Original article 49
Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study Benjamin Rollanda,b,f, Thomas Valinh, Carole Langloisc, Marine Auffreta,d, Sophie Gautiera,d,f, Sylvie Deheula,d, Thierry Danela,e,f, Régis Bordeta,d,f and Olivier Cottencina,b,g 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. Int Clin Psychopharmacol 30:49–53 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
dual diagnosis (Conner et al., 2003). As of today, the use of low doses of baclofen in alcohol dependence has been studied more than that of HDB (Addolorato et al., 2002, 2007; Garbutt et al., 2010), and low-dose baclofen was not found to be associated with significant safety concerns (Addolorato and Leggio, 2010). Conversely, preliminary reports have found that in cases of drug self-intoxication, mixing HDB with other sedative agents enhances the risk for coma (Franchitto et al., 2014).
Baclofen is a γ amino-butyric acid type B receptor agonist that has been approved for spasticity for several decades. Since 2008, off-label prescribing practices of high-dose baclofen (HDB), that is, up to 400 mg/day or more (Rolland et al., 2012), have been widespread among French physicians for the treatment of alcohol dependence (Rolland et al., 2014; Dupouy et al., 2014). Presently, such empirical practice is based on limited evidence, whereas many adverse events (AEs) have been reported with the use of HDB for alcohol dependence, including dose-related sedative effects, for which the potentiation of alcohol remains unknown (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013). Moreover, alcohol-dependent patients show frequent psychiatric comorbidities, which may worsen the alcohol outcome (Bischof et al., 2005) and expose them to the toxicological effects of alcohol and of other sedative agents, such as benzodiazepines or antipsychotics. Suicide attempts, especially by drug selfintoxication, are observed frequently in patients with 0268-1315 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
International Clinical Psychopharmacology 2015, 30:49–53 Keywords: alcoholism, baclofen, borderline personality disorder, drug-related side effects and adverse reactions, treatment outcome a CAMTEA, Supervised Off-label Prescribing System in Addiction Medicine, Departments of bAddiction Medicine, cBiostatistics, dPharmacovigilance, e CSAPA, CHU Lille, Departments of fPharmacology, EA 1046, gNeurosciences, LNFP, EA 4559, Univ Lille Nord de France, Lille and hDepartment of Adult Psychiatry, CH Douai, Douai, France
Correspondence to Benjamin Rolland, MD, PhD, Service d’Addictologie, CHU Lille, Hôpital Fontan2, Rue André Verhaeghe, CS 70001, 59037 Lille Cedex, France Tel: + 33 320 445 838; fax: + 33 3 20 44 57 78; e-mail: [email protected] Received 8 August 2014 Accepted 24 September 2014
In March 2014, the French Health Agency issued a temporary recommendation for use, which now frames the prescribing of HDB for alcohol dependence (Agence Française du Médicament et des produits de santé, 2014). In this regulatory measure, patients with a history of schizophrenia or bipolar disorder or with an unremitted major depressive disorder should be excluded from HDB prescription. However, there is no mention of personality disorders, notably, borderline personality disorder (BPD). BPD is a severe psychiatric disorder that is characterized by a pattern of different clinical features, including poorly DOI: 10.1097/YIC.0000000000000054
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50 International Clinical Psychopharmacology 2015, Vol 30 No 1
developed or unstable self-image, instability in life paths, hypersensitivity in relationships with others, impulsivity, depressivity, and risk taking (Skodol et al., 2002). Patients with BPD are often comorbid with alcohol dependence (Grant et al., 2008; Fein and Nip, 2012). Individuals with BPD more frequently show other substance use disorders and often receive different types of psychotropic medications. They are also more likely to attempt suicide and self-intoxicate with medications (Grant et al., 2008). There are no data that specifically address the consequences of initiating HDB in patients with BPD. Although two French clinical trials comparing HDB with placebo in alcohol dependence are currently terminating (ALPADIR study, NCT01738282, 2012; BACLOVILLE study, NCT01604330, 2012), BPD was a noninclusion criterion of the former and was not screened in the latest trial. Consequently, these studies will not provide any specific information on the efficacy and the tolerability of HDB in patients with BPD. Since 2010, a supervised team-based system for prescribing and monitoring off-label HDB in alcohol dependence has been implemented in the Nord-Pas-deCalais region, France (Rolland et al., 2010). This system, named ‘Consultation et Avis Multidisciplinaires pour Traitements d’Exception en Addictologie’ (CAMTEA), that is, ‘supervised off-label prescribing system in addiction medicine’, gathers both addiction and pharmacovigilance specialists. Within CAMTEA, daily alcohol consumption and baclofen doses are recorded systematically on sheets by patients and completed in case of missing data during medical consultations (Rolland et al., 2010). Moreover, the occurrence of every AE is documented and recorded in the French pharmacovigilance database. Within CAMTEA, the collection of longitudinal clinical data is thus exhaustive and prospectively defined. We compared the different safety outcomes among the patients of our cohort who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for BPD and a group of paired control patients selected from the cohort who had no history of psychiatric disorder.
