Nalmefene: Definition, Mechanism of Action, Uses, Dosage, Side Effects, Alternatives

Nalmefene is an opioid receptor modulator used primarily in the treatment of alcohol use disorder (AUD). Approved in Europe, Nalmefene offers a flexible, as-needed option for reducing alcohol consumption. On August 7, 2024, the FDA approved Zurnai, the first nalmefene auto-injector for opioid overdose treatment in patients aged 12 and older.

Nalmefene works by blocking opioid receptors in the brain, particularly the μ and δ receptors, reducing the rewarding effects of alcohol. This helps curb cravings and supports harm reduction strategies in alcohol addiction.

Its primary use is to manage alcohol dependence in adults who do not require immediate detoxification. It is also explored for treating opioid overdose and certain behavioral addictions like gambling disorder. 

A clinical study by van den Brink W et al. (2013), titled “Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level,” found that nalmefene reduced heavy drinking days by 3.2 per month and lowered alcohol intake by 14.3 grams daily. It has also been investigated in experimental settings for opioid overdose and substance craving.

The standard dosage for alcohol dependence is one 18 mg tablet taken orally, ideally 1 to 2 hours before anticipated drinking. Unlike daily medications, Nalmefene is used only when needed, offering greater flexibility.

Common side effects include nausea, dizziness, insomnia, and headaches. Serious adverse reactions, such as psychiatric disturbances and liver toxicity, occur in vulnerable individuals and require stopping treatment.

Alternatives to Nalmefene for alcohol addiction include FDA-approved medications such as Naltrexone, Acamprosate, and Disulfiram. These drugs target different mechanisms and are chosen based on individual treatment goals and medical profiles.

What Is Nalmefene?

Nalmefene is a prescription opioid antagonist and receptor modulator used in the treatment of alcohol use disorder (AUD). Marketed under the brand name Selincro in some regions, Nalmefene works by selectively interacting with the brain’s opioid receptors, blocking the mu- (μ) and delta- (δ) opioid receptors while partially activating the kappa-opioid receptor. This action helps reduce the rewarding effects of alcohol and ease withdrawal-related discomfort. Unlike some treatments that require daily use, Nalmefene is taken as needed, making it a flexible option for managing alcohol dependence.

What is the Chemical Composition of Nalmefene?

Nalmefene has the chemical formula C21H25NO3 and a molecular weight of 339.43 g/mol. It is structurally related to naltrexone and acts as a synthetic opioid receptor modulator. Nalmefene’s structure allows it to bind selectively to mu- (μ), delta- (δ), and kappa-opioid receptors, with a distinct activity that supports its use in reducing alcohol cravings and consumption.

Is Nalmefene FDA Approved for Alcohol Dependence?

No, Nalmefene is not FDA-approved for alcohol dependence in the United States. Although it is recognized as a prescription medication for alcohol addiction treatment in Europe under the brand name Selincro, the FDA has not authorized its use in the U.S. due to limited regulatory submissions. The European Medicines Agency (EMA) approved Nalmefene in 2013 based on clinical trials demonstrating reduced alcohol intake in high-risk drinkers. However, regulatory concerns and the lack of long-term U.S.-based trials have delayed its adoption domestically.

What is the Mechanism of Action of Nalmefene?

The mechanism of action of Nalmefene is modulating the brain’s opioid system to reduce the rewarding effects of alcohol. It acts as an antagonist at mu- (μ) and delta- (δ) opioid receptors, blocking the activation triggered by alcohol consumption. This inhibition prevents the release of endorphins, which in turn reduces dopamine levels in the nucleus accumbens, a key part of the brain’s reward system. As a result, the pleasurable sensations associated with drinking are diminished, leading to a reduced urge to consume alcohol.

Nalmefene has partial agonist activity at the kappa- (κ) opioid receptor, which helps counteract the dysphoria and stress-related cravings seen with total opioid antagonism. This balanced receptor activity makes Nalmefene particularly effective for individuals who drink to alleviate stress or emotional discomfort.

Scientific evidence supports this mechanism: a 2005 PET imaging study by  Ingman, K., Hagelberg, N., Aalto, S., et al. 2005, titled “Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing,” demonstrated that Nalmefene maintains prolonged occupancy of central opioid receptors, particularly in brain regions associated with addiction. 

More recent research, such as the 2022 review by Burnette EM, Nieto SJ, G. et al. 2022, titled “Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder,” confirms that Nalmefene’s action on neurotransmitter systems plays an important role in reducing alcohol consumption in individuals with alcohol use disorder (AUD).

How Is Nalmefene Used in Alcohol Addiction Treatment?

