oxycodone/naloxone

Action and Spectrum

Actions and Spectrum: 

oxycodone is an opioid analgesic, while naloxone is an opioid receptor antagonist. When combined with a medication, such as a fixed-dose combination tablet, they are used to manage pain while reducing the risk of opioid-induced constipation. oxycodone acts as an agonist, binding to opioid receptors in the brain and also spinal cord, thereby reducing pain perception.

It primarily targets the mu-opioid receptors but also interacts with kappa and delta opioid receptors. By activating these receptors, oxycodone produces analgesic effects and can cause other effects associated with opioids, such as respiratory depression, sedation, and euphoria. oxycodone is a potent opioid classified as a Schedule II controlled substance because its high potential for abuse and addiction. 

naloxone, on the other hand, acts as an antagonist. It binds strongly to opioid receptors but does not activate them. Instead, naloxone displaces other opioids, including oxycodone, from the receptors and blocks their effects. naloxone is primarily used to reverse the effects of opioid overdose by rapidly reversing respiratory depression and restoring normal breathing. It has a high affinity for mu-opioid receptors but can also interact with kappa and delta opioid receptors to a lesser extent. 

When oxycodone and naloxone are combined in a fixed-dose combination, the naloxone component is included to deter the abuse of the medication. When taken as prescribed, naloxone has limited oral bioavailability, so it does not significantly affect the analgesic properties of oxycodone. However, if the combination tablet is crushed or dissolved for injection, the naloxone becomes active and can precipitate opioid withdrawal symptoms in individuals dependent on opioids. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

Abdominal pain (3%) 

Back pain (3%) 

Vomiting (2-5%) 

Headache (3-4%) 

Pruritus (2%) 

Constipation (3%) 

Nausea (7-8%) 

Insomnia (1-2%) 

Anxiety (1-3%) 

Black Box Warning

Black Box Warning: 

• Addiction, Abuse, and Misuse: oxycodone/naloxone carries a high potential for addiction, abuse, and misuse, which can lead to overdose and death.  
• Life-Threatening Respiratory Depression: The combined use of oxycodone and naloxone can result in profound respiratory depression. 
• Accidental Ingestion: oxycodone/naloxone tablets are formulated to be extended-release, and their accidental ingestion by children or others, especially if they are not tolerant to opioids, can result in a fatal overdose of oxycodone.  
• Neonatal Opioid Withdrawal Syndrome. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Known hypersensitivity: The medication is contraindicated in individuals with known hypersensitivity or allergic reaction to oxycodone, naloxone, or any of the other components of the product. 
• Respiratory depression: oxycodone/naloxone is contraindicated in individuals with severe respiratory depression, as it may further suppress respiratory function. 
• Acute or severe bronchial asthma or hypercarbia: The combination is contraindicated in individuals with acute or severe bronchial asthma or hypercarbia, as it may exacerbate respiratory compromise. 
• Paralytic ileus: oxycodone/naloxone is contraindicated in individuals with paralytic ileus, a condition characterized by a non-functioning or obstructed bowel, as it may further impair gastrointestinal motility. 
• Monoamine oxidase inhibitor (MAOI) use: oxycodone/naloxone is contraindicated in individuals who are currently using or have recently used MAOIs or within 14 days of discontinuing MAOI therapy. Concomitant use can result in potentially life-threatening reactions, such as serotonin syndrome. 

Caution 

• Respiratory depression: oxycodone/naloxone can cause respiratory depression, especially in individuals who are elderly, debilitated, or have pre-existing respiratory conditions. Close monitoring of respiratory function is necessary, particularly when initiating treatment or adjusting the dosage. 
• Misuse, abuse, and addiction: oxycodone/naloxone has a high potential for misuse, abuse, and addiction, similar to other opioids. Patients should be monitored for signs of opioid misuse or addiction, and healthcare providers should use caution when prescribing to individuals with a history of substance abuse or addiction. 
• Interactions with other central nervous system depressants: The concomitant use of oxycodone/naloxone with other central nervous systems depressants, such as benzodiazepines, sedatives, tranquilizers, or alcohol, may result in additive central nervous system depressant effects. Caution should be exercised when combining these medications, as it can enhance the risk of respiratory depression, sedation, and impaired cognitive function. 
• Head injury or increased intracranial pressure: oxycodone/naloxone should be used cautiously in individuals with head injuries, as it may increase the risk of respiratory depression and further elevate intracranial pressure. 
• Impaired gastrointestinal function: The combination may cause or worsen constipation. Patients with pre-existing gastrointestinal motility disorders should be closely monitored, and appropriate measures to manage constipation should be implemented. 
• Hepatic or renal impairment: Patients with hepatic or renal impairment may experience altered metabolism and elimination of oxycodone and naloxone. Dosage adjustments or careful monitoring may be necessary for these individuals. 
• Hypotension: oxycodone/naloxone may cause hypotension, particularly in volume-depleted individuals or with pre-existing hypotension. Blood pressure should be monitored regularly, and caution should be exercised when administering the medication to patients with low blood pressure. 
• Withdrawal symptoms in opioid-dependent individuals: Abrupt discontinuation or rapid tapering of oxycodone/naloxone may result in withdrawal symptoms in opioid-dependent individuals. A gradual tapering schedule should be followed when discontinuing the medication. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk: Yes (oxycodone), Not known (naloxone) 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• 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: 

oxycodone/naloxone is a combination medication that includes oxycodone, an opioid analgesic, and naloxone, an opioid receptor antagonist. oxycodone acts as an agonist, binding to opioid receptors in the brain and also spinal cord to reduce pain perception. It primarily targets mu-opioid receptors but interacts with kappa and delta receptors, producing analgesic effects and potential side effects such as respiratory depression and sedation. naloxone, on the other hand, acts as an antagonist, binding firmly to opioid receptors without activating them.

