Chris Alford

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Energy drinks mixed with alcohol: misconceptions, myths, and facts

Background Whilst energy drinks improve performance and feelings of alertness, recent articles suggest that energy drink consumption combined with alcohol may reduce perception of alcohol intoxication, or lead to increased alcohol or drug use. This review discusses the available scientific evidence on the effects of mixing energy drinks with alcohol. Methods A literature search was performed using the keywords “energy drink and Red Bull®” and consulting Medline/Pubmed, PsycINFO, and Embase. Results There is little evidence that energy drinks antagonize the behavioral effects of alcohol, and there is no consistent evidence that energy drinks alter the perceived level of intoxication of people who mix energy drinks with alcohol. No clinically relevant cardiovascular or other adverse effects have been reported for healthy subjects combining energy drinks with alcohol, although there are no long-term investigations currently available. Finally, whilst several surveys have shown associations, there is no direct evidence that coadministration of energy drinks increases alcohol consumption, or initiates drug and alcohol dependence or abuse. Conclusion Although some reports suggest that energy drinks lead to reduced awareness of intoxication and increased alcohol consumption, a review of the available literature shows that these views are not supported by direct or reliable scientific evidence. A personality with higher levels of risk-taking behavior may be the primary reason for increased alcohol and drug abuse per se. The coconsumption of energy drinks being one of the many expressions of that type of lifestyle and personality.

Effects of 5 weeks of administration of fluoxetine and dothiepin in normal volunteers on sleep, daytime sedation, psychomotor performance and mood

This was a placebo-controlled, double-blind randomized crossover study of long-term (5 weeks) administration of fluoxetine (20 mg/day) and dothiepin (75 mg/day for 1 week followed by 150 mg/day for 4 weeks) in 12 healthy male volunteers. Subjects were studied on day 10 and day 36 of treatment, with tests of nocturnal sleep, driving performance, continuous electroencephalogram (EEG), sleep during scheduled naps, computerized visual attention tasks, saccadic eye movement measurement and visual analogue ratings of mood. Both drugs had a marked suppressive effect on nocturnal rapid eye movement (REM) sleep; these effects were less at 36 days than at 10 days, and fluoxetine decreased and dothiepin increased REM in daytime naps. Sleep fragmentation after fluoxetine is similar to that reported in the literature. We found no sleep-promoting effects of dothiepin, in contrast to our previous single-dose study, and no subjective sleep effects of either drug. Subjects were less sleepy after both antidepressants than placebo at 5 weeks measured by sleep latencies and EEG. Saccadic eye movement measures were significantly faster after 5 weeks of fluoxetine than after 5 weeks of placebo. Reaction times to a peripheral stimulus during computerized tracking task were shorter after 10 days of dothiepin compared with placebo. Driving performance, visual attention and mood ratings showed no treatment effects. Subjective health reports during each 5 weeks of treatment were similar in number for the two drugs but showed a different profile of side-effects.

Caffeine-induced sleep disruption: effects on waking the following day and its reversal with an hypnotic

The effects of 4 mg/kg and 8 mg/kg caffeine nocte as a model of insomnia, and its potential for reversal with an hypnotic (temazepam 20 mg) were investigated in two double‐blind placebo controlled crossover studies, each with six healthy volunteers. Following an adaption night and day, two nights per treatment were assessed with multiple sleep latency tests (MSLTs), performance measures and subjective questionnaires undertaken the following day. In comparison to placebo significant (P < 0.05) increases in sleep onset latency of 30 and 40 min were seen for low and high doses respectively. Significant reductions in sleep duration were limited to the higher dose (total sleep time 80 min, sleep efficiency 17 per cent), as were reductions in slow wave sleep and non‐REM sleep which contrasted with increased waking. However, contrast analysis revealed significant dose‐related effects for these measures, whilst the lower dose produced more stable effects across nights, suggesting it as more suitable for a model of insomnia in healthy sleepers. Significant decrements in critical flicker fusion (CFF) performance and reduced MSLT latencies reflected increased daytime sleepiness following both doses; although significant subjective changes to sleep and sleep tendency next day were limited to the higher dose. Co‐administration of temazepam elixir successfully reversed increased sleep latency seen with the lower caffeine dose and improved subjective sleep, but significant effects on other sleep measures were more limited despite improved mean trends. Similarly, improvements in CFF performance and MSLT latencies failed to achieve significance, suggesting a possible limitation of the hypnotic in overcoming the effects of sleep disturbance and consequences for waking function next day.

