Dolors Capellà

Spontaneous reporting of adverse drug reactions to non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the third most commonly prescribed group of drugs in Spain. We present here the profile of adverse drug reactions (ADRs) attributed to them and reported to the Spanish System of Pharmacovigilance (SSPV) between 1983 and 1991, together with a preliminary analysis of topical, slow-release (SR) and enteric-coated (EC) preparations.Out of 18 348 reports of ADRs included in the SSPV database, 1609 (8.8%) implicated an NSAID. NSAIDs ranked second after antibiotics (15.1% of all reports) among the most commonly implicated drugs. Half of the patients were more than 55 years old, and 60% were women.Diclofenac (364 reports), piroxicam (282), indomethacin (197), naproxen (155), and ketoprofen (137) were the most commonly implicated NSAIDs in reports of ADRs.The most commonly reported ADRs were gastrointestinal (39%), cutaneous (20%), and those affecting the central and peripheral nervous system (9%). Seven reactions had a fatal outcome, and 138 were considered life threatening. Forty-nine reports included previously undescribed ADRs.There were 98 reports describing ADRs attributed to topical NSAIDs; 5 of these described 11 general reactions, such as duodenal ulcer, gastrointestinal bleeding, diarrhoea, dyspnoea, facial oedema, aggravation of bronchospasm, and angioedema.One hundred and sixty-eight reports referred to SR and EC preparations. The ratio of gastrointestinal to non-gastrointestinal reactions to SR-EC diclofenac was higher in the case of SR-EC diclofenac than in the case of plain diclofenac (P=0.037); similarly, the ratio of CNS to non-CNS reactions to SR-EC indomethacin was also higher than the corresponding ratio with plain indomethacin (P=0.002). Although differential selective reporting of these preparations cannot be excluded, these results raise doubts about the relative safety of SR and EC preparations of NSAIDs in practice.

Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.

Background The aim of this study was to describe the patterns of cannabis use and the associated benefits reported by patients with fibromyalgia (FM) who were consumers of this drug. In addition, the quality of life of FM patients who consumed cannabis was compared with FM subjects who were not cannabis users. Methods Information on medicinal cannabis use was recorded on a specific questionnaire as well as perceived benefits of cannabis on a range of symptoms using standard 100-mm visual analogue scales (VAS). Cannabis users and non-users completed the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI) and the Short Form 36 Health Survey (SF-36). Results Twenty-eight FM patients who were cannabis users and 28 non-users were included in the study. Demographics and clinical variables were similar in both groups. Cannabis users referred different duration of drug consumption; the route of administration was smoking (54%), oral (46%) and combined (43%). The amount and frequency of cannabis use were also different among patients. After 2 hours of cannabis use, VAS scores showed a statistically significant (p<0.001) reduction of pain and stiffness, enhancement of relaxation, and an increase in somnolence and feeling of well being. The mental health component summary score of the SF-36 was significantly higher (p<0.05) in cannabis users than in non-users. No significant differences were found in the other SF-36 domains, in the FIQ and the PSQI. Conclusions The use of cannabis was associated with beneficial effects on some FM symptoms. Further studies on the usefulness of cannabinoids in FM patients as well as cannabinoid system involvement in the pathophysiology of this condition are warranted.

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting

AIMS Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV. METHODS Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response. RESULTS Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups. CONCLUSION Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.

Stimulating adverse drug reaction reporting: Effect of a drug safety bulletin and of including yellow cards in prescription pads

AbstractBackground: The effectiveness of voluntary reporting systems in pharmacovigilance highly depends on the number of assembled reports. Aim: The aim of this study was to measure the effect of the periodical distribution of a bulletin on drug safety issues and of including yellow cards in prescription pads on the rate of adverse drug reaction (ADR) reporting. Study Design and Methods: The Catalan Centre of Pharmacovigilance began its activities at the end of 1982. Since 1985, an ADR bulletin (ADRB) has been mailed approximately quarterly to all physicians in its catchment area, with one yellow card enclosed. Additionally, from 1991–1994, a yellow card was included in the prescription pads of the Catalan Health Service. Time series methodology, with adjustment of the monthly number of reports to an Auto-Regressive Integrated Moving Average (ARIMA) model, was used to evaluate the effect of these two measures. Results: From January 1983—October 1995, 6240 spontaneous ADR reports were received, and 41 issues of the ADRB were sent out. Initially, the mean monthly spontaneous ADR reporting rate was 34.4 (SD = 14.1; n = 106 months). After the inclusion of yellow cards in prescription pads, the mean monthly spontaneous ADR reporting rate increased to 53.9 (SD = 14.4; n = 48 months). According to an ARIMA model, when a bulletin was send out (MONTH1), a mean increase of 9.4 reports was produced in that month, plus 12.3 additional reports in the following month (MONTH2), and 6.3 in the second month after sending the ADRB (MONTH3). A yellow card in the prescription pads elicits a monthly mean increase of 19.8 in the number of reports. Conclusions: The present study suggests that ADRBs elicit a temporal increase of the ADR reporting rate. Including a yellow card in prescription pads was followed by an even greater increase in the reporting rate, possibly because it guarantees that yellow cards are available at the workplace.

