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Nalmefene: choice in alcohol dependence

Gareth Malson reports on a new drug licensed for those who cannot completely abstain

By Gareth Malson

Gareth Malson reports on a new drug licensed for those who cannot completely abstain

Alcohol dependence

The term “dependence” was introduced by a World Health Organization expert committee in 1964 to replace “addiction”. The dependence syndrome is defined as a cluster of physiological, behavioural and cognitive phenomena in which the use of a substance (be it a psychoactive drug, tobacco or alcohol) takes on a much higher priority for an individual than behaviours that once had greater value.

A central characteristic is a strong and sometimes overpowering desire to take the substance. Dependence encompasses both physical and psychological elements. Psychological refers to the experience of impaired control over use of the substance and physical refers to tolerance and withdrawal symptoms.

The “Tenth revision of the international classification of diseases and health problems (ICD-10)” lists criteria for diagnosing dependence.

Adapted from WHO webpages on substance abuse.

Who it is for

wine“Many people have reasons to limit their drinking,” says Jonathan Chick, a consultant psychiatrist for Spire Edinburgh Hospitals. “Most are able to do so without help; others find it difficult.” (See Panel.)

Most pharmaceutical interventions for alcohol dependence either alleviate the symptoms of detoxification or help patients to sustain abstinence.

“There is a long tradition of recommending complete abstinence . . . , which works for some people. But many will not, cannot or do not want to abstain. Previously, counselling has been effective for some patients and there are treatments, such as acamprosate, that help maintain abstinence — these are particularly useful in patients who have needed to detox for medical reasons,” he told The Journal. So for some patients, having an intermediate treatment goal of reducing alcohol intake can be a useful option.

Nalmefene (Selincro; Lundbeck), a treatment licensed to reduce the amount of alcohol drunk is now available although it is not the first drug to be used in this way. Graham Parsons, a medicines optimisation pharmacist for North, East and West Devon Clinical Commissioning Group, has a special interest in substance misuse. He pointed out: “Naltrexone is currently recommended by NICE as an option for helping people to reduce their alcohol intake — although it does not currently have a licence for this indication.”

Selincro is indicated for adults who continue to have a high level of alcohol consumption two weeks after the first consultation with their doctor. Its summary of product characteristics defines “high level” as drinking more than 60g and 40g of pure alcohol per day for men and women, respectively. (For reference, a bottle of wine contains around 70g of pure alcohol.) The licence does not cover use in patients who have physical symptoms of alcohol withdrawal.

How it works

Nalmefene exerts its effect via opioid receptors in the central nervous system. Andrew Jones, medical director for Lundbeck UK, explained: “In people with alcohol dependence, the alcohol they drink causes a release of endorphins within the mesolimbic system. Through their effect on opioid receptors, these endorphins stimulate the release of dopamine, which in turn generates the cravings to drink more alcohol.

“By antagonising both µ- and d-opioid receptors, nalmefene prevents the alcohol-induced release of dopamine, reducing the drive to continue drinking.

“Nalmefene is also a partial agonist at the ?-opioid receptor. There is some evidence from pre-clinical models that this activity might have beneficial effects on motivation, but this remains to be established in man.” By comparison, naltrexone has no effect on kappa receptors.

Professor Chick added: “Patients whom the drug helps feel less urge to carry on drinking alcohol once they start. It isn’t intended to aid abstinence, but to reduce the number of heavy-drinking days that a patient experiences.”

Nalmefene does not prevent intoxication.

Research

The effect of nalmefene has been assessed in several placebo-controlled trials. A summary document,1 published in September 2012 by the National Institute for Health Research’s Horizon Scanning Centre, highlights the key findings from the industry-sponsored SENSE and ESENSE trials.

In the SENSE trial, 675 patients were randomised to receive nalmefene 18mg (n=509) or placebo (n=166).2 After 24 weeks, the nalmefene group had, on average, 0.9 fewer heavy drinking days than the placebo group (P=0.16), and had drunk 3.5g less alcohol per day (P<0.232). This increased to 1.6 fewer heavy drinking days (P=0.017) and 6.5g less alcohol per day (P<0.036) after 52 weeks.

There were also statistically significant reductions in gamma glutamyl transpeptidase (GGT; P=0.01) and alanine transaminase (ALT; P=0.037), which may be indicative of high levels of drinking and alcoholic liver disease, respectively.

In ESENSE1, 604 patients were randomised to receive nalmefene or placebo for 24 weeks.3 After the end of the trial, the nalmefene group had, on average, 2.3 fewer heavy drinking days than the placebo group (P=0.002) and had drunk 11.0g less alcohol per day (P<0.001).The reductions in GGT and ALT were, again, significantly greater in the nalmefene group (P<0.05).

ESENSE2 was similarly designed. The results were similar although the difference in mean alcohol drunk per day and reduction in GGT between the groups was not significant.

“In these studies, liver enzyme levels have shown improvement with nalmefene,” says Professor Chick. “This assessment of an objective parameter is useful. Often with drug trials based on self-report, there is a risk of bias which might favour the drug, since side effects can subvert the blinding of patient and investigator.”

However, he did highlight one issue with the current evidence base. “The main studies were somewhat selective. Patients with unstable mental health conditions were excluded from the studies, as were patients with established liver disease. It would be useful if we had published data on the use of nalmefene in these patient groups.”

Mr Parsons adds: “So far, clinical studies have only compared nalmefene with placebo. It would be useful to have a trial that compared nalmefene with naltrexone.”

