Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial

2. INTRODUCTION
 Worldwide, harmful use of alcohol is responsible for 5.9% of all deaths and
 It is a causal factor in more than 200 disease and injury conditions.
 Alcoholic liver disease (ALD) is one of the leading causes of alcohol-related death.
 Abstinence from alcohol is crucial to reducing morbidity and mortality associated with
ALD

3.  There are currently no approved treatments for alcohol-use disorders for those with
advanced liver disease.
 Current pharmacotherapies are limited by hepatotoxicity in patients with significant liver
disease
 Baclofen, a selective (GABA)B receptor agonist with minimal liver metabolism, is emerging as
a potential treatment for alcohol dependence with few reported hepatic side-effects.
 Preclinical studies have demonstrated baclofen to diminish self administration of alcohol,
maintenance and reinstatement of alcohol-drinking behaviour.

4. Treatment guidelines for alcohol dependance
 1. Detoxification
 2. Anticraving Drugs
 3. Aversion therapy

5. 1. Detoxification
i. Fixed-scheduled dosing - Chlordiazepoxide orally every 6h for 3d (50 – 100 mg per dose
day 1, then 25-50 mg per dose)
ii. Front-loading - Diazepam 20 mg orally every 2h while symptomatic until
resolution
iii. Symptom-triggered therapy - Chlordiazepoxide 25-100 mg orally hourly whenever symptomatic
 If unable to take oral medication or in the presence of hepatic synthetic dysfunction, lorazepam
1-4 mg may be substituted
 All patients receive thiamine 50-100 mg daily, first dose parentrally.

6. 2. Anticraving Drugs
 Acamprostate 666mg TDS
 Topiramate 25 – 50 mg/ day
 Naltrexone 50 – 150 mg/day
 Baclofen
 SSRI
3. Aversion therapy
 Disulfiram 250mg 1 OD

7. BACLOFEN
 Centrally acting muscle relaxant
 It is an analogue of the inhibitory neurotransmitter GABA
 acts as a selective GABA B receptor agonist.
 The GABA receptors have been divided into:
 1. GABA A receptor
 Intrinsic ion channel receptor
 Increases Cl conductance;
 blocked by bicuculline
 facilitated by BZDs.
 2. GABA B receptor
 G-protein coupled receptor;
 Hypererpolarizes neurones by increasing K+ conductance and decreasing Ca2+ flux;
 Bicuculline insensitive;
 blocked by saclofen.

8.  The primary site of action of baclofen is in the spinal cord where it depresses both polysynaptic
and monosynaptic reflexes. As such, it does produce muscle weakness
 less sedative than diazepam.
 It reduces spasticity in many neurological disorders like multiple sclerosis, ALS,spinal injuries
 Baclofen is well absorbed orally and is primarily excreted unchanged in urine with a t1/2 of 3--4
hours.
 Side effects are drowsiness, mental confusion,weakness and ataxia; serum transaminases may rise.
Sudden withdrawal after chronic use may cause hallucinations, tachycardia and seizures.
 The key effects of baclofen on the Alcohol Addicted patient are:
 Anti-craving
 Anxiolytic
 The effects of balcofen on the reward pathway is postulated as possible mechanism of its action.
The reward pathway has been identified as an important region in emergence of alcohol and drug
dependence.

10. AIM
 Evaluate the efficacy of two doses of baclofen (30 mg/day and 75 mg/day)
vs. placebo in a randomised, placebo-controlled double-blind study

11. HYPOTHESIS
Patients treated with baclofen will
 (a) significantly reduce their drinking compared with placebo, (as measured by
 the days abstinent,
 time to lapse and relapse,
 number of drinks per drinking day,
 number of heavy drinking days), and
 (b) severity of dependence and craving along with measures of anxiety, depression, stress and
clinical markers of liver injury will be significantly reduced with baclofen compared with those on
placebo.