Materials and methods Participants
Between January 2011 and June 2013, 204 patients who fulfilled the DSM-IV criteria for alcohol dependence were prescribed HDB for at least 2 months and included in the CAMTEA monitoring cohort. The participants had no other substance use disorder, except for the use of tobacco. They had to have failed or refused abstinence care programs and approved medications for abstinence maintenance. They had to provide written confirmation that they had been informed of the off-label nature of HDB, including the enhanced safety unknowns surrounding such type of medications. The patient’s
comprehensive medical history, including the psychiatric history, was noted at the initiation of the treatment. Data collection
The patients to whom HDB was prescribed had to record their daily alcohol consumptions and baclofen daily doses on reporting sheets, which were, if needed, secondarily completed by prescribers during consultations, according to the model of the alcohol timeline follow-back instrument (Sobell et al., 1988). Once a month, using a predefined list of AEs, the prescribers checked with the patient as to whether AEs had occurred during the previous month. Each AE was reported to the Pharmacovigilance Unit, which defined whether the AE was ‘serious’, that is, when the patient outcome was (a) death, (b) life-threatening, (c) hospitalization (initial or prolonged), (d) disability or permanent damage, (e) congenital anomaly/birth defect, (f) required intervention to prevent permanent impairment or damage, or (g) whether the AE may jeopardize the patient and may require medical or surgical intervention (Food and Drug Administration, 2014). On a monthly basis, the patients were instructed to score the maximum subjective sedation that they had experienced in the previous month using a 0–10 visual analog scale. Groups
From the cohort of 204 participants, 23 fulfilled the DSM-IV criteria for BPD. The diagnostic criteria were checked clinically by at least one psychiatrist (B.R., T.V., or T.D.). A total of 144 participants in the cohort had no previous history of psychiatric disorder, except alcohol dependence. Every participant with BPD was paired with two control participants among the 144 who had no history of psychiatric disorder. The participants were matched for sex and age. The matching was performed before any analysis was carried out. The following two groups were as follows: the BPD group (n = 23) and the control group (n = 46). Different features and outcomes were compared between both groups. Comparison of features and outcomes
Outcomes were studied over the 1-year course after the introduction of HDB. Between-group comparisons were performed for the following variables: (a) sex ratio (included in the pairing); (b) mean age (included in the pairing); (c) average weekly alcohol consumption (AWAC) in the month before the introduction of baclofen in grams of alcohol/week (g/w); (4) rates of patients using benzodiazepines at baseline; (e) mean dose of benzodiazepines at baseline, standardized in equivalent doses of diazepam (mg/day) (Ashton, 2007); (f) rates of patients using antipsychotics at baseline; (g) mean dose of antipsychotics at baseline, standardized in equivalent doses of olanzapine (mg/day) (Gardner et al., 2010); (h) the mean length of follow-up in months; (i) the mean proportion of full months with no heavy drinking day
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Baclofen safety in borderline patients Rolland et al. 51
(HDD), that is, no more than 50 g of alcohol in a day; (j) the mean proportion of HDDs during the follow-up; (k) AWAC in the last recorded month of follow-up in g/w; (l) average maximal subjective sedation (0–10 on visual analog scale); (m) rates of patients in whom at least one ‘serious’ AE (Food and Drug Administration, 2014) was reported; and (n) rates of patients in whom baclofen had to be discontinued because of AEs.
In the BPD group, baclofen was discontinued because of AEs in 12 of 23 participants. The types of AEs were as follows: very heavy sedation (n = 8); insomnia (n = 2); seizures (n = 1); and repeated self-poisoning (n = 1). In the control group, baclofen was discontinued because of AEs in six of 46 participants. The types of AEs were as follows: very heavy sedation (n = 4); insomnia (n = 1); and seizures (n =1).
Statistical analyses
Discussion
The control group was generated using propensity score matching methods to reduce recruitment bias: according to the propensity score, a group of 23 patients with BPD were matched with control patients with no previous history of psychiatric disorder (two control vs. one BPD), which led to an even distribution of potential confounding factors (age, ± 5 years; and sex).
All between-group comparisons are detailed in Table 1.
The aim of the present study was to compare the safety and drinking outcomes between BPD patients and control patients who had been paired previously for age and sex and had no other psychiatric history, except for alcohol dependence. Overall, we found that the drinking and safety outcomes were worse in BPD patients than in control patients with alcohol dependence. Two previous cohort studies have addressed the efficacy and safety of HDB in patients with alcohol use disorders (De Beaurepaire, 2012; Rigal et al., 2012). These studies were purely descriptive. The psychiatric comorbidities were screened, but not personality disorders; thus, it is impossible to note whether patients with BPD were included in these cohort studies. The rates of serious AEs were not reported in the first study, whereas in the second study, if it was mentioned that 88% of patients reported AEs, they were all stated as ‘benign’. In the first study, the rate of treatment discontinuation because of AEs was estimated to be 3.3%, whereas this rate was not reported in the second study. As the authors of the first study acknowledged, many participants recruited in their cohort were particularly willing to be treated with HDB because of the specific media coverage of this molecule in France. This was less likely the case in our patients, notably in BPD patients in whom HDB was often introduced because of failure of the previous medications. In fact, the AEs that we had observed were consistent with those that were observed nationally (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013).