Nalmefene is used in alcohol addiction treatment as a targeted, as-needed medication to help reduce alcohol consumption in individuals with alcohol use disorder (AUD). Patients are advised to take Nalmefene 1 to 2 hours before they expect to drink, making it a flexible alternative to daily-use medications. This approach allows for moderation without requiring full abstinence, supporting autonomy and gradual behavior change.

Nalmefene is most effective when combined with cognitive behavioral therapy (CBT) or structured counseling. Studies such as ESENSE 1 and ESENSE 2 study by Paille F, Martini H., et al. 2014, titled “Nalmefene: a new approach to the treatment of alcohol dependence,” have shown that this combination significantly lowers heavy drinking days and overall alcohol intake. 

A 2019 phase-IV clinical trial by Barrio P, Roncero C, Ortega L, Guardia J, Yuguero L, Gual A. et al. titled “The More You Take It, the Better It Works: Six-Month Results of a Nalmefene Phase-IV Trial,” demonstrated that long-term use of Nalmefene alongside psychosocial support helps in alcohol addiction treatment and reduce alcohol consumption by 40% to 60% over 6 months.

What Are the Other Uses of Nalmefene?

The other uses of Nalmefene include its application in treating opioid overdose, in addition to its primary role in managing alcohol dependence by reducing cravings and consumption. While naloxone is the preferred first-line treatment due to its quick onset and short duration, Nalmefene’s longer half-life provides extended protection against respiratory depression from long-acting opioids. 

This extended action also increases the risk of withdrawal symptoms in opioid-dependent individuals. A study by Wang DS et al. 1998, titled “Nalmefene: A Long-Acting Opioid Antagonist. Clinical Applications in Emergency Medicine,” supports its clinical efficacy in emergency overdose cases, although its use remains secondary to naloxone in most treatment settings.

Early research indicates Nalmefene helps manage behavioral addictions like pathological gambling by modulating the brain’s reward pathways and reducing compulsive behavior.

What Is the Recommended Dosage of Nalmefene?

The recommended dosage of Nalmefene for alcohol dependence is one 18 mg tablet taken on an as-needed basis, 1 to 2 hours before a planned drinking occasion. This targeted dosing strategy differs from daily-use medications and supports flexible management based on individual drinking behavior. Dosage adjustments are required in cases of adverse effects like nausea, dizziness, or insomnia. 

Patients with impaired liver or kidney function need alternative treatment plans due to altered drug metabolism, and Nalmefene is not recommended for those with severe hepatic or renal impairment or those experiencing acute alcohol withdrawal. Regular medical evaluations help ensure that the standard dose remains effective and tolerable for each individual.

How Is Nalmefene Taken?  

Nalmefene is taken primarily in oral tablet form, with an 18 mg dose used on an as-needed basis before anticipated alcohol consumption. It offers a flexible, harm-reduction approach rather than requiring daily use. In rare or investigational cases, it is administered intravenously for opioid overdose treatment.

Nalmefene is taken in the following ways:

• Oral Administration (Tablets): Nalmefene is most commonly taken orally as an 18 mg tablet. It is used on an as-needed basis, 1 to 2 hours before anticipated alcohol consumption. This method is ideal for individuals with alcohol dependence who aim to reduce drinking rather than achieve total abstinence.
  
• Intravenous (IV) Administration (Investigational Use): Nalmefene has also been explored in IV form for opioid overdose treatment. While it offers a longer duration of action than naloxone, its use is limited due to the higher risk of extended withdrawal symptoms. IV use is reserved for investigational or emergency contexts.
  
• Other Routes (Not Common): Currently, there is no approved nasal spray or subcutaneous form of Nalmefene in widespread use. Research into alternative delivery methods is ongoing but not standard practice at this time.

Should Nalmefene Be Taken With or Without Food?

Yes, Nalmefene can be taken with or without food. According to the European Medicines Agency’s product information for Selincro (Nalmefene), food intake does not significantly impact the drug’s absorption or effectiveness. Clinical pharmacokinetic studies have shown that while a high-fat meal slightly delays the time it takes for Nalmefene to reach peak blood levels, it does not reduce its overall efficacy in treating alcohol dependence. Therefore, patients take Nalmefene based on personal preference or convenience without needing to coordinate with meals.

What Should You Do If You Miss a Dose of Nalmefene?

Take the missed dose of Nalmefene as soon as you remember, especially if alcohol consumption is still anticipated. However, if it’s close to the time of your next planned dose, skip the missed dose and continue with your usual schedule. Do not double up on doses to make up for a missed one. Since Nalmefene is taken on an as-needed basis rather than daily, timing is important to ensure its effectiveness in reducing alcohol cravings.

What Are the Side Effects of Nalmefene?

