Naltrexone | Naltrexone – Bupropion Combination – Mechanism of Action, Psychopharmacology and Clinical Application

MECHANISMS OF ACTION

Naltrexone is pharmacologically different from opioids, and as such, naltrexone is not associated with tolerance or dependence.

Dopaminergic neurons in the ventral tegmental area project to the NA, and this constitutes the reward pathway. These neurons are under tonic inhibition by GABA-ergic interneurons within VTA. GABA release from these neurons is under negative regulation by the mu-opioid receptor (MOR).

When alcohol is ingested, endogenous opioids are released, e.g. endorphins resulting in inhibition of GABA release in NA and removal of dopamine inhibition and hence release of DA in NA.

Naltrexone acts by reducing the relative value of opioids or alcohol by modulating the rewarding effects that come from the activation of the opiate system. [Dudek et al. 2016]

• Naltrexone does this by primarily blocking mu-opiate receptor occupancy and thereby reducing the amount of dopamine released from the nucleus accumbens
• The decrease in activity in the mesolimbic dopamine reward pathway attenuates the positive effects of substances of abuse and the development of cravings and maintenance.

Of note, it has been observed that naltrexone’s effect requires patients to be motivated and highly compliant to achieve clinical efficacy and success in sustained remission. [Chick 1996]; [Volpicelli et al 1997]

Naltrexone – Bupropion combination

Combined bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with appetite regulation.

In the arcuate nucleus of the hypothalamus, bupropion stimulates pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte-stimulating hormone (α-MSH), which in turn binds to and stimulates melanocortin 4 receptors (MC4-R).

When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors.

The binding of β-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH.

Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying the effects of bupropion on energy balance. [Billes et al., 2014]

PHARMACOKINETICS

Oral naltrexone is recommended to start at 12.5 mg/day or 25 mg/day in patients at risk of adverse events and then gradually increase to a 50 mg/day maintenance dose. However, clinical trial data suggest that dosages of up to 150 mg/day can be used effectively and safely. [Oslin et al. 1999]; [Anton et al. 2006]

Naltrexone tablets are rapidly absorbed within the gastrointestinal tract; however, it is subject to first-pass metabolism by the liver with oral bioavailability estimated to only be between 5 and 40%. Naltrexone metabolism results in the generation of the major metabolite, 6­ß-naltrexol; the mean elimination half-life of the parent drug and its metabolite are 4 hours and 13 hours, respectively.

Naltrexone depot formulations are also available as injectables or implants with an injectable naltrexone formulation approved for alcohol dependence by the FDA. [Lobmaier et al., 2011]

DOSING

A dose of 50 mg once daily is recommended for most patients. Start with 25 mg/day for two weeks to check for adverse effects.

The placebo-controlled studies that demonstrated the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcoholism used a dosing regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks. Some US studies have used 100 mg /day. [Maudsley guidelines, 13th edition]

It should be prescribed for up to 6 months or longer for those who perceive a benefit and wish to continue taking it. [NICE guideline, 2011]

Treatment should be discontinued in those who continue to drink for 4-6 weeks after starting the medication. [NICE guideline, 2011]

A patient is a candidate for treatment with Naltrexone if:

• Willing to take medication to help with alcohol dependence
• Opioid free for 7-10 days
• No severe or active liver or kidney problems (typical guidelines suggest liver function tests no greater than 3 times the upper limits of normal and bilirubin normal)
• Not allergic to Naltrexone GH, and no other contraindications are present.

Treatment initiation guidelines for Naltrexone [NICE guideline, 2011]

1. Treatment should not be attempted unless the patient has remained opioid-free for at least 7-10 days. Self-reporting of abstinence from opioids in opioid addicts should be verified by analysing the patient’s urine for the absence of opioids. The patient should not be manifesting withdrawal signs or reporting withdrawal symptoms.

2. If there is any question of occult opioid dependence, perform a NARCAN Challenge Test. If signs of opioid withdrawal are still observed following NARCAN challenge, treatment with Naltrexone should not be attempted. The NARCAN challenge can be repeated in 24 hours.

3. Treatment should be initiated carefully, with an initial dose of 25 mg of Naltrexone.  If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter

Naltrexone -Bupropion combination (CONTRAVE) – Naltrexone HCl 8 mg and bupropion HCl 90 mg

Indications: [PI]

Adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in

• Adult patients > 18 years
• Initial Body Mass Index (BMI) of ≥ 30 kg/m2 (obese) or • ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of one or more weight-related comorbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension)
• Discontinue treatment after 16 weeks if patients have not lost at least 5% of their initial body weight

The maximum recommended daily dose is two tablets taken twice daily (32 mg naltrexone hydrochloride and 360 mg bupropion hydrochloride), which is reached at the start of week 4

Week 1

• 1 tablet morning dose

Week 2

• 1 tablet morning and evening

Week 3

• 2 tablets morning and  1 tablet evening

Week 4 Onward

• 2 tablets morning 2 tablets evening

DRUG INTERACTIONS

The combination of naltrexone with other therapies of a common indication is of considerable clinical interest, particularly in drugs with different mechanisms of action:

• Acamprosate is a synthetic analogue of the amino acid taurine that has efficacy in treating alcohol dependence through its modulation of NMDA receptor activity in the glutamate system. Coadministration of acamprosate and naltrexone has been well-tolerated, with no negative effects on pharmacokinetics. [Mason et al. 2002]
• Gabapentin is an anticonvulsant that can improve the neurochemical imbalances that underpin symptoms of withdrawal. As such, coadministration of gabapentin during the early stages of naltrexone therapy has been shown to help improve some of the early symptoms of withdrawal and thereby improving withdrawal outcomes. [Anton et al. 2011]

Other known drug interactions are not as well researched; however, other medicines that contain opioids (i.e. opioid analgesics and cough and cold preparations) may not be as effective. If opioid administration is necessary, such as in an emergency, greater doses of opioids will be required, in which case the resulting respiratory depression will also be greater.

SIDE EFFECTS OF NALTREXONE

Naltrexone is well tolerated with a low incidence of adverse reactions. [Croop et al. 1997]

Naltrexone has no abuse potential, and patients do not appear to develop tolerance. The most commonly observed adverse events are nausea, vomiting, headache, dizziness, fatigue, nervousness, anxiety and somnolence.

• Naltrexone is cautioned in pregnant and nursing women as it is unknown whether there is any effect on the foetus or whether it is excreted in human milk.
• Naltrexone should not be prescribed to patients with chronic pain syndromes unless the potential benefits outweigh the risk due to the recurring need for opioid analgesics.

Oral naltrexone comes with a black box warning due to its potential capacity to cause hepatocellular injury. As such, patients with acute liver disease are suggested to require frequent liver function monitoring. Furthermore, in patients with acute hepatitis or liver failure, naltrexone is contraindicated due to the potential hepatotoxic effects.

• Interestingly, not all studies have shown that there is a risk of hepatotoxicity, with Yen and colleagues showing that at the recommended daily dose, naltrexone actually reduced levels of ALT and AST in the liver. [Yen et al. 2006]

CLINICAL EVIDENCE

Alcohol use disorder:

• Naltrexone significantly reduces relapse to heavy drinking. [Donoghue et al., 2015]

Opioid Use Disorder: 

• Naltrexone is evidence-based in relapse prevention in opioid addiction, with the implant being more effective than oral naltrexone or placebo. [Krupitsky et al. 2012]

Other Addiction Disorders:

• Due to benefits in other addictions, naltrexone has been proposed as a pan-addiction treatment in addictions such as nicotine use disorder, stimulant use disorder, gambling disorder, trichotillomania and kleptomania. [Aboujaoude & Salame 2016]

Clinical Evidence for Naltrexone and Bupropion Combination: 

• While not routine, Naltrexone/Bupropion combination is evidence-based in the treatment of antipsychotic weight gain. [Greig and Keating, 2015] [Read more about managing obesity and weight gain in psychiatry]
• Studies have shown the combination is associated with a decrease in body weight by 3.2-5.2% compared with placebo. In comparison, approximately half of treated patients experience a greater than 5% decrease in body weight. In diabetic patients, a decrease of glycated haemoglobin by approximately 0.5% was also noticed. The most common adverse effects of the drug include nausea, vomiting and headache. Thus it may also be useful in obese patients with an alcohol use disorder.
• Naltrexone/bupropion is generally safe if avoided in patients with uncontrolled hypertension, a history of seizures or receiving certain medications, such as MAOI or long-term opioid analgesics.

Smoking

• Naltrexone/bupropion is associated with abstinence in smokers (30-40%) and minimises tobacco abstinence-associated weight gain. [Pappa et al., 2018]

Methamphetamine Use Disorder

• Naltrexone / Bupropion has been trialled in MUD with low rates of abstinence but higher rates than placebo. [Trivedi, 2021]

Chronic Pain Disorders: 

• Naltrexone is predominantly used as an opioid antagonist; however, low dose naltrexone has been paradoxically shown to exert an analgesic effect.[Greeley et al. 1988]
• In chronic pain disorders such as fibromyalgia, analgesia can be acquired via the administration of 1/10^th of the dose and that this effect is independent of its activity on opioid receptors. [Younger et al. 2014]

Gastrointestinal Disorders: 

• Furthermore, low dose naltrexone has also been suggested to reduce symptom severity in several gastrointestinal disorders such as irritable bowel syndrome, Crohn’s disease, chronic idiopathic constipation, and inflammatory bowel disease.
• This short-term blockade of endogenous opioid receptors causes an increase in the endogenous opioid neuropeptide, enkephalin, a potent analgesic, vasoactive, and immunomodulatory peptide. [Mclaughlin and Zagon 2015]

Self-injurious behaviour in learning disabilities

• Limited evidence base. [Maudsley guidelines, 13th edition]

SUMMARY

Naltrexone is a long-lasting opioid antagonist approved for the treatment of alcohol and opioid dependence.

Naltrexone effectively attenuates the rewarding effect through its blocking action on opioid receptors causing a reduction in both pleasure and cravings.

Studies report that it has no abuse potential making it an attractive option in treating patients with substance abuse issues.