In the BPD group, 22 serious AEs were reported in 15 of 23 participants (concomitant mean daily baclofen dose, 124.5 ± 67.2 mg/day; concomitant reported AWAC, 684 ± 529 g/w). The types of serious AEs in patients with BPD were as follows: hospitalization for acute alcohol intoxication (n = 12); hospitalization for self-poisoning (n = 5); suicide by hanging (n = 2); hospitalization for seizures (n = 1); acute pancreatitis (n = 1); and hospitalization for home accidents (n = 1). In the control group, only three serious AEs were reported in three patients (concomitant mean daily baclofen dose, 132.4 ± 65.2 mg/ day; concomitant AWAC, 360 ± 307 g/w). The causes of serious AEs in control patients were as follows: hospitalization for acute alcohol intoxication (n = 1); hospitalization for seizures (n = 1); and hospitalization for traffic accidents (n = 1).
The nonplacebo nature of our study design did not aim to determine to what extent the between-group differences observed were attributed to baclofen, BPD, or the enhanced coexposure to psychotropic medications that were found in BPD patients. Our study essentially aimed at comparing several safety outcomes between BPD patients and nonpsychiatric patients who were similar in terms of age, sex, length of follow-up, and baclofen dose. The differences observed in drinking outcomes might be hypothesized as resulting from the BPD condition. Nevertheless, the fact that BPD worsens the prognosis of alcohol dependence has not been established, and several findings have suggested that BPD does not influence the long-term outcome among alcohol-dependent patients (Di Sclafani et al., 2007; Zanarini et al., 2011; Fein and Nip, 2012). However, these studies have
The qualitative variables are shown as frequency and percentage. The continuous variables, because of the nonparametric nature of comparisons, are reported as median and mean ± SD. The proportion comparisons were performed using χ2-tests. Comparisons between the quantitative parameters were performed using Mann–Whitney U-tests. The significance threshold was fixed at 0.05 for all of the tests. Statistical analyses were carried out using XLSTAT2014 (Addinsoft, Paris, France) (http://www.xlstat.com/en/). Ethical aspects
The procedures for deidentifying, collecting, and analyzing data were previously provided to and approved by the local ethics committee (Avis CCTIRS #13.290). All of the participants signed a written consent form, which authorized the use of the clinical data collected for research purposes.
Results
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52 International Clinical Psychopharmacology 2015, Vol 30 No 1
Comparison of the sociodemographic and clinical features and the efficacy and safety findings between two groups of patients receiving baclofen for alcohol dependence: a group of 23 patients with BPD and a group of 46 control participants who were matched for age and sex with the BPD group from a pool of 144 individuals with no previous history of psychiatric disorder (two controls vs. one BPD)
Table 1
Sex ratio (F/M) [n (%] Mean age ± SD (years) Mean duration of follow-up ± SD (months) AWAC over the month before treatment (sd/week) Patients with benzodiazepines at baseline [n (%)] Mean initial dose of benzodiazepines (mg/day; equivalent dose of diazepam) Patients with antipsychotics at baseline [n (%)] Mean initial dose of antipsychotics (mg/day; equivalent dose of olanzapine) Average baclofen dose received (mg/day) Lost to follow-up [n (%)] Mean % of months with no HDDs ± SD Mean % of HDDs across the follow-up AWAC over the last month of treatment (sd/week) Average maximal subjective sedation (0–10 on visual analog scale) Patients with at least one serious AE reported [n (%)] Treatment discontinuation because of AE [n (%)]
BPD (n = 23)
Control (n = 46)
P
10 (43.5)/13 (66.5) 44.5; 45.3 ± 11.2 8; 8.0 ± 4.0 84; 87.2 ± 70.9 21 (91.3) 20; 23.2 ± 11.9 8 (34.8) 0; 5.1 ± 8 93; 102.2 ± 42.7 11 (23.9) 0%; 19.7 ± 24 74.3 ± 25.3 50; 61.3 ± 49.7 3; 3.7 ± 3.5 15 (65.2) 12 (52.2)
20 (43.5)/26 (66.5) 45; 45.2 ± 11.2 8; 7.7 ± 4.2 53; 68.2 ± 86.7 14 (30.4) 0; 5.6 ± 10.1 3 (6.5) 0; 0.6 ± 2.3 90.5; 94.6 ± 39.7 2 (8.7) 66%; 52 ± 33.5 41.7 ± 33.3 0; 14.7 ± 24.1 0; 2 ± 2.6 2 (6.5) 6 (13.0)
1 0.96 0.77 0.190 < 10E − 4 < 10E − 4 0.008 0.002 0.44 0.077 < 10E − 4 < 10E − 4 < 10E − 4 0.039 < 10E − 4 0.001
Sex ratios and mean ages were matched, whereas mean durations of follow-up and average doses of baclofen were comparable between the two groups. Conversely, BPD patients experienced significantly fewer months with no HDDs, increased rate of HDDs during the follow-up, and increased AWAC in the last recorded month of treatment. Moreover, BPD patients reported significantly more subjective sedation and experienced significantly more frequently at least one serious AE. Baclofen had to be discontinued because AEs occurred more frequently in BPD patients. These safety discrepancies might be explained, in part, by the more frequent prescriptions and higher doses of benzodiazepines and antipsychotics in BPD patients and by the more important maximal baclofen doses in BPD patients. The quantitative parameters were compared using nonparametric tests and are reported as median values; mean ± SD. AE, adverse event; AWAC, average weekly alcohol consumption; BPD, borderline personality disorder; HDD, heavy drinking day; sd, standard-drink (i.e. 10 g of alcohol).
