Slow-release oral morphine sulfate abuse: results of the postmarketing surveillance systems for psychoactive prescription drug abuse in France.

BACKGROUND: Few data are available concerning the diversion and abuse of morphine sulfate. In France, morphine sulfate abuse is currently investigated by the health authorities. The aim of our study was to provide data on morphine sulfate abuse in France, collected during the period 1996-2011. METHODS: The French monitoring system for psychoactive medication abuse collected data from several sources: spontaneous reporting of cases of abuse or dependence (NotS; 'Notifications Spontanées'), specific periodic surveys from specialized care centers (OPPIDUM; 'Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse'), and community pharmacists (OSIAP; 'Ordonnances Suspectes Indicateur d'Abus Possible'). RESULTS: A total of 649 cases (75% men, median age: 34 years) were spontaneously reported: 578 cases of abuse and 71 cases of use as opiate maintenance treatment. The medication formulation was Skenan(®) (614 cases), and Moscontin(®) (35 cases). All surveys (NotS, OPPIDUM, and OSIAP) showed an overrepresentation of Skenan(®) (87.9-94.6% of cases) that was intravenously injected in 60.4-61.2% of the cases. Data analysis showed that patients abusing morphine sulfate have a long history of drug abuse and a history of polydrug use. CONCLUSION: All the data presented in this study highlight the level of morphine sulfate abuse, specify the modalities of use (intravenous route), and show the risks associated with abuse (infectious diseases). This study outlines the usefulness of our epidemiological tools, and provides evidence supporting intensive surveillance.

[Psychiatric disorders associated with high-dose methadone (>100 mg/d): a retrospective analysis of treated patients]. / Co-morbidités psychiatriques associées à des fortes posologies de méthadone (> 100 mg/j) : analyse rétrospective d'une cohorte de patients traités.

BACKGROUND: Recent studies show that high-dose methadone (>100 mg/d) allow a better control of the consumptions of illicit opiates by treated patients. OBJECTIVE: The aim of this retrospective study was to analyze data of patients requiring high-dose methadone (>100 mg/d) as well as associated factors. METHODS: We retrospectively reviewed charts of treated patients with high-dose methadone followed in the maintenance methadone treatment center between 01/01/07 and 01/07/10. The following variables (medical history, psychiatric comorbidities, associated drugs, and polyaddictions), were assessed with high-dose methadone, using an univariate and then a multavariate analysis. The threshold value of 130 mg/day (median of maximal daily dose) was used to perform analysis. RESULTS: During the study period, 78 patients, mainly men (75.6%), with a median age of 34 years [22-57] were included. The both groups with posology of methadone ≤ 130 mg/d (n=44) versus posology of methadone >130 mg/d (n=34) were close in term of demographic characteristics, consumption of drugs and associated treatments. Plasma methadone concentrations were higher in patients with the daily doses of methadone superior than 130 mg/d (NS), as well as the methadone metabolite (EDDP, p=0.048). Among studied factors, the presence of psychiatric comorbidities was significantly associated with high-dose methadone (threshold 130 mg/d) [OR 4,6 IC 95% (1.412;14.925)]. Seven patients presented with complications related to methadone: cardiac disorder (3), libido troubles (3) and hypofertility (1). CONCLUSION: Patients requiring high-dose methadone are polydrug addicts. In our study, patients with psychiatric comorbidities needed daily dose of methadone significantly more raised.

Hepatitis after intravenous injection of sublingual buprenorphine in acute hepatitis C carriers: report of two cases of disappearance of viral replication after acute hepatitis.