Sleep and daytime sleepiness the next day following single night-time dose of fluvoxamine, dothiepin and placebo in normal volunteers

To explore the effects of sedating and non-sedating antidepressants, we conducted a placebo-controlled, double-blind cross-over study in 12 normal subjects of the effects of a single night-time dose of fluvoxamine 100 mg, dothiepin 100 mg or placebo on night-time sleep recorded at home, and sleepiness and performance the following day. Night-time sleep was altered significantly by both drugs, with main effects on rapid eye movement (REM) sleep and sleep continuity. Dothiepin increased total sleep time, REM latency and stage 2 sleep and decreased arousals, wake after sleep onset and stage 1, whereas fluvoxamine decreased total sleep time and REM time and increased wake after sleep onset. Sleep latencies in daytime naps were significantly shorter for dothiepin and longer for fluvoxamine, showing that subjects were more sleepy when taking dothiepin. Electroencephalograms (EEG) performed during performance tasks failed to distinguish significantly between drugs. There were no significant differences between groups on our measures of tracking performance or reaction time; however, these tasks were designed primarily to provide a standard setting in which to monitor continuous EEG, and were unsuitable to detect sleepiness effects themselves. Saccadic eye movement velocity, acceleration and deceleration showed small non-significant changes after both drugs. Mood self ratings showed no significant differences among the groups. Subjective measures of night-time sleep reflected the objective measures of sleep continuity, and the items for difficulty and speed of wakening in the morning were significantly higher (i.e. more difficulty and slower) in the dothiepin group. The home-recorded sleep findings after fluvoxamine in this study were very similar to sleep laboratory studies with other antidepressant drugs, thus providing more validation of the home recording method.

Mixing alcohol with energy drink (AMED) and total alcohol consumption : a systematic review and meta-analysis

It has been suggested that consuming alcohol mixed with energy drink (AMED) may increase total alcohol consumption. Aims of this systematic review and meta‐analysis were (i) to compare alcohol consumption of AMED consumers with alcohol only (AO) consumers (between‐group comparisons), and (ii) to examine if alcohol consumption of AMED consumers differs on AMED and AO occasions (within‐subject comparisons). A literature search identified fourteen studies. Meta‐analyses of between‐group comparisons of N = 5212 AMED consumers and N = 12 568 AO consumers revealed that on a typical single drinking episode AMED consumers drink significantly more alcohol than AO consumers (p = 0.0001, ES = 0.536, 95%CI: 0.349 to 0.724). Meta‐analyses of within‐subject comparisons among N = 2871 AMED consumers revealed no significant difference in overall alcohol consumption on a typical drinking episode between AMED and AO occasions (p = 0.465, ES = −0.052, 95%CI: −0.192 to 0.088). In conclusion, between‐group comparisons suggest that heavy alcohol consumption is one of the several phenotypical differences between AMED and AO consumers. Within‐subject comparisons revealed, however, that AMED consumption does not increase the total amount of alcohol consumed on a single drinking episode.

NICE review: not nice for patients!

