Continuing Education Activity

Oxycodone is a potent opioid that can be useful when used judiciously for pain. However, it can cause physical dependence and addiction. The immediate-release formulation of oxycodone is FDA approved for the management of acute or chronic moderate to severe pain, for which the use of opioid medication is deemed appropriate and for which other pain management strategies are insufficient. The extended-release formulation is FDA approved for the management of pain severe enough to require continuous long-term opioid treatment and for which there are no alternative options to treat the pain. The oxycodone to morphine dose equivalent ratio is approximately 1 to 1.5 for immediate-release and 1 to 2 for extended-release formulations. This activity reviews the indications, side effects, and contraindications for oxycodone and highlights the role of the interprofessional team in helping patients manage their pain.

Objectives:

• Identify the mechanism of action of oxycodone.
• Describe the adverse effects of oxycodone.
• Review the contraindications to oxycodone.
• Summarize the importance of collaboration and communication within the interprofessional team to enhance care coordination and help patients effectively and safely manage their pain.

Indications

Oxycodone is an opioid agonist prescription medication. The oxycodone immediate-release formulation is FDA-approved for the management of acute or chronic moderate to severe pain, for which other treatments do not suffice, and for which the use of opioid medication is appropriate.[1] The extended-release formulation is FDA-approved for the management of pain severe enough to require continuous (24 hours per day) long-term opioid treatment and for which there are no alternative options to treat the pain.[2] The oxycodone to morphine dose equivalent ratio is approximately 1 to 1.5 for immediate-release and 1 to 2 for extended-release formulations.[3]

Mechanism of Action

Oxycodone is a semisynthetic opioid with agonistic properties on mu, kappa, and delta-type opioid receptors, with the strongest affinity being for mu-type receptors.[4] Upon binding to these G-protein coupled receptors, oxycodone stimulates the exchange of GDP on the G-alpha subunit for GTP, resulting in the inhibition of adenylate cyclase and a decrease in intracellular cAMP. This signal cascade leads to a consequent inhibition of the nociceptive neurotransmitters acetylcholine, dopamine, GABA, noradrenaline, and substance P and the hormones glucagon, insulin, somatostatin, and vasopressin. As with other opioids, oxycodone causes hyperpolarization and reduced excitability of neurons in the central nervous system (CNS). This generalized CNS depression results from the agonistic effect on kappa-type receptors, leading to N-type voltage-gated calcium channel closure. In contrast, stimulation of the mu and delta-type receptors opens calcium-dependent inward-rectifying potassium channels.[5]

Pharmacokinetics

• The onset of action is 10 to 30 minutes for the immediate-release formulation and about 1 hour for controlled-release.
• Duration range is from 3 to 6 hours for immediate-release or 12 hours in controlled-release formulations.
• The plasma half-life is 3 to 5 hours, and stable plasma levels are reached within 24 to 36 hours.
• Oxycodone is metabolized by the hepatic enzymes CYP3A4 and CYP2D6, producing the metabolites noroxycodone and oxymorphone, respectively. These metabolites get excreted from the body via the kidneys.[6]

Administration

Oxycodone is widely available in tablet, capsule, and oral solution formulations. 

• Immediate-release tablets are available in 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, while capsules are 5 mg strength. Oral solution is available in 5 mg / 5 ml strength, and oral concentrate is available in 100 mg/5 mL strength. Manufacturers discontinued the 160 mg dose in May 2001 due to the high misuse potential.
• Extended release tabelts are available in 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg and 80 mg strengths. Tablets are intended to be taken whole and must not be broken, chewed, crushed, or dissolved in liquid. 
• Abuse-Deterrent tablets are available in 9 mg, 13.5 mg, 18 mg, 27 mg, and 36 mg strengths.
• Oxycodone is available in combination with other analgesics, including acetaminophen, aspirin, or ibuprofen.
• In some countries, oxycodone may be available in intramuscular and/or intravenous forms.

Adult Dosing

• Acute pain: Initial recommended doses of oxycodone are in the 5 to 15 mg range, every 4 to 6 hours as needed for adequate analgesia of acute pain. Further dosing should titrate upwards for pain control, with attention and monitoring for potential side effects.
• Chronic pain: It is recommended to titrate dosage slowly upwards, starting at the lowest possible dose for analgesia (2.5 to 10 mg every 4 to 6 hours) for patients with chronic pain. However, the medication should be taken at regularly scheduled intervals for chronic pain management to prevent the reoccurrence of pain instead of treating the pain after it has started.