When taken orally as prescribed, the naloxone component has limited oral bioavailability, allowing the analgesic properties of oxycodone to be maintained. However, suppose the combination tablet is crushed or dissolved for injection. In that case, naloxone becomes active and can precipitate opioid withdrawal symptoms in opioid-dependent individuals, serving as a deterrent to misuse and abuse. 

Pharmacodynamics: 

Mechanism of action: oxycodone/naloxone involves the combined effects of oxycodone as an opioid agonist and naloxone as an opioid receptor antagonist. Here’s a breakdown of their mechanisms of action: 

oxycodone: oxycodone acts as an agonist, binding to opioid receptors primarily in the C.N.S (central nervous system). It primarily targets mu-opioid receptors but interacts with kappa and delta opioid receptors to a lesser extent. By binding to these receptors, oxycodone activates them, leading to various effects, including analgesia (pain relief), sedation, respiratory depression, and euphoria. The activation of mu-opioid receptors inhibits the release of neurotransmitters in pain signaling, reducing pain perception. 

naloxone: naloxone, on the other hand, acts as a competitive antagonist at opioid receptors, primarily targeting mu-opioid receptors. It has a high affinity for these receptors but does not activate them. Instead, naloxone competes with and displaces other opioids, such as oxycodone, from the opioid receptors. By doing so, naloxone blocks the effects of opioids and reverses their actions. naloxone is commonly used as an antidote for opioid overdose, mainly to counteract the life-threatening respiratory depression caused by excessive opioid effects. 

In the combination medication of oxycodone/naloxone, naloxone is included to deter abuse and misuse. When taken orally as directed, the naloxone component has limited systemic bioavailability due to extensive first-pass metabolism in the liver. However, suppose the combination tablet is crushed or dissolved for injection. In that case, naloxone becomes active and can precipitate opioid withdrawal symptoms in opioid-dependent individuals as a deterrent to misuse and abuse. 

Pharmacokinetics: 

Absorption 

After oral administration, oxycodone/naloxone is absorbed from the gastrointestinal tract. The absorption rate and extent can vary based on the specific formulation of the medication. oxycodone is readily absorbed, while naloxone has limited oral bioavailability. However, when taken as directed, naloxone has minimal systemic exposure due to extensive first-pass metabolism in the liver. 

Distribution 

Once absorbed, oxycodone is extensively distributed throughout the body, crossing the blood-brain barrier and binding to opioid receptors in the central nervous system. oxycodone has a relatively high volume of distribution, indicating its wide distribution into tissues. The distribution of naloxone is limited, as it is primarily metabolized in the liver before reaching the systemic circulation. 

Metabolism 

oxycodone is metabolized in the liver by various enzymes, including cytochrome P450 (CYP) 3A4, to produce its active metabolites, such as oxymorphone. naloxone is also extensively metabolized in the liver, primarily through glucuronidation, resulting in inactive metabolites. 

Elimination and Excretion 

Most of the metabolized oxycodone and naloxone, along with their metabolites, are excreted through the kidneys in urine. A small portion of the drugs and their metabolites may be eliminated through feces via biliary excretion. 

Adminstartion

Administration: 

Oral administration 

oxycodone/naloxone (brand name Targiniq ER) is typically available as extended-release tablets for oral administration. The medication should be taken exactly as prescribed by a healthcare professional.  

• Dosage: The appropriate dosage and dosing frequency of oxycodone/naloxone will be determined by the prescribing healthcare professional based on the individual’s specific needs and condition.  
• Swallowing: The tablets should be swallowed whole, not chewed, crushed, or dissolved. Altering the tablets can rapidly release oxycodone, which can increase the risk of overdose. 
• Timing: oxycodone/naloxone is usually taken every 12 hours. The medication should be taken at the same time(s) each day to maintain consistent pain control. 
• Food: oxycodone/naloxone can be taken with or without food. However, it is advisable to follow the specific instructions the prescribing healthcare professional provides. 
• Avoid alcohol: It is crucial to avoid consuming alcohol while taking oxycodone/naloxone, as alcohol can increase the medication’s sedative and potentially dangerous side effects. 
• Storage: oxycodone/naloxone should be stored at room temperature, away from moisture and heat. It should be kept out of reach of children and individuals who should not have access to it. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: oxycodone/naloxone 

Pronounced: [ ox-i-KOE-done-hye-droe-KLOR-ide, nal-OX-one] 

Why do we use oxycodone/naloxone? 

oxycodone/naloxone is a medication that combines the opioid analgesic oxycodone with the opioid receptor antagonist naloxone. It is primarily used to manage pain in individuals who require continuous opioid treatment for an extended period.  

• Chronic Pain Management: oxycodone/naloxone is prescribed to manage chronic pain conditions that require around-the-clock opioid treatment. It is used when other alternative treatments have proven insufficient pain relief. 
• Opioid-Induced Constipation: The naloxone component in oxycodone/naloxone helps mitigate the common side effect of opioid-induced constipation. naloxone acts locally in the gastrointestinal tract to counteract the constipating effects of oxycodone without significantly affecting the analgesic properties of oxycodone when taken orally as directed.