The side effects of Nalmefene are nausea, dizziness, insomnia, and headache. These side effects are primarily related to its role as an opioid receptor modulator. According to the Royal Free London NHS Foundation Trust, these symptoms are mild to moderate and occur during the initial weeks of treatment. However, serious risks involve psychiatric disturbances, liver toxicity, or withdrawal symptoms, especially in vulnerable individuals. In some cases, these effects lead to discontinuation of treatment.

The side effects of Nalmefene are as follows:

Common Side Effects of Nalmefene

Most users experience manageable side effects, particularly during the early phase of treatment. These symptoms improve with continued use.

Common side effects of Nalmefene include:

• Nausea: Nausea is the most frequently reported side effect, affecting 34.2% of users, particularly during the initial phase of treatment, according to the Royal Free London NHS Foundation Trust. Although temporary, it leads to discomfort that affects medication adherence.
• Dizziness: Dizziness occurs in about 18.0% of patients and is commonly experienced in the early stages of use, as noted by the Royal Free London NHS Foundation Trust. This sensation lessens over time but interferes with balance and concentration.
• Insomnia: Insomnia affects approximately 12.4% of individuals taking Nalmefene, potentially disrupting sleep patterns, especially during the first few weeks of therapy, as reported by the Royal Free London NHS Foundation Trust. This leads to fatigue and mood disturbances during the day.
• Headache: Headache is experienced by 11.8% of users and decreases with continued use, according to the Royal Free London NHS Foundation Trust. It is usually mild but is bothersome for some patients.
• Fatigue: Fatigue is another common complaint, particularly during dose initiation, with patients reporting persistent tiredness. This effect interferes with daily activities and overall quality of life.
• Dry Mouth: Dry mouth occurs temporarily and is usually manageable with increased fluid intake. It contributes to discomfort but is rarely severe enough to require discontinuation.
• Increased Sweating: Increased sweating is occasionally reported, especially during physical activity or stressful situations. While not dangerous, it is inconvenient or uncomfortable for some users.
• Decreased Appetite: Decreased appetite is also noted in some cases, which lead to slight weight loss over time. This side effect is more prominent in individuals sensitive to appetite changes.

Serious Side Effects of Nalmefene

While less common, serious adverse effects require immediate discontinuation and medical attention.

Serious side effects of Nalmefene include:

• Psychiatric Disturbances: Psychiatric disturbances such as anxiety, confusion, and hallucinations have been reported, particularly in individuals with pre-existing mental health conditions. A case study by Salles J, Ponté C, Schmitt L. et al. 2019, titled “Psychotic Decompensation During Nalmefene Treatment in a Patient With Schizoaffective Disorder: A Case Report.” documented psychotic decompensation in a patient with schizoaffective disorder during Nalmefene treatment, underscoring the need for psychiatric evaluation.
• Suicidal Ideation: Suicidal ideation has been observed in some patients taking Nalmefene, with reports linking the drug to an increase in suicidal thoughts. This highlights the importance of close monitoring in individuals with a history of depression or other mood disorders.
• Liver Toxicity: Liver toxicity, while rare, has been associated with elevated hepatic enzymes, particularly in those with underlying liver disease. According to the National Institute of Diabetes and Digestive and Kidney Diseases 2012, titled “Naltrexone,” liver function should be regularly monitored during treatment.
• Precipitated Opioid Withdrawal: Precipitated opioid withdrawal occurs if Nalmefene is given to individuals unknowingly dependent on opioids. This results in severe symptoms such as agitation, vomiting, and sweating due to its potent opioid antagonist action.
• Gastrointestinal Distress: Gastrointestinal distress, including severe nausea and vomiting, has led to treatment discontinuation in some patients. These symptoms require supportive care or a reassessment of therapy.
• Excessive Sweating and Shaking: Excessive sweating and shaking are commonly linked to acute withdrawal episodes triggered by Nalmefene. These symptoms are more likely in opioid-dependent individuals and require medical supervision.
• Cardiovascular Issues: Cardiovascular issues, though uncommon, include fluctuations in blood pressure or heart rate. Such effects necessitate prompt medical evaluation to rule out serious complications.
• Debilitating Fatigue: Debilitating fatigue has been reported in certain cases, causing significant weakness that interferes with daily activities. This requires dosage adjustment or discontinuation if it persists.

What Are the Alternatives to Nalmefene for Alcohol Addiction?

The alternatives to Nalmefene for alcohol addiction are Naltrexone, Acamprosate, and Disulfiram, all of which are FDA-approved and widely used for treating alcohol use disorder (AUD). These medications differ in their mechanisms of action, with some helping to reduce cravings, others maintaining abstinence, or creating an aversive reaction to drinking. They offer flexible treatment options based on the individual’s recovery goals and clinical needs.