essentially focused on abstinence as the primary outcome, whereas in our findings, baclofen was prescribed for drinking reduction. Moreover, the observed betweengroup differences in drinking outcomes could, in part, result from a lower efficacy of HDB in patients with BPD. This observation would be consistent with the fact that both antiepileptic and antipsychotic medications are occasionally considered to be more efficacious for comorbid BPD and alcohol dependence than the usual anticraving medications (Gianoli et al., 2012). Similarly, significantly higher rates of serious AEs and AEs leading to treatment discontinuation were observed in the BPD group, and many of these AEs were related to self-poisoning. BPD patients showed a high proportion of self-injurious behaviors, including self-poisoning, which are not always associated with suicidality (Lengel and Mullins-Sweatt, 2013). We found that self-poisoning was more likely to occur in the BPD group. Furthermore, two cases of suicide by hanging were observed in the BPD group. In the 2013 French pharmacovigilance national report on the off-label use of baclofen, many cases of attempted suicide were reported (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013), which raised concerns among pharmacovigilance and drug safety specialists. In fact, the imputability of medications in suicidal behaviors is hard to determine and the notified psychiatric history of patients can also be cursory in pharmacovigilance reports (Gibbons and Mann, 2011). Our findings suggest that the baclofen-associated suicidality could be more related to psychiatric comorbidities, such as BPD, than to an intrinsic baclofen-induced AE. However, further studies are needed to confirm this hypothesis.
The BPD condition is likely not the sole factor that influences the safety features of baclofen in this population. A significantly higher number of patients with BPD had to stop using baclofen because of protracted sedative AEs. Sedation is by far the most common baclofen-related AE. The fact that patients with BPD were more vulnerable to developing major sedation could result from the frequent additional sedative medications that BPD patients received, especially benzodiazepines and antipsychotics. As discussed previously, BPD patients experienced more frequent HDDs during their follow-up, which could also contribute toward increasing the overall level of reported sedation. In future analyses carried out in our cohort, we will aim to determine whether the amounts of AWAC and daily doses of baclofen can predict the occurrence of major sedation in patients. The features of the BPD participants and the comparison with control participants should be discussed. In our BPD sample, there were more male than female patients, which is a strength because of the usually greater proportion of women among BPD patients (Skodol et al., 2002). However, if BPD is often comorbid with addictive disorders, it has been shown that male BPD patients more often have substance use disorders, whereas female BPD patients more often show eating disorders (Tadić et al., 2009). This observation could explain why there were more men in our sample. Conclusion
In France, on the basis of the national pharmacovigilance reports, which emphasized the frequency and occasionally the severity of HDB-related neuropsychiatric AEs, the decision was made to exclude from HDB treatment patients with schizophrenia, bipolar disorder, and unremitted depression.
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Baclofen safety in borderline patients Rolland et al. 53
However, it was not found that these types of pathologies were the most likely to show safety issues with baclofen. Our findings suggest that the use of HDB in comorbid BPD is associated with enhanced neuropsychiatric concerns.
Acknowledgements Conflicts of interest
Benjamin Rolland is the main investigator in a clinical trial funded by ETHYPHARM, which is developing a labeled form of baclofen for alcohol use disorders. He has received sponsorship to attend scientific meetings from Lundbeck and Reckitt Benckiser. Olivier Cottencin is an associate investigator in a clinical trial funded by ETHYPHARM. He has received sponsorship to attend scientific meetings from Lundbeck, BMS Otsuka, Janssen Cilag, Reckitt Benckiser, Pfizer, and Bouchara Recordati. Régis Bordet speaks or chairs in symposia supported by Lundbeck, BMS, Otsuka. For the remaining authors there are no conflicts of interest.
