Research Roundup Winter 2014

Welcome to the latest research round up from the Addiction Research Group based in the Department of Psychological Sciences, University of Liverpool. We have been working very hard over the winter months (because typing keeps hands warm in badly heated offices), and this is what we have produced…

We have published three review papers covering a broad range of topics in addiction. 

The first by Pawel Jedras and colleagues, published in Neuroscience and Neuroeconomics (open access) examined the role of drug anticipation in addiction and reward. They examined the available evidence, discussing the necessary role of drug expectancy in conditioned responses to drug-related cues, the role of impulsivity and the underlying neural circuitry of anticipation. Finally, they provided a discussion of how perceived drug availability can lead to poor treatment responses and what might be done to mitigate this. 

Our second review was by Margot Peeters (who visited us from the Netherlands) with Matt Field. They conducted a narrative review, published in Alcohol and Alcoholism, summarising the evidence base for cognitive impairments in heavy drinking adolescents, with an emphasis on elucidating any causal relationship(s). They examined both cognitive impairments and impulsivity as risk factors for alcohol use in youth, but also the possibility that heavy drinking may cause further cognitive impairments and impulsiveness due to neurotoxic effects on the brain. 

Our final review paper was by Andy Jones and colleagues, published in Frontiers in Psychiatry (open access). The aim of this review was to identify the psychological and environmental variables that may cause state changes in (dis)inhibition leading to increases in drinking and drug use. Some of these variables include stress, self-control depletion and exposure to cues. They concluded that identifying these variables and targeting them for treatments may help reduce the risk of heavy drinking, drug use and relapse. 

We have also published some interesting original research:

Paul Christiansen published a paper in Drug and Alcohol Dependence demonstrating that individualised stimuli may increase the predictive validity of attentional bias tasks. Using a Stroop task containing words related to the individual’s favourite drink, they found performance predicted variance in drinking above and beyond performance on a Stroop using general alcohol words. This paper was a direct follow up to a commentary Paul and Matt published in 2012. 

Abi Rose and colleagues published a paper in Psychopharmacology, investigating the relationship between alcohol-induced risk taking using the Balloon Analogue Risk Task (BART) and urge to drink. They found that alcohol increased risk taking and urge to drink. Furthermore, it was found that risk taking after alcohol consumption mediated alcohol priming, suggesting that those susceptible to alcohol-induced risk taking may be more likely to drink excessively, due to an increased urge to drink.

In other news, we have been travelling around the country to disseminate our research. 

The addiction group is a core member of the UK Centre for Tobacco and Alcohol Studies (UKCTAS), a leading centre of tobacco and alcohol research and policy excellence. The inaugural meeting of UKCTAS in York in September was attended by Matt Field, Abi Rose, Eric Robinson, Jay Duckworth, Lisa Di Lemma and Inge Kersbergen.

Matt Field attended the Society for the Study of Addiction conference in York in November and gave an invited talk on the contributions of basic science to our understanding of addiction.

Andy Jones, Eric Robinson and Matt Field also attended the UK Society for Behavioural Medicine (UKSBM) in Oxford in December.  Andy gave a poster and short oral presentation discussing ‘Response Inhibition in everyday life. Validating a mobile version of the Stop-Signal Task’. Eric gave an oral presentation entitled ‘GPs don't know what obesity looks like and this reduces their likelihood of initiating treatment’. Congratulations to Eric, who was awarded a prestigious early career award at UKSBM.

We also attended the North West Alcohol Conference, at the Hilton hotel in Liverpool in November. Jay, Inge and Natasha did an excellent job of summarising the conference highlights here

Finally, Matt is working as an advisor for Alcohol Concern’s Dry January campaign. If you are taking the challenge yourself and finding it a bit of a struggle, you can log on to the Facebook page or follow the Twitter feed for advice, details here

That is a wrap for this research roundup. Thank you for reading! As always, if you would like to get in touch about anything featured here please contact Prof. Matt Field, and if you are interested in taking part in our research please contact Andy Jones.

