CONTRAVE

Indications

• Smoking cessation in nicotine-dependent patients
• Major depressive disorder (off-label use)
• Seasonal affective disorder (off-label use)

Dosage

Adults: Initially, 150 mg daily for 6 days, then increase to 150 mg twice daily. The maximum recommended dose is 300 mg per day, but caution is advised in those with

Mechanism of action

Bupropion inhibits the reuptake of norepinephrine and dopamine in the central nervous system, enhancing the levels of these neurotransmitters in the synaptic cleft. This action is believed to contribute to its antidepressant effects and its efficacy in aiding smoking cessation by reducing withdrawal symptoms and cravings. Additionally, bupropion may have a stimulatory effect on nicotinic acetylcholine receptors, which plays a role in its ability to assist with nicotine dependence.

Pharmacodynamics

The pharmacodynamics of bupropion involve increased synaptic concentrations of norepinephrine and dopamine, leading to an elevation in mood and a reduction in the urge to smoke. The drug's distinct mechanism allows it to modulate dopaminergic pathways linked to reward and addiction, thus facilitating smoking cessation. Bupropion also offers potential anxiolytic properties, although this effect is more variable and not its primary indication.

Pharmacokinetics

Bupropion is well absorbed following oral administration, with peak plasma concentrations occurring within 1.5 to 3 hours. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 2B6, producing active metabolites. The elimination half-life of bupropion is approximately 21 hours, while its metabolites can have longer half-lives. The drug is cleared primarily through urine. In patients with hepatic impairment, dose adjustments are necessary due to altered metabolism.

Contra-indications

• History of seizure disorder
• Severe hepatic impairment
• Concurrent use of monoamine oxidase inhibitors (MAOIs)
• Eating disorders (e.g., anorexia nervosa, bulimia nervosa)

Adverse effects

• Abdominal pain
• Anxiety
• Constipation
• Dizziness
• Dry mouth
• Fever
• Gastrointestinal disorders
• Headache
• Hyperhidrosis
• Hypersensitivity reactions
• Insomnia
• Nausea
• Skin reactions
• Altered taste
• Tremor
• Vomiting
• Decreased appetite
• Asthenia
• Chest pain
• Confusion
• Tachycardia
• Tinnitus
• Vasodilation
• Visual disturbances
• Angioedema
• Arthralgia
• Bronchospasm
• Delusions
• Depersonalization
• Dyspnea
• Hallucinations
• Hepatic disorders
• Irritability
• Memory loss
• Movement disorders
• Muscle complaints
• Palpitations
• Paresthesia
• Parkinsonism
• Postural hypotension
• Seizures
• Sleep disorders
• Stevens-Johnson syndrome
• Thrombocytopenia
• Suicidal behaviors

Interactions

• Increased risk of seizures with concurrent use of other medications that lower seizure threshold
• May increase the metabolism of certain drugs by inducing hepatic enzymes
• Risk of serotonin syndrome when used with serotonergic drugs (e.g., SSRIs, SNRIs)
• Tobacco smoke may reduce bupropion plasma concentrations, requiring dose adjustments

Precautions

• Monitor blood pressure before and during treatment
• Use with caution in patients with a history of depression or suicidal thoughts
• Elderly patients should be monitored closely for side effects
• Patients should be advised to report any clinical worsening of depression or unusual changes in behavior

Pregnancy

Avoid-no information available.

Indications

• Opioid dependence
• Alcohol dependence
• Adjunct to prevent relapse in formerly opioid-dependent patients

Dosage

Adults: Initially, 25 mg daily, then increased to 50 mg daily. The total weekly dose may be divided and given on 3 days of the week for improved compliance.

Mechanism of action

Naltrexone works by competitively inhibiting opioid receptors, particularly the mu-opioid receptor. This action blocks the euphoric and sedative effects of opioid drugs, thereby reducing the reinforcing effects that can lead to opioid misuse. It also modulates the reward pathway associated with alcohol consumption, helping to decrease cravings and consumption.

Pharmacodynamics

As an opioid antagonist, naltrexone exhibits a high affinity for opioid receptors. When administered, it displaces opioids from these receptors, preventing their activation. This results in the attenuation of the effects of opioids, including analgesia and euphoria. In alcohol dependence, naltrexone modulates the release of neurotransmitters associated with reward and craving, leading to decreased alcohol consumption and cravings.

Pharmacokinetics

Naltrexone is administered orally and is well-absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism in the liver, resulting in an oral bioavailability of approximately 5-40%. The drug is primarily metabolized by the liver via cytochrome P450 enzymes, producing active metabolites like 6-beta-naltrexol. The elimination half-life of naltrexone is roughly 4 hours, while its active metabolite has a longer half-life, contributing to the duration of action. Naltrexone is excreted mainly in urine, both as unchanged drug and metabolites.

Contra-indications

• Severe hepatic impairment
• Acute hepatitis
• Acute hepatic failure
• Current opioid dependence
• Hypersensitivity to naltrexone or any component of the formulation

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Decreased appetite
• Anxiety
• Restlessness
• Tachycardia
• Tremor
• Sleep disorders
• Dizziness
• Chest pain
• Weight loss
• Myalgia
• Skin reactions
• Mood alterations
• Hallucinations
• Withdrawal syndrome

Interactions

• Opioids: Naltrexone may precipitate withdrawal symptoms in opioid-dependent patients
• CNS depressants: Enhanced sedation or respiratory depression may occur
• Alcohol: Concurrent use may increase adverse effects

Precautions

• Hepatic impairment: Use with caution in mild to moderate impairment; avoid in severe impairment
• Renal impairment: Caution in mild to moderate impairment; avoid in severe impairment
• Pre-treatment screening for opioid dependence is necessary
• Monitor for signs of suicidal behavior and liver function during treatment

Pregnancy

Use only if the potential benefits justify the risks to the fetus, as there is limited data on safety.