12. STUDY DESIGN
 The study was a 12-week randomised, double-blind, placebo-controlled trial in which
participants who were alcohol dependent, with or without liver disease received
 10 mg or baclofen three times a day,
 25 mg of baclofen three times a day,
 or matching placebo for a 12-week period.
 The study was conducted over a 36-month period at three sites (Royal Prince Alfred Hospital,
North Shore Hospital and Westmead Hospital) in Australia between 2013 and 2016.
 The study was approved by the Human Ethics Review Committee of the Sydney Local Health
District.

13. INCLUSION CRITERIA
a) alcohol dependence according to the ICD-10 criteria;
b) age 18–75;
c) adequate cognition and English language skills to give valid consent and complete
research interviews;
d) willingness to give written informed consent;
e) abstinence from alcohol for between 3 and 21 days before enrolment;
f) resolution of any clinically evident alcohol withdrawal and
g) less than 48 h after ceasing any diazepam required for withdrawal management.

14. EXCLUSION CRITERIA
a) active major mental disorder associated with psychosis or significant suicide risk,
b) pregnancy or lactation,
c) concurrent use of any psychotropic medication other than antidepressants (provided these are
taken at stable doses for at least 2 months);
d) unstable substance use;
e) clinical evidence of persisting hepatic encephalopathy (drowsiness, sleep inversion or asterixis);
f) pending incarceration;
g) lack of stable housing;
h) peptic ulcer; and
i) unstable diabetes mellitus.

15. Definition of ALD
 ALD was defined as the presence of symptoms and/or signs referable to liver disease or its
complications, in which alcohol use is considered to play a major aetiological role.
 Alcohol use will have exceeded an average of 60 g/day in women and 80 g/day in men for >10
years.
 [ One standard drink = 10 grams of alcohol = one ordinary beer = a small glass of wine. More
than 6 standard drinks/day for men, and 4 standard drinks for women, is known to cause
harm. ]
 If other cofactors such as chronic hepatitis C are present, a significant contribution of alcohol
to liver disease will be considered present if a period of supervised abstinence (for example in
hospital) leads to a ≥50% improvement in liver enzymes.

17. STUDY PROCEDURES
 Participants were informed about the study objectives, the nature of adherence therapy, the
profile of baclofen and that the medication they would receive would be chosen at random.
 Screening - medical history and physical examination.
 Patients who had significant withdrawal symptoms [ CIWA-Ar score of >10 ] were referred for
detoxification treatment according to local detoxification guidelines.

20.  If eligible, participants were then scheduled for the enrolment visit (baseline interviews and
initial treatment) within 1 week.
 All attempts were made to obtain drinking information (via phone or medical records) during
the study period regardless of medication adherence.

21. Randomisation and masking
 Participants randomly were allocated 1:1:1 = placebo : baclofen 30mg : baclofen 75mg
 Allocation was made by a computer-generated block randomisation sequence
 Participants, clinicians and research team members were masked.

22. INTERVENTIONS
 Randomised participants received upward and downward titrations of medication for the 84
days of treatment.
 Specifically, participants took a capsule of 10 mg or 25 mg:
 1 × day for the first 2 days,
 2 × day on days 3–4,
 3 × day on days 5–80,
 2 × day on days 81–82 and
 1 × day for the last 2 days.
 The placebo pills, which were identical in appearance, were also titrated upward and
downward to maintain the double blind.

23.  All participants received one medical assessment and
 five follow-up medical reviews at weeks 1, 3, 6, 9, 12.
 Participants were monitored for adverse events and prescribed the study medication at each
appointment.
 In addition, all participants received brief adherence therapy delivered by research
psychologists. Adherence therapy is aimed at ambivalence and misperceptions about
medication.

