levallorphan

Action and Spectrum

Actions and Spectrum: 

levallorphan is a synthetic opioid receptor antagonist initially developed for its potential use in treating opioid overdose. It belongs to the opioid receptor antagonist class of drugs, which means it can block the effects of the opioids by binding to opioid receptors in the brain and peripheral tissues. levallorphan has a high affinity for opioid receptors and can effectively displace and reverse the effects of opioids. 

Action:  

levallorphan is a competitive antagonist at opioid receptors, particularly the mu-opioid receptors. It binds to these receptors and prevents opioids from exerting their effects. This antagonistic action is helpful in situations of opioid overdose, where levallorphan can rapidly reverse respiratory depression and other dangerous effects caused by excessive opioid use. 

Spectrum:  

levallorphan has been used mainly as an experimental drug for research and has not gained widespread clinical use. It was investigated as a potential opioid overdose treatment, but its use has been limited due to certain drawbacks and concerns: 

• Partial Agonist Activity: levallorphan has been found to possess partial agonist activity at some opioid receptors, particularly the kappa-opioid receptors. This partial agonist activity could limit its effectiveness and predictability when reversing opioid overdose. 
• Limited Efficacy: In some cases, levallorphan might not fully reverse the effects of opioids, especially if opioids with a very high affinity for the receptors are involved. 
• Side Effects: Like any medication, levallorphan can have side effects, including those related to its pharmacological actions, such as changes in mood, pain perception, and gastrointestinal effects. 
• Newer Alternatives: Over time, other opioid receptor antagonists like naloxone have become more commonly used for treating opioid overdose due to their more specific and reliable action. Naloxone has been extensively studied, is widely available, and is considered the standard of care for opioid overdose reversal. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Anxiety 

Disorientation 

Confusion 

Hallucinations 

Dysphoria 

Dizziness 

Paranoia 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: levallorphan should not be used in patients with known hypersensitivity/allergic reactions to the drug or its components. 
• Patients Dependent on Opioids: levallorphan’s antagonistic action can precipitate withdrawal symptoms in individuals who are physically dependent on opioids. Therefore, it might be contraindicated in patients who are actively using opioids or who have opioid dependence. 
• Patients with Respiratory Conditions: Opioid receptor antagonists like levallorphan can reverse the respiratory depressant effects of opioids. However, in patients with severe respiratory conditions, such as chronic obstructive pulmonary disease/asthma, a sudden reversal of opioid effects could potentially lead to acute respiratory distress. 
• Patients with Cardiovascular Instability: levallorphan might sometimes affect cardiovascular function. It could potentially lead to changes in heart rate, blood pressure, or other cardiovascular parameters. Therefore, caution might be needed in patients with significant cardiovascular instability. 
• Patients with Seizure Disorders: Some opioid receptor antagonists have been associated with diminishing the seizure threshold. Patients with a history of seizure disorders might need careful consideration before using levallorphan. 
• Patients on Opioid Analgesic Therapy: levallorphan’s antagonistic effects can counteract the therapeutic effects of opioid analgesics. Therefore, it should be avoided in patients currently using opioids for pain management. 
• Patients on Mixed Agonist-Antagonist Opioids: levallorphan might interact with mixed agonist-antagonist opioids, potentially leading to unpredictable effects or reduced effectiveness of treatment. 
• Pregnancy and Breastfeeding: There might be insufficient data on the safety of levallorphan use during pregnancy and breastfeeding. In general, caution is exercised when using medications in pregnant or breastfeeding individuals. 

Caution 

• Opioid Dependence: levallorphan’s antagonistic action can induce opioid withdrawal symptoms in patients physically dependent on opioids. Caution should be exercised when using levallorphan in patients with opioid dependence, and the potential for withdrawal symptoms should be considered. 
• Respiratory Conditions: levallorphan’s ability to reverse the respiratory depressant effects of opioids could lead to acute respiratory distress in patients with underlying respiratory conditions, like chronic obstructive pulmonary disease/asthma. Careful monitoring and appropriate medical management are advised. 
• Cardiovascular Instability: levallorphan might influence cardiovascular function. Patients with incredibly hemodynamically unstable cardiovascular conditions should be monitored when administering levallorphan. 
• Seizure Disorders: Some opioid receptor antagonists, including levallorphan, have been associated with the potential to lower the seizure threshold. Patients with a history of seizure disorders should be closely monitored if levallorphan is used. 
• Mixed Agonist-Antagonist Opioids: levallorphan might interact with mixed agonist-antagonist opioids, leading to unpredictable effects or potentially reducing treatment efficacy. 
• Pregnancy and Breastfeeding: Limited data might be available on the safety of levallorphan during pregnancy and breastfeeding. Before considering its use in pregnant or breastfeeding individuals, the potential benefits and risks should be carefully evaluated. 
• Central Nervous System (CNS) Effects: Opioid receptor antagonists can have effects on the central nervous system, including changes in mood, pain perception, and consciousness. Caution should be exercised when administering levallorphan to patients with conditions that could be affected by these CNS effects. 
• Individual Variability: Responses to medications can vary widely among individuals. Caution is advised when using levallorphan in patients with known sensitivities, allergies, or individual variations in drug metabolism. 
• Drug Interactions: levallorphan might interact with other medications, especially those that affect the opioid receptor system. Potential drug interactions should be evaluated before prescribing levallorphan. 
• Medical History: A patient’s complete medical history, including pre-existing conditions and medications, should be considered before using levallorphan. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• <b>Category B: There was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: There was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence, these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

