Introduction   There are dozens of opioid combination products available in a range of tablet strengths and liquids.  They are typically prescribed for moderate pain that is episodic (e.g., breakthrough pain) on a PRN basis.  These products contain either acetaminophen, aspirin or ibuprofen, with an opioid:  codeine (e.g., Tylenol #2-4), hydrocodone (e.g., Lorcet, Lortab, Vicodin, Vicoprofen), and oxycodone (e.g. Percocet, Percodan, Tylox, Roxicet). Other formulations also may contain caffeine and/or a barbiturate.  This Fast Fact will review information for rationally prescribing opioid combination products. 

Intrinsic analgesic potency Milligram for milligram, oxycodone and hydrocodone are the most potent opioids in this group; they are roughly equianalgesic to each other.  Codeine is less potent. Propoxyphene used to be the least potent opioid of the group, but due to metabolite safety concerns, it is no longer available in the US market.    

Toxicity The dose-limiting property of all the combination products is the aspirin, acetaminophen, or ibuprofen, not the opioid (see below).  Patients receiving any of the four opioids may experience classic opioid side effects: nausea, constipation, pruritus, or sedation, along with the potential for tolerance and physical dependence with chronic use.  Differences in side effect severity among the different opioids is largely idiosyncratic.  While many codeine-based products tend to be class 3 (as opposed to class 2) controlled substances, this does not mean that codeine-based combination products are safer. In fact, codeine is associated with higher toxicity (more emetogenic, etc) from its metabolites when compared to oxycodone and hydrocodone.   

Cost Generic products are readily available and typically make these products inexpensive. 

Range of available doses 

• Codeine products: 15-60 mg codeine/tablet
• Oxycodone or hydrocodone: 2.5–10 mg opioid/tablet
• Acetaminophen doses range from 325–750 mg/tablet

Recommendations There is mounting concern about combination opioids due to high levels of organ damage brought on by supratherapeutic dosing of the non-opioid product (e.g., acetaminophen, ibuprofen) (1). Many patients are not aware of all the acetaminophen they are ingesting via various over the counter (OTC) products. Therefore, clinicians should consider alternatives to a combination product. For example, instead of prescribing oxycodone/acetaminophen as an as needed analgesic, a safer option may be to provide oxycodone IR as the as needed analgesic and then encourage the patient to take acetaminophen separately as a scheduled medication (e.g., 975 mg by mouth three times a day).  If clinicians choose to prescribe a combination product, below are recommended principles. 

• Prescribe generic products whenever possible.
• Prescribe only one combination product at any given time.  Avoid writing orders that include multiple products (e.g. “X” for mild pain, “Y” for moderate pain, etc).
• Based on their limited half-lives, codeine, oxycodone and hydrocodone will significantly wear off after 4 hours, therefore end of dose failure issues are to be expected when dosing combination products at q6 hours or greater as needed (see Fast Fact #18) (2).
• Inform patients of their individualized daily limit for each non-opioid medication. For example, for most patients, they should not exceed 3 gms of acetaminophen a day.  If a patient is on an ibuprofen-based product, make sure that they avoid concomitant use of other NSAIDs as well.
• Pay close attention to the total daily dose of acetaminophen/aspirin/ibuprofen consumed.
• Note: the dose of acetaminophen per tablet in combination products can range from 325-750 mg.  Thus, with a recommended limit of < 3 grams per day, this equals 9 tablets @ 325 mg or 4 tablets @ 750 mg tablet.  Patients with renal or liver dysfunction are at higher risk for adverse effects (3).
• Ask patients to review all OTC medications they are taking. For example, cold syrups, brand names of acetaminophen or ibuprofen, other NSAIDs. Account for them in their daily dosing calculations. 
• When in doubt, collaborate with a clinical pharmacist.

References 

1. Harris G.  Ban is advised on 2 top pills for pain relief. The New York Times June 30, 2009.
2. AGS Panel on Chronic Pain in Older Persons. The Management of chronic pain in older persons. J Am Geriatric Soc. 1998; 46:635-651.
3. Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Publication No. 94-0592. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, 1994.
4. MB Max, R Payne, WT Edwards, et al.  Principles of analgesic use in the treatment of acute pain and cancer pain. 4th Edition.  Glenview, IL: American Pain Society; 1999.

Version History:  This Fast Fact was originally edited by David E Weissman MD.   2nd Edition published July 2006; 3rd Edition May 2015; 4th Edition in May 2021; reviewed and updated again in December 2025.
Conflicts of Interest: None to report.