Breast-feeding

Avoid due to potential toxicity to the infant.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral solution
• Capsules
• Oral suspension

Indications

• Major depressive disorder (MDD)
• Seasonal affective disorder
• Smoking cessation aid

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Refer to the BNF for specific dosing guidelines based on indication and patient characteristics.

Mechanism of action

Bupropion works by weakly inhibiting the reuptake of norepinephrine and dopamine in the neuronal synapse through binding to the norepinephrine transporter (NET) and dopamine transporter (DAT). This prolongs the action of these neurotransmitters, enhancing mood and reducing cravings associated with smoking cessation.

Pharmacodynamics

Bupropion is chemically distinct from classical antidepressants, being a relatively weak inhibitor of norepinephrine and dopamine uptake while not affecting serotonin levels significantly. It does not inhibit monoamine oxidase and exhibits minimal activity at serotonin transporter sites. Bupropion produces central nervous system stimulant effects and has been associated with mild amphetamine-like activity, indicating potential for abuse.

Pharmacokinetics

Bupropion is absorbed well after oral administration, with a bioavailability of approximately 5% due to extensive first-pass metabolism. It is metabolized primarily in the liver to several active metabolites, including hydroxybupropion. The elimination half-life ranges from 12 to 30 hours, depending on the formulation. Bupropion and its metabolites are primarily excreted in urine.

Contra-indications

• Seizure disorders
• Eating disorders (e.g., bulimia, anorexia nervosa)
• Concurrent use of monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Insomnia
• Dry mouth
• Dizziness
• Tremors
• Anxiety
• Increased sweating
• Nausea
• Vomiting
• Constipation
• Headache
• Potential for seizures

Interactions

• methylthioniniumchloride+bupropion: Severe (increases risk of severe hypertension)
• bupropion+moclobemide: Severe (increases risk of severe hypertension)
• bupropion+galantamine: Moderate (increases exposure)
• isavuconazole+bupropion: Moderate (increases exposure)
• bupropion+risperidone: Moderate (increases exposure)
• bupropion+atomoxetine: Moderate (increases exposure)
• bupropion+anticholinesterases, centrally acting: Moderate (increases exposure)
• bupropion+eliglustat: Moderate (increases exposure)
• bupropion+fesoterodine: Moderate (increases exposure)
• lumacaftor+bupropion: Moderate (decreases exposure)

Precautions

• Monitor for signs of seizures, particularly in patients with risk factors
• Use with caution in patients with a history of substance abuse
• Monitor for worsening of mood or emergence of suicidality
• Assess for potential drug interactions before prescribing

Pregnancy

Bupropion is classified as Category C. Risk cannot be ruled out; should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Bupropion is excreted in breast milk; caution is recommended when administering to nursing mothers.

Storage

Store at room temperature, away from excess heat and moisture. Keep out of reach of children.

Formulations

• Tablets (immediate-release)
• Tablets (sustained-release)
• Tablets (extended-release)

Indications

• Opioid dependence
• Alcohol use disorder
• Management of opioid overdose (as part of a comprehensive treatment strategy)

Dosage

Children: Refer to BNF for Children for appropriate dosing in children and adolescents.

Adults: Refer to BNF for specific dosing guidelines. Typical adult dose for alcohol dependence is 50 mg once daily.

Mechanism of action

Naltrexone acts as a competitive antagonist at mu (μ), kappa (κ), and delta (δ) opioid receptors in the central nervous system, with the highest affinity for the μ receptor. By binding to these receptors, naltrexone prevents the activation of opioid receptors by endogenous opioids, thereby attenuating the effects of opioid drugs, including euphoria and respiratory depression. The major metabolite, 6-β-naltrexol, also possesses antagonist properties, contributing to the overall effects of the drug.

Pharmacodynamics

As a pure opioid antagonist, naltrexone significantly reduces or completely blocks the subjective effects associated with opioid use, including euphoria and craving. It is particularly useful in preventing relapse in individuals recovering from opioid addiction, as it can precipitate withdrawal symptoms in those who are physically dependent on opioids, thus discouraging continued use.

Pharmacokinetics

Naltrexone is well-absorbed after oral administration, with peak plasma concentrations typically reached within one hour. It undergoes extensive first-pass metabolism in the liver, primarily to its active metabolite, 6-β-naltrexol. The elimination half-life of naltrexone is approximately 4 hours, while that of 6-β-naltrexol is longer, supporting prolonged receptor antagonism. Both naltrexone and its metabolite are excreted primarily in urine.

Adverse effects

• Nausea
• Vomiting
• Headache
• Dizziness
• Fatigue
• Anxiety
• Insomnia
• Abdominal pain
• Myalgia

Interactions

• naltrexone+opioids: Unknown (decreases efficacy)

Precautions

• Use with caution in patients with liver impairment.
• Monitor for signs of opioid withdrawal in opioid-dependent patients when initiating treatment.

Pregnancy

Naltrexone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether naltrexone is excreted in human milk. Caution should be exercised when administering to nursing women.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Oral tablet

Mechanism of action

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. Unicyclic aminoketone with noradrenergic and dopaminergic activity. Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever when injected i.p. with bupropion (17.0 mg/kg), and another lever when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU 19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic dopamine uptake blocker benztropine produced limited partial sub

Pharmacodynamics

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 [DB01560], 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. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg.

Mechanism of action

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. Naltrexone competes for opiate receptors and displaces opioid drugs from these receptors, thus reversing their effects. It is capable of antagonizing all opiate receptors.

Pharmacodynamics

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.