OBJECTIVE: To report 2 cases of acute hepatitis related to intravenous administration of buprenorphine in hepatitis C-infected patients. CASE SUMMARY: Two patients, aged 33 and 50 years, respectively, who were hepatitis C virus (HCV) carriers were treated with sublingual buprenorphine 8 mg/day for addiction. Several years after initiation of buprenorphine, they were hospitalized because of clinical hepatitis with jaundice that developed after intravenous injection of buprenorphine. Serum alanine aminotransferase rose to 100 times the upper limit of normal (ULN) in the first patient and to 21 times the ULN in the second. As cofactors, the first patient had consumed alcohol, and the second patient took aspirin 600 mg in addition to the injection of buprenorphine 20 mg 4 days before the onset of jaundice. After stopping the intravenous injections, both patients continued sublingual buprenorphine therapy, with no relapse of hepatitis. Interestingly, in these 2 patients, buprenorphine-induced hepatitis was followed by the disappearance of HCV RNA. DISCUSSION: Most cases of hepatotoxicity related to buprenorphine have occurred in hepatitis C-infected patients. The main mechanism for buprenorphine-induced hepatitis is a mitochondrial defect, exacerbated by cofactors with additional potential to induce mitochondria dysfunction (eg, HCV, alcohol, concomitant medications). According to the Naranjo probability scale, buprenorphine was found to be the probable cause of acute hepatitis in both patients. In addition, we assessed the relationship between intravenous buprenorphine and acute hepatitis using 2 scales for causality assessment of hepatotoxicity (the Council for International Organizations of Medical Sciences scale and the Maria & Victorino scale). The diagnosis of intravenous buprenorphine-induced hepatitis was classified as probable in both cases. In addition, these 2 cases illustrate that acute hepatitis in a carrier of chronic HCV may occasionally facilitate the clearance of virus. CONCLUSIONS: Although buprenorphine is well tolerated when used at recommended sublingual doses, patients should be informed about the risk of acute hepatitis with misuse of the drug by the intravenous route. These cases illustrate that, in carriers of chronic HCV, acute hepatitis may modify the host's immunotolerance and facilitate clearance of the virus.

Antipsychotics-induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database.

PURPOSE: First- and second-generation antipsychotics commonly cause mild gastrointestinal hypomotility. Intestinal necrosis may be a consequence of such gastrointestinal perturbations. MATERIAL AND METHODS: We reviewed all the observations of ischaemic colitis and gastrointestinal necrosis notified to the French Pharmacovigilance database (FPD) between 1997 and the end of 2006. RESULTS: Thirty-eight cases of ischaemic colitis and gastrointestinal necrosis associated with antipsychotics were analysed. The average age of the patients was 42.7 +/- 14.7 years (15-77 years). The digestive complication was an intestinal necrosis in 27 cases, an ischaemic colitis in 10 cases (with perforation in three cases), and one perforation. Surgical procedure (partial or total resection of the colon and/or small intestine) was performed in 24 patients. Six patients died despite surgery. Among the whole population, the outcome was fatal in 14 patients, 13 patients recovered with sequelae, six patients fully recovered, and the outcome remained unknown in five cases.In 55.2% of the cases, the patients were treated with more than one antipsychotic medication. The most frequently involved antipsychotics were: clozapine, levomepromazine, cyamemazine, haloperidol. Associated antimuscarinic drugs (excluding antipsychotics) were found in 68.4% of patients. DISCUSSION/CONCLUSION: Intestinal necrosis associated with antipsychotics is very rare; however mortality is high, with a rapid worsening of patients towards septic shock in spite of mild clinical symptoms. It is therefore essential to monitor the patients receiving antipsychotics especially when they are prescribed concomitant medications. The occurrence of non-specific clinical symptoms such as abdominal pain associated with vomiting and/or diarrhea should draw attention.

Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database.

BACKGROUND: The most common adverse effects of voriconazole reported during clinical trials were disturbances of vision (30% of pts.), skin rashes (17.3%), and elevations in hepatic enzymes level (approximately 10% of pts.; varying with enzymes). However, postmarketing data concerning safety of voriconazole are limited. OBJECTIVE: To describe voriconazole adverse drug effects (ADEs) after 4 years of the drug's availability in France and determine their occurrence. METHODS: All cases of ADEs including voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 were analyzed. For each case, the following data were recorded: age, sex, indication, concomitant disease, concomitant medications, and ADE description. Causality link between voriconazole and ADEs was performed using the Naranjo probability scale. RESULTS: A total of 227 ADE cases were reported in 178 adults and 9 children (<12 y), with 66% occurring in males. The patients' median age was 49.6 (2-80) years. ADEs included liver function test abnormalities (23%), visual disturbances (18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events (10%), hematologic disorders (8%), and renal disturbances (4%). Other less commonly identified ADEs included headache, nausea, vomiting, and diarrhea. Drug-drug interactions were observed in 7 cases. According to the Naranjo criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful. CONCLUSIONS: Most ADEs found in this study are well documented in the literature, except for cardiac complications, which are rarely reported. Few ADEs related to drug interactions were observed; however, due to the extensive metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be aware of potential interactions between voriconazole and other drugs metabolized through this pathway.

Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma.

