Sylvie Deheul

Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation

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.

Rectal Bleeding and Hemostatic Disorders Induced by Dabigatran Etexilate in 2 Elderly Patients

OBJECTIVE: To report rectal bleeding associated with hemostatic disorders in 2 elderly patients treated with dabigatran etexilate. CASE SUMMARY: A 79-year-old woman (weight, 69 kg) was hospitalized in a gastroenterology unit for severe rectal bleeding. She had been treated for 2 months with dabigatran etexilate 110 mg twice daily for chronic atrial fibrillation. On admission, her creatinine clearance (CrCl) was 20.7 mL/min/1.73 m2, prothrombin time (PT) less than 10% (reference range 70-130%), and international normalized ratio (INR) 14.5 (venous blood). Eleven days after admission, hematologic and renal function were normalized and rectal bleeding stopped. An 84-year-old man (weight, 71 kg) was admitted for rectal bleeding with acute renal failure and dehydration that began while he was treated with dabigatran etexilate 110 mg twice daily for atrial fibrillation. On admission, CrCl was 33.5 mL/min/1.73 m2, PT 13%, and INR 7.53 (venous blood). Dabigatran etexilate was stopped on admission. At the end of the hospitalization, CrCl was 66.5 mL/min/1.73 m2, PT 54%, and INR 1.53. In both cases, an objective causality assessment revealed that those adverse reactions were probably related to dabigatran etexilate. DISCUSSION: In these 2 cases of rectal bleeding during dabigatran etexilate therapy, coagulation monitoring showed elevated PT and INR; neither patient had been exposed to vitamin K antagonists. These cases indicate the importance of PT and INR monitoring when using dabigatran etexilate, mainly in patients with a high risk of overdose, such as elderly patients or those with renal function impairment. CONCLUSIONS: It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drugs anticoagulant effects.

Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder.

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.

Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study.

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.

Severe Tinnitus Induced by Off-Label Baclofen

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.

Baclofen for alcohol-dependence: anticraving or partial substitution?

To the Editors: A lthough the report by Ayan-Oshodi et al claims that LY404,039 does not have appreciable affinity for the dopamine D2 receptor, this claim is not correct. The only report where LY404,039 has been tested on the cloned D2 receptor clearly showed that LY404,039 inhibited the binding of 2 nM [H]domperidone to the human cloned D2 receptor with a dissociation constant of 8.2 nM at the high-affinity site of the D2 receptor and a dissociation constant of 1640 nM at the low-affinity site, as shown in Figure 1. Furthermore, the in vitro action of LY404,039 (Fig. 1, bottom) suggests a partial agonist action at D2 receptors. Nevertheless, these preclinical actions do not appear to be sufficient for LY404,039 to exert a convincing clinical antipsychotic action.

Proactive Regional Pharmacovigilance System Versus National Spontaneous Reporting for Collecting Safety Data on Concerning Off-Label Prescribing Practices: An Example with Baclofen and Alcohol Dependence in France

IntroductionOff-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.ObjectiveThe 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.MethodThe 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.ResultsA 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.ConclusionA 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.

Illicit drugs or medicines taken by parachuting

Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty‐five cases of parachute use were identified and most (n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4‐methylenedioxymethamphetamine (MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs.

Baclofen‐induced edema in alcohol use disorders

Although alcohol use disorders (AUDs) constitute an important burden of disease in Europe, the currently approved medications remain insufficiently efficacious, and off‐label drugs may be required. Baclofen is a gamma‐amino butyric acid type B (GABA‐B) receptor agonist that was originally approved for spasticity. In this indication, baclofen can be delivered orally or intrathecally. Recently, baclofen 30mg/day has been reported to be a promising therapeutic option for AUDs. Moreover, a baclofen dose–response effect has been suspected in AUDs, and high‐dose baclofen (HDB), that is, more than 80mg/day, is increasingly being used in current clinical practice. However, the global tolerability of baclofen at such doses remains largely unexplored. Some types of adverse drug reactions (ADRs) may occur at high doses and may even be preferentially induced in patients with persistent alcohol abuse. Due to the lack of data, several addiction centers of the Nord‐Pas‐de‐Calais region, France, have joined with the regional department of pharmacovigilance to create a system named CAMTEA, which delivers HDB prescriptions for AUDs only under strict monitoring, including follow‐up by pharmacovigilance specialists, to better spot ADRs. Such a system may thus detect ADRs that were not described with the oral form at a dose of 80mg/day or in patients without an AUD. Recently, a national pharmacovigilance report in France found that off‐label baclofen could induce previously unknown ADRs. Notably, this identified lower extremity edema. However, in this document, ADRs were not assessed using validated methods for determining causality. We report herein the occurrence of lower extremity edema in three patients with persistent AUDs during their off‐label treatment with baclofen. In each case, the causality of baclofen in triggering edema was assessed using Naranjo’s scale, which is a validated tool for determining the likelihood that a given drug induced a specific ADR. Case Series

The dose–effect relationship of baclofen in alcohol dependence: A 1-year cohort study

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence.