Is gabapentin a promising drug for the treatment of alcohol dependence

 This post was originally written by Matt Field for the Mental Elf. You can see the original here.

Alcohol misuse is responsible for about 4% of all deaths annually, and in the UK it costs the NHS more than £3 billion per year.  A number of medications are currently licensed for the treatment of alcohol dependence. Unfortunately the medications don’t work for everyone and in the USA at least, fewer than 10% of alcoholics receive any drug therapy to help them to stop drinking or at least cut down. So, alternative medications are needed.

The drug gabapentin is licensed for the treatment of epileptic seizures, and it works by modulating GABA (gamma-Aminobutyric acid) activity in the brain. The drug may also be an effective treatment for alcohol dependence. This is because patients report depressed mood, craving, and sleep disturbance as they go through alcohol withdrawal. These symptoms, which can persist for several weeks, are associated with relapse to drinking.  Gabapentin seems to minimise the activation of the stress response in the amygdala that is partially responsible for these effects of alcohol withdrawal.

Previous studies have investigated gabapentin (versus placebo) for the prevention of relapse to drinking in alcohol dependence. All of the previous studies suggested that gabapentin could be effective, although these studies either tended to have small sample sizes, or they gave a dose of gabapentin that was probably too low. The current study from Mason et al (2013) aimed to overcome the limitations of the previous trials, by testing two doses of the drug against placebo in a large sample of alcohol-dependent patients.

Methods

This was a three-arm, double-blind, randomised controlled trial of two doses of gabapentin versus placebo. Alcohol-dependent patients (N = 150), who had been abstinent for alcohol for at least three days, were randomly allocated to groups that received either:

• Placebo
• ‘Low dose’ gabapentin (up to 900mg per day)
• ‘High dose’ gabapentin (up to 1,800mg per day)

The gabapentin groups initially received lower doses of the drug that were gradually increased until they reached the target dose. Participants were then maintained on the target dose for 11 weeks, until in week 12 the dose was titrated downwards such that all participants were receiving placebo at the end of the week. There was also a follow-up visit at week 24, although the report contains conspicuously little detail about that. All participants received psychosocial support in addition to medication, in the form of weekly manual-guided counselling and encouragement to attend local self-help groups (e.g. Alcoholics Anonymous) or other psychological treatments.

Outcome measures were:

• A responder analysis based on the rate of complete abstinence at week 12
• A responder analysis based on the rate of ‘no heavy drinking’ at week 12
• The number of drinks consumed per week over the 12 weeks of the trial
• The number of heavy drinking days per week over the 12 weeks of the trial
• Alcohol craving, sleep quality, and depression over the 12 weeks

Results

• It was notable that the authors altered the primary outcome measures from those that were declared when the trial was registered, although they did justify this, and they reported the originally registered analyses anyway
• 85 of 150 participants completed the study, and the average time that participants remained in the 12-week trial was just over 9 weeks. However, the dropout rates were similar across the different groups

Overall, gabapentin had a clear dose-dependent effect on most of the outcome measures:

• Gabapentin improved the rate of complete abstinence over the course of the 12 week trial, which was:
• 4.1% in the placebo group
• 11.1% in the 900mg group
• 17.0% in the 1,800mg group
• Number Needed to Treat (NNT) = 8; OR = 4.8, 95% CI = 0.9 to 35 for the 1800mg vs. placebo comparison
• Gabapentin had similar effects on the rate of ‘no heavy drinking’ over the course of the 12 week trial, which were:
• 22.5% in the placebo group
• 29.6% in the 900mg group
• 44.7%  in the 1,800mg group
• NNT = 5; OR = 2.8, 95% CI = 1.1 to 7.5
• Both doses of gabapentin led to reductions in the number of drinks consumed per week and the number of heavy drinking days per week, over the course of the trial. However, it was not clear if these effects were dose-dependent (the differences between the 900mg and 1800mg doses did not seem to be robust)
• Relative to participants who received placebo, participants who received the high dose (1800mg) showed marked improvements in craving, sleep quality and depressed mood over the course of the trial
• Only 65 participants who completed the 12 week trial returned for the follow-up at week 24.  Nonetheless, the dose-related effects of prior gabapentin treatment on the four drinking-related variables were maintained at follow-up
• Finally, the drug was well tolerated. There were no deaths or serious adverse events. Nine participants dropped out due to adverse events, but these participants were evenly distributed among the placebo, 900mg and 1800mg gabapentin groups

Discussion

The results of this trial are encouraging because they suggest that gabapentin may be an effective medication for the treatment of alcohol dependence, in particular it may reduce the frequency of heavy drinking and increase the rate of abstinence if given during the first few months when people are attempting to abstain from alcohol.

