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

Nalmefene influences brain chemistry to help individuals with alcohol use disorder (AUD) cut down on their drinking. Unlike abstinence-based treatments, Nalmefene is taken as needed before drinking episodes, making it a flexible option for those looking to gradually control their alcohol intake without requiring complete sobriety.

Nalmefene works by blocking opioid receptors in the brain, particularly mu, delta, and kappa receptors, reducing the rewarding effects of alcohol. This leads to lower endorphin and dopamine release, weakening alcohol’s reinforcing properties. Altering neurotransmitter activity, it helps curb cravings and heavy drinking episodes, making it an effective pharmacological approach for managing AUD.

The primary use of Nalmefene is reducing heavy drinking in alcohol-dependent individuals who are not seeking immediate abstinence. Clinical study by  The study by van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. et al. 2013, titled “Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies,” show that it reduces the number of heavy drinking days by 3.2 days per month and lower total alcohol consumption by 14.3 grams per day. It has also been explored for treating opioid overdose and substance cravings in some experimental settings.

The standard dosage of Nalmefene for AUD is 18 mg taken once daily as needed, one to two hours before anticipated drinking. Unlike Naltrexone, which requires daily use, Nalmefene provides a more patient-centered approach, allowing individuals to take it only when necessary, reducing overall medication exposure while maintaining effectiveness.

Common side effects of Nalmefene include nausea, dizziness, insomnia, and headache. In contrast, severe side effects include liver toxicity, psychiatric effects such as anxiety or hallucinations, and opioid withdrawal in opioid-dependent users. While adverse effects are mild to moderate, some patients experience tolerability issues leading to treatment discontinuation.

Alternatives to Nalmefene for AUD include Naltrexone, Acamprosate, and Disulfiram, all of which are FDA-approved. Naltrexone works similarly by blocking opioid receptors but requires daily use. Acamprosate helps maintain abstinence by balancing brain chemistry, and Disulfiram creates a deterrent effect by inducing unpleasant reactions when alcohol is consumed.

What Is Nalmefene?

Nalmefene, marketed under the brand name Selincro in some regions, is a prescription opioid receptor modulator and opioid antagonist used primarily to reduce alcohol consumption in individuals with alcohol dependence. Nalmefene functions by selectively binding to mu (μ), delta (δ), and kappa (κ) opioid receptors, exhibiting antagonistic effects at the mu- and delta-opioid receptors and partial agonist activity at the kappa-opioid receptor. 

This mechanism of Nalmefene distinguishes it from naltrexone, another opioid antagonist, as Nalmefene’s kappa partial agonism contributes to reducing withdrawal-related dysphoria. Due to its unique receptor profile, it helps modulate the brain’s reward system while minimizing the negative emotional effects associated with opioid blockade. Nalmefene is taken on an as-needed basis before anticipated alcohol consumption, differing from continuous daily treatments like naltrexone.

Is Nalmefene FDA-approved in the U.S.?

No, Nalmefene is not FDA-approved in the United States for the treatment of alcohol dependence or any other condition. However, it is approved in Europe under the brand name Selincro. It has been authorized by the European Medicines Agency (EMA) since 2013 for the reduction of alcohol consumption in individuals with alcohol dependence who have a high drinking risk level (≥60g/day for men and ≥40g/day for women). Despite its European approval, regulatory submissions for FDA approval have not been pursued or granted, limiting its availability in the U.S.

What Is the Mechanism of Action of Nalmefene?

The mechanism of action of Nalmefene is blocking opioid receptors (mu, delta, and kappa) to reduce the brain’s reward response to alcohol. Nalmefene acts as an antagonist at mu- (μ) and delta- (δ) opioid receptors, which are involved in the endorphin-mediated reinforcement of alcohol consumption.

By preventing alcohol-induced activation of these receptors, Nalmefene inhibits the release of endorphins, reducing dopamine release in the nucleus accumbens, a key structure in the brain reward system. This modulation dampens the pleasurable and reinforcing effects of alcohol, leading to a decreased urge to drink. 

Nalmefene exhibits partial agonist activity at kappa-opioid (κ) receptors, which is thought to counteract the dysphoria and stress-related drinking that result from complete opioid blockade. A study by Ingman, K., Hagelberg, N., Aalto, S. et al. 2005, titled “Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing” using positron emission tomography (PET) imaging has confirmed Nalmefene’s ability to occupy opioid receptors in the human brain, demonstrating significant receptor binding in areas associated with addiction, such as the ventral striatum. Clinical trials, including randomized controlled studies by Burnette EM, Nieto SJ, G. et al. 2022, titled “Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder,” support Nalmefene’s role in modulating neurotransmitter activity to reduce alcohol intake.