Administration

Each Selincro tablet contains 18.06mg of nalmefene. “Patients will need to take one tablet on each day that they plan to drink alcohol,” says Professor Chick. “The intention is that over around six months, the number of days on which they need to take a tablet will reduce.” No dose reduction is required in patients with mild or moderate hepatic impairment but severe impairment (Child-Pugh class C) is a contraindication.

The manufacturer advises caution if nalmefene is prescribed for over a year.
One of nalmefene’s licensing conditions is that it must be prescribed in conjunction with psychosocial support. “Psychosocial support is a generic term that covers a wide spectrum of interventions,” Mr Parsons explains. “It may involve seeing a GP or a therapist, or attending mutual aid support groups such as Alcoholics Anonymous or Smart Recovery.

For patients with a significant drinking problem, it might involve the local drug and alcohol service. To an extent, the patient decides what level of support they need — with help from their clinician — and this will be outlined in their care plan.”

It is recommended that the tablet is taken one to two hours before the patient starts to drink but if he or she has started to drink before the day’s dose, the tablet should be taken as soon as possible. Tablets should be swallowed whole because nalmefene may cause skin sensitisation.

Key points

  • Nalmefene (Selincro) aims to help alcoholic patients who cannot completely abstain. In such patients reduction of alcohol intake is an intermediate treatment goal.
  • The maximum dose is one tablet a day and treatment must include psychosocial support.
  • There are potential interactions between nalmefene and opioid analgesics.
  • Nalmefene is a licensed alternative to the off-label use of naltrexone to help patients reduce alcohol intake. There is no requirement to monitor liver function.

Safety

“Nalmefene’s most common side effect so far has been shown to be nausea,” Professor Chick points out. “Some patients adapt to it within two to three days; others discontinued treatment as a result.” The summary of product characteristics for Selincro also lists insomnia, dizziness and headache as “very common” adverse effects.

How can pharmacists help patients prescribed nalmefene? Mr Parsons suggests: “As with any medicine, it is important for pharmacists to offer patients the necessary support to aid compliance. Also, with nalmefene, pharmacists may be the first healthcare professional to identify when a patient is becoming disengaged with treatment. If this happens, the pharmacist should consider having a discussion with the patient or their prescriber — whichever is more appropriate.”

Pharmacists should also be aware of potential drug interactions. “As an opioid receptor blocker, nalmefene is not suitable for patients who are taking opioid analgesics to manage acute or, especially, chronic pain conditions,” Mr Parsons points out. In addition, in emergency situations greater doses of opioids may be needed for the desired effect in patients taking nalmefene, with close monitoring.

There is also potential for a pharmacokinetic interaction with inducers and inhibitors of the UGT2B7 enzyme.

Cost

At £78.05 (excluding VAT) for 28 tablets, nalmefene costs more than 28 naltrexone 50mg tablets (£41.62 excluding VAT). It is also more expensive than a 28-day supply of acamprosate (£28.80) and disulfiram (£13.87). Is this additional investment worth it for the NHS?

Professor Chick believes so: “Alcoholism is a very expensive disease for the NHS to treat. Any intervention that can reduce or prevent the long-term problems associated with alcoholism should be made available.”

Place in therapy

Mr Parsons does not see nalmefene as the panacea for society’s alcohol problem. “There are no safety or efficacy data relating to its long-term use — ie, more than one year. I’m also not generally a supporter of the prn approach to treatment and, much like naltrexone, nalmefene is merely a pharmaceutical aid to support psychosocial interventions.”

That said, he does see some value in its arrival: “Some clinicians may choose to use nalmefene because of its licence. They may also prefer it to naltrexone because there is no requirement to monitor liver function before and during treatment — as there is with naltrexone.

Plus, the prn approach may well be beneficial in some circumstances for certain people’s drinking habits. For example, if they have certain triggers that may be managed with a dose of nalmefene prior to the patient experiencing the trigger.”

Is interest in the drug more likely to come from primary or secondary care? Professor Chick predicts: “Gastrointestinal and liver specialists may well be interested in using this drug, as might psychiatrists. However, it may also prove a popular intervention for GPs since many patients do not want to be referred to specialists or to counselling groups.”  

About the author

Gareth Malson is a pharmacist and freelance writer.

References

1.    Horizon Scanning Centre. Nalmefene (Selincro) for the reduction of alcohol consumption — first line pharmacological therapy for alcohol dependence. September 2012. www.hsc.nihr.ac.uk (accessed 11 July 2013).
2.    van den Brink W, Sorensen P, Torup L, et al. Long-term efficacy, tolerability, and safety of nalmefene as-needed in alcohol-dependence: A randomised, double-blind, placebo-controlled study. Alcoholism - Clinical and Experimental Research 2012;36:247A (SI Suppl.1); Abstract 0945.
3.    Mann K , Bladstrom A , Torup L et al. Shifting the paradigm: ESENSE 1: a randomised, double- blind, placebo-controlled study of nalmefene, as-needed use in alcohol dependent patients. Alcoholism - Clinical and Experimental Research 2012;36:246A (SI Suppl.1); Abstract 0944.
4.    Gual A, He Y, Torup L, et al. ESENSE2: A randomised, double-blind, placebo-controlled study of nalmefene, as-needed use in alcohol dependent patients. Alcoholism - Clinical and Experimental Research 2012;36:246A (SI Suppl. 1); Abstract 0944

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11127115

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