However this trial does have its flaws, not least the decision to switch the primary outcome measures from those that were originally registered, the high dropout rate, and the short-term follow-up period (12 weeks after medication was discontinued), for which data were available from only a small number of participants.

In mitigation, the authors defended their decision to change the outcome measures, and they reported the originally-registered outcome measures anyway; and high dropout rates are unfortunately common for all alcoholism treatments.

One strength of the study is that all patients received a psychosocial intervention as well. We know that even minimal psychosocial interventions are very effective for this population (and we can see this in the present study based on the improvement over time in the placebo group), so any additional benefit of the drug is impressive.

The next step is to investigate how gabapentin (particularly the high dose) compares to medications that are currently licensed for alcohol dependence, such as acamprosate and naltrexone (discussed here by the Mental Elf). One previous trial did test the combination of naltrexone and gabapentin, but did not compare the two medications with each other. It is also notable that although the participants in the present study were alcohol-dependent, none of them required detoxification, which means that they were not severely physically dependent. It is important to find out if the drug is useful in more severely dependent alcoholics. The authors argue that more doctors may be willing to prescribe gabapentin for their alcohol-dependent patients, given that they probably already prescribe the drug for patients with other conditions, and the same cannot be said for acamprosate or naltrexone.

As noted in an enthusiastic commentary on the paper that appeared in the same issue of the journal, the drug is off-patent which means that it would be very cheap to prescribe. Unfortunately this also means that pharmaceutical firms have no financial incentive to get the drug licensed for the treatment of alcohol dependence, and government support would be needed to make this happen.

To end on a note of caution: it is important to identify new treatments for alcohol dependence, including new medications, because the disorder is notoriously difficult to treat and it is desirable for clinicians and patients to have a choice of different treatments. However like all other treatments, gabapentin is unlikely to be a panacea: more than 80% of participants who received the high dose of gabapentin were still drinking at the end of this trial. When you turn the results on their head in this way, the reported odds ratio of 4.8 starts to look a little less impressive.

Links

Mason, B. J., Quello, S., Goodell, V., Shadan, F., Kyle, M., & Begovic, A. (2013). Gabapentin treatment for alcohol dependence: a randomized controlled trial. JAMA Internal Medicine, published online 4^th November 2013, doi: doi:10.1001/jamainternmed.2013.11950

Commentary: Nunes, E. (2013). Gabapentin: A new addition to the armamentarium for alcohol dependence? JAMA Internal Medicine, published online 4^th November 2013.

Mood management can improve smoking cessation in patients with past and current depression

This post was originally written by Abi Rose for the Mental Elf. You can find the original here.

 There is a high rate of co-morbidity between depression and smoking; rates of smoking are approximately double in those with depression compared with the general population.

In addition, smokers with depression tend to have higher rates of nicotine dependence, suffer greater negative affect during abstinence/withdrawal, are more likely to fail in quit attempts, and are therefore more at risk of smoking-related morbidity and mortality.

Given such issues, it is important to identify ways to make smoking cessation more successful in this patient population; however, health professionals don’t often encourage these patients to quit as they believe depressive symptoms may get worse. The evidence actually suggests the opposite; depressive symptoms are likely to get better in individuals who successfully quit smoking.

Given the associations between smoking, smoking relapse and depression, a Cochrane review was recently published which brings together and examines the existing evidence on smoking cessation programmes with and without mood management components (van der Meer et al., 2013). The review aimed to determine the effectiveness of smoking cessation interventions, with and without mood management components, in smokers with current or past depression.

Methods

Out of 106 studies reviewed, the Cochrane meta-analysis included 49 trials. Included studies were RCTs testing the effectiveness of pharmacological or psychosocial interventions for smoking cessation in smokers with current/past depression. Study participants were adult smokers with current/past depression, defined as major depression (DSM-IV) or depressive symptoms (measured by scales such as Beck’s Depression Inventory).

Results

Dichotomous treatment outcomes were measured via risk ratio (RR), which is calculated by:

 

 An RR greater than 1.0 favours the intervention group (95% confidence intervals [CI] of the RR are also reported).

The primary outcome of interest was smoking status at a minimum of six months from first quit day.

The authors used ‘sustained cessation rates’ where available, i.e., continuous abstinence from quit date or prolonged abstinence (may include lapses which are not regarded as treatment failure). Participants lost to follow-up were assumed to be continuing smoking.