The alternatives to Nalmefene for alcohol addiction are as follows:

Naltrexone

Naltrexone is an opioid receptor antagonist taken daily to reduce the pleasurable effects of alcohol. It works by blocking endorphin release triggered by alcohol consumption, thereby reducing the urge to drink. Clinical research by Anton RF et al. 2008, titled “Naltrexone for the management of alcohol dependence,” demonstrates its ability to decrease heavy drinking days by up to 25%, making it one of the most commonly prescribed treatments for alcohol addiction in the United States.

Acamprosate

Acamprosate (Campral) is a neuromodulator that restores balance to glutamate and GABA activity in the brain, which is disrupted by chronic alcohol use. Unlike medications that reduce cravings, Acamprosate is designed to help individuals who have already stopped drinking stay sober. A study by Mason BJ and Heyser CJ 2010, titled “Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence,” supports its use in preventing relapse and maintaining long-term abstinence. It is taken 3 times daily and is particularly beneficial for preventing relapse in individuals who have already stopped drinking.

Disulfiram

Disulfiram (Antabuse) is an aversive therapy that deters alcohol consumption by causing a severe physical reaction when alcohol is ingested, such as nausea, vomiting, and palpitations. It does not affect cravings but is highly effective for individuals committed to sobriety who need external reinforcement. Disulfiram’s value lies in its deterrent effect, helping patients avoid drinking by associating alcohol with discomfort. 

How Does Nalmefene Differ from Other Alcohol Addiction Medications?

Nalmefene differs from other alcohol addiction medications in its dosing strategy and mechanism. Unlike Naltrexone, which is taken daily, Nalmefene is used on an as-needed basis before anticipated drinking. This allows for more flexibility and supports harm reduction rather than enforcing abstinence. It also acts as a partial agonist at kappa-opioid receptors, unlike other treatments that are purely antagonistic, which help reduce stress-related drinking behaviors.

How Effective is Nalmefene for Alcohol Addiction Treatment?

Nalmefene is effective in reducing alcohol consumption, particularly in patients with alcohol dependence who are not ready to quit entirely. According to the ESENSE 1 and 2 clinical trials by Paille F, Martini H. et al., 2014, Nalmefene significantly reduced heavy drinking days and total alcohol intake compared to placebo. A 2019 Phase IV trial by Barrio P. et al. showed a 40% to 60% reduction in alcohol consumption over six months of use.

Who Should Not Take Nalmefene?

Individuals with certain health conditions, like kidney impairment and a history of psychosis, should not take Nalmefene due to safety concerns. Individuals with severe liver or kidney impairment should avoid Nalmefene, as the drug is metabolized and excreted through these organs, and compromised function increases toxicity. 

People experiencing acute alcohol withdrawal are also advised against its use, as it worsens withdrawal symptoms. Patients who are dependent on opioids should not take Nalmefene since it causes precipitated withdrawal by suddenly blocking opioid receptors. 

Pregnant or breastfeeding women should also avoid Nalmefene, as its safety has not been established in fetal development or lactation. 

Individuals with a history of psychosis should refrain from using Nalmefene due to the risk of psychiatric side effects such as hallucinations and mood disturbances. Nalmefene is not approved for use in children and adolescents under the age of 18.

Can You Take Nalmefene During Pregnancy?

No, you cannot take Nalmefene during pregnancy or breastfeeding. Animal studies by Medscape have shown adverse effects on fetal development, and there is limited human clinical data to confirm safety. The FDA has not established Nalmefene as safe for use in pregnancy, so it should only be used if the potential benefit justifies the potential risk to the fetus.

Do You Need a Prescription for Nalmefene?

Yes, you need a prescription for Nalmefene as it is a regulated medication used for alcohol use disorder. Nalmefene must be prescribed by a licensed healthcare professional after assessing the patient’s medical history and treatment needs.

Can You Stop Taking Nalmefene Suddenly?

Yes, you can stop taking Nalmefene suddenly without experiencing withdrawal symptoms. Unlike opioids or certain psychiatric medications, Nalmefene does not cause physiological dependence and can be discontinued without tapering.

Does Nalmefene Have Withdrawal Symptoms?

No, Nalmefene itself does not cause withdrawal symptoms, as it is not addictive. However, it triggers precipitated withdrawal in individuals who have opioids in their system. This occurs because Nalmefene blocks opioid receptors abruptly, leading to symptoms like agitation, sweating, and vomiting.

How Long Does Nalmefene Stay in Your System?

Nalmefene stays in your system for approximately 24 hours after a single dose. Its half-life is around 10 to 11 hours, meaning it takes that long for the drug’s concentration in the blood to reduce by half. Due to this duration, it offers prolonged opioid receptor blockade, which is especially useful in alcohol reduction strategies.