Efficacy of opiate maintenance therapy and adjunctive interventions for opioid dependence with comorbid cocaine use disorders: a systematic review and meta-analysis of controlled clinical trials

Aims: To determine the efficacy of Opiate Maintenance Therapy (OMT) and adjunctive interventions for dual heroin and cocaine dependence by means of a meta-analysis. Method: We searched for and retrieved randomized controlled clinical trials. We used RevMan 5.0 with random effects modeling for statistical analysis and for comparisons of relative risk, effect sizes, and confidence intervals. Subsequent moderator variables and sensitivity analyses were performed. Results: Thirty-seven studies, which have enrolled 3,029 patients, have been included in this meta-analysis. High doses of OMT were more efficacious than lower ones in the achievement of sustained heroin abstinence (RR = 2.24 [1.54, 3.24], p < .0001) but had no effect on cocaine abstinence. At equivalent doses, methadone was more efficacious than buprenorphine on cocaine abstinence (RR = 1.63 [1.20, 2.22], p = .002) and also appeared to be superior on heroin abstinence (RR = 1.39 [1.00, 1.93], p = .05). Several pharmacological and psychological potentiation strategies have been investigated. An improvement on sustained cocaine abstinence was achieved with indirect dopaminergic agonists (RR = 1.44 [1.05, 1.98], p = .03) and with contingency management (CM) focusing on cocaine abstinence (RR = 3.11 [1.80, 5.35], p < .0001). Conclusions: Dual opioid and cocaine dependence can be effectively treated with OMT in combination with adjunctive interventions. Higher OMT doses are preferable to lower ones and methadone to buprenorphine. OMT can be enhanced with indirect dopaminergic drugs and with CM focusing on cocaine abstinence.

Efficacy of indirect dopamine agonists for psychostimulant dependence: a systematic review and meta-analysis of randomized controlled trials.

Psychostimulant dependence is characterized by dopamine deficit, which could be reversed with indirect dopamine agonists (IDAs). A systematic review and meta-analysis of randomized, parallel-group, placebo-controlled clinical trials assessing the efficacy of IDAs in psychostimulant-dependent individuals were conducted. The study outcomes were psychostimulant abstinence, assessed by means of urinalysis, and retention in treatment. Risk of bias was determined using a Cochrane Collaboration instrument. Twenty-nine studies fulfilled the inclusion criteria, involving 2,467 participants. Compared with placebo, IDAs increased psychostimulant abstinence (standardized mean difference = 0.20; 95% confidence interval, 0.06-0.35; p = .005) but did not increase retention in treatment. Efficacy was larger in comorbid heroin-dependent individuals and was positively related with treatment length. No study was considered fully free of bias. IDAs appear to be efficacious for reducing psychostimulant use but did not improve retention. Efforts should be undertaken to reduce the risk of bias of clinical trials with psychostimulant-dependent individuals.

Novedades sobre las potencialidades terapéuticas del Cannabis y el sistema cannabinoide

Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.

Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression.

Atomoxetine is a non‐stimulant drug that could be an alternative to methylphenidate, whose benefit : risk balance for the treatment of adults with attention deficit hyperactivity disorder (ADHD) has recently been shown to be unclear. This study aimed to compare all‐cause discontinuation rate between atomoxetine and placebo in adults with ADHD. Secondarily, efficacy and safety were investigated.

Case-Population Studies in Pharmacoepidemiology

The case-population approach aims at providing a risk estimate by comparing the incidence of the disease of interest among those exposed to the drug under study with the incidence among the non-exposed. For that purpose, the cases with the disease of interest have to be ascertained independently of the exposure status. Their rate and pattern of exposure have to be ascertained by interview with a structured questionnaire. Information on the patterns and the prevalence of drug consumption is needed in order to estimate the rate of exposure, and drug consumption statistics can be used to this end. In this paper, we review the main characteristics of studies using this approach or a similar one, and studies where series of cases exposed to the drug of interest were compared with drug consumption statistics. We looked at selected basic methodological requirements. Most of the studies reviewed suffer from incomplete case ascertainment, inaccurate definition of the disease of interest, incomplete information on exposures and other risk factors, and/or limited control of potential confounding, among other limitations. All the reviewed studies had several limitations regarding the estimation of the population at risk.The methods used in case-population studies should be clearly described, particularly with respect to the identification of the cases (numerator) and the estimation of the consumption prevalence (denominator). Case-population studies can give approximate risk estimates, but the method should be validated by comparing its results with those of case-control studies.

Utilization of antihypertensive drugs in certain European countries

SummaryThe consumption of various groups of antihypertensive drugs in Spain during the period 1977–1981 has been measured by the DDD method. The total consumption of the drugs did not change much during this time. Combinations of thiazides with other hypotensives accounted for more than half the total antihypertensive drugs used. The consumption of rauwolfia and its derivatives, and of dihydralazine, was higher than of β-blockers and methyldopa. Total consumption of antihypertensives in 1981 was 37.5 DDDs/1 000 inhab/day, which was much lower than in Denmark (136.6 DDDs/1 000 inhab/day), Finland (114.5), Iceland (92.2), Norway (89.4) and Sweden (138.7). Wide qualitative differences between countries were also identified. Although other factors may play a role, it is suggested that these striking differences may be due to differences in general health policy and in the pharmaceutical markets.