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The 'temporary recommendation for use' (TRU) is a French novel regulatory measure for off-label drug. The first TRU to be issued by the French drug agency (in March 2014) pertained to the off-label use of baclofen for alcohol dependence (AD). We performed a questionnaire-based survey of the on-the-ground application of the baclofen TRU among community pharmacies in northern France. A pharmacist from 70 of the 219 pharmacies contacted (response rate: 32.0%) completed the questionnaire. The mean ± standard deviation number of off-label baclofen prescriptions for AD was 2.3 ± 2.2 per pharmacy per month. 65.2% of these prescriptions were issued by primary care physicians. 65.7% of the pharmacists had never seen 'TRU' written on the prescription, and 80.3% delivered a prescription without checking whether the patient had been included by the prescriber in the TRU. The main criterion used to identify off-label prescribing was the patient's medical history (according to 74.6% of pharmacists) and the prescription of an above-threshold dose (73.1%). 87.1% of the pharmacists were aware of the baclofen TRU, and 42.9% had actually read the document. 17.9% of the pharmacists estimated that the TRU had changed their attitude to off-label baclofen prescription, and 29.9% (20 out of 67) of them wanted to be more involved in the TRU process. Community pharmacists were well informed about the off-label use of baclofen for AD and the TRU. However, a majority of baclofen prescribers did not fulfill the TRU requirements while a majority of pharmacists did not exert any control over these off-label prescriptions. In practice, in 2015 the TRU measure had thus a limited impact on both the baclofen prescribing and delivery practices., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Objective: Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence., Methods: Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC., Results: One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64])., Conclusion: The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses., (Copyright © 2017 John Wiley & Sons, Ltd.)

Introduction: Off-label prescribing (OLP) may raise serious safety concerns that traditional spontaneous reporting of adverse drug reactions (ADRs) may not identify in a timely manner. In France, the 'Multidisciplinary Consultation Service for Off-Label Prescribing in Addiction Medicine' (CAMTEA) is a proactive regional system established to identify ADRs associated with the OLP of baclofen for alcohol dependence., Objective: The aim was to demonstrate, using the French pharmacovigilance database (FPVD), that CAMTEA allowed for the reporting of a substantial amount of ADRs, comparable in nature to those provided via spontaneous reporting., Method: The 2012-2013 FPVD notifications associated with baclofen OLP were extracted. The ten most frequent types of ADRs among 'serious' and 'non-serious' reports were listed. The frequency of each type of ADR was compared between CAMTEA and spontaneous reporting, and the magnitudes of the differences were assessed using standardized differences., Results: A total of 428 baclofen reports (1043 ADRs) were identified, among which 221 (51.64%) originated from CAMTEA. The ten most frequent ADRs in 'serious' reports were (1) confusion (17.3%), (2) seizures (11.5%), (3) drowsiness/sedation (11.5%), (4) agitation (10.9%), (5) coma (9.6%), (6) hallucinations (7.7%), (7) falls (7.1%), (8) behavioral disorders (5.8%), (9) withdrawal syndrome (5.1%), and (10) space-time disorientation (5.1%). A standardized difference of <0.2 was identified for six out of the ten most frequent 'serious' ADRs, and eight of the ten 'non-serious' ADRs., Conclusion: A proactive regional pharmacovigilance system could collect a substantial amount of safety data on a specific OLP practice. The profile of the ADRs collected was similar to that seen in the nationwide spontaneous reporting system.

Background: In France, baclofen is frequently used off-label for alcohol use disorder (AUD). Baclofen has been associated with diverse adverse events (AEs), but the causality of these AEs has never been properly assessed., Methods/design: BACLOPHONE is a prospective multicenter cohort study conducted in the Hauts-de-France and Normandie French regions. BACLOPHONE consists of the phone-based monitoring of 792 patients during their first year of baclofen treatment for AUD. Two initial phone interviews assess the medical history, current medications, and substance use as well as complete the alcohol use identification test (AUDIT) and severity of alcohol dependence questionnaire (SADQ). Daily alcohol use and baclofen doses are noted throughout the follow-up. For every reported AE, additional phone interviews determine the seriousness of the AE, the causality of baclofen using validated causality algorithms, and the final outcome. The main objective of the study is to determine the rate of patients who stop baclofen due to an AE during the first year of treatment., Discussion: BACLOPHONE will provide important safety data on baclofen as a complement to the forthcoming efficacy data of randomized clinical trials.

High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p<0.001), from 0.9% for AWAC=0 to 9.4% for AWAC >35. There was also a significant gradual risk for EMS associated with DDB (<0.001). Multivariate analysis demonstrated a significant interaction between DDB and AWAC on EMS risk (p=0.047). Each 20mg/d increase in DDB was associated with an OR of EMS in AWAC >35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Community pharmacists' liability is involved when they dispense off-label prescriptions (OLPs). However, their attitudes to off-label prescribing are little known, while in France off-label baclofen use for alcohol dependence is increasing., Objective: To determine community pharmacists' attitudes to off-label prescribing of baclofen., Method: A postal questionnaire was sent to 219 community pharmacies in the Nord-Pas-de-Calais region, France, previously identified as delivering at least five boxes of oral baclofen monthly. The questionnaire examined whether pharmacists delivered baclofen for alcohol dependence, how pharmacists detected off-label prescribing of baclofen, who were the most frequent prescribers (general practitioners or specialists), and pharmacists' attitudes to OLPs., Results: Eighty pharmacies responded (36.5 %). Detection criteria for OLPs were supra-threshold dose (77.3 %) and "off-label" written on prescription (52.5 %). General practitioners were the most frequent prescribers of off-label baclofen. Pharmacists were more likely to refuse to fill prescriptions not marked "off-label" (6.0 %) than correctly marked prescriptions (1.5 %). 85 % of respondents considered they lacked information on off-label use., Conclusion: Although community pharmacists felt they were poorly informed on off-label baclofen, the majority nevertheless delivered the drug. Since our survey, off-label baclofen prescribing has been strictly controlled in France. Pharmacists' current attitudes will need further evaluation.

