from http://dtb.bmj.com/ on November 9, 2014 - Published by group.bmj.com DTB | Nalmefene forDownloaded alcohol dependence
DTB CME/CPD* BNF 4.10.1
Nalmefene for alcohol dependence The burden of morbidity and mortality resulting from alcohol dependence is high. World Health Organization (WHO) figures suggest that in the UK the prevalence of alcohol use disorders in those aged 15 years and older is around 6.4% for men and 1.5% for women.1 Reduction of harm resulting from alcohol dependence remains a high priority in all four devolved health services in the UK.2–5 Several medicines are licensed for the maintenance of abstinence in alcohol-dependent patients. However, until recently no drug was licensed for the management of alcohol dependence in people who are still drinking. Nalmefene (Selincro, Lundbeck), an opioid modulator licensed for the reduction of alcohol consumption, was launched in the UK in May 2013.6,7 Here we discuss the evidence for its effectiveness and safety and consider its place in therapy.
Background In the 10th revision of the International Classification of Diseases (ICD-10), harmful drinking is defined as a pattern of alcohol consumption that causes health problems that may be physical or mental. Dependence is recognised as a “cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.”8 The most recent UK guideline on the management of alcohol dependence, published in 2011 by the National Institute for Health and Care Excellence (NICE), advises that the most appropriate treatment goal for most alcohol-dependent people is abstinence.9 For people with harmful drinking and mild dependence, moderate drinking may be an appropriate goal, as long as there are no significant co-morbidities and adequate social support is available. NICE recommends offering psychological interventions to all patients presenting with harmful drinking or mild alcohol dependence. (See Box 1 for current NHS guidance on alcohol consumption.) A combination of pharmacological and psychological interventions may be appropriate for those with moderate to severe alcohol dependence, after successful alcohol withdrawal. NICE recommends that pharmacological interventions should be administered by staff who are specialist and competent in this area.9 Acamprosate, disulfiram and naltrexone are licensed for the maintenance of abstinence in people who have successfully withdrawn from alcohol.10
Box 1: current NHS guidance on alcohol consumption11 Avoid regularly drinking more than: Men: 3–4 units per day Women: 2–3 units per day Binge drinking is defined as:
mechanisms behind alcohol dependence are not fully understood, it is proposed that nalmefene is able to reduce the reinforcing effects of alcohol consumption.12 Nalmefene is licensed for the reduction of alcohol consumption in adults with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms, and who do not require immediate detoxification.6 The marketing authorisation specifies that nalmefene should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption, and only for those patients who continue to have a high drinking risk 2 weeks after initial assessment. Nalmefene is available as an 18mg tablet for oral use and is licensed for use on an as-needed basis; patients should take one tablet on days on which they perceive a risk of drinking, preferably 1–2 hours before the anticipated time of drinking.6 The maximum dose is one tablet per day.
Clinical efficacy Regulatory guidance
Assessment of efficacy of a drug designed to reduce alcohol consumption but not eliminate it is potentially problematic. The European Medicines Agency (EMA) has published a guideline on the development of medicines for the treatment of alcohol dependence.13 The guidance recommends that where the aim of treatment is moderation rather than abstinence, the co-primary endpoints of change in total alcohol consumption and reduction in the number of heavy drinking days should be used. Total alcohol consumption should be expressed as grams of pure alcohol per day (see Box 2) and heavy drinking days are defined in line with the World Health Organization (WHO) criteria for high drinking risk.13,14 The WHO criteria are intended for research purposes only, and define medium-risk drinking as ≥41g of alcohol in a single day for a man (5 UK units) or ≥21g for a woman (2.5 UK units). High drinking risk is defined as ≥61g for a man (7.5 UK units) or ≥41g for a woman (5 UK units).11,14
Men: drinking >8 units per day Women: drinking >6 units per day
What is nalmefene? Nalmefene is an opioid modulator which acts as an antagonist at μ and δ opioid receptors, and as a partial agonist at κ receptors.6 Although the
54
* DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
| DTB | Vol 52 | No 5 | May 2014dtb.bmj.com
▶
DTB | Nalmefene for alcohol dependence
Downloaded from http://dtb.bmj.com/ on November 9, 2014 - Published by group.bmj.com
of trial in the nalmefene and placebo groups. Reductions in the nalmefene group were greater than those seen with placebo (see table).