More Resources on Addiction:

• Alcohol Addiction Symptoms: Definition, Physical, Psychological, Behavioral, Withdrawal, Co-Occurring
• CAGE Questionnaire: Definition, Description, Scoring, Usage, Advantages and Limitations
• AUDIT Alcohol Assessment: Description, Scoring, Usage, Benefits and Challenges

Does Nalmefene Reduce Alcohol Cravings?

Yes, Nalmefene effectively reduces alcohol cravings and overall consumption in individuals with alcohol dependence. Clinical trials, including the 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 Nalmefene reduces heavy drinking days (HDD) and total alcohol consumption compared to placebo. In a 2019 study 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,” participants taking Nalmefene experienced a 40 to 60% reduction in total alcohol intake over six months. 

Unlike abstinence-based treatments, Nalmefene allows for a targeted, as-needed approach, where patients take the medication only when they anticipate drinking. This approach helps reduce the reinforcing effects of alcohol while maintaining patient autonomy. The drug’s ability to modulate opioid receptor activity without requiring total abstinence makes it particularly effective for individuals seeking to gradually reduce alcohol consumption rather than quitting outright.

What Are the Uses of Nalmefene?

The uses of Nalmefene are primarily in the treatment of alcohol dependence and the management of opioid overdose. It is mostly prescribed to reduce alcohol consumption in individuals with alcohol use disorder (AUD). It has also been studied for its potential role in reversing opioid overdoses, though it is less commonly used for this purpose.

The uses of Nalmefene are as follows:

• Alcohol Dependence Treatment: Nalmefene is approved in Europe for the reduction of alcohol consumption in individuals with alcohol dependence who do not require immediate detoxification. Unlike abstinence-based treatments, it is taken on an as-needed basis to reduce heavy drinking episodes rather than enforcing complete sobriety.

  The study by van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. et al. 2013, titled “Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies,” found that as-needed Nalmefene (18 mg) significantly reduced heavy drinking days by 3.2 days per month and total alcohol consumption by 14.3 g/day compared to placebo. Patients in the Nalmefene group showed greater clinical status and liver function improvements, though they experienced more adverse events and dropouts than placebo patients.

• Potential Use in Opioid Overdose: Although not as commonly used as naloxone, Nalmefene is an opioid antagonist for reversing opioid overdoses.

  It has a longer half-life than naloxone, which theoretically makes it more effective for preventing the recurrence of respiratory depression caused by long-acting opioids. However, its prolonged action also increases the risk of precipitated 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,” have suggested that while Nalmefene is effective in opioid overdose cases, naloxone remains the preferred first-line treatment due to its rapid onset and shorter duration of action.

How Is Nalmefene Used for Alcohol Addiction?

Nalmefene is used for alcohol addiction as an as-needed medication to help individuals reduce their alcohol consumption.

Unlike naltrexone, which is taken daily, nalmefene is taken only on days when the patient anticipates a risk of drinking. The recommended dosage is one 18 mg tablet, preferably 1 to 2 hours before the anticipated drinking time.

If the patient has already started drinking without taking nalmefene, they should take one tablet as soon as possible.

This approach allows for flexibility and aligns with harm reduction strategies, aiming to decrease heavy drinking episodes rather than enforcing complete abstinence. Nalmefene is integrated with psychosocial support interventions, such as the BRENDA model, which combines medical management with cognitive-behavioral strategies to enhance motivation and adherence. Nalmefene is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States, and therefore, it is not prescribed to alcohol-dependent patients in the U.S. However, it has been approved for use in Europe and other regions.

What Other Conditions Can Nalmefene Treat?

Nalmefene can treat conditions beyond alcohol dependence, including potential applications in managing opioid use disorder and certain behavioral addictions.

Nalmefene can treat the following conditions:

• Opioid Use Disorder (OUD): As an opioid receptor antagonist, nalmefene has been explored as a treatment option for OUD. Its ability to block opioid receptors helps reduce cravings and prevent relapse in individuals recovering from opioid addiction.
• Behavioral Addictions: Preliminary research suggests that nalmefene is beneficial in treating certain behavioral addictions, such as pathological gambling. By modulating the brain’s reward system, nalmefene potentially reduces the reinforcing behaviors associated with these addictions.

What Are the Dosage Guidelines for Nalmefene? 

