Oxycodone

Mechanism of Action

Oxycodone is a semisynthetic opioid with agonistic properties on mu, kappa, and delta-type opioid receptors, with the strongest affinity for mu-type receptors.[5] Upon binding to these G-protein–coupled receptors, oxycodone stimulates the exchange of guanosine diphosphate (GDP) on the G-alpha subunit for guanosine triphosphate (GTP), inhibiting adenylate cyclase and decreasing intracellular cyclic adenosine monophosphate (cAMP). This signal cascade leads to a consequent inhibition of the nociceptive neurotransmitters acetylcholine, dopamine, gamma-aminobutyric acid (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.[6]

Pharmacokinetics

Absorption: The onset of action is 10 to 30 minutes for the immediate-release formulation and about 1 hour for the controlled release. The plasma half-life is 3 to 5 hours, and stable plasma levels are reached within 24 to 36 hours. The duration ranges from 3 to 6 hours for immediate release or 12 hours for controlled-release formulations.

Distribution: Oxycodone exhibits a distribution volume of 2.6 L/kg. The plasma protein binding of oxycodone is approximately 45%.

Metabolism: Oxycodone is metabolized by the hepatic enzymes CYP3A4 and CYP2D6, producing the metabolites nor-oxycodone and oxymorphone, respectively. Oxymorphone has a greater affinity for μ-opioid receptors compared to oxycodone.[7]

Elimination: Metabolites get excreted from the body via the kidneys.[8] The clearance is  0.8 L/min.

Administration

Available Dosage Forms and Strengths 

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

• Immediate-release tablets: These are available in 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg, while capsules are 5 mg strength. The oral solution is available in 5 mg/5 mL strength, and the oral concentrate is in 100 mg/5 mL strength. Manufacturers discontinued the 160 mg dose in May 2001 due to the high misuse potential.

• Extended-release tablets: These are available in 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg strengths. Tablets are not intended to be broken, chewed, crushed, or dissolved in liquid. 

• Abuse-deterrent tablets: These are available in 9 mg, 13.5 mg, 18 mg, 27 mg, and 36 mg strengths.

Oxycodone is also available in combination with other analgesics, including acetaminophen, aspirin, or ibuprofen. In some countries, oxycodone may be available in intramuscular and/or intravenous forms.

Dosages

Adult dosing

• Acute pain: Initial recommended doses of oxycodone are in the 5 mg to 15 mg range, every 4 to 6 hours as needed for adequate analgesia of acute pain. Further dosing should be titrated upwards for pain control, with attention and monitoring for adverse effects.

• Chronic pain: The dosage should be slowly titrated upwards, starting at the lowest possible dose for analgesia (2.5 mg 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 be titrated upwards for pain control, with attention and monitoring for potential adverse 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 Populations

Hepatic 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.

Renal impairment: No dose adjustment is necessary if creatinine clearance (CrCl) exceeds 60 mL/min. If CrCl is less than 30 mL/min, a recommended dose reduction to 75% to 50% of the usual dose is advised.[9] 

Pregnancy considerations: Maternal oxycodone use during pregnancy may result in severe 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. A lack of studies exists on oxycodone use in lactating women and its effect on milk production. Monitor for potential adverse reactions (excessive sedation and respiratory depression) in infants with maternal administration of opioids, including oxycodone. The healthcare provider should monitor for withdrawal symptoms when a nursing mother discontinues breastfeeding her infant or when the mother discontinues oxycodone administration.[10] While some sources recommend not more than 30 mg of oxycodone to breastfeeding women, others recommend against using it while breastfeeding.[11]

Older patients: Dose reduction may be necessary for this demographic; therefore, initiating treatment at one-third to one-half of the usual doses and closely monitoring patients is advisable. Any upward titration should be done cautiously and at a slow rate.