We read with interest Professor David Nutt’s critique of the recent National Institute for Clinical Excellence (NICE) review contrasting the Z-drug hypnotics with what NICE has described as ‘shorteracting’ benzodiazepines (Nutt, 2005). NICE concluded that there is a lack of appropriate evidence to discriminate clinically between the Z-drugs and what they describe as shorter-acting benzodiazepines, placing loprazolam, lorazepam, lormetazepam and temazepam in this group. This evaluation included their effectiveness, adverse effects and abuse potential. Unfortunately, the major conclusion from NICE was that cost should be a prime factor when prescribing. We believe that NICE has missed an important opportunity to promote good clinical practice regarding hypnotic use through endorsing the Z-drugs as superior to the benzodiazepines. Furthermore, their recommendations will lead to poorer patient experience or non-compliance with hypnotic treatment, particularly amongst the elderly, and increase the likelihood of accidents with an associated wider health cost that has not been acknowledged in their review. Hypnotic prescription levels can be estimated to be in the region of 10 million general practitioner prescriptions per annum in England (British Medical Association, 2000; Dundar et al., 2004; Morgan et al., 2004), indicating that this is a sizeable treatment group who should be offered appropriate hypnotic treatment. The effects of insomnia include problems with falling asleep, maintaining sleep and waking early (American Sleep Disorders Association, 1990; American Psychiatric Association, 1994). With the advent of the relatively short-acting Z-drugs, there are now suitable products to treat these separate categories. By contrast to the listed ‘short-acting’ benzodiazepines in the NICE review with half lives ranging from 8 to more than 10 h, all Z-drugs are relatively short-acting. The ultra short half-life of zaleplon (1 h) makes it very suitable for sleep onset insomnia. Zolpidem (1.9 h) is also suitable for this and can help those individuals with sleep maintenance problems by virtue of its longer half-life. Zopiclone, having the longest half-life (> 4 hours), may be more suited to those with sleep maintenance problems and early waking. The role of the psychopharmacologist may be summarized as aiming: (i) to help determine clinical efficacy and treatment potential for drugs and (ii) to discriminate between a class of therapeutic compounds on the basis of their side-effects profiles. So what can we as psychopharmacologists offer NICE to help them reach a better informed decision? In relation to the first point, the shorter onset and more rapid elimination of the Z-drugs means that more appropriate prescribing may be undertaken on the basis of a differential diagnosis of the type of primary insomnia indicated above. With regards to the second point, if therapeutic equivalence was assumed, then is there a difference in side-effects profiles that can also inform treatment choice? It would be predicted that the longer half-lives of the benzodiazepines (> 8–10 h) will be associated with greater residual effects, and this is borne out by the literature. Comparative evaluation of the side-effects profiles, or behavioural toxicity, of the benzodiazepines has shown an increase in sedative hangover effects with higher dosing and longer-acting benzodiazepines, including the classic amnestic effects of benzodiazepines, together with poorer psychomotor performance (Subhan and Hindmarch, 1984; Vermeeren, 2004; Verster et al., 2004). Lorazepam has been used as a standard active reference compound because of its reliable sedative side-effects. When this is contrasted with the lower incidence of side-effects in general for the Z-drugs and the substantial lack of residual effects for zaleplon and zolpidem, a clear distinction can be observed (Salva and Costa, 1995; Wagner and Wagner, 2000; Drover, 2004). The very short (1 h) half-life of zaleplon means that this compound may be taken during the night. Administration 1 h before waking has produced minimal residual effects, with none recorded when taken 3 h before waking (Hindmarch et al., 2001) and the ability to drive a car was also unaffected 4 h after administration in the middle of the night (Verster et al., 2002). Zaleplon allows patients to wait and see if they really need a hypnotic because they can take it during the night after having set a time limit for natural sleep onset. This helps break the fear/dependency cycle, putting the patient back in control of their sleep problem, aiding self-efficacy (Bandura, 1997; Doghramji, 2000; Scharf, 2001) and reducing excessive hypnotic consumption (reducing costs). Journal of Psychopharmacology 19(2) (2005) 129–132

The Alcohol Mixed with Energy Drink Debate: Masking the Facts! A Commentary on “Mixing an Energy Drink with an Alcoholic Beverage Increases Motivation for More Alcohol in College Students” by Marczinski and Colleagues (in press)