Pediatric Dosing

• Acute pain: Initial recommended doses of oxycodone are 0.05 to 0.15 mg/kg, every 4 to 6 hours as needed for adequate analgesia of acute pain. Further dosing should titrate upwards for pain control, with attention and monitoring for potential side effects.
• Chronic pain: It is recommended to titrate dosage slowly upwards, starting at the lowest possible dose for analgesia for patients with chronic pain. However, the medication should be taken at regularly scheduled intervals for chronic pain management to prevent the reoccurrence of pain instead of treating the pain after it has started.

Specific Patient Population

• Patients with Liver Impairment: Dose reduction may be necessary for patients with hepatic failure. Initiating a starting dose at one-third to one-half the usual doses and close monitoring is recommended. Titration upwards should proceed at a careful rate.
• Patients with Renal Impairment: If CrCl is more than 60 ml/minute, no dose adjustment is necessary. If CrCl <30 mL/minute, 75% to 50% of the usual dose is recommended.[7] 
• Geriatric Patients: Dose reduction may be necessary for the elderly; initiating a starting dose at one-third to one-half the usual doses and close monitoring is recommended. Titration upwards should proceed at a careful rate.
• Pregnancy Considerations: Maternal oxycodone use during pregnancy may result in serious and sometimes fatal events, as opioids can cross the placental barrier. These events may include preterm delivery, congenital abnormalities, and reduced fetal growth. In addition, with prolonged exposure, babies born to opioid-dependent mothers may suffer from potentially life-threatening neonatal opioid withdrawal syndrome. Therefore, clinicians should discuss the neonatal risks of oxycodone therapy in pregnant women or consider alternative treatments.
• Breastfeeding Considerations: Oxycodone is excreted in variable concentrations into human milk. There is a lack of study on oxycodone use in lactating women and its effect on milk production. Access the maternal need for oxycodone and perform a risk-benefit analysis of oxycodone use. Monitor for potential adverse reactions (excessive sedation and respiratory depression) in infants with maternal administration of opioids, including oxycodone. Monitor for withdrawal symptoms when breastfeeding is stopped, or oxycodone administration is stopped to mother.[8] While some sources recommend not more than 30 mg of oxycodone to breastfeeding women, others recommend against using it while breastfeeding.[9]

Opioid Overdose Prevention

• Discuss the naloxone for the emergency treatment of oxycodone overdose with the patient and/or caregiver and assess the need for access to naloxone, especially when initiating and renewing a treatment with oxycodone. Naloxone is available by prescription from clinicians, as part of a community-based program, or directly from a pharmacist. Clinicians should consider prescribing naloxone based on the patient’s medical history, clinical need, and risk for overdoses, such as a history of an opioid use disorder or concomitant use of other CNS depressants. Providers can also prescribe naloxone when the patient has household members (e.g., children) or close contacts at risk for overdose or accidental ingestion.[10]

Adverse Effects

Oxycodone has the potential for addiction, and it is classified as a control substance.[11] The side effect profile of oxycodone is similar to that of other opioid medications. Constipation is the most common overall side effect. The intensity of these side effects tends to decrease over time.[12] 

Most Common (more than 5%)

• Asthenia
• Constipation
• Dizziness
• Dry mouth
• Headache
• Nausea
• Pruritus
• Somnolence
• Sweating
• Vomiting

Other Reported Side Effects

Cardiovascular

• Bradycardia
• Hypotension
• Palpitations

Dermatologic

• Diaphoresis
• Photosensitivity
• Rash

Gastrointestinal

• Anorexia
• Abdominal pain
• Diarrhea
• Glossitis

Neurologic

• Confusion
• Drowsiness
• Hallucinations
• Increased cerebrospinal (CSF) pressure
• Irritability
• Sedation
• Seizures

Respiratory

• Cough
• Respiratory depression[13]

Contraindications

Oxycodone therapy is contraindicated in patients with:

• Respiratory depression
• Bronchial asthma (in unmonitored settings)
• Hypercarbia
• Hypersensitivity to oxycodone
• Known or suspected ileus or GI obstruction

While there is limited information involving studies of allergenic cross-reactivity in opioid medications, the possibility of a cross-sensitivity cannot be fully excluded. For patients with an opioid allergy, a clear description of the allergic reaction should be explored and properly documented before considering oxycodone. Patients who are found to have a true allergic reaction to other opioid medications should avoid oxycodone therapy when possible.