Opioid Overdose Prevention

Discuss 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 opioid use disorder or concomitant use of other CNS depressants. Providers can also prescribe naloxone when the patient has household members, such as children, or close contacts at risk for overdose or accidental ingestion.[12]

Adverse Effects

Oxycodone has the potential for addiction and is classified as a controlled substance.[13] The adverse effect profile of oxycodone is similar to that of other opioid medications. Constipation is the most common overall adverse effect. The intensity of these adverse effects tends to decrease over time.[14] 

Common Adverse Effects

The most common adverse reactions, occurring in more than 5% of patients, include asthenia, constipation, dizziness, dry mouth, headache, nausea, pruritus, somnolence, sweating, and vomiting.

Additional Reported Adverse Effects

Cardiovascular: Other reported adverse effects include cardiovascular symptoms such as bradycardia, hypotension, and palpitations.

Dermatologic: Adverse effects in the dermatologic category encompass diaphoresis, photosensitivity, and rash.

Gastrointestinal: Gastrointestinal adverse effects include anorexia, abdominal pain, diarrhea, and glossitis.

Neurologic: Neurologic adverse effects comprise confusion, drowsiness, hallucinations, increased cerebrospinal pressure, irritability, sedation, and seizures.

Respiratory: The adverse effects of the respiratory system include cough and respiratory depression.[15]

Drug-Drug Interactions

CYP3A4 and CYP2D6 inhibitors: Coadministration with CYP3A4 inhibitors, such as erythromycin, ketoconazole, and ritonavir, increases oxycodone plasma concentrations, intensifying opioid effects, particularly when introduced post-stabilization. Discontinuation of a CYP3A4 inhibitor may lead to diminished opioid efficacy or withdrawal symptoms.[16][17]

Risk mitigation: Healthcare providers should consider dosage reduction of oxycodone tablets if necessary. They should also monitor for respiratory depression and sedation and adjust the oxycodone dosage accordingly if discontinuing a CYP3A4 inhibitor. Clinicians are advised to monitor for signs of opioid withdrawal as well.

CYP3A4 inducers: Coadministration with CYP3A4 inducers such as rifampin, carbamazepine, and phenytoin may decrease oxycodone plasma concentrations, decreasing therapeutic effectiveness and triggering withdrawal.

Risk mitigation: Healthcare providers should consider increasing the dosage of oxycodone hydrochloride tablets as necessary. They should also monitor for signs of opioid withdrawal and contemplate reducing the oxycodone dosage upon discontinuing a CYP3A4 inducer.[18]

Benzodiazepines and CNS depressants: Coadministration with general anesthetics, antipsychotics, other opioids, alcohol, zolpidem, and eszopiclone heightens the risk of hypotension, respiratory depression, sedation, and fatal outcomes. Caution is advised.

Risk mitigation: When deemed suitable, naloxone should be prescribed for emergency opioid overdose treatment.[19]

Serotonergic drugs: Coadministration with agents influencing the serotonergic neurotransmitter system is associated with the potential development of serotonin syndrome.

Risk mitigation: Healthcare providers should carefully observe patients during treatment initiation and dose adjustments. If suspected serotonin syndrome arises, consideration should be given to discontinuing oxycodone hydrochloride tablets.[20]

Monoamine oxidase inhibitors (MAOIs): Interaction between MAOIs such as tranylcypromine, phenelzine, linezolid, and opioids may lead to serotonin syndrome or opioid-related toxicity, including respiratory depression and coma.

Risk mitigation: Healthcare providers should avoid the use of oxycodone within 14 days of discontinuing MAOIs to mitigate risks. In urgent opioid situations, it is recommended to implement test doses, incremental titration, and closely monitor the patient's blood pressure, as well as symptoms of central nervous system and respiratory depression.[21]

Mixed agonist/antagonist opioid analgesics: Coadministration with buprenorphine, nalbuphine, and butorphanol pentazocine may diminish the analgesic effect or prompt withdrawal symptoms.

Risk mitigation: Concurrent use of these medications should be avoided.[22]

Muscle relaxants: Coadministration may enhance neuromuscular blockade, intensifying respiratory depression.