To the Editor: In their study “Mixing an Energy Drink with an Alcoholic Beverage Increases Motivation for More Alcohol in College Students,” Marczinski and colleagues (in press) conclude that “An energy drink may elicit increased alcohol priming. This study provides laboratory evidence that AmED beverages may lead to greater motivation to drink versus the same amount of alcohol consume alone.” However, on inspection of the study, we believe that this conclusion is premature and that issues with the design, analysis, and interpretation of the data may merit different conclusions. The first, less serious issue relates to the nature of the vehicle, Squirt, which is described by the manufacturers as a caffeine-free citrus soda. If we assume that the participants had some knowledge of Red Bull, then the sensory characteristics of the vehicle and alcohol compared with energy drink and alcohol mixed with energy drink (AmED) may have produced different expectancies, potentially confounding the main outcomes of the study. The second, more substantive issue relates to the analyses performed. The study utilized a between-subjects design and compared the effects of a placebo (Squirt lemon drink), alcohol, Red Bull energy drink, and AmED. The study includes several subjective measures but focuses on “desire to drink” which was assessed at baseline then at 10, 20, 40, 60, and 80-minutes postdrink. These scores were appropriately subjected to a 2 (Alcohol) × 2 (Energy Drink) × 2 (Gender) × 6 (Time) analysis of variance with time as a repeated measures factor. This revealed a significant interaction (p = 0.046). An appropriate analysis would then be to compare treatment groups at each time point which the authors then did using independent samples t-tests comparing alcohol and AmED groups. The authors state “No differences between alcohol and AmED for any of the time points were observed, although there was a nonsignificant trend for higher ratings for AmED versus alcohol alone at 40 minutes, t(38) = 1.47, p = 0.075.” The between-groups comparison, therefore, failed to reveal any significant effects. In addition to the above, the authors compared, within each group, each time point with their respective baseline scores using paired samples t-tests. Unfortunately, this analysis tells us nothing about the differences between groups (Nieuwenhuis et al., 2011), for example, whether there are any differences between the alcohol and the AmED groups. However, they have used the results of the within-groups analysis to make inferences about differences between groups, even though they have shown these to be nonsignificant. This same analytical approach was used by some of these authors in an earlier study which then also drew erroneous conclusions (Marczinski et al., 2011). Additionally, such analyses can be greatly influenced by chance baseline differences in the same measure and by regression to the mean. Indeed, inspection of baseline “desire for alcohol” ratings (table 1) reveals large variations in mean baseline scores (energy drink 13.00, vehicle 7.80, alcohol 6.65, and AmED 4.65). This reflects sampling variability associated with the study and provides a range estimate (8 units) with which to compare posttreatment differences. From the graph (fig. 1), the maximum differences between alcohol and AmED appear to be of a similar magnitude supporting the lack of significant differences found. These baseline scores directly predict the magnitude (and duration) of apparent change from baseline scores. Thus, using their questionable analyses, the authors report that consumption of Red Bull alone (with the highest baseline score) reduced “desire for alcohol” at 40 and 80 minutes. The alcohol drink increased “desire for alcohol” at 10 and 20 minutes, while the AmED with the lowest baseline score resulted in increased rating, relative to baseline at 10, 20, 40, and 80 minutes. It is notable that the consumption of vehicle alone, with the third lowest baseline score, resulted in significantly higher “desire for alcohol” restricted to 10 minutes postdrink—surely the most remarkable result of the study! Indeed, if these data are taken at face value then surely the fact that drinking citrus-flavored soda primes alcohol craving at all would be the cause of a major health concern. Of course a more realistic interpretation would compare scores between groups and conclude that there are no effects. Despite the fact that there were no significant between-group differences for this measure, at several points in the discussion section the authors state “we observed that a priming dose of AmED increased these desire ratings for a longer time period compared with a priming dose of alcohol alone,” and “…, participants desired more alcohol following AmED compared with alcohol alone, although they liked and felt the 2 types of alcoholic beverages in a similar fashion.” In the discussion section, Marczinski and colleagues (in press) characterize their results as “remarkable” because “Previous research suggests that this amount of caffeine alone would not reliably alter physiological or subjective state” (i.e., typically 46 mg caffeine). Indeed, it has been consistently shown that coadministering caffeine (<300 mg) generally does not significantly alter performance impairment caused by alcohol, nor do these levels of caffeine alter mood, or perception of intoxication (for a review, see Verster et al., 2012). Based on this empirical evidence, caffeine does not generally counteract the sedative effects of alcohol, and the nonsignificant results of the current study confirm previous findings. Nevertheless, Marczinski and colleagues (in press) interpret their data as suggesting that “…the energy drink mixer might increase the reinforcing aspect of alcohol.” There is a current fashion to attribute “high risk” to mixing alcohol with energy drinks, in the face of data which does not support such a contention. In fact, findings from Marczinski and others consistently demonstrate that mixing alcohol with energy drink does not increase the desire to drink more (Marczinski et al., in press) and does not alter the perception of subjective intoxication (Alford et al., 2012; Attwood et al., 2012; Marczinski et al., 2011, in press). Marczinski and colleagues (in press) continue the discussion by stating “Considering that drug wanting (i.e., incentive salience) produces addictive behavior (Robinson and Berridge, 1993), the results of our study might therefore provide an explanation for why consumers of AmEDs are more likely to become alcohol-dependent (Arria et al., 2011).” Again, this hypothesis is not supported by the data presented by Marczinski and colleagues (in press) in which drug “wanting” (as observed in craving) was not assessed. Instead, it was simply asked whether participants had a greater desire for alcohol after AmED compared with consuming alcohol alone. The results showed that this was not the case. Second, no significant differences were observed in “feeling” the beverage (whatever this means) and “liking” the beverage between AmED and alcohol only. Therefore, none of these subjective measures significantly distinguished between the alcohol and AmED treatments. The data presented by Marczinski and colleagues (in press) do not provide any evidence for the proposed relationship between AmED consumption and the risk of becoming alcohol-dependent (Arria et al., 2011), a relationship that has been disputed by several other researchers (Verster and Alford, 2011; Verster et al., 2012) and described as an “imaginary link” (Skeen and Glenn, 2011). In conclusion, the data do not support the proposal that “The results of the current study suggest that increased translational research may better elucidate possible underlying mechanisms explaining why AmEDs may lead to increased drinking.” Marczinski and colleagues (in press) have confirmed that the desire to drink more was not significantly different after consuming AmED compared with consuming alcohol alone. Moreover, it was never assessed whether these subjects actually drink more after consuming AmED. Finally, grant awarding agencies such as NIAAA should critically examine research proposals in this field to determine if the assumptions are based on scientifically verifiable facts. A succession of studies and surveys on AmED consumption has been shown to be of poor methodological quality which has resulted in a series of unjustified concerns and wrong conclusions (Verster et al., 2012). While there might be justifiable concerns, these need to be reinforced with high quality empirical data, and appropriate analyses. Presenting results without reference to the conventions of scientific reporting reduces the credibility of the alcohol research community as a whole.