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Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study Benjamin Rollanda,b,f, Thomas Valinh, Carole Langloisc, Marine Auffreta,d, Sophie Gautiera,d,f, Sylvie Deheula,d, Thierry Danela,e,f, Régis Bordeta,d,f and Olivier Cottencina,b,g 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. Int Clin Psychopharmacol 30:49–53 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
dual diagnosis (Conner et al., 2003). As of today, the use of low doses of baclofen in alcohol dependence has been studied more than that of HDB (Addolorato et al., 2002, 2007; Garbutt et al., 2010), and low-dose baclofen was not found to be associated with significant safety concerns (Addolorato and Leggio, 2010). Conversely, preliminary reports have found that in cases of drug self-intoxication, mixing HDB with other sedative agents enhances the risk for coma (Franchitto et al., 2014).
Baclofen is a γ amino-butyric acid type B receptor agonist that has been approved for spasticity for several decades. Since 2008, off-label prescribing practices of high-dose baclofen (HDB), that is, up to 400 mg/day or more (Rolland et al., 2012), have been widespread among French physicians for the treatment of alcohol dependence (Rolland et al., 2014; Dupouy et al., 2014). Presently, such empirical practice is based on limited evidence, whereas many adverse events (AEs) have been reported with the use of HDB for alcohol dependence, including dose-related sedative effects, for which the potentiation of alcohol remains unknown (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013). Moreover, alcohol-dependent patients show frequent psychiatric comorbidities, which may worsen the alcohol outcome (Bischof et al., 2005) and expose them to the toxicological effects of alcohol and of other sedative agents, such as benzodiazepines or antipsychotics. Suicide attempts, especially by drug selfintoxication, are observed frequently in patients with 0268-1315 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
International Clinical Psychopharmacology 2015, 30:49–53 Keywords: alcoholism, baclofen, borderline personality disorder, drug-related side effects and adverse reactions, treatment outcome a CAMTEA, Supervised Off-label Prescribing System in Addiction Medicine, Departments of bAddiction Medicine, cBiostatistics, dPharmacovigilance, e CSAPA, CHU Lille, Departments of fPharmacology, EA 1046, gNeurosciences, LNFP, EA 4559, Univ Lille Nord de France, Lille and hDepartment of Adult Psychiatry, CH Douai, Douai, France
Correspondence to Benjamin Rolland, MD, PhD, Service d’Addictologie, CHU Lille, Hôpital Fontan2, Rue André Verhaeghe, CS 70001, 59037 Lille Cedex, France Tel: + 33 320 445 838; fax: + 33 3 20 44 57 78; e-mail: [email protected] Received 8 August 2014 Accepted 24 September 2014
In March 2014, the French Health Agency issued a temporary recommendation for use, which now frames the prescribing of HDB for alcohol dependence (Agence Française du Médicament et des produits de santé, 2014). In this regulatory measure, patients with a history of schizophrenia or bipolar disorder or with an unremitted major depressive disorder should be excluded from HDB prescription. However, there is no mention of personality disorders, notably, borderline personality disorder (BPD). BPD is a severe psychiatric disorder that is characterized by a pattern of different clinical features, including poorly DOI: 10.1097/YIC.0000000000000054
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50 International Clinical Psychopharmacology 2015, Vol 30 No 1
developed or unstable self-image, instability in life paths, hypersensitivity in relationships with others, impulsivity, depressivity, and risk taking (Skodol et al., 2002). Patients with BPD are often comorbid with alcohol dependence (Grant et al., 2008; Fein and Nip, 2012). Individuals with BPD more frequently show other substance use disorders and often receive different types of psychotropic medications. They are also more likely to attempt suicide and self-intoxicate with medications (Grant et al., 2008). There are no data that specifically address the consequences of initiating HDB in patients with BPD. Although two French clinical trials comparing HDB with placebo in alcohol dependence are currently terminating (ALPADIR study, NCT01738282, 2012; BACLOVILLE study, NCT01604330, 2012), BPD was a noninclusion criterion of the former and was not screened in the latest trial. Consequently, these studies will not provide any specific information on the efficacy and the tolerability of HDB in patients with BPD. Since 2010, a supervised team-based system for prescribing and monitoring off-label HDB in alcohol dependence has been implemented in the Nord-Pas-deCalais region, France (Rolland et al., 2010). This system, named ‘Consultation et Avis Multidisciplinaires pour Traitements d’Exception en Addictologie’ (CAMTEA), that is, ‘supervised off-label prescribing system in addiction medicine’, gathers both addiction and pharmacovigilance specialists. Within CAMTEA, daily alcohol consumption and baclofen doses are recorded systematically on sheets by patients and completed in case of missing data during medical consultations (Rolland et al., 2010). Moreover, the occurrence of every AE is documented and recorded in the French pharmacovigilance database. Within CAMTEA, the collection of longitudinal clinical data is thus exhaustive and prospectively defined. We compared the different safety outcomes among the patients of our cohort who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for BPD and a group of paired control patients selected from the cohort who had no history of psychiatric disorder.
