Naltrexone and bupropion
Naltrexone and bupropion Uses, Dosage, Side Effects, Food Interaction and all others data.
Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs).
Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour . Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected.
Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity.
Naltrexone acts as a competitive antagonist at opioid receptor sites. It blocks the action of opioids and precipitates withdrawal symptoms in opioid-dependent individuals.
Naltrexone, a pure opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and other opioids. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.
| Trade Name | Naltrexone and bupropion |
| Generic | Bupropion + naltrexone |
| Type | Oral |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Bupropion Hydrochloride is used for the treatment of depression. Bupropion is also used for smoking cessation.
Naltrexone is used for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Naltrexone has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.
Naltrexone and bupropion is also used to associated treatment for these conditions: Attention Deficit Hyperactivity Disorder (ADHD), BMI >30 kg/m2, Major Depressive Disorder (MDD), Seasonal Affective Disorder (SAD), Cessation, Smoking, Weight LossAlcohol Dependency, BMI >30 kg/m2, Cholestatic pruritus, Opioid Dependence, Severe Pain
How Naltrexone and bupropion works
Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT).
Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example.
When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute.
When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways.
Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affintiy for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.
Dosage
Naltrexone and bupropion dosage
The usual adult target dose for Bupropion is 300 mg/day, given as 150 mg, twice daily. Dosing should begin at 150 mg/day given as a single daily dose in the morning. If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hours between successive doses.
Increasing the dosage above 300 mg/day: As with other antidepressants, the full antidepressant effect of Bupropion Hydrochloride may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Bupropion Hydrochloride should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.
Maintenance: The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on Bupropion Hydrochloride, it is generally recognised that acute episodes of depression require several months or longer of antidepressant drug treatment.
Opioid dependence:
- Initially:25 mg; increase to 50 mg daily if no withdrawal signs occur.
- Maintenance: 350 mg wkly given as 50 mg daily or divided in 3 doses (given on 3 days of the wk) for improved compliance.
Adjunct in alcohol dependence: 50 mg daily.
Side Effects
Agitation, anxiety, and insomnia often occur during the initial stages of Bupropion therapy. Other relatively common side effects reported with Bupropion include fever, dry mouth, headache or migraine, dizziness, nausea and vomiting, constipation, tremor, sweating, and skin rashes. Hypersensitivity reactions, ranging from pruritus and urticaria, less commonly, angio-oedema, dyspnoea, and anaphylactoid reactions have been reported.
Abdominal pain, nausea, vomiting; anxiety, insomnia, lethargy, headache, musculoskeletal pain; anorexia, diarrhoea, constipation; increased thirst; chest pain; chills, dizziness; sexual dysfunction; rash, liver function abnormalities and reversible idiopathic thrombocytopenia. Inj-site reactions.
Toxicity
Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest.
In the mouse, rat and guinea pig, the oral LD50s were 1,100-1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally >1,000 mg/kg) produce salivation, depression/reduced activity, tremors, and convulsions.
Precaution
It should be used with extreme caution, in patients with history of seizure disorders or in patients with other predisposing factors such as severe hepatic cirrhosis or a CNS tumour, and in those undergoing abrupt withdrawal from alcohol or Benzodiazepines. The use of Bupropion in patients with other risk factors for seizures (for example, alcohol abuse, a history of head trauma, diabetes, and drugs known to lower the seizure threshold) should only be undertaken when there are compelling clinical reasons. Bupropion should be used with caution in patients with bipolar depression or psychoses and in patients with a recent history of myocardial infarction or unstable heart disease and in hepatic or renal impairment.
Hepatic or renal impairment. Monitor LFTs regularly. Patients should be opioid-free for at least 7-10 days prior to initiating naltrexone therapy. Strictly warn patients against the use of opioids while on naltrexone. Monitor for inj-site reactions. Pregnancy, lactation. History of bleeding disorders (including thrombocytopenia).
Interaction
Bupropion should not be given concurrently with or within 14 days of stopping an MAOI. The use of alcohol should be minimised or avoided completely because it may alter the seizure threshold. Similarly, other drugs that lower the seizure threshold, such as other antidepressants, antimalarials, antipsychotics, sedating antihistamines, Quinolones, Tramadol, Theophylline, or systemic corticosteroids, should be used with extreme caution together with Bupropion. Carbamazepine, Phenobarbital, or Phenytoin may induce the metabolism of Bupropion while other drugs such as Cimetidine or Ritonavir may inhibit its metabolism. Interaction may occur between Bupropion and Orphenadrine, Cyclophosphamide, and Ifosfamide. Caution should be exercised when it is given with drugs such as some antidepressants, antipsychotics, β blockers, and type 1C antiarrhythmics.
May reduce effects of opiate-containing preparations e.g. those used for cough and cold, diarrhoea and pain. Increased or decreased serum levels with drugs that alter hepatic metabolism. Potentially increased hepatotoxic effects with disulfiram. Increased risk of naltrexone-induced lethargy and somnolence with thioridazine. May increase insulin requirements.
Volume of Distribution
- 1350 L [intravenous administration]
Elimination Route
Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL).
Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day.
Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day.
Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/
In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.
Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.
Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.
Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.
Half Life
24 hours
4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.
Clearance
- ~ 3.5 L/min [after IV administration]
Elimination Route
Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.
Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration.
Pregnancy & Breastfeeding use
Pregnancy Category C. There are no adequate and well controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.
Lactation: Bupropion and its metabolites are secreted in human milk. Because Bupropion is excreted in human milk, a decision should be made whether to discontinue breast feeding or to discontinue the drug.
Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
Contraindication
It is contraindicated in patients with a seizure disorder. Bupropion Hydrochloride is contraindicated in patients treated with other medications that contain Bupropion because the incidence of seizure is dose dependent. Bupropion may induce seizure and consequently its use is contraindicated in patients with epilepsy. The drug is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated for bulimia with Bupropion Hydrochloride. The concurrent administration of Bupropion Hydrochloride and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of MAO inhibitor and initiation of treatment with Bupropion Hydrochloride. Bupropion Hydrochloride is contraindicated in patients who have shown an allergic response to Bupropion or the other ingredients that make up Bupropion Hydrochloride.
Patients concurrently dependent on opioids; acute hepatitis or hepatic failure; acute opioid withdrawal; patients on therapeutic opioid analgesics.
Special Warning
Child and adolescent: Not recommended for child and adolescent under 18 years of age
Acute Overdose
Symptoms: In addition to those events reported under Adverse Reactions, overdose has resulted in symptoms including drowsiness, loss of consciousness and electrocardiogram (ECG) changes eg, conduction disturbances or (including QRS prolongation) arrhythmias; cases of fatal outcome have been reported.
Treatment: In the event of overdose, hospitalisation is advised. ECG and vital signs should be monitored. Ensure an adequate airway, oxygenation and ventilation. The use of activated charcoal is recommended. No specific antidote for bupropion is known. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Symptoms: Clonic-tonic convulsions and respiratory failure.
Management: Supportive and symptomatic.
Storage Condition
Store at 20-25° C.
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