Carbamazepine (CBZ) and oxcarbazepine (OXCBZ) are both antiepileptic drugs, which are prescribed as first-line drugs for the treatment of partial and generalized tonic-clonic epileptic seizures. In this paper, a specific and sensitive liquid chromatography-electrospray ionization mass spectrometry method was described for the simultaneous determination of carbamazepine (CBZ), oxcarbazepine (OXCBZ) and eight of their metabolites [CBZ-10,11-epoxide (CBZ-EP), 10,11-dihydro-10,11-trans-dihydroxy-carbamazepine (DiOH-CBZ), 10-hydroxy-10,11-dihydroCBZ (10-OH-CBZ), 2-hydroxycarbamazepine (2-OH-CBZ), 3-hydroxycarbamazepine (3-OH-CBZ), iminostilbene (IM), acridone (AO) and acridine (AI)] in human plasma. The work-up procedure involved a simple precipitation with acetone. Separation of the analytes was achieved within 50 min using a Zorbax eclipse XD8 C8 analytical column. The mobile phase consisted of a mixture of acetonitrile-formate buffer (2 mM, pH 3). Detection was performed using a quadrupole mass spectrometer fitted with an electrospray ion source. Mass spectrometric data were acquired in single ion recording mode at m/z 237 for CBZ, m/z 180 for CBZ-EP and AI, m/z 236 for OXCBZ, m/z 237 for 10-OH-CBZ, m/z 253 for 2-OH-CBZ, 3-OH-CBZ and DiOH-CBZ, m/z 196 for AO and m/z 194 for IM. For all analytes, the drug/internal standard peak height ratios were linked via a quadratic relationship to plasma concentrations. The extraction recovery averaged 90% for CBZ, 80% for OXCBZ and was 80-105% for the metabolites. The lower limit of quantitation was 0.5mg/l for CBZ, 0.4 mg/l for OXCBZ and ranged from 0.02 to 0.3 mg/l for the metabolites. Precision ranged from 2 to 13% and accuracy was between 86 and 112%. This method was found suitable for the analysis of plasma samples collected during therapeutic drug monitoring of patients treated with CBZ or OXCBZ.

[Assessment of renal abnormalities in 107 HIV patients treated with tenofovir]. / Evaluation de la tolérance rénale du ténofovir dans une cohorte de 107 patients.

OBJECTIVES: The objectives of our study were to assess frequency, severity and outcome of renal abnormalities, as well as to determine the risk of developing hypophosphataemia in HIV-infected patients receiving tenofovir. METHODS: An observational study was conducted in real-life conditions, during a 6-month period, in 107 HIV patients receiving tenofovir. RESULTS: Mild-to-moderate hypophosphataemia (<0.77 mmol/L) occurred during follow-up, at least once in 43% of patients and at least twice in 27%. Antiretroviral therapy including ritonavir + lopinavir was significantly associated with the occurrence of hypophosphataemia (relative risk = 2.6; p = 0.03). Frequency of abnormal proteinuria was 22%. CONCLUSION: Creatinine clearance, phosphataemia, proteinuria and glycosuria should be closely monitored in patients receiving tenofovir therapy.

[Drug-induced movement disorders: tardive syndromes]. / Mouvements anormaux d'origine médicamenteuse: les syndromes tardifs.

Persistent drug-induced movement disorders (tardive syndromes) remain an important clinical problem and consist of a variety of involuntary movements appearing in a patient exposed to a dopamine-blocking agent. The current state of knowledge on this topic is summarised in this article. Clinical aspects (tardive dyskinesia, tardive dystonia and other forms), prevalence, risk factors, prevention and management are discussed.

[Acute haemorrhagic pericarditis following influenza vaccination]. / Péricardite aiguë hémorragique avec tamponnade après vaccination antigrippale.

INTRODUCTION: Pericarditis following influenza vaccination is a rare complication. The few cases reported in the literature were all benign. OBSERVATION: An 87 year-old man developed a haemorrhagic pericarditis following an influenza vaccination. The outcome was rapidly favourable after surgical pericardiectomy followed by treatment with colchicine. In the absence of etiology, the hypothesis of post-vaccination pericarditis was proposed. COMMENTS: Despite its low incidence, the hypothesis of post-vaccination pericarditis must be evoked. Diagnosis therefore relies on various arguments. Although usually benign, medical and surgical treatments were required in our patient.

An overview of the use of music therapy in the context of Alzheimer's disease: a report of a French expert group.