24. ASSESSMENTS
 At baseline, information regarding alcohol dependence and demographic variables were
gathered.
 Alcohol consumption in the previous 30 days was determined using the Timeline Followback
(TLFB) alcohol consumption form and a daily monitoring diary.
 clinical assessment for symptoms and signs of liver disease - by a physician.
 Full blood count, liver tests (bilirubin, GGT, ALP, ALT, AST, albumin), coagulation tests (INR) and
creatinine were tested at baseline.

25.  The Childs-Pugh score,
 Maddrey Discriminant Function and
 Modified End-Stage Liver Disease (MELD) scores were obtained by standard clinical methods.
 Severity of alcohol dependence was assessed using the Alcohol Dependence Scale (ADS),
 Craving was measured by the Penn Alcohol Craving Scale (PACS),
 depression, anxiety and stress levels measured by the Depression Anxiety Stress Scale (DASS)
and
 Sleep problems were assessed by the Insomnia Severity Index (ISI).
 In addition, structured psychiatric diagnostic interview using the Mini-International
Neuropsychiatric Interview (MINI).

26. The Childs-Pugh score

29. Alcohol Dependence Scale

34. Insomnia Severity Index

35.  The TLFB, DASS, PACS, ISI were performed at each visit
 ADS and blood tests were assessed at 12 weeks.
 The validity of self-report for alcohol consumption was assessed via serum analysis for %CDT
(carbohydrate deficient transferrin) in a randomly selected 25% of participants. [ CDT is a
biomarker for chronic alcohol intake of more than 60 g ethanol/d. It has been reported to be
superior to conventional markers like GGT and MCV. ]
 Adherence to medication was assessed by
 self-report,
 pill count of the returned medication package,
 the daily monitoring diary and
 urinanalysis of baclofen levels in a randomly selected 50% of participants.

36. Primary outcomes
 Time to first lapse (1 standard drink where one standard drink is 10 g of absolute alcohol);
 Time to relapse (≥4 drinks for women, ≥5 drinks for men);
 Average drinks per drinking day (week-12 follow-up) and
 Number of heavy drinking days (week- 12 follow-up);
 Percentage days abstinent and
 Percentage of patients abstinent (over the 12 week trial).

37. Secondary outcomes
 Alcohol dependence severity;
 craving;
 DASS scores for depression, anxiety and stress;
 sleep disturbance;
 liver function tests;
 frequency of adverse events and
 treatment adherence.

38. STATISTICAL ANALYSIS
 Two planned analyses were conducted:
 (a) placebo v. baclofen (composite of the two doses), followed by
 (b) 30 mg v. 75 mg to determine any dose–response effect.
1. Survival analyses (Kaplan–Meier estimates and log-rank test) were conducted to examine the
effect of treatment on length of time to relapse and lapse.
2. The primary outcome alcohol consumption variables (percentage of days abstinent, number
of heavy drinking days, average drinks per drinking day at week 12 ) were analysed using
MANOVA.

39. 3. Repeated assessments from baseline, week 6 and week 12 were analysed using mixed
models (alcohol dependence severity; craving; DASS scores for depression, anxiety and
stress; sleep disturbance; liver function tests).
4. The χ2-test were employed to detect any significant differences on abstinence rate, side-
effect profile, ‘blindedness’, treatment retention and medication adherence rates.
 Data were analysed using SPSS 23.

40. STATISTICAL TESTS

41. 1. Survival Analysis
 Method for analyzing data where the outcome variable is the time until the occurrence of an event
of interest.
 The event can be death, disease, marriage, etc. The time to event (survival time)can be measured in
days, weeks, years, etc.
 Subjects are usually followed over a specified time period and the focus is on the time at which the
event of interest occurs.
 The dependent variable is composed of two parts:
1. the time to event and the
2. the event status - if it occurred or not.
 In this study –
 the event - relapse
 The survival time is time to relapse