Materials and methods Participants
Between January 2011 and June 2013, 204 patients who fulfilled the DSM-IV criteria for alcohol dependence were prescribed HDB for at least 2 months and included in the CAMTEA monitoring cohort. The participants had no other substance use disorder, except for the use of tobacco. They had to have failed or refused abstinence care programs and approved medications for abstinence maintenance. They had to provide written confirmation that they had been informed of the off-label nature of HDB, including the enhanced safety unknowns surrounding such type of medications. The patient’s
comprehensive medical history, including the psychiatric history, was noted at the initiation of the treatment. Data collection
The patients to whom HDB was prescribed had to record their daily alcohol consumptions and baclofen daily doses on reporting sheets, which were, if needed, secondarily completed by prescribers during consultations, according to the model of the alcohol timeline follow-back instrument (Sobell et al., 1988). Once a month, using a predefined list of AEs, the prescribers checked with the patient as to whether AEs had occurred during the previous month. Each AE was reported to the Pharmacovigilance Unit, which defined whether the AE was ‘serious’, that is, when the patient outcome was (a) death, (b) life-threatening, (c) hospitalization (initial or prolonged), (d) disability or permanent damage, (e) congenital anomaly/birth defect, (f) required intervention to prevent permanent impairment or damage, or (g) whether the AE may jeopardize the patient and may require medical or surgical intervention (Food and Drug Administration, 2014). On a monthly basis, the patients were instructed to score the maximum subjective sedation that they had experienced in the previous month using a 0–10 visual analog scale. Groups
From the cohort of 204 participants, 23 fulfilled the DSM-IV criteria for BPD. The diagnostic criteria were checked clinically by at least one psychiatrist (B.R., T.V., or T.D.). A total of 144 participants in the cohort had no previous history of psychiatric disorder, except alcohol dependence. Every participant with BPD was paired with two control participants among the 144 who had no history of psychiatric disorder. The participants were matched for sex and age. The matching was performed before any analysis was carried out. The following two groups were as follows: the BPD group (n = 23) and the control group (n = 46). Different features and outcomes were compared between both groups. Comparison of features and outcomes
Outcomes were studied over the 1-year course after the introduction of HDB. Between-group comparisons were performed for the following variables: (a) sex ratio (included in the pairing); (b) mean age (included in the pairing); (c) average weekly alcohol consumption (AWAC) in the month before the introduction of baclofen in grams of alcohol/week (g/w); (4) rates of patients using benzodiazepines at baseline; (e) mean dose of benzodiazepines at baseline, standardized in equivalent doses of diazepam (mg/day) (Ashton, 2007); (f) rates of patients using antipsychotics at baseline; (g) mean dose of antipsychotics at baseline, standardized in equivalent doses of olanzapine (mg/day) (Gardner et al., 2010); (h) the mean length of follow-up in months; (i) the mean proportion of full months with no heavy drinking day
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Baclofen safety in borderline patients Rolland et al. 51
(HDD), that is, no more than 50 g of alcohol in a day; (j) the mean proportion of HDDs during the follow-up; (k) AWAC in the last recorded month of follow-up in g/w; (l) average maximal subjective sedation (0–10 on visual analog scale); (m) rates of patients in whom at least one ‘serious’ AE (Food and Drug Administration, 2014) was reported; and (n) rates of patients in whom baclofen had to be discontinued because of AEs.
In the BPD group, baclofen was discontinued because of AEs in 12 of 23 participants. The types of AEs were as follows: very heavy sedation (n = 8); insomnia (n = 2); seizures (n = 1); and repeated self-poisoning (n = 1). In the control group, baclofen was discontinued because of AEs in six of 46 participants. The types of AEs were as follows: very heavy sedation (n = 4); insomnia (n = 1); and seizures (n =1).
Statistical analyses
Discussion
The control group was generated using propensity score matching methods to reduce recruitment bias: according to the propensity score, a group of 23 patients with BPD were matched with control patients with no previous history of psychiatric disorder (two control vs. one BPD), which led to an even distribution of potential confounding factors (age, ± 5 years; and sex).
All between-group comparisons are detailed in Table 1.
The aim of the present study was to compare the safety and drinking outcomes between BPD patients and control patients who had been paired previously for age and sex and had no other psychiatric history, except for alcohol dependence. Overall, we found that the drinking and safety outcomes were worse in BPD patients than in control patients with alcohol dependence. Two previous cohort studies have addressed the efficacy and safety of HDB in patients with alcohol use disorders (De Beaurepaire, 2012; Rigal et al., 2012). These studies were purely descriptive. The psychiatric comorbidities were screened, but not personality disorders; thus, it is impossible to note whether patients with BPD were included in these cohort studies. The rates of serious AEs were not reported in the first study, whereas in the second study, if it was mentioned that 88% of patients reported AEs, they were all stated as ‘benign’. In the first study, the rate of treatment discontinuation because of AEs was estimated to be 3.3%, whereas this rate was not reported in the second study. As the authors of the first study acknowledged, many participants recruited in their cohort were particularly willing to be treated with HDB because of the specific media coverage of this molecule in France. This was less likely the case in our patients, notably in BPD patients in whom HDB was often introduced because of failure of the previous medications. In fact, the AEs that we had observed were consistent with those that were observed nationally (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013).