The dosage guidelines for Nalmefene are one 18 mg tablet taken on an as-needed basis, ideally 1 to 2 hours before an anticipated drinking episode, for the reduction of alcohol consumption in individuals with alcohol dependence. Unlike daily medications such as naltrexone, Nalmefene follows a targeted dosing approach, allowing for flexible use based on drinking risk.

In some cases, dosage adjustments are necessary based on patient response. If significant side effects, such as nausea, dizziness, or insomnia, occur, patients require dosage titration or closer monitoring to assess tolerability.

Due to altered drug metabolism, individuals with comorbid conditions, such as liver or kidney impairment, need dose modifications or alternative treatments. Nalmefene is not recommended for patients with severe hepatic or renal impairment or those experiencing acute withdrawal symptoms.

Regular clinical evaluations ensure that each patient’s standard dose remains effective and well-tolerated.

How Is Nalmefene Administered? 

Nalmefene is administered orally in tablet form, as an 18 mg dose taken on an as-needed basis before anticipated alcohol consumption. Unlike daily treatments, it is used flexibly to help reduce alcohol intake rather than enforce abstinence, making it a harm-reduction approach for alcohol dependence.

Nalmefene is administered in the following ways:

• Oral Administration (Tablets): The most common form of Nalmefene is an 18 mg oral tablet, taken 1 to 2 hours before drinking to reduce alcohol cravings and consumption. It is prescribed primarily for individuals with alcohol dependence who are not seeking complete abstinence but want to reduce heavy drinking.
• Intravenous (IV) Administration (Investigational Use): Although not widely used, Nalmefene has been studied for IV administration in opioid overdose reversal due to its opioid antagonist properties.

  Compared to naloxone, its longer duration of action helps prevent relapse into respiratory depression, but it also increases the risk of prolonged withdrawal symptoms, limiting its routine use in emergency settings.

What Are the Side Effects and Risks of Nalmefene? 

The side effects and risks of Nalmefene are primarily related to its action as an opioid receptor modulator, with common effects including nausea, dizziness, and insomnia. In contrast, severe risks involve psychiatric disturbances and liver toxicity in vulnerable patients.

Most side effects are mild to moderate. Some patients experience significant adverse reactions that require medication discontinuation.

The side effects and risks of Nalmefene are as follows:

• Common Side Effects: Nalmefene causes nausea (34.2%), dizziness (18.0%), insomnia (12.4%), and headache (11.8%) in most users, especially during the first few weeks of treatment, according to “Nalmefene” by Royal Free London NHS Foundation Trust. These symptoms lessen with continued use but lead to treatment discontinuation in some cases.
• Psychiatric Effects: Nalmefene cause mood disturbances, including anxiety, confusion, and hallucinations, particularly in patients with a history of psychiatric disorders, as studied 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.” Some reports suggest a possible link to increased suicidal ideation, requiring close monitoring, especially in high-risk individuals.
• Liver Toxicity and Metabolic Risks: While rare, hepatic enzyme elevations have been observed, necessitating liver function monitoring in patients with pre-existing liver disease.

  According to the National Institute of Diabetes and Digestive and Kidney Diseases 2012, titled “Naltrexone,” some users experience changes in appetite and metabolic disturbances. However, these effects are not well-documented in large-scale studies.

• Withdrawal and Precipitated Opioid Withdrawal: In individuals with undiagnosed opioid dependence, Nalmefene triggers acute withdrawal symptoms, including severe agitation, vomiting, and sweating, due to its opioid antagonist properties.

  Patients should be screened for opioid use before initiating treatment.

Who Should Avoid Taking Nalmefene?  

Individuals with opioid dependence, severe liver or kidney impairment, or certain psychiatric conditions should avoid taking Nalmefene due to the risk of serious adverse effects. Its opioid antagonist properties trigger withdrawal in opioid users, while its metabolic and neuropsychiatric effects exacerbate underlying health conditions.

The following individuals should avoid taking Nalmefene:

• Opioid-Dependent Individuals: Nalmefene is a pure opioid antagonist, meaning it precipitates sudden and severe withdrawal symptoms in individuals who are currently using or dependent on opioids. Symptoms include vomiting, sweating, agitation, and severe pain, making it unsafe for those with active opioid use.

  Patients must undergo screening for opioid use before starting Nalmefene.

• Individuals with Severe Liver or Kidney Impairment: Since Nalmefene is metabolized in the liver and excreted through the kidneys, patients with severe hepatic (Child-Pugh Class C) or renal impairment (eGFR < 30 mL/min) experience toxic accumulation of the drug. Clinical guidelines recommend avoiding Nalmefene in such cases due to the potential for liver toxicity and worsened renal function.
• Patients with Uncontrolled Psychiatric Disorders: Individuals with a history of severe depression, suicidal ideation, or psychotic disorders experience worsened mood symptoms, hallucinations, or increased suicidal thoughts when taking Nalmefene.