Effects of Sleep Medications on Cognition, Psychomotor Skills, Memory and Driving Performance in the Elderly

Sleep disturbances occur more often in the elderly than in patients in any other age category. Traditional treatment regimens for insomnia in older patients have emphasized benzodiazepines. The useful anxiolytic and hypnotic properties of these agents have made them the most widely prescribed class of drugs in the world. Concern has been expressed however about the significant side effect profile associated with these agents. There is now considerable evidence that all benzodiazepines show significant dose-dependent impaired daytime performance on a variety of memory, cognitive and psychomotor tests. In addition, the risk of falls, hip fractures, and traffic accidents is significantly increased in patients who are treated with benzodiazepines. There is little evidence that benzodiazepine hypnotics are still effective after chronic use. On the other hand, several impairments persist when using these hypnotics over long time. Recently, the nonbenzodiazepine drugs zolpidem and zaleplon have been introduced and are claimed to be relatively safe (i.e. less daytime sedation) when compared to benzodiazepines. Zopiclone, a non-benzodiazepine hypnotic, shows no advantages over benzodiazepines with respect to daytime performance. Several factors may interact with the effects of hypnotics on daytime functioning, including normal cognitive decline during aging, the effects of insomnia itself on daytime functioning, the presence or absence of co-morbid disorders, and pharmacokinetic changes accompanying aging. The impact of hypnotics on daytime performance further depends on various drug-related factors including the administered dose, half-life, time between intake and performance, duration of treatment, gender, and individual differences. In contrast, zolpidem and zaleplon do not significantly impair daytime performance when administered at bedtime at the recommended dose. Although further studies of drug effects in elderly insomniacs are necessary, the available evidence suggests that these short acting and relatively safer non-benzodiazepine hypnotics are a preferred alternative therapy for treating insomnia in the elderly.

Hangover research needs: proceedings of the 5th Alcohol Hangover Research Group meeting.

Hangover is the most commonly reported negative consequence of heavy alcohol consumption. A large variety of symptoms have been reported the day after heavy drinking, which together are called the alcohol hangover. Frequently reported hangover symptoms include thirst, headache, drowsiness, and reduced alertness [1]. Although hangover is a common phenomenon in society and has serious socioeconomic consequences, it has received relatively little research attention. To increase research and international collaboration to examine the alcohol hangover, in 2010 the Alcohol Hangover Research Group (AHRG) was founded. This paper covers the research topics discussed at the 5th Alcohol Hangover Research Group meeting, held August 1–2, 2013 in Keele, UK.