (TTH). Both drugs were administered orally. Of 54 randomized patients, 40 were compliant to the protocol. More patients on IndoProCaf than on nimesulide were pain-free at 2 h post-dose (45% vs. 10%; P<0.05), reached a pain reduction of at least 50% at 2 (75% vs. 30%; P<0.05) and 4 h post-dose (90% vs. 58%; P<0.05), and had a statistically significant lower mean time to a 50 and 100% pain reduction in the second TTH episode. A higher percentage of patients reached a 50 or 100% pain reduction at 2 h post-dose with IndoProCaf compared with nimesulide, in two of two treated TTH episodes. A clinically and statistically significant change within each treatment group over time was found for the severity of pain, the headache intensity difference (HID), the sum of headache intensity difference (SHID), the maximum headache intensity difference (MAXHID), the headache relief (HER), the sum of total headache relief (TOTHER) and the maximum headache relief (MAXHER). In conclusion, IndoProCaf showed to be superior, but globally not statistically different from nimesulide in the treatment of episodic TTH. Both drugs were very effective and well tolerated.

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 (Fisher's 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 (Fisher's 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.

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.

Quality assurance system using ISO 9000 series standards to improve the effectiveness and efficacy of the Headache Centre.

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.

Serum time course of naltrexone and 6 beta-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.

Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study.

BACKGROUND & AIMS: The efficacy of currently available therapeutic agents for cholestatic pruritus is often disappointing. The aim of this study was to assess the antipruritic effect of naltrexone, an oral opiate receptor antagonist. METHODS: Sixteen patients with pruritus of chronic cholestasis were randomized to receive naltrexone (4-week course of 50 mg naltrexone daily) or placebo. Pruritus, quality of sleep, fatigue (using visual analogue scales), side effects, and liver function were assessed every 2 weeks. Serum naltrexone and 6 beta-naltrexol concentrations in all patients and 5 healthy controls were measured during the first day of naltrexone treatment. RESULTS: Mean changes with respect to baseline were significantly different, in favor of the naltrexone group, for daytime itching (-54% vs. 8%; P < 0.001) and nighttime itching (-44% vs. 7%, P = 0.003). In 4 naltrexone-treated patients, side effects (transient in 3 cases) consistent with an opiate withdrawal syndrome were noted. No deterioration of the underlying disease was observed. Naltrexone and 6 beta-naltrexol levels did not differ between patients and controls, and there was no significant association with treatment response. CONCLUSIONS: For patients with cholestatic liver disease and itching, refractory to regular antipruritic therapy, oral naltrexone may be an effective and well-tolerated alternative.

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.

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. 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.

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 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).

High efficacy and low frequency of headache recurrence after oral sumatriptan. The Oral Sumatriptan Italian Study Group.

This multicentre, double-blind study compared (100 mg) sumatriptan administered orally with placebo in treating an acute attack of migraine; 238 patients were studied over a 48-h period. Four hours after treatment, 92 of the 142 evaluable sumatriptan patients (65%) showed significant reductions (P < 0.001) in headache severity, clinical disability and accompanying symptoms compared with 32 of the 80 evaluable placebo-treated patients (40%). The duration of attack prior to taking medication and the history of persistent migraine do not influence the observed difference between the two treatment regimens (sumatriptan and placebo), which remained statistically significant (P < 0.001) in both cases. The incidence of headache recurrence in patients who experienced relief 4 h after initial treatment was low, occurring in 16 (17%) and 4 (13%) of the sumatriptan- and placebo-treated patients, respectively. Only patients with a history of migraine attacks lasting longer than 24 h suffered headache recurrences, and these recurrences were not consistent with the International Headache Society definition of migraine. Treatment with sumatriptan was well tolerated.

Effects of chronic treatment with phenazone on the hot-plate test and [3H]serotonin binding sites in pons and cortex membranes of the rat.

Many reports indicate that nonsteroidal anti-inflammatory drugs exert their antinociceptive effect through adrenergic and serotoninergic systems. We investigated the acute and chronic effects of phenazone on the pain threshold and on brain serotonin binding sites. A relationship between phenazone serum levels and the antinociceptive effect was found; acute treatment with phenazone provokes a significant decrease in serotonin binding sites both in the pons and cerebral cortex after 2, 4 and 8 h, but not after 24 h. After 15 and 30 days of treatment, the number of binding sites increases both in the pons and cortex.

Production of lipid hydroperoxides and depletion of reduced glutathione in liver mitochondria after acute ethanol administration to rats.

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.

Plasma glutathione level in paracetamol daily abuser patients. Changes in plasma cysteine and thiol groups after reduced glutathione administration.

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.

[New aspects of therapy in hemicrania]. / Nuovi aspetti di terapia nell'emicrania.

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.

Determination of naltrexone and 6 beta-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.

Dapiprazole compared with clonidine and a placebo in detoxification of opiate addicts.

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.

Effects of long-term treatment with naltrexone on hepatic enzyme activity.

The influence of naltrexone on liver function in heroin addicts was studied, with respect to the metabolizing function by using the antipyrine clearance and to cellular damage by monitoring plasma levels of hepatic enzymes. The clearance of antipyrine was not affected by naltrexone treatment, and, during the study period, the use and withdrawal of benzodiazepines and alcohol did not change this parameter; moreover, there was no relationship between changes in plasma hepatic enzymes and antipyrine half-life. Mean plasma levels of hepatic enzymes did not show significant modification in the course of treatment with naltrexone.

Pharmacokinetics of tiaprofenic acid after oral administration in fasting patients during and between migraine attacks.

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.