Background      Short-acting oral opioids are among the most prescribed drugs in palliative care.  Despite national analgesic guidelines, the use of excessive intervals for short-acting oral opioids continues to pose a significant barrier to good analgesic care among patients with pain from life-limiting illnesses such as metastatic cancer. Understanding the pharmacological rationale for dosing intervals is key to proper prescribing and patient counseling.

Short-Acting Hydrophilic Oral Opioids       Short-acting oral opioids are administered as either single agents (oral morphine, hydromorphone, or oxycodone) or as combination products (hydrocodone or oxycodone) containing acetaminophen, aspirin, or ibuprofen.  For all these products, the peak analgesic effect occurs in 60-90 minutes with an expected total duration of analgesia of 2-6 hours.  Standard reference sources generally cite a 4-hour dosing interval for the single-agent opioids, versus 4- or 6-hour intervals for combination products (PDR, Micromedex).  However, the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline (1994) recommends dosing intervals for all short-acting opioids at an interval or every 3-4 hours, an interval more consistent with patient reports of pain relief and the half-life of oral opioids. 

Note:  lipophilic opioids (e.g., methadone, oxymorphone, fentanyl, and buprenorphine) have very different pharmacokinetics and different prescribing standards would apply.  See Fast Facts #75, 86, 181, 103, 221, 168, 358) for more information about these individual opioids. While codeine is a lipophilic opioid, it is rarely recommended as an analgesic due to concerns about its metabolites and metabolism,

Is there a danger to more frequent drug administration? 

• For oral, as-needed (PRN) sing-agent opioids, there is no danger with a dosing interval of every 2 hours in patients with normal renal function who are currently tolerating the opioid without sedation and are closely being supervised. Since the peak effect will be reached in 60-90 minutes, if it has not achieved analgesic effect nor dose-limiting side effects (e.g., sedation), it is safe to give another PRN dose 2 hours later. In outpatient settings, clinicians may be worried about prescribing the number of pills necessary to provide access to every 2 hours prn usage.  In that scenario, a clinician could write the prescription as q2 hours prn but then include a maximum number of pills per day in the prescription notes.
• For scheduled opioids, dosage depends on duration of action/ drug half-life.  For standard immediate-release oral opioids (e.g., immediate release oxycodone or morphine) dosing every 4 hours when awake is generally a reasonable schedule, although this may vary between medications and may be prolonged in impaired renal function.  Since scheduled opioids are given regardless of need or buildup of medication, more caution is generally indicated than for PRN usage.  Consider adding an order to hold for sedation. 
• For combination products, the concern is excessive amounts of the non-opioid medication (e.g., acetaminophen).  Generally, total acetaminophen dose should not exceed 4 grams/day (2 grams/day if hepatic dysfunction or HCV.) If desired, a combination product with 325 mg acetaminophen may be given as frequently as every 2 hours as needed, or two pills may be given every 4 hours.  However, in many cases it is better to separate out and schedule the desired dose of acetaminophen and utilize a single-agent opioid PRN.

Summary

• For PRN usage, consider prescribing the short-acting opioids listed above at intervals of every 2 hours with a maximum number of pills per day noted in outpatient prescriptions. 
• Closely monitor daily acetaminophen intake when combination products are used; consider scheduling a single-agent oral opioid as an alternative and scheduling the desired daily acetaminophen dose separately.
• Provide explicit patient/family counseling regarding safe and allowable dosing intervals.
• Review your institutional opioid policies – ask if there is a hospital policy or guidelines for oral opioid doing intervals; if not, such guidelines should be developed to help guide practice.

References:

1. Cleary JF. Pharmacologic management of cancer pain.  J Palliat Med. 2007; 10:1369-1394.
2. Physicians Desk Reference.  Available at:  http://pdr.net. Last accessed December 15, 2020.
3. Micromedex.  Available at:  http://www.micromedex.com.  Last accessed December 15, 2020
4. The Executive Committee of the Medical Staff. MD Anderson Cancer Pain Adult Guidelines 2020.  Available at https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-cancer-pain-web-algorithm.pdf.  Last accessed December 15, 2020.
5. Bruera E, Higginson I, von Gunten CF.  Textbook of Palliative Medicine and Supportive Care, 2^nd Edition. 2016; CRC Press:395-400 and 505-510.

Version History:  This Fast Fact was originally edited by David E Weissman MD.  2^nd Edition published July 2005; 3^rd Edition May 2015. 4^th edition published December 2020 and copy-edited in April 2023.
Conflicts of Interest: None to report