In the BPD group, 22 serious AEs were reported in 15 of 23 participants (concomitant mean daily baclofen dose, 124.5 ± 67.2 mg/day; concomitant reported AWAC, 684 ± 529 g/w). The types of serious AEs in patients with BPD were as follows: hospitalization for acute alcohol intoxication (n = 12); hospitalization for self-poisoning (n = 5); suicide by hanging (n = 2); hospitalization for seizures (n = 1); acute pancreatitis (n = 1); and hospitalization for home accidents (n = 1). In the control group, only three serious AEs were reported in three patients (concomitant mean daily baclofen dose, 132.4 ± 65.2 mg/ day; concomitant AWAC, 360 ± 307 g/w). The causes of serious AEs in control patients were as follows: hospitalization for acute alcohol intoxication (n = 1); hospitalization for seizures (n = 1); and hospitalization for traffic accidents (n = 1).
The nonplacebo nature of our study design did not aim to determine to what extent the between-group differences observed were attributed to baclofen, BPD, or the enhanced coexposure to psychotropic medications that were found in BPD patients. Our study essentially aimed at comparing several safety outcomes between BPD patients and nonpsychiatric patients who were similar in terms of age, sex, length of follow-up, and baclofen dose. The differences observed in drinking outcomes might be hypothesized as resulting from the BPD condition. Nevertheless, the fact that BPD worsens the prognosis of alcohol dependence has not been established, and several findings have suggested that BPD does not influence the long-term outcome among alcohol-dependent patients (Di Sclafani et al., 2007; Zanarini et al., 2011; Fein and Nip, 2012). However, these studies have
The qualitative variables are shown as frequency and percentage. The continuous variables, because of the nonparametric nature of comparisons, are reported as median and mean ± SD. The proportion comparisons were performed using χ2-tests. Comparisons between the quantitative parameters were performed using Mann–Whitney U-tests. The significance threshold was fixed at 0.05 for all of the tests. Statistical analyses were carried out using XLSTAT2014 (Addinsoft, Paris, France) (http://www.xlstat.com/en/). Ethical aspects
The procedures for deidentifying, collecting, and analyzing data were previously provided to and approved by the local ethics committee (Avis CCTIRS #13.290). All of the participants signed a written consent form, which authorized the use of the clinical data collected for research purposes.
Results
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52 International Clinical Psychopharmacology 2015, Vol 30 No 1
Comparison of the sociodemographic and clinical features and the efficacy and safety findings between two groups of patients receiving baclofen for alcohol dependence: a group of 23 patients with BPD and a group of 46 control participants who were matched for age and sex with the BPD group from a pool of 144 individuals with no previous history of psychiatric disorder (two controls vs. one BPD)
Table 1
Sex ratio (F/M) [n (%] Mean age ± SD (years) Mean duration of follow-up ± SD (months) AWAC over the month before treatment (sd/week) Patients with benzodiazepines at baseline [n (%)] Mean initial dose of benzodiazepines (mg/day; equivalent dose of diazepam) Patients with antipsychotics at baseline [n (%)] Mean initial dose of antipsychotics (mg/day; equivalent dose of olanzapine) Average baclofen dose received (mg/day) Lost to follow-up [n (%)] Mean % of months with no HDDs ± SD Mean % of HDDs across the follow-up AWAC over the last month of treatment (sd/week) Average maximal subjective sedation (0–10 on visual analog scale) Patients with at least one serious AE reported [n (%)] Treatment discontinuation because of AE [n (%)]
BPD (n = 23)
Control (n = 46)
P
10 (43.5)/13 (66.5) 44.5; 45.3 ± 11.2 8; 8.0 ± 4.0 84; 87.2 ± 70.9 21 (91.3) 20; 23.2 ± 11.9 8 (34.8) 0; 5.1 ± 8 93; 102.2 ± 42.7 11 (23.9) 0%; 19.7 ± 24 74.3 ± 25.3 50; 61.3 ± 49.7 3; 3.7 ± 3.5 15 (65.2) 12 (52.2)
20 (43.5)/26 (66.5) 45; 45.2 ± 11.2 8; 7.7 ± 4.2 53; 68.2 ± 86.7 14 (30.4) 0; 5.6 ± 10.1 3 (6.5) 0; 0.6 ± 2.3 90.5; 94.6 ± 39.7 2 (8.7) 66%; 52 ± 33.5 41.7 ± 33.3 0; 14.7 ± 24.1 0; 2 ± 2.6 2 (6.5) 6 (13.0)
1 0.96 0.77 0.190 < 10E − 4 < 10E − 4 0.008 0.002 0.44 0.077 < 10E − 4 < 10E − 4 < 10E − 4 0.039 < 10E − 4 0.001
Sex ratios and mean ages were matched, whereas mean durations of follow-up and average doses of baclofen were comparable between the two groups. Conversely, BPD patients experienced significantly fewer months with no HDDs, increased rate of HDDs during the follow-up, and increased AWAC in the last recorded month of treatment. Moreover, BPD patients reported significantly more subjective sedation and experienced significantly more frequently at least one serious AE. Baclofen had to be discontinued because AEs occurred more frequently in BPD patients. These safety discrepancies might be explained, in part, by the more frequent prescriptions and higher doses of benzodiazepines and antipsychotics in BPD patients and by the more important maximal baclofen doses in BPD patients. The quantitative parameters were compared using nonparametric tests and are reported as median values; mean ± SD. AE, adverse event; AWAC, average weekly alcohol consumption; BPD, borderline personality disorder; HDD, heavy drinking day; sd, standard-drink (i.e. 10 g of alcohol).
