All About Oxy

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With the death of the entertainer Prince attributed to a fentanyl overdose, and new FDA warnings, opioids have been making headlines. Since the most common reason patients visit the emergency department is for pain, it is not surprising that emergency physicians prescribe and administer medications such as oxycodone on a daily basis. Here are some of the basics about how oxycodone works, and also the reason why chronic users may be at even higher risk of unexpected respiratory depression.

How It Works
Oxycodone is a semi-synthetic opioid with analgesic properties. Oxycodone binds to mu, kappa, and delta opioid receptors in the central nervous system, causing inhibition of ascending pain pathways, alteration of pain perception, and producing generalized CNS depression. The mechanism is complex, but likely involves inhibition of the adenyl cyclase system, causing a fall in cyclic AMP, decreased release of neurotransmitters, and subsequent reduced transmission of nerve stimulation.1 Onset of action is within 10–15 minutes of administration, and the half-life is 3–4 hours for immediate-release oxycodone, and 12 hours for extended-release oxycodone (sold as OxyContin, reformulated to be more tamper-resistant in 2010). Oxycodone is commonly supplied as a combination product with acetaminophen (sold as Percocet, Roxicet and others).

Major Indications
Oxycodone is indicated for severe pain not responsive to non-opioid medications, including severe cancer and postoperative pain.

Notable History
First used in clinical practice in the early 1900s, oxycodone’s abuse potential was recognized as early as the 1960s, when the U.S. government classified it as a Schedule II drug. As its use and misuse increased, a lucrative illegal market developed, with oxycodone selling on the street for between $5–18 per 10 mg per pill. Oxycontin, which is a slow-release formulation of the drug, was particularly problematic as abusers learned to crush the drug into a fine powder and snort it or dissolve it in water and inject it, defeating its time-release properties to achieve an immediate and intense high. Manufacturers responded by producing a crush-proof Oxycontin in 2010, but this did little to curb the epidemic, as users simply turned to other readily available options like heroin.

Recently In The News For
Between 1999 and 2010, the rate of death from overdose of prescription opioids in the U.S. quadrupled, most of which were unintentional overdoses,3 a rise which parallels the large increase in use of prescription opioids during the same time frame.4 Fatal overdose from prescription opioids now exceeds deaths from heroin and cocaine combined.4 In response to this epidemic of prescription opioid abuse and fatal overdoses, the U.S. Food and Drug Administration (FDA) recently issued a public safety warning about the entire class of opioid pain medications, and is requiring labeling changes for all opioid pain medications warning of these risks. Changes include a new boxed warning about the risks of misuse, abuse, addiction, overdose, and death. In addition, the FDA is requiring a wording change to clarify that because of these risks, immediate-release opioids should be reserved for severe pain in which alternative non-opioid treatments are inadequate.6 Numerous states have started prescription drug monitoring programs, electronic databases that track all opioid prescriptions in the state.

Adverse Events
The most serious side effects of oxycodone are life-threatening respiratory depression and central nervous system depression, which can lead to apnea, coma, and death. Additionally, gastrointestinal side effects of nausea/vomiting and constipation are common, seen in up to 25% of adults taking oxycodone. Constipation in particular can be severe, and it is reasonable to prescribe a stool softener such as docusate or pro-motility agent like senna to patients taking oxycodone.

Cautions
Because of the risk of life-threatening respiratory depression, patients should be prescribed the lowest possible dose and monitored closely for respiratory depression, especially during initiation of therapy or dose escalation. Patients should be advised to swallow tablets whole, since crushing, chewing, or dissolving tablets can cause rapid release and a potentially fatal dose. Because of the risk of CNS depression, patients should be cautioned about not driving, operating heavy machinery, or performing other tasks requiring mental alertness while taking oxycodone. In addition, patients on oxycodone should be monitored for behaviors which may indicate opioid addiction, misuse, and abuse. Oxycodone should be kept away from children because accidental ingestion, particularly extended release oxycodone, can be fatal. Finally, overdose of combination oxycodone-acetaminophen products have been associated with acute liver failure, in some cases leading to liver transplant and death.

Dosing And Adjustments
Immediate release: Oxycodone 5 to 15 mg every 4 to 6 hours as needed. Extended release: Oxycodone ER 10 mg every 12 hours (for use in opioid-naive patients). Ox-ycodone ER 60mg and 80 mg strengths should only be used in patients who opioid-tolerant, defined as patients already taking at least 60 mg morphine orally daily, transdermal fentanyl 25 mpg per hour, oxycodone 30 mg orally daily, hydromorphone 8 mg orally daily, or an equivalent dose of another opiod for at least 1 week.6

Special Considerations
Oxycodone is pregnancy class B or C, depending on the manufacturer. Oxycodone crosses the placenta and adverse events were observed in some animal reproductive studies. Oxycodone should not be used immediately prior to or during labor because of risk of respiratory depression in the neonate. Maternal oxycodone use in pregnancy can also cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated promptly. Oxyocodone is excreted into breast mild and breast-feeding is not recommended in US labeling and is contraindicated in Canadian labeling.6

Cost
Oxycodone HCl 5 mg tablets, $54 for 100 capsules.6 Oxycodone-acetaminophen combination product, $137 for 100 tablets.7 Oxycodone extended release (Oxycontin) 10 mg tablets, $302 for 100 tablets.

Peds Pain
In 2015, the FDA approved peds dosing of oxycodone ER for children aged ≥11 years (provided they are already receiving and tolerating opioids for at least 5 consecutive days with a minimum of 20 mg/day of oxycodone or its equivalent for at least 2 days immediately preceding dosing with oxycodone).

The FDA’s decision was guided by data obtained from the manufacturer of oxycodone, which conducted safety and pharmacokinetic studies on peds dosing after an earlier request from the FDA.

Peds oxycodone is only considered on-label for long-term pain management for which there is no other medical alternative, such as in oncological treatment, and following serious trauma or non-routine major surgery.


REFERENCES

  1. Gallego AO, Barón MG, Arranz EE. Oxycodone: A pharmacological and clinical review. Clinical and Translational Oncology. 2007;9(5):298-307.
  2. Olkkola KT, Hagelberg NM. Oxycodone: New ‘old’ drug. Curr Opin Anaesthesiol. 2009;22(4):459-462. doi: 10.1097/ACO.0b013e32832bc818 [doi].
  3. Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014;370(22):2063-2066.
  4. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315-1321.
  5. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146-155.
  6. Lexicomp. oxyocodone: Drug information. www.uptodate.com. Updated 2016. Accessed June 5, 2016.
  7. Lexicomp. oxycodone and acetaminophen: Drug information. www.uptodate.com. Updated 2016. Accessed June 8, 2016., 2016.
  8. Midwest Medical Examiner’s office Press Release http://i2.cdn.turner.com/cnn/2016/images/06/02/prince.toxicology.pdf

ABOUT THE AUTHORS

Karen Serrano, MD is an assistant professor in the department of emergency medicine at the University of North Carolina.

Dr. Shenvi is an assistant professor in the department of emergency medicine at the University of North Carolina. She authors RX Pad each month in EPM.

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