  Clinical study by Fudala PJ, Heishman SJ, Henningfield JE, Johnson RE. et al. 1991, titled “Human pharmacology and abuse potential of nalmefene,” suggest a higher incidence of anxiety, confusion, and agitation in these populations, necessitating extreme caution or avoidance.

• Pregnant or Breastfeeding Women: There is limited clinical data on the safety of Nalmefene during pregnancy and lactation. Animal studies by Medscape suggest potential risks to fetal development, and since the drug is transferred through breast milk, its use is not recommended unless the benefits outweigh the risks.
• Individuals with a Known Hypersensitivity to Nalmefene: Patients with a history of severe allergic reactions to Nalmefene or its excipients should avoid it to prevent anaphylactic reactions, which include rash, difficulty breathing, and swelling.

Does Nalmefene Interact with Other Medications? 

Yes, Nalmefene interacts with opioid-containing medications, CNS depressants, and certain psychiatric drugs, but it has relatively few significant drug interactions compared to other medications. As an opioid receptor antagonist, its most significant interaction is with opioids, where it blocks their effects or triggers withdrawal in dependent individuals.

Nalmefene interacts with the following medications:

• Opioid-Containing Medications (e.g., Morphine, Oxycodone, Buprenorphine): Nalmefene blocks opioid receptors, reducing the effectiveness of opioid pain relievers and medications used for opioid dependence, such as buprenorphine or methadone. In opioid-dependent individuals, it induces sudden withdrawal symptoms, including nausea, vomiting, sweating, and agitation, requiring careful screening before use.
• CNS Depressants (e.g., Benzodiazepines, Alcohol, Sedatives): While Nalmefene is used to reduce alcohol consumption, combining it with CNS depressants like benzodiazepines (e.g., diazepam, lorazepam) leads to increased sedation, dizziness, and cognitive impairment.

  Patients using sedatives should be monitored for excessive drowsiness or impaired motor function.

• Antidepressants and Antipsychotics (e.g., SSRIs, SNRIs, Antipsychotics): Although no direct pharmacokinetic interactions have been confirmed, some studies suggest that Nalmefene alters neurotransmitter activity when combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients with psychiatric disorders should be closely monitored for worsened mood symptoms or increased anxiety when starting Nalmefene.

Which Medications Are the Alternatives to Nalmefene for Alcohol Addiction? 

Medications that are alternatives to Nalmefene for alcohol addiction include Naltrexone, Acamprosate, and Disulfiram, all of which are FDA-approved treatments for alcohol use disorder (AUD). These alcohol addiction medications work through different mechanisms, targeting alcohol cravings, withdrawal symptoms, or the body’s response to alcohol consumption.

The following medications are the alternatives to Nalmefene for alcohol addiction:

• Naltrexone: Like Nalmefene, Naltrexone is an opioid receptor antagonist, but it is taken daily rather than on an as-needed basis. It reduces the pleasurable effects of alcohol by blocking endorphin release, thereby decreasing the urge to drink.

  A study by Anton RF. et al. 2008, titled “Naltrexone for the management of alcohol dependence,” shows that Naltrexone reduces heavy drinking days by up to 25% and is commonly prescribed in the U.S. for alcohol dependence.

• Acamprosate (Campral): Acamprosate modulates glutamate and GABA activity in the brain, helping to restore the neurochemical balance disrupted by chronic alcohol use. Unlike Nalmefene and Naltrexone, which focus on reducing drinking, Acamprosate is best suited for maintaining abstinence after detox, as studied by Mason BJ, Heyser CJ. et al. 2010, titled “Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence.” It is taken 3 times daily and is particularly beneficial for preventing relapse in individuals who have already stopped drinking.
• Disulfiram (Antabuse): Disulfiram blocks alcohol metabolism, leading to a severe reaction (flushing, nausea, vomiting, and palpitations) when alcohol is consumed.

  This creates a deterrent effect, making drinking highly unpleasant. Unlike Nalmefene, Disulfiram does not reduce cravings but is effective for individuals committed to abstinence who need external reinforcement to avoid alcohol.

How Does Nalmefene Compare to Naltrexone for Alcohol Addiction Treatment?

Nalmefene compares to Naltrexone for alcohol addiction treatment as both are opioid antagonists that reduce alcohol consumption by blocking opioid receptors and decreasing the brain’s reward response to drinking.