It's Christmas!

This post was originally written by Natasha Clarke and taken from her personal blog, which you can find here.

So Christmas is over once more. It’s been a month of overindulgence and excessiveness particularly with alcohol, made acceptable simply by using the phrase “It’s Christmas”. I’ll give you some examples:

1. My Grandma replacing her morning tea with sherry
2. My orange juice (alright 3 orange juices) containing more bubbly than fruity goodness.
3. My friend drinking a whole bottle of wine on the train before arriving on New Year’s Eve. On his own.

These are things that are not normal in everyday life; if I started every day with a bucks fizz I’d have a serious problem. Yet, over Christmas, it is almost weird not to do these things. Thankfully it’s not just me; as a nation we drink 41% more in December than the monthly average. Furthermore, a recent survey of over 2000 adults by the British heart foundation (BHF) found that 58% of Britons think it is standard behaviour to drink by 1pm on Christmas day, and 16% want to have a tipple earlier, at 11am. I’m also guessing many of these first drinks will be top-ups from the night before, after a Christmas Eve spent drinking at the pub.

There are many explanations as to why we consume more alcohol: tradition, sociability and relaxation are an obvious handful. However, reasons may not always be so celebratory. For example the survey mentioned previously found that 9% of people drank so they did not feel left out of family celebrations, and this rises in the older generation, with 12% consuming alcohol on Christmas Day to fit in. I can emphasise this using a conversation my Grandma had with a teetotal family member- “You don’t drink?” – “I don’t like people who don’t drink, they’re boring”. Thankfully this didn’t lead to him reaching for the whiskey bottle, but pressure by others can be a core reason for non-drinkers changing their behaviour on this special day. Another reason for increased drinking is pressure and stress, with one in five of those surveyed by the BHF consuming more than they would usually to help them de-stress.

What does this overconsumption mean? Starting with the bleak death statistics, figures in 2010 and 2011 where the underlying cause was alcohol and drugs were 13% above the daily average between December the 21^st and January 19^th. Some of these deaths are due to drink driving; in 2012 the Association of Chief Police Officers (ACPO) Christmas anti-drink and drug driving campaign showed 7123 drivers tested positive, failed or refused their breathalyser. Being over the limit significantly increases reaction times and therefore your risk of crashing. There is also the “holiday heart phenomenon”, this is the incidence of cardiac arrhythmias following excessive alcohol consumption, which most often occur on Mondays (e.g. after a particularly heavy weekend) or between Christmas and New Year’s Day. These are grave facts which may only affect a minority of us, but are extremely important to keep in mind.

Of course there are aspects of increased consumption likely to relate to all of us. Firstly there are the things we do when drunk that we wouldn’t usually, when the excitement of the festive period lead to illness, injuries or a night spent in a cell for being drunk and disorderly. To highlight this on Mad Friday Manchester Police used the hashtag #MadMancFriday on Twitter to expose some of the humiliating and regrettable things we get up to on the biggest night out before Christmas. Then there are long term effects on our body, a month of overindulgence leads to noticeable effects on our appearance. In particular I’m referring to the extra weight that slowly creeps up on us. We eat more, we don’t exercise, and we are too hung over to exercise. Although many of these calories are more attributable to the box of quality streets and the dozen mince pies, a lot of them can be due to alcohol’s empty calories. For example: three glasses of Buck’s fizz, one bottle of red wine, three beers, one baileys and one port equates to just under 2000 calories, nearly a woman’s daily allowance. It’s also around 25 units, more than the recommended allowance in a week for both males and females.

Obviously overindulgence is something of a normality when it comes to Christmas and New Year celebrations, and it definitely wouldn’t be as joyous if we spent our time calculating our units and calories, replacing our champagne with Schloer and our roasties with a salad. But, it’s fascinating just how much our behaviour can change depending on the time of year. All I can say is thank the lord for Dry Jan and post-Christmas diets.

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