Box 2: calculating units of alcohol15 Alcohol by volume (ABV)=amount of pure alcohol as a percentage of the total volume of liquid in a drink
One unit=10mL or 8g of pure alcohol Number of units=strength (ABV) × volume (mL) ÷ 1,000
Efficacy data
A major limitation with both trials was the high number of people who reduced their drinking between the screening study visits and randomisation 1–2 weeks later (18% of patients in ESENSE1 and 33% in ESENSE2). Since these patients had little scope for additional improvement, a post-hoc analysis was performed using only data from patients who continued to have a high drinking risk level at randomisation. Data from both trials were pooled, but only those people who continued to have a high drinking risk 1–2 weeks after the screening visit were included.19
Two randomised double-blind phase III trials of nalmefene (ESENSE1 and ESENSE2) have been published.12,16 Both trials enrolled patients from sites predominantly in northern and western Europe, although none were in the UK. Patients were diagnosed with alcohol dependence as defined by the 2000 text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and who reported drinking heavily on at least 6 of the previous 28 days.17 A heavy drinking day was defined as any day where ≥60g of alcohol was consumed by a man, or ≥40g by a woman (note slight variance from WHO definition). Patients were excluded if their average alcohol consumption was below the WHO-defined cut-offs for medium risk, or if they had been abstinent for at least 14 days in the previous 28.
In this analysis, the number of monthly heavy drinking days in the placebo group was reduced by 9.4 days from 22.4 at baseline; with nalmefene the change was a decrease of 12.6 days from a baseline of 22.9. The treatment difference between the two groups was –3.2 heavy drinking days per month in favour of nalmefene (95% CI –4.8 to –1.6, p
DTB CME/CPD* BNF 4.10.1
Nalmefene for alcohol dependence The burden of morbidity and mortality resulting from alcohol dependence is high. World Health Organization (WHO) figures suggest that in the UK the prevalence of alcohol use disorders in those aged 15 years and older is around 6.4% for men and 1.5% for women.1 Reduction of harm resulting from alcohol dependence remains a high priority in all four devolved health services in the UK.2–5 Several medicines are licensed for the maintenance of abstinence in alcohol-dependent patients. However, until recently no drug was licensed for the management of alcohol dependence in people who are still drinking. Nalmefene (Selincro, Lundbeck), an opioid modulator licensed for the reduction of alcohol consumption, was launched in the UK in May 2013.6,7 Here we discuss the evidence for its effectiveness and safety and consider its place in therapy.
Background In the 10th revision of the International Classification of Diseases (ICD-10), harmful drinking is defined as a pattern of alcohol consumption that causes health problems that may be physical or mental. Dependence is recognised as a “cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.”8 The most recent UK guideline on the management of alcohol dependence, published in 2011 by the National Institute for Health and Care Excellence (NICE), advises that the most appropriate treatment goal for most alcohol-dependent people is abstinence.9 For people with harmful drinking and mild dependence, moderate drinking may be an appropriate goal, as long as there are no significant co-morbidities and adequate social support is available. NICE recommends offering psychological interventions to all patients presenting with harmful drinking or mild alcohol dependence. (See Box 1 for current NHS guidance on alcohol consumption.) A combination of pharmacological and psychological interventions may be appropriate for those with moderate to severe alcohol dependence, after successful alcohol withdrawal. NICE recommends that pharmacological interventions should be administered by staff who are specialist and competent in this area.9 Acamprosate, disulfiram and naltrexone are licensed for the maintenance of abstinence in people who have successfully withdrawn from alcohol.10
Box 1: current NHS guidance on alcohol consumption11 Avoid regularly drinking more than: Men: 3–4 units per day Women: 2–3 units per day Binge drinking is defined as:
mechanisms behind alcohol dependence are not fully understood, it is proposed that nalmefene is able to reduce the reinforcing effects of alcohol consumption.12 Nalmefene is licensed for the reduction of alcohol consumption in adults with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms, and who do not require immediate detoxification.6 The marketing authorisation specifies that nalmefene should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption, and only for those patients who continue to have a high drinking risk 2 weeks after initial assessment. Nalmefene is available as an 18mg tablet for oral use and is licensed for use on an as-needed basis; patients should take one tablet on days on which they perceive a risk of drinking, preferably 1–2 hours before the anticipated time of drinking.6 The maximum dose is one tablet per day.