essentially focused on abstinence as the primary outcome, whereas in our findings, baclofen was prescribed for drinking reduction. Moreover, the observed betweengroup differences in drinking outcomes could, in part, result from a lower efficacy of HDB in patients with BPD. This observation would be consistent with the fact that both antiepileptic and antipsychotic medications are occasionally considered to be more efficacious for comorbid BPD and alcohol dependence than the usual anticraving medications (Gianoli et al., 2012). Similarly, significantly higher rates of serious AEs and AEs leading to treatment discontinuation were observed in the BPD group, and many of these AEs were related to self-poisoning. BPD patients showed a high proportion of self-injurious behaviors, including self-poisoning, which are not always associated with suicidality (Lengel and Mullins-Sweatt, 2013). We found that self-poisoning was more likely to occur in the BPD group. Furthermore, two cases of suicide by hanging were observed in the BPD group. In the 2013 French pharmacovigilance national report on the off-label use of baclofen, many cases of attempted suicide were reported (Agence Nationale de Sécurité du Médicament et des produits de santé, 2013), which raised concerns among pharmacovigilance and drug safety specialists. In fact, the imputability of medications in suicidal behaviors is hard to determine and the notified psychiatric history of patients can also be cursory in pharmacovigilance reports (Gibbons and Mann, 2011). Our findings suggest that the baclofen-associated suicidality could be more related to psychiatric comorbidities, such as BPD, than to an intrinsic baclofen-induced AE. However, further studies are needed to confirm this hypothesis.
The BPD condition is likely not the sole factor that influences the safety features of baclofen in this population. A significantly higher number of patients with BPD had to stop using baclofen because of protracted sedative AEs. Sedation is by far the most common baclofen-related AE. The fact that patients with BPD were more vulnerable to developing major sedation could result from the frequent additional sedative medications that BPD patients received, especially benzodiazepines and antipsychotics. As discussed previously, BPD patients experienced more frequent HDDs during their follow-up, which could also contribute toward increasing the overall level of reported sedation. In future analyses carried out in our cohort, we will aim to determine whether the amounts of AWAC and daily doses of baclofen can predict the occurrence of major sedation in patients. The features of the BPD participants and the comparison with control participants should be discussed. In our BPD sample, there were more male than female patients, which is a strength because of the usually greater proportion of women among BPD patients (Skodol et al., 2002). However, if BPD is often comorbid with addictive disorders, it has been shown that male BPD patients more often have substance use disorders, whereas female BPD patients more often show eating disorders (Tadić et al., 2009). This observation could explain why there were more men in our sample. Conclusion
In France, on the basis of the national pharmacovigilance reports, which emphasized the frequency and occasionally the severity of HDB-related neuropsychiatric AEs, the decision was made to exclude from HDB treatment patients with schizophrenia, bipolar disorder, and unremitted depression.
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Baclofen safety in borderline patients Rolland et al. 53
However, it was not found that these types of pathologies were the most likely to show safety issues with baclofen. Our findings suggest that the use of HDB in comorbid BPD is associated with enhanced neuropsychiatric concerns.
Acknowledgements Conflicts of interest
Benjamin Rolland is the main investigator in a clinical trial funded by ETHYPHARM, which is developing a labeled form of baclofen for alcohol use disorders. He has received sponsorship to attend scientific meetings from Lundbeck and Reckitt Benckiser. Olivier Cottencin is an associate investigator in a clinical trial funded by ETHYPHARM. He has received sponsorship to attend scientific meetings from Lundbeck, BMS Otsuka, Janssen Cilag, Reckitt Benckiser, Pfizer, and Bouchara Recordati. Régis Bordet speaks or chairs in symposia supported by Lundbeck, BMS, Otsuka. For the remaining authors there are no conflicts of interest.
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