42. ….Survival Analysis
 One can then estimate two functions that are dependent on time,
1. The survival function gives - probability of surviving (or not experiencing the relapse) up
to that time.
2. The hazard function – probability of not surviving (relapse), given that an individual has
survived up to the specified time.
1. the Kaplan Meier method, a survival function - used to estimate survival
probabilities. It gives survival data, including the median survival time
2. the log-rank test - to test for overall differences between estimated survival
curves of two or more groups of subjects, such as males versus females
(relapse for baclofen vs placebo )

43. 2.MANOVA
 Multivariate analysis of variance (MANOVA) is an extension of the univariate analysis of
variance (ANOVA).
 In an ANOVA, we examine the effects of one independent variable on one dependent
variable.
 Whereas a MANOVA, examine the effects of one independent variable on MULTIPLE
dependent variable.
 In this study the dependant variables are - percentage of days abstinent, number of heavy
drinking days, average drinks per day at week 12
 Independent variable – baclofen or placebo.

44. ……MANOVA
 If the overall MANOVA is significant, we conclude that the respective intervention (baclofen)
is significant.
 After obtaining a significant MANOVA for an interaction (baclofen), then ANOVA is used to
identify the specific dependent variables that contributed to the significant overall effect.
 Assumption - The dependent variable should be normally distributed within groups.

45. 3.MIXED MODELS
 It is similar to ANOVA
 Analyzes results from repeated measures in which the outcome is continuous and measured
at fixed time points.
 In this study : Alcohol dependence; craving; depression, anxiety and stress; sleep disturbance;
liver function – measured at baseline, week 6 and week 12
 assume that the dependent variable is continuous, and measured on an interval or ratio
scale and that data are normally distributed.
 Because of their advantage in dealing with missing values, mixed effects models are often
preferred over ANOVA.

46. 4.CHI SQUARE TEST
 It is a non parametric test.
 It is used to measure the differences between what is observed and what is expected according
to an assumed hypothesis.
 For chi square test the data are frequencies rather than number.
 If the difference between observed and expected value is zero there is no significant difference.
 But if the difference is more than zero there is a significant difference.

47. RESULTS

50. Results
 There were no significant differences between treatment groups at baseline confirming
successful randomisation and no differences between baclofen (composite groups) and
placebo.
 Overall,
 the mean age was 48 (s.d. = 10) years,
 29% were women,
 49% unemployed,
 average alcohol consumption was 15.03 (s.d. = 9.87) drinks per drinking day and
 the average length of abstinence before randomisation was 4.7 days.
 ALD was present in 56% (n = 58) of participants

51. Results
For all participants,
 the mean length of time on medication was
 66.03 days (s.d. = 28.25) for those randomised to placebo,
 61.97 (s.d. = 28.45) for those randomised to baclofen 30 mg and
 66.62 (s.d. = 27.48) for those randomised to baclofen 75 mg.
 Analysis of urinary baclofen revealed 98% consistency with the self-report of pill count.
 Analysis of CDT% revealed 96% consistency with self report of alcohol consumption.
 There were no significant differences between groups on adherence rates (χ2<0.96) or for
time on medication (F = 0.26).

52. Results - Efficacy

53.  Survival analyses revealed significant treatment effects (placebo v. baclofen composite) for
the number of days to first lapse ( P<0.05, ) and the number of days to relapse ( P<0.05).
 MANOVA revealed a significant effect for percentage days abstinent (P<0.01) but not for the
other alcohol consumption outcome variables

54.  [The NNT is the number of patients need to be treated in order to have an impact on one person
 The number needed to treat based on the criterion of continuous abstinence was
 8.3 for baclofen
 9.1 for 30 mg/day and
 7.7 for 75 mg/day doses of baclofen.
 With regards to between-dose comparisons for baclofen, there were no significant differences
between the 30 mg/day v. the 75 mg/day dose
 for the number of days to first lapse (log rank: χ2 = 0.42, P = 0.52) or
 the number of days to relapse (log rank: χ2 = 0.05, P = 0.83).
 No significant overall treatment effect between doses attributed to alcohol consumption (P<0.35).