Clinical efficacy Regulatory guidance
Assessment of efficacy of a drug designed to reduce alcohol consumption but not eliminate it is potentially problematic. The European Medicines Agency (EMA) has published a guideline on the development of medicines for the treatment of alcohol dependence.13 The guidance recommends that where the aim of treatment is moderation rather than abstinence, the co-primary endpoints of change in total alcohol consumption and reduction in the number of heavy drinking days should be used. Total alcohol consumption should be expressed as grams of pure alcohol per day (see Box 2) and heavy drinking days are defined in line with the World Health Organization (WHO) criteria for high drinking risk.13,14 The WHO criteria are intended for research purposes only, and define medium-risk drinking as ≥41g of alcohol in a single day for a man (5 UK units) or ≥21g for a woman (2.5 UK units). High drinking risk is defined as ≥61g for a man (7.5 UK units) or ≥41g for a woman (5 UK units).11,14
Men: drinking >8 units per day Women: drinking >6 units per day
What is nalmefene? Nalmefene is an opioid modulator which acts as an antagonist at μ and δ opioid receptors, and as a partial agonist at κ receptors.6 Although the
54
* DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
| DTB | Vol 52 | No 5 | May 2014dtb.bmj.com
▶
DTB | Nalmefene for alcohol dependence
Downloaded from http://dtb.bmj.com/ on November 9, 2014 - Published by group.bmj.com
of trial in the nalmefene and placebo groups. Reductions in the nalmefene group were greater than those seen with placebo (see table).
Box 2: calculating units of alcohol15 Alcohol by volume (ABV)=amount of pure alcohol as a percentage of the total volume of liquid in a drink
One unit=10mL or 8g of pure alcohol Number of units=strength (ABV) × volume (mL) ÷ 1,000
Efficacy data
A major limitation with both trials was the high number of people who reduced their drinking between the screening study visits and randomisation 1–2 weeks later (18% of patients in ESENSE1 and 33% in ESENSE2). Since these patients had little scope for additional improvement, a post-hoc analysis was performed using only data from patients who continued to have a high drinking risk level at randomisation. Data from both trials were pooled, but only those people who continued to have a high drinking risk 1–2 weeks after the screening visit were included.19
Two randomised double-blind phase III trials of nalmefene (ESENSE1 and ESENSE2) have been published.12,16 Both trials enrolled patients from sites predominantly in northern and western Europe, although none were in the UK. Patients were diagnosed with alcohol dependence as defined by the 2000 text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and who reported drinking heavily on at least 6 of the previous 28 days.17 A heavy drinking day was defined as any day where ≥60g of alcohol was consumed by a man, or ≥40g by a woman (note slight variance from WHO definition). Patients were excluded if their average alcohol consumption was below the WHO-defined cut-offs for medium risk, or if they had been abstinent for at least 14 days in the previous 28.
In this analysis, the number of monthly heavy drinking days in the placebo group was reduced by 9.4 days from 22.4 at baseline; with nalmefene the change was a decrease of 12.6 days from a baseline of 22.9. The treatment difference between the two groups was –3.2 heavy drinking days per month in favour of nalmefene (95% CI –4.8 to –1.6, p