US Boxed Warnings

• Opioid analgesic risk evaluation and mitigation strategy
• Addiction, abuse, and misuse
• Risks with concomitant use with benzodiazepines or other CNS depressants and cytochrome P450 3A4 inducers/inhibitors. Monitor patients receiving oxycodone and any of these classes of medicines.[14]
• Accidental ingestion
• Life-threatening respiratory depression
• Pregnancy is not an absolute contraindication to oxycodone therapy; however, the FDA lists Neonatal opioid withdrawal as a US Boxed Warning.

Monitoring

Patients taking oxycodone require monitoring for the presence of constipation, pain relief, other side effects, and appropriate usage. Their blood pressure, heart rate, and respiratory rate should also be monitored, especially for the first 24 to 72 hours after initiating therapy or increasing dosage. If pain continues to increase after stabilizing dosage, the clinician should investigate alternative causes of pain before increasing medication dosage or frequency. If adverse effects develop, consider decreasing the dosage to find an appropriate therapeutic level without unacceptable adverse effects. Patients taking oxycodone should be monitored or cautioned when starting a new medication that is a known CYP450 inhibitor. Inhibition of these enzymes can lead to potentially fatal oxycodone concentrations in the blood.[14] In addition, this medication should not be abruptly discontinued in patients who may be opioid-dependent, as this could precipitate withdrawal symptoms. If oxycodone therapy requires termination, consider decreasing in increments of 10% to 50% of the dose every few days to a few weeks while monitoring for withdrawal symptoms. Newer abuse-deterrent formulations could also be used to prevent the misuse and abuse of oxycodone.[15]

Due to the high misuse potential and possibly fatal results of an oxycodone overdose, prescriptions should be written for the lowest therapeutic dose and only for the period the patient is expected to be in pain. Close follow-up should be arranged. Many hospital systems, states, and government agencies in the United States have published guidelines to help physicians with pain management and opioid prescriptions. The legislation is evolving in the United States, and in some states, state law will require signed informed consent to prescribe opioid medications to a patient. In opioid-naive patients with acute pain, long-acting opioids are not an advisable approach to pain control.[16] For patients who require long-term opioid therapy for pain management, regularly scheduled visits should be conducted to reassess their pain level and monitor possible indications of opioid abuse.[17]

Toxicity

Signs and symptoms of an oxycodone overdose include bradycardia, hypotension, miosis, respiratory depression, somnolence, muscle flaccidity, cold and clammy skin, and death.[17] Its use is also linked with acute hepatic injury, especially when used in higher doses and in combination with high acetaminophen doses.[18] When a person overdoses on oxycodone, an opioid antagonist such as naloxone should be administered. Clinicians should not give opioid antagonists in the absence of clinically significant respiratory or circulatory depression. Repeat dosing may be necessary as the duration of action of these drugs can vary from 30 to 120 minutes.[10]

Enhancing Healthcare Team Outcomes

Healthcare workers who prescribe opiates should be familiar with the recent changes in their state laws. Liberal prescribing of these agents is no longer recommended and can lead to legal difficulties with the DEA. Patients with pain should receive pain management with alternative means, and a pain consultant should be involved. Healthcare providers are recommended to follow REMS guidelines to ensure proper prescribing of opioids. Currently, the DEA scans all healthcare workers who frequently write opiate prescriptions, and any mortality in a patient can lead to loss of the DEA certificate and even license to practice medicine.[19]

Nurses, pharmacists, and physicians should educate patients about the dangers of opioids and their misuse. All interprofessional healthcare team members should be familiar and knowledgeable about the signs of opioid misuse and overdose and report any concerns to the prescribing clinician. Pharmacists can report "doctor shopping" when they see it. They can also recommend alternative agents for pain control, as many trials are underway to seek different means to control pain that has historically been treated with opioid drugs. Nursing will also inform the prescriber of any concerns about the misuse, is a source of counsel for the patient, and is often the point of contact for the pharmacist. The entire interprofessional healthcare team needs to function collaboratively to control the patient's pain and prevent potential misuse and dependence on opioid medications like oxycodone. [Level 5]