55. Results – Side effect

56. Adverse events
There were four serious adverse events as follows:
 one death (baclofen 30 mg) that was unrelated to study medication (liver cancer present on
study entry);
 two admissions to hospital because of suicidal ideation and alcohol intoxication that were
judged to be possibly related to study medication;
 one overdose (baclofen 75 mg group, without ALD) that was judged to be related to study
medication.

57. ALD v. non-ALD

58. ALD v. non-ALD
 There were significant difference in the baseline characteristics between the ALD v. non-ALD
subgroups.
 But within the ALD subgroup, there were no significant differences between baseline
characteristics between baclofen and placebo.
 In the ALD subgroup, there were significant differences between baclofen (two dose group
composite) and placebo for the number of days to first lapse and relapse but not for the non-
ALD subgroup.
 No significant overall effect for treatment for alcohol consumption variables in the ALD group.
 adverse event and side-effects were similar in both groups

59. DISCUSSION
 The current results showed that low–medium dose baclofen can have significant benefits on
drinking outcomes relative to placebo in patients with liver disease.
 These findings are consistent with several double-blind RCTs demonstrating efficacy of
baclofen
 No significant improvements on LFT which may be because of the low rates of abstinence
overall.
 Baclofen did not improve measures of alcohol dependence, craving depression, sleep or
anxiety.

60.  Several double blind RCTs that have failed to demonstrate any efficacy of baclofen relative to
placebo
1. Concomitant psychotherapy - In the current study, participants received brief adherence
therapy only in contrast to motivational enhancement therapy and CBT in other studies.
2. Varying levels of drinking characteristics - Whereas our sample had 15 drinks per drinking
day, the other studies had sample with lower baseline drinking levels.

61.  Patients with ALD have have an extended history of heavy drinking and lower cortical GABA
levels.
 It may be that individual alterations in GABA receptor activity due to chronic drinking predict
response to GABAergic agents such as baclofen.
 Further, Addolorato et al demonstrated with greater severity of ALD, there is more response
to baclofen.

62.  Chick & Nutt et al - baclofen could be a potential agent for a substitution therapy for alcohol
dependence because of similarities with the neuropharmacological actions of alcohol.
 Baclofen found to have biphasic effects on alcohol – increases stimulation and gives feeling of
intoxication but also sedation, leading the authors to conclude that the efficacy of baclofen is
more likely to be because of alcohol substitution effects rather than antireinforcing
properties.
 Patients who are alcohol dependent with liver disease drinking heavily before
commencement of pharmacotherapy could be the appropriate clinical subgroup for
substitution therapy with baclofen.

63.  It is well documented that baclofen is highly toxic in overdose.
 High-dose baclofen caused a range of adverse events including episodes of sedation after
concurrent alcohol consumption.
 Indeed, case studies suggest that patients with some comorbid psychiatric conditions (such
as personality disorders, bipolar disorder) or comorbid substance use are unsuitable for
baclofen.

64. STRENGTHS
 Randomised - There were no significant differences between treatment groups at baseline
confirming successful randomisation
 double-blind ( integrity – strong )
 placebo-controlled trial – helps to demonstrate efficacy and safety
 safety of participants was ensured by an independent data safety and monitoring board
 The self-report for alcohol consumption was validated with serum analysis for %CDT
(carbohydrate deficient transferrin)
 Adherence was confirmed by urinanalysis of baclofen levels
 Appropriate statistical tests were used

65. LIMITATIONS
 Age 18–75;
 Criteria for Alcohol use - 60 g/day in women and 80 g/day in men for >10 years.

66. CONCLUSION
 The current trial demonstrated that baclofen (30–75 mg/day) is an effective treatment in
people with alcohol dependence with and without liver disease drinking at an average level
of 15 drinks per drinking day.
 However, safety data raise doubt about the use of higher doses of baclofen and suggest that
prescribing should be limited to specialist services where careful treatment supervision is
provided.