levallorphan is a synthetic opioid receptor antagonist with an affinity for mu, kappa, and delta opioid receptors. By competitively binding to these receptors, it blocks the effects of opioids, effectively reversing their actions. However, levallorphan also possesses partial agonist activity at kappa opioid receptors, which can complicate its use as an antagonist. Initially explored for its potential in opioid overdose treatment, its limited clinical use is due to concerns about its partial agonism, the potential for precipitating withdrawal in opioid-dependent individuals, and the availability of more established opioid receptor antagonists like naloxone. 

Pharmacodynamics: 

Mechanism of action: levallorphan is a synthetic opioid receptor antagonist, and its mechanism of action primarily depends on its ability to bind to and block opioid receptors in the body. It has a complex mechanism due to its interactions with different types of opioid receptors.  

• Opioid Receptors: Opioid receptors are proteins found in the nervous system and other tissues that mediate the effects of opioids, like pain relief, euphoria, and respiratory depression. There are several types of opioid receptors, including mu (μ), kappa (κ), and delta (δ) receptors. 
• Binding to Opioid Receptors: levallorphan has an affinity for mu, kappa, and delta opioid receptors. When administered, it competes with endogenous opioids (like endorphins) and exogenous opioids (such as morphine) for binding to these receptors. 
• Antagonistic Action: levallorphan is an antagonist at mu, kappa, and delta receptors. This means that when it binds to these receptors, it does not activate the receptors like opioids would. Instead, it blocks the receptors, preventing opioids from binding and exerting their effects. 
• Reversing Opioid Effects: By blocking the effects of opioids, levallorphan can effectively reverse the actions of opioids. This is particularly relevant in cases of opioid overdose, where opioids can lead to dangerous respiratory depression. levallorphan’s antagonistic action can help restore normal respiration and consciousness by displacing opioids from the receptors. 
• Partial Agonism at Kappa Receptors: It’s important to note that levallorphan also has partial agonist activity at Kappa opioid receptors. This means that while it predominantly blocks the effects of opioids, it might also produce some opioid-like effects (albeit weaker) at these receptors. 

Pharmacokinetics: 

Absorption 

levallorphan’s absorption might vary depending on the route of administration, which could include intravenous (IV) or intramuscular (IM) injection. IV administration would result in rapid and complete absorption. 

Distribution 

levallorphan’s distribution within the body involves transport through the bloodstream and distribution to various tissues. It might have a relatively large volume of distribution due to its potential to bind to opioid receptors in the central nervous system and peripheral tissues. 

Metabolism 

The metabolism of levallorphan might involve enzymatic processes in the liver. It could undergo various biotransformation reactions, potentially resulting in the formation of metabolites with varying pharmacological activities. 

Elimination and Excretion 

levallorphan and its metabolites would be excreted primarily through renal excretion (via urine) and potentially through feces. The exact mechanisms and routes of excretion might depend on the specific metabolic pathways and elimination rates. 

Adminstartion

Administration: 

levallorphan might be administered via intravenous (IV) or intramuscular (IM) injection. IV administration likely results in a more rapid onset of action. 

Dosing: The appropriate dose of levallorphan would depend on factors such as the patient’s weight, the severity of opioid overdose, and the specific opioids involved. Dosing would be determined by a healthcare professional based on these factors. 

Monitoring: Patients receiving levallorphan should be closely monitored for any adverse effects, changes in vital signs, and signs of opioid withdrawal or reversal of opioid effects. 

Reversal of Effects: levallorphan’s primary purpose is to reverse the effects of opioids, especially respiratory depression. It achieves this by competitively binding to opioid receptors and displacing the opioids. The goal is to restore normal respiration and consciousness in cases of opioid overdose. 

Medical Setting: Due to the potential complications associated with opioid overdose and levallorphan’s effects, its administration is typically carried out in a medical setting, such as an emergency department or by emergency medical services (EMS) personnel. 

Follow-Up Care: After levallorphan administration, patients would likely require ongoing medical evaluation and care to ensure that the effects of the opioids are fully reversed and to manage any potential withdrawal symptoms. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: levallorphan 

Why do we use levallorphan? 

levallorphan is an opioid receptor antagonist initially developed to reverse the effects of opioid overdose.  

• Opioid Overdose Reversal: levallorphan was initially investigated as a potential medication for reversing the effects of opioid overdose. It acts by competitively binding to opioid receptors, displacing the opioids and reversing the respiratory depression and other dangerous effects of opioid overdose. 
• Research and Studies: levallorphan has been used in research settings to study the pharmacological effects of opioid receptor antagonists. It has been used better to understand the interactions between opioids and opioid receptor antagonists and to explore potential applications in pain management and addiction treatment.