OBJECTIVES: The aim of this overview is to present the developments of music therapy in France, its techniques, mechanisms and principal indications, mainly in the context of Alzheimer's disease. METHODS: An international review of the literature on music therapy applied to Alzheimer's disease was conducted using the principal scientific search engines. A work group of experts in music therapy and psychosocial techniques then considered the different points highlighted in the review of literature and discussed them. RESULTS AND DISCUSSION: Clinical and neurophysiological studies have enlightened some positive benefits of music in providing support for people with Alzheimer's disease or related disorders. Music therapy acts mainly through emotional and psycho-physiological pathways. It includes a series of techniques that can respond to targeted therapeutic objectives. Some studies have shown that music therapy reduces anxiety, alleviates periods of depression and aggressive behaviour and thus significantly improves mood, communication and autonomy of patients. CONCLUSION: Psychosocial interventions, such as music therapy, can contribute to maintain or rehabilitate functional cognitive and sensory abilities, as well as emotional and social skills and to reduce the severity of some behavioural disorders.

Neuroleptic malignant syndrome-like reaction precipitated by antipsychotics in a patient with gamma-butyrolactone withdrawal.

We report the case of a patient with chronic abuse of gamma-butyrolactone (GBL, 3 bottles per week for 4 months), who in the course of the management of acute agitation and hallucinations developed symptoms compatible with both neuroleptic malignant syndrome and GBL withdrawal symptoms.Some GHB withdrawal symptoms are similar to those of neuroleptic malignant syndrome, and the administration of antipsychotics might worsen the neurological condition of patients. So, it seems important to rapidly detect drugs taken by patients with mental agitation, to optimize management and minimize complications related to drugs.

Neurotoxicity related to valganciclovir in a child with impaired renal function: usefulness of therapeutic drug monitoring.

OBJECTIVE: To report a case of neurotoxicity related to antiviral drugs, discuss the involvement of concomitant medications, and document the pharmacokinetics of ganciclovir (administered as valganciclovir) in a child with impaired renal function. CASE SUMMARY: A 13-year-old boy with acute lymphoblastic leukemia was treated for cytomegalovirus retinitis with valganciclovir 450 mg every 2 days in the course of hematopoietic stem cell transplantation. Concomitant medication included omeprazole, furosemide, and acetaminophen. During treatment, when creatinine clearance decreased to 20 mL/min, the child presented with acute neurotoxicity, consisting of mental confusion and hallucinations, which resolved when all medications were stopped. Valganciclovir therapeutic monitoring showed high ganciclovir concentrations in the plasma (3.85 microg/mL) and cerebrospinal fluid (2.6 microg/mL) 48 hours after the last valganciclovir dose. After recovery of neurologic function, valganciclovir was resumed at a lower dosage (225 mg twice a week) with therapeutic drug monitoring and was well tolerated. However, the cytomegalovirus infection was not resolved. The leukemia relapsed, and the patient had terminal renal failure and died. The Naranjo probability scale indicated a probable relationship between valganciclovir and neurotoxicity. DISCUSSION: Drugs taken by this child (acyclovir, valganciclovir, omeprazole) have been reported to induce neurotoxicity, with the pharmacokinetics of the first 2 being altered by renal failure. At the time when acyclovir was first administered, symptoms of neurotoxicity were already apparent. Moreover, plasma concentrations of ganciclovir were very high during the course of the neurotoxicity. Thus, the adverse effects seemed related to an overdosage of valganciclovir and were worsened by the addition of acyclovir. CONCLUSIONS: This case is informative because few clinical and pharmacokinetic data are available concerning the use of valganciclovir in children. A study should be performed to determine the proper pediatric dose of valganciclovir with and without renal impairment to prevent the occurrence of adverse effects.

Comparison of pharmacovigilance algorithms in drug hypersensitivity reactions.

BACKGROUND: A firm diagnosis of drug hypersensitivity, because it may re-induce the reaction, is seldom confirmed. Causality assessment algorithms are therefore of interest. AIMS: The objective of this work was to compare three algorithms in the diagnosis of drug hypersensitivity. METHODS: Evaluation of 120 clinical histories of drug hypersensitivity was carried out: 60 involving beta-lactams (50%) and 60 involving non-steroidal anti-inflammatory drugs (50%). Each of these groups of patients underwent a standardised allergy diagnosis, which included a detailed anamnesis, skin tests and, often, provocation tests under strict hospital surveillance. Unaware of the final allergy diagnosis, scores were established for all of the cases and compared using algorithms suggested by Begaud and coworkers [2, 20], Jones [13] and Naranjo et al. [21]. RESULTS: Although the methods of Jones [13] and Naranjo et al. [21] were perfectly concordant (k=1), no concordance was noted using the Begaud and coworkers [2, 20] method. CONCLUSIONS: All three algorithms are dissimilar regarding the diagnosis of drug hypersensitivity.