However, they differ in dosing, FDA approval, and availability. Nalmefene is taken as needed before drinking episodes, while Naltrexone is a daily medication.

In terms of mechanism of action, both drugs primarily block mu-opioid receptors, but Nalmefene also has greater affinity for kappa-opioid receptors, which contribute to reducing the urge to drink and limiting alcohol’s reinforcing effects. A 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: results from a subgroup analysis of two randomized controlled 6-month studies,” show that Nalmefene reduces heavy drinking days by 3.2 days per month, while Naltrexone has been associated with a 25% reduction in heavy drinking episodes.

Regarding effectiveness, research comparing the two drugs suggests similar efficacy in reducing alcohol intake, but Nalmefene’s as-needed use provides more flexibility for patients who do not want to commit to daily medication. However, Naltrexone has stronger evidence for long-term abstinence support and is FDA-approved in the U.S., whereas Nalmefene is not FDA-approved but is available in Europe under the brand name Selincro.

Both medications are effective, but Naltrexone is more widely used due to FDA approval and extensive clinical support, while Nalmefene offers an alternative for those seeking a non-daily treatment approach.

Are There Non-medication Alternatives to Nalmefene?

Yes, there are several non-medication alternatives to Nalmefene, including behavioral therapies, support groups, and lifestyle interventions, which help individuals manage alcohol use disorder (AUD) without pharmacological treatment. These approaches focus on modifying drinking behaviors, enhancing motivation to change, and providing social support.

The non-medication alternatives to Nalmefene are as follows:

• Cognitive-Behavioral Therapy (CBT): CBT is a structured, evidence-based therapy that helps individuals identify and change negative thought patterns related to drinking. Psychology Today, in “Cognitive Behavioral Therapy for Relapse Prevention,” shows that CBT reduces alcohol consumption and relapse rates by 40 to 60% by teaching coping strategies, stress management, and problem-solving skills.
• Motivational Interviewing (MI): MI is a goal-oriented counseling method that enhances a person’s motivation to reduce drinking by resolving ambivalence.

  Research by Jhanjee S. et al. 2014, titled “Evidence based psychosocial interventions in substance use,” indicates that MI increases treatment engagement and improves long-term alcohol reduction outcomes, especially when combined with other therapies.

• Support Groups: AA follows a 12-step program emphasizing abstinence, peer support, and spiritual growth, while SMART Recovery offers a scientific, self-empowerment approach using behavioral therapy principles. A New York Times article stated that AA claims that up to 75% of its members stay abstinent compared to those who do not engage in support groups.
• Lifestyle Interventions: Physical activity, meditation, and proper nutrition reduce alcohol cravings, improve mental health, and support recovery.

  Regular exercise has been linked to lower relapse rates and improved emotional regulation in AUD patients.

Can You Buy Nalmefene Over the Counter in the U.S.?

No, you cannot buy Nalmefene over the counter (OTC) in the U.S. It is a prescription drug and has not been FDA-approved for alcohol addiction treatment in the country. As a controlled medication, it requires a doctor’s prescription and is currently only available in Europe under the brand name Selincro for alcohol dependence.

Can You Drink Alcohol While Taking Nalmefene?

Yes, you can drink alcohol while taking Nalmefene, but it reduces the pleasurable effects of alcohol, helping to lower consumption. It does not cause an adverse reaction like Disulfiram, but patients should follow physician recommendations, as heavy drinking while on Nalmefene still poses health risks such as liver strain and intoxication.

How Long Does Nalmefene Stay in Your System?

Nalmefene stays in your system for about 24 hours, with a half-life of approximately 10 to 14 hours, as studied by  Wang DS et al. 1998, titled “Nalmefene: A Long-Acting Opioid Antagonist. Clinical Applications In Emergency Medicine.” It is metabolized in the liver and primarily eliminated through urine. Its effects on opioid receptors last longer than its presence in the bloodstream, meaning it influences alcohol consumption patterns for several days after use.

Can Nalmefene Cause Withdrawal Symptoms?

Nalmefene cannot cause withdrawal symptoms in alcohol-dependent individuals, as it does not contain alcohol or sedative properties. However, in opioid-dependent users, Nalmefene triggers sudden withdrawal, leading to nausea, sweating, agitation, and flu-like symptoms due to its opioid-blocking effects.

Is Nalmefene Safe for Long-term Use? 

Yes, Nalmefene is safe for long-term use, with most side effects (nausea, dizziness) being mild to moderate and decreasing over time. Its effectiveness in reducing alcohol consumption persists for at least 6 to 12 months, making it a viable long-term treatment for alcohol dependence when monitored by a healthcare provider.