Risk mitigation: Healthcare providers should vigilantly monitor patients for respiratory depression. Considering the increased risk, prescribing naloxone for emergency opioid overdose treatment is advisable.[23]

Diuretics: Opioids may impact diuretic efficacy by affecting antidiuretic hormone release.

Risk mitigation: Healthcare providers should monitor diuresis and changes in blood pressure, adjusting diuretic dosages accordingly.[24][25]

Anticholinergic drugs: Coadministration elevates the risk of urinary retention and severe constipation.

Risk mitigation: Clinicians should vigilantly monitor for signs of urinary retention or compromised gastric motility during concurrent usage with anticholinergic drugs.[26][27]

Contraindications

Warnings and Precautions

Oxycodone therapy is contraindicated in patients with respiratory depression, acute bronchospasm, hypercarbia, hypersensitivity to oxycodone, and known or suspected ileus or gastrointestinal obstruction.

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

Box Warnings

• Opioid analgesic risk evaluation and mitigation strategy (REMS) [28]

• Risks of addiction, abuse, and misuse

• Risks associated with concomitant use of oxycodone with benzodiazepines, other CNS depressants, and cytochrome P450 3A4 inducers/inhibitors. Healthcare providers should monitor patients receiving oxycodone and any of these classes of medicines.[18]

• Accidental ingestion of the drug

• Life-threatening respiratory depression

• Although pregnancy is not an absolute contraindication to oxycodone therapy, the FDA lists neonatal opioid withdrawal as a Box Warning.[29]

Monitoring

Patients taking oxycodone require monitoring for the presence of constipation, pain relief, adverse 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 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.[18] 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 it 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.[30]

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 therapeutic period. Close follow-up should be arranged. Many hospital systems, states, and government agencies in the United States have published guidelines to help clinicians 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 advisable for pain control.[31] 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.[32] The effective utilization of Prescription Drug Monitoring Programs (PDMPs) facilitates monitoring, enabling clinicians to identify and address opioid misuse and promoting safer prescribing practices.[33]

Toxicity

Signs and Symptoms of Overdose

Signs and symptoms of an oxycodone overdose include bradycardia, hypotension, miosis, respiratory depression, somnolence, muscle flaccidity, cold and clammy skin, and death.[32] The use is also linked with acute hepatic injury, especially in higher doses and in combination with high acetaminophen doses.[34] 

Management of Overdose

When a person overdoses on oxycodone, an opioid antagonist such as naloxone should be administered. Clinicians should not give opioid antagonists such as naloxone 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. The FDA has recently approved a 4 mg naloxone hydrochloride nasal spray for over-the-counter usage, the first naloxone product sanctioned for nonprescription use.[35]

Enhancing Healthcare Team Outcomes

Clinicians who prescribe opiates should be familiar with the recent changes in state laws. Liberal prescribing of these agents is no longer recommended and can lead to legal difficulties with the Drug Enforcement Administration (DEA). Patients with pain should receive pain management with alternative means, and a pain consultant should be involved. Clinicians are recommended to follow REMS guidelines to ensure the proper prescribing of opioids. Currently, the DEA scans all healthcare professionals who frequently write opiate prescriptions, and any mortality in a patient can lead to the loss of the DEA certificate and the license to practice medicine.[36]

Nurses, pharmacists, and physicians should educate patients about the dangers of opioids and their misuse. All interprofessional healthcare team members should be familiar with and knowledgeable about the signs of opioid misuse and overdose and report any concerns to the prescribing clinician. Pharmacists can report instances of "doctor shopping" when identified and can also suggest alternative pain management options. Given the ongoing trials exploring various methods for pain control traditionally treated with opioids, their input is invaluable. The entire interprofessional healthcare team must collaborate and work together cohesively in managing the patient's pain effectively while striving to prevent potential misuse and dependency on opioid medications such as oxycodone.