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Objective Rapid relapses after successful withdrawal occur even in apparently motivated benzodiazepine (BZD)-dependent patients. Regardless of known personality or biological (re-adaptation) issues, the aim of this open-label, single-arm, seminaturalistic study was to search for any detoxification errors contributing to failures. Methods The data came from 350 inpatients. Based on serum-BZD evolution criteria, the procedure was divided into four stages: substitution, accumulation, elimination and post-elimination observation. After switching the patients to a long-acting substitute (diazepam), to prevent data falsification due to unwanted overaccumulation, the doses were expeditiously reduced under laboratory feedback until accumulation stopped. With the start of effective elimination, the tapering rate slowed and was individually adjusted to the patient’s current clinical state. The tracking of both serum-BZD concentration and the corresponding intensity of withdrawal symptoms was continued throughout the entire elimination phase, also following successful drug withdrawal. Detoxification was concluded only after the patient's post-elimination stabilization. Results Regardless of various initial serum-BZD concentration levels and the customized dose-reduction rate, and despite the novel lab-driven actions preventing initial overaccumulation, elimination was systematically proven to be protracted and varied within the 2- to 95-day range after the final dose. Within this period, withdrawal syndrome culminated several times, with varying combinations of symptoms. The last crisis occurrence (typically 2–3 weeks after withdrawal) correlated with the final serum-BZD elimination. The factors that prolonged elimination and delayed the final crisis were patient age, duration of addiction, adjunct valproate medication and elimination stage start parameters growing with former overaccumulation. Conclusions The low-concentration detoxification stage is critical for patients’ confrontations with recurring withdrawal symptoms. Underestimated elimination time following drug withdrawal and premature conclusions of detoxification expose patients to unassisted withdrawal crises. Concentration tracking defines proper limits for medical assistance, preventing early relapses.

Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.

No information is currently available on genetic determinants of short-term response to drug withdrawal in medication overuse headache (MOH). In the present study, we aimed to evaluate the role of 14 polymorphisms in 8 candidate genes potentially relevant for drug addiction (OPRM1, DRD2, DBH, COMT, BDNF, SLC6A4, 5HT2A, and SLC1A2) as predictors for detoxification outcome of MOH patients at 2 months of follow-up.Genotyping was conducted by PCR, PCR-RFLP analysis, or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. The association between gene variants and risk of unsuccessful detoxification was evaluated by univariate and multivariate logistic regression analyses.One hundred and eight MOH patients with effective drug withdrawal therapy and 65 MOH patients with unsuccessful detoxification were available for the analysis. In the multivariable logistic regression analysis, triptan overuse (odds ratio (OR) 0.271, 95% confidence interval (CI) 0.083-0.890, P = 0.031) and TT genotype carriage of DRD2 NcoI (OR 0.115, 95% CI 0.014-0.982, P = 0.048) emerged as independent predictors for unsuccessful detoxification. In addition, carriers of at least four of the six top-ranked gene variants (P 0.10) were found at higher odds for unsuccessful detoxification than patients with ≤3 high-risk genotypes (OR 3.40, 95% CI 1.65-7.01, P = 0.001).This exploratory study suggests that DRD2 NcoI may be a genetic determinant of detoxification outcome in MOH patients. Our findings also show that an approach based on the combination of multiple genetic markers could be clinically useful for identification of MOH patients at higher risk for unsuccessful detoxification.

Objective: Withdrawal of a drug from the market for safety reasons is a serious and sometimes complex decision. The scientific evidence supporting drug withdrawals in the past years is critically appraised. Methods: With data provided by the Spanish Medicines Agency, all drugs withdrawn from the Spanish market for safety reasons from January 1990 to December 1999 were identified. The adverse drug reactions (ADRs) were classified by the year of withdrawal, by the organ/system affected and by the alleged type of reaction (Rawlins and Thompson classification). A systematic review of the literature was performed. Results: A total of 22 drugs were withdrawn from the market due to safety reasons. In 18 of 22 cases (82%), the evidence supporting the drug withdrawal came from individual case reports, cases series or the combination of data provided by randomised clinical trials and case reports. Hepatic (eight cases) and cardiac (five cases) reactions accounted for 59% (13 of 22) of the total withdrawals. In 10 of 22 (45%) cases, drug withdrawal was clearly due to type-B reactions. Only four withdrawals were based on evidence from observational studies including a comparison group. Conclusion: Case reports are the main source of information used to withdraw a drug from the market for safety reasons. It is necessary to improve the quality of evidence supporting the withdrawal process of drugs linked to unexpected and severe ADRs. The use of large databases to perform cohort or nested case-control analyses is the most efficient and reliable method to study type-A class effect ADRs. The implementation of such databases in different countries could increase the quality of the information on ADRs by allowing researchers to conduct efficiently these type of studies.