Patients with current depression

• Analysis of 11 trials (N = 1844) showed a significant positive effect on smoking cessation by adding psychosocial mood management (RR 1.47, CI 1.13-1.92)  
• Due to insufficient data, the effects of antidepressants on smoking cessation only investigated the effect of buproprion. 
• Analysis of 5 trials (N = 410) showed an insignificant positive effect on smoking cessation (RR 1.37, CI 0.83-2.27)

Patients with past depression

 

• Analysis of 13 trials (N = 1469) showed a significant positive effect on smoking cessation (at ≥6 month follow-up) by adding psychosocial mood management (RR 1.41, CI 1.13-1.77)
• Analysis of 4 trials (N = 404) showed a significant positive effect for the use of bupropion (RR 2.04, CI 1.31-3.18) 
• Analysis of 3 trials (N = 432) showed an insignificant positive effect on smoking cessation by giving NRT (RR 1.17, CI 0.85-1.60)

Some trials investigated the effects of other pharmacotherapies (e.g., naltrexone) and psychosocial treatments (e.g., nurse staged care), however, due to the heterogeneity between trials, no pooled effects could be estimated.

• For individuals with current and past depression, including a psychosocial mood management component to smoking cessation treatments increases the likelihood of successful smoking cessation.
• While bupropion may increase smoking cessation in those with past depression, there is no evidence for increased effectiveness in those with current depression.
• There is not enough evidence to determine the effectiveness of other antidepressants or treatments without specific mood management components (e.g., NRT and psychosocial interventions), for smokers with past/current depression.

Sum up

• Given that smokers with past/current depression tend to be more severely nicotine dependent and struggle more with successfully quitting, it is important to identify interventions which will enhance successful quit attempts.
• Health professionals are encouraged to advise patients with a history of depression to use a smoking cessation programme which includes a mood management component.
• There was a lot of heterogeneity in the trials included in this meta-analysis (e.g., how depression was assessed, outcome measures used) and a lack of information regarding the history of depression (e.g., one episode vs. multiple episodes). These factors limit the implications of this research and highlight that more research is needed in this group of smokers.
• Trials with mood management components tended to include more treatments sessions. Although this may be a reason for increased effectiveness, most studies investigating associations between number of sessions and treatment success have been non-significant, suggesting that it is the inclusion of mood management components that are important.
• The finding that bupropion enhances treatment outcomes in those with past, but not current, depression is counterintuitive. Given the fairly low number of trials investigating this effect, and that the association between enhanced treatment effectiveness in those with past depression was fairly weak, more research is needed to validate this finding.
• Existing evidence is positive for the use of psychosocial smoking interventions without mood management components; however, these trials often exclude smokers with past/current depression. Research is needed to determine whether more general psychosocial interventions can be effective in smokers with some history of depression.
• The overall findings and limitations highlighted by this review reflect those of an earlier review on smoking cessation interventions in patients with depression (Gierisch et al., 2010)

Links

van der Meer RM, Willemsen MC, Smit F, Cuijpers P. Smoking cessation interventions for smokers with current or past depression. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006102. DOI: 10.1002/14651858.CD006102.pub2.

Gierisch JM, Bastian LA, Calhoun PS, McDuffie JR, Williams JW Jr. Comparative Effectiveness of Smoking Cessation Treatments for Patients With Depression: A Systematic Review and Meta-analysis of the Evidence (PDF). VA-ESP Project #09-010; 2010

NICE guidelines on smoking cessation:

http://guidance.nice.org.uk/PH48

http://www.nice.org.uk/nicemedia/pdf/ph010guidance.pdf

 

Culture eats strategy for breakfast, but maybe strategy will have more luck over dinner: review of the North West Alcohol Conference 2013

We recently attended the North West Alcohol Conference in Liverpool. PhD students Natasha Clarke, Inge Kersbergen and Jay Duckworth summarise the highlights.

Natasha Clarke

Professor David Walker, Deputy Chief Medical Officer of the NHS, gave the first talk. This focussed on The National Alcohol Strategy; the proposal put forward by the government to tackle our society’s harmful use of alcohol. The key issue raised was the disappointment of Public Health England with the government’s reluctance to introduce minimum unit pricing (MUP), despite initial plans to implement it. Evidence from Canada and the Sheffield Alcohol Policy Model indicate the implementation of a 45p MUP may decrease alcohol consumption and reduce hospital admissions, yet the strategy states that more evidence is needed. The sudden backtrack is suggested to be due to intense lobbying from the alcohol industry; for example, the Wine and Spirit Trade Association (WTSA) launched a campaign against the proposal and claim that MUP would unfairly penalise the majority of responsible consumers. Previous research has shown that the industry will selectively use evidence in order to support policies that are in line with their commercial interests, and WHO stress that industry should have no role in forming alcohol policy.