Optimal management of methotrexate intoxication in a child with osteosarcoma.

OBJECTIVE: To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with osteosarcoma treated with high-dose MTX. CASE SUMMARY: During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations, acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2 and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient. Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations observed. DISCUSSION: According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo probability scale indicated a probable relationship between the complications and MTX. CONCLUSIONS: This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be considered.

Transitory ataxia related to topically administered lidocaine.

OBJECTIVE: To report 2 cases of transitory cerebellar ataxia related to lidocaine administered topically for endoscopy. case summaries: Two patients developed transitory cerebellar ataxia a few minutes after local anesthesia using lidocaine 10% spray and lidocaine 2% orally for a bronchoscopy and transesophageal echocardiography. This effect completely disappeared in 3-5 hours. In neither case was an alternate etiology of cerebellar ataxia identified. The second patient had previously experienced a similar reaction to lidocaine. DISCUSSION: Several central neurologic effects of lidocaine have been reported, but until now, only few cases of cerebellar ataxia. In these 2 cases, the Naranjo probability scale indicated that a probable and a highly probable relationship existed between lidocaine administration and the transitory cerebellar ataxia. CONCLUSIONS: Cerebellar ataxia may occur after local anesthesia with lidocaine; therefore, care must be taken to avoid overdose, even when administered topically.

Adverse drug events associated with hospital admission.

OBJECTIVE: To increase the knowledge base on the frequency, causality, and avoidability of adverse drug events (ADEs) as a cause for admission in internal medicine or when occurring during hospitalization. METHODS: A prospective study was performed for 6 periods of 8 days each. Epidemiologic data (e.g., age, gender, medical history), drug utilization, and adverse drug reactions on patients hospitalized during these periods were collected by a pharmacy student. RESULTS: A total of 156 patients (70 men and 86 women) were included in the study. The patients' mean age +/- SD was 66.5 +/- 18.1 years and mean length of stay was 13.2 +/- 9 days. Renal and hepatic insufficiency and previous history of drug intolerance were observed in 17.9%, 10.2%, and 2% of the hospitalized patients, respectively. Thirty-eight ADEs occurred in 32 patients; in 15 cases, ADEs were identified as the reason for admission, 10 cases occurred during hospitalization, and 13 cases were present at admission, but were not the cause of admission. The most frequent ADEs involved the neurologic (23.6%), renal (15.7%), and hematologic (13.1%) systems. Among these 38 ADEs, 22 were considered avoidable (57.9%); 20 of these were associated with therapeutic errors (inappropriate administration, drug-drug interactions, dosage error, drug not stopped despite the onset of ADEs). Patients with ADEs stayed longer in the hospital and took more drugs both before and during their hospital stay (p < 0.05). CONCLUSIONS: Most of the ADEs observed in this study were avoidable. The risk/benefit ratio of administered drugs could be improved with better knowledge of the patients' medical history and the risk factors of ADEs.

Are drugs a risk factor of post-ERCP pancreatitis?

BACKGROUND: Pancreatitis is the most severe complication of ERCP. The aim of this study was to assess whether the use of potentially pancreatotoxic drugs is a risk factor for post-ERCP pancreatitis. METHODS: Risk factors for post-ERCP pancreatitis and all drugs taken during the month before ERCP were recorded retrospectively in a database. Patients with other causes of acute pancreatitis or chronic pancreatitis were excluded from the analysis. Post-ERCP pancreatitis was defined as abdominal pain and/or vomiting associated with amylase/lipase plasma levels equal to or greater than twice the upper normal value. RESULTS: A total of 173 patients (95 men, 78 women; mean age, 68 [16] years) were included. Post-ERCP pancreatitis occurred in 31 patients (18%). Several risk factors were identified in a multivariate analysis: difficulty in cannulation (p<0.001), endoscopic sphincterotomy (p<0.005), and female gender (p=0.02). Having taken potent pancreatotoxic drugs increased the occurrence of post-ERCP pancreatitis: odds ratio 3.7: 95% confidence intervals [1.1,12.4], p=0.04. CONCLUSIONS: Use of pancreatotoxic drugs before or during ERCP significantly increased the risk of post-ERCP pancreatitis. Thus, discontinuation of the use of such drugs before ERCP seems justified whenever possible.