Dapsone, a sulfone active against a wide range of bacteria, is mainly used for Mycobacterium leprae. Moreover, because of its immunosuppressive effect, it is used for many auto-immune diseases [1]. Methaemoglobinemia is an expected adverse drug reaction of dapsone, seldom symptomatic. Long-term administration of dapsone at standard doses (100 mg/day) results in methaemoglobinemia in about 15% of patients [2]. When symptomatic (dyspnea, cyanosis, neurological disorders), methaemoglobinemia is treated with methylene blue (1–2 mg/kg) [3]. Rebounds have been described after dapsone withdrawal, with a maximum delay of 64 h [4]. We report a case of dapsone-induced methaemoglobinemia which relapsed 10 days after drug withdrawal. A 25-year-old woman was diagnosed with systemic lupus erythematosus in January 2009. Organs involved were skin and joints, and hydroxychloroquine alone was prescribed. In October 2009, she developed a bullous dermatitis and dapsone was added to hydroxychloroquine on 26 October 2009. About 1 month later, on 24 November, she was admitted to the hospital for severe dyspnea. Physical examination was normal except for cutaneous cyanosis. Chest computed tomography and electrocardiogram were normal. Arterial blood gas analysis showed pH: 7.63, PaO2: 110 mmHg, PaCO2: 15 mmHg, haemoglobin: 11 g/dL, SaO2: 99.1%; methaemoglobin: 17%. Methylene blue (2 mg/kg) was injected intravenously. Twenty minutes later, the patient was asymptomatic and arterial methaemoglobin was 4%. Dapsone was discontinued and the patient left the hospital on 26 November. Ten days later, she consulted for relapse of dyspnea. Arterial blood gas analysis showed methaemoglobin at 14%. No symptomatic treatment was done and methaemoglobin rate decreased spontaneously to 5% the next day. Hydroxychloroquine was stopped. The compliance of the patient was not doubtful, and no other cause of intoxication causing methaemoglobinemia was found. Methaemoglobinemia in dapsone intoxication is due to the ability of dapsone hydroxylamine, a metabolite of the drug, to react with haemoglobin (Fe) to form methaemoglobin (Fe) [5]. Methaemoglobin is unable to bind dioxygen, which results in functional anaemia. The clinical G. Moulis Service de Medecine Interne, Centre Hospitalier Universitaire de Toulouse, Universite Paul-Sabatier, Toulouse, France e-mail: gmoulis@hotmail.com

Temazepam, 7.5 mg was evaluated in the sleep laboratory in 8 elderly insomniacs, using a 14-night protocol (4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights). With short-term use temazepam was found to be effective, producing a significant improvement in total wake time from baseline (100 vs. 145 min). With continued drug administration, total wake time remained below baseline but not significantly so (125 vs. 145 min). During drug administration, there were no major CNS and behavioral adverse effects reported such as daytime sedation, memory impairment or hyperexcitability (daytime anxiety). Following drug withdrawal, there was no significant increase in wakefulness, i.e., no rebound insomnia (150 vs. 145 min). In summary, temazepam, 7.5 mg is effective in elderly subjects with short-term use and has a minimum of adverse effects. Use of hypnotic drugs is an adjunctive therapy which should be for a short-term period with subsequent short-term intermittent use as needed. Because of its low propensity for producing rebound insomnia, temazepam can be effectively used in this manner.

Brotizolam 0.25 mg was evaluated in a sleep laboratory study of 10 normal subjects. The study covered 10 consecutive nights and included 4 placebo-baseline nights, 3 nights on the drug and 3 placebo-withdrawal nights, which permitted assessment of initial drug effects, side effects and withdrawal phenomena, such as rebound insomnia. There was a significant increase in total sleep time with drug administration; the improvement in sleep occurred primarily in the first third of the night following the onset of sleep. During the day after nightly drug administration, the presence of rebound anxiety was suggested by an increase in reports of anxiety/tension as compared to baseline. Following drug withdrawal there was a significant increase in total wake time above baseline level, to 40% above baseline on the first and third nights of withdrawal.

The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug.

In 39 patients who had been treated with metoprolol 100-200 mg daily or placebo for three years after acute myocardial infarction, serum lipids and lipoproteins were studied while the patients were on treatment as well as after its withdrawal. Withdrawal was performed over 1 week. Treatment had to be reinstituted in 6 patients (1 ex placebo and 5 ex metoprolol) because of aggravated symptoms. During the entire study period total cholesterol was significantly higher in the metoprolol withdrawal group and LDL cholesterol tended to be higher. HDL cholesterol in both groups increased significantly during the initial 28-day period following withdrawal of treatment. In both groups VLDL triglycerides tended to decrease during the first 28 days without treatment. Other lipoprotein fractions in both groups were unchanged. Overall, in patients who tolerated the ending of 3 years of treatment with metoprolol after myocardial infarction, there was no significant effect on lipoprotein fractions as compared to a placebo group.

Nine patients with essential hypertension completed a clinical trial designed to study the effects and side effects of administration and withdrawal of guanfacine (2 mg tds) and methyldopa (250 mg tds) on blood pressure, heart rate, and plasma noradrenaline. The study was of randomised doubleblind crossover design with two active therapy phases of eight weeks each, preceded by an initial 4 week placebo phase, separated by an intermediate 2 week placebo phase, and followed by a final 2 week placebo phase. Patients took bendrofluazide 5 mgs daily throughout the entire trial, during both active and placebo periods. Each patient was admitted to hospital at the end of the 8 week active treatment phases, so that the effects of drug withdrawal on blood pressure, heart rate, plasma noradrenaline and side reactions, could be closely observed and monitored. The main conclusions from analysis of the results were that: 1. The hypotensive efficacy of guanfacine and methyldopa was very similar in the doses used, each of the two drugs lowering the supine mean arterial pressure by about 15 mm Hg and the supine diastolic pressure by about 10 mm Hg. 2. The frequency of side effects was greater with guanfacine than with methyldopa. 3. There was no signficant early rebound phenomenon after withdrawal of either methyldopa or guanfacine. 4. There was tendency for the blood pressure to rise slowly and marginally above initial placebo values, 2 weeks after cessation of guanfacine treatment though this was not significant. It was however, accompanied by a significant increase in plasma noradrenaline at 2 weeks. This was not seen 2 weeks after cessation of methyldopa. There was no single incidence of worrying rebound hypertension or withdrawal symptoms either early or late in any patient following cessation of methyldopa or guanfacine.