So what is being done? The government has committed to a ban of “below cost sales”, with cost being duty + VAT. This is equal to roughly 21p per unit for beer and 28p per unit for spirits, prices significantly lower than the original proposed MUP. It is estimated that only 1.3% of all units of alcohol sold will be affected by this and that a threshold of 45p would have a considerably larger impact. The government also mentions a pledge through the responsibility deal to take 1 billion units out of the market by 2015; the Health Committee doesn’t think this will have any significant impact. A further emphasis was placed on education campaigns, despite evidence showing their ineffectiveness in reducing alcohol-related harm.

What was clear is that the government are not doing enough. Words and promises (especially ones that are broken) will not produce changes in the nations’ health. An audience member asked David Walker… “Can you change culture?” The answer was “Yes, we can”. Using smoking and driving behaviours as previous examples he explained that these are health aspects to which our outlook as a nation has changed. Smoking attitudes took decades to alter and faced similar pressure from the industry. The verdict was that we must continue to fight for better policy, but an equal match of input from public health and industry is continuing to prove difficult.

Inge Kersbergen

Discussions then continued in different breakout sessions. Colin Shevills and Ali Wheeler made a compelling case for changing licensing regulations. Licensed premises are popping up everywhere in the country. You can now buy alcohol in a large variety of places: in cinemas, indoor playgrounds, and even hairdressers. And the more traditional licensed premises keep growing in number as well. All whilst we know from research that the density of licensed premises is related to more alcohol-related harm and crime. The licensing act is still operating under the premise that licenses are granted where possible, even if licensing committees and communities want to limit the amount of licensed premises in an area.  Licensing committees have very limited power when it comes to restricting licenses in high density areas or taking licenses away. However, they do possess two powerful tools to limit alcohol availability: Early Morning Alcohol Restriction Orders (EMROs) and Late Night Levys (LNLs).  

An EMRO restricts sales of alcohol in a specific area at a set time between midnight and 6am. Premises that are in violation of this order will receive a fine. The LNL is an additional fee for licensed premises if they want to sell alcohol between midnight and 6am. At first glance these policies seem very similar. The difference lies in how voluntarily businesses restrict their selling times. At the start of November 2013 a LNL has been introduced in the city of Newcastle.  So far, it seems like this levy has the effect of an EMRO, as many businesses voluntarily decided not to pay the additional fee, but to stop selling alcohol at midnight instead. The proposed EMRO in Blackpool, on the other hand, was met with a lot of resistance from the business owners. The speakers argue that it is therefore important that businesses do not feel forced into restricting their selling hours to get their full cooperation. Local licensing committees should make more use of the tools they have, get more freedom to limit licensed premises in their area and be able to involve the local community in their decision making.

Jay Duckworth

Further suggestions for policy change came from Mark Gilman, Strategic Recovery Lead at Public Health England and the National Treatment Agency for Substance Misuse. Gilman, a passionate speaker, offered advice which he concedes many see as “unscientific, folky [and] quirky”. His idea is that we need to place more emphasis on twelve-step programs in which addicts are forced to confront matters of “spirituality”. Initiatives such as Alcoholics Anonymous (AA) are of this breed, asking addicts to admit they are “powerless over alcohol” and to recognise that a “Power greater than they can restore their sanity”. As Gilman admits, this may be a difficult pill to swallow for many. First, non-spiritual individuals will find it problematic to attain the “spiritual awakening” necessary for success in many 12-step approaches. Additionally, though AA is effective at reducing rates of drinking there are many equally effective treatments available which come without the mystical baggage. That being said, there is an essential feature of 12-step programs which should be acknowledged as an important part of recovery: social support from people who are abstinent from alcohol. Social networks of abstainers appear to be one of the primary reasons why involvement in 12 step programs helps people to abstain from alcohol.

The next speaker was Wim van den Brink, Professor of Psychiatry and Addiction at the Academic Medical Centre of the University of Amsterdam. Following directly from the previous speaker, van den Brink started by saying that, “I agreed with almost everything you said, but I’m going to disagree on some points just to make it interesting…” And so he did. He focused on his own recently published research which tested the efficacy of the drug Nalmefene on an alcohol-dependent population. Two clinical trials had shown that Nalmefene reduced drinking significantly in patients relative to placebo. In his talk, van den Brink focussed on additional analyses that compared the effects of the drug on those who reduced their drinking between screening (when their drinking was assessed by a doctor) and randomization (to receive either Nalmefene or placebo), and those who did not. These analyses showed that many of the patients reduced their drinking after screening and for this group, Nalmefene had no effect. On the other hand, Nalmefene led to large reductions in drinking among patients who did not reduce their drinking after the initial clinical assessment.

These two talks complemented each other nicely because they suggest that broad social factors play an important role in recovery from alcohol problems. For some problem drinkers, simple assessment of drinking by a doctor (which can be considered a ‘minimal’ psychological intervention) is enough to help them to reduce their drinking. Whereas others may need medication, such as Nalmefene, in order to cut down.