The use of high dose baclofen for alcohol-dependence emerged in France from 2008 based on empirical findings, and is still off-label. However, due to the rapid increase in this prescribing practice, the French health authorities have decided to frame it using an extraordinary regulatory measure named "temporary recommendation for use" (TRU). Baclofen prescribers from CAMTEA, a regional team-based off-label system for supervising baclofen prescribing, which was developed much prior to the TRU, discuss herein the pros and cons of this measure and the applicability of its different aspects in the daily clinical practice., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

In France, the off-label use of high-dose baclofen (HDB) for alcohol dependence is spreading. HDB induces frequent neuropsychiatric adverse events (AEs). Borderline personality disorder (BPD) is a major axis-two psychiatric disorder that exposes to frequent comorbid alcohol dependence and increased risky behaviors. We investigated the drinking and safety outcomes of patients with BPD treated with HDB for comorbid alcohol dependence. In a prospective cohort of 204 patients with alcohol dependence treated by HDB, 23 patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for BPD. We paired two control participants without a psychiatric history with each BPD patient according to age and sex. We compared the average lengths of follow-up, average doses of baclofen received, rates of heavy drinking days, rates of serious AEs, and rates of AEs resulting in baclofen withdrawal. Between BPD patients (n=23) and controls (n=46), there were no significant differences in mean age (45.3±11.2 vs. 45.2±11.2 years), sex ratio (43.5% women), mean duration of follow-up (8.0±4.0 vs. 7.7±4.2 months; P=0.77), and average daily dose of baclofen (102.2±42.7 vs. 94.6±9.7 mg/day; P=0.44). However, the mean rate of heavy drinking days (74.3±25.3 vs. 41.7±33.3%; P<10E-4), the rate of serious AEs (65.2 vs. 6.5%; P<10E-4), and the rate of treatment discontinuation after AEs (52.2 vs. 8.6%; P<10E-4) were significantly higher in BPD. The benefit/risk balance of HDB appears to be unfavorable in comorbid BPD patients compared with nonpsychiatric patients.

Objective: The γ-aminobutyric acid type B (GABA-B) receptor agonist baclofen is approved for spasticity up to the dose of 80 mg/d. Recently, off-label use of high-dose baclofen (HDB), up to 400 mg/d, has been increasing for treating alcohol use disorders (AUDs), although the efficacy and safety profiles of HDB are relatively unknown. We report 2 cases of tinnitus in patients treated with HDB for AUD., Case Summaries: The first case concerns a 60-year-old man who reported tinnitus when he reached a 180 mg/d dose of baclofen after 3 months of treatment. Tinnitus persisted until the dose was reduced to 90 mg/d. The second case concerns a 45-year-old woman who presented with tinnitus when she reached a 210 mg/d dose of baclofen after 4 months of treatment. Tinnitus persisted until the dose was reduced to 60 mg/d., Discussion: Using the Naranjo scale, imputability to baclofen was considered probable in both cases. GABA-B receptors have been reported to be implicated in both the etiology and the treatment of tinnitus. There may be an individual susceptibility to develop tinnitus under baclofen therapy because of some GABA-B genetic polymorphisms that remain to be determined., Conclusion: HDB may be responsible for the occurrence of severe tinnitus, possibly in a dose-dependent manner. This appears to be coherent with the previously known involvement of GABA-B receptors in the pathophysiology of tinnitus.

The off-label prescribing of high dose baclofen (HDB) has been recently spreading in France. The impact of HDB on subjects with liver cirrhosis remains poorly known. The main pharmacodynamic and pharmacokinetic data on baclofen result from studies on healthy subjects or using low doses of treatment. The specific biodisponibility and elimination of HDB have not been studied yet in cirrhosis. National pharmacovigilance reports suggest that a careful use of baclofen or even HDB could be possible in compensated cirrhosis. However, theoretical risks of baclofen overdose exist in cases of hepatorenal syndrome or portosystemic shunt. Baclofen could also induce a specific pharmacological potentiation of hepatic encephalopathy and gastropathy. Within CAMTEA, a regional team-based multidisciplinary system for delivering and monitoring off-label medications in alcohol use disorders, a set of predefined precautions for using baclofen in cirrhosis have been implemented, until further information becomes available. These precautions notably consist of a protocolized process for declaring adverse events, and a hepatologic follow-up associated with the usual multidisciplinary care system set up within CAMTEA., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Baclofen is a γ-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes.

Off-label prescribing matches the using of medications outside the summary of product characteristics. Adverse drug reactions are often poorly studied in off-label situations, which may expose patients to additional safety risks, and impose taking specific precautions. The current off-label prescribing practice of baclofen for alcohol-dependence in France is a typical illustration of such a situation. CAMTEA is a regional system set up in 2010 in Northern France, which gathers addiction and pharmacovigilance specialists, and aims at strengthening the prescription supervising and the monitoring of some off-label medication used for addictive disorders, especially baclofen. Until now, institution or office-based pharmacists have not been implicated, whereas they engaged their liability when delivering off-labeled treatment and they may highly contribute to the patient monitoring and the spotting of adverse events. We propose hereby possible measures for involving pharmacists into the patient supervising system developed within CAMTEA. In the current French context concerning the off-label use of baclofen, which will be the first off-label prescribing practice to be framed by a new legal disposition called "temporary use recommendation", the key role of pharmacists should be highlighted., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies., (© 2010 Société Française de Pharmacologie et de Thérapeutique.)