What Is the Maximum Safe Dose of Opioids?

Charts and tables are readily available from multiple sources that attempt to correlate certain doses of oxycodone to other opioid narcotics. “Maximum safe dose” is patient-specific and dependent on current and previous opioid exposure, as well as on whether the patient is using such medications chronically.

When using single-agent opioid preparations (noncombination products), there is no maximum dose when appropriately titrated. The dose should be slowly escalated until adequate pain relief is seen or side effects preclude further escalation.[1,2] When using combination opioid products containing acetaminophen, aspirin, or ibuprofen (such as Percocet, Percodan, and Combunox), the dose limiting toxicity is generally attributable to acetaminophen, aspirin, or ibuprofen respectively. The maximum amount of acetaminophen should be no more than 4 g/day considering all combined acetaminophen in 24 hours. Using more than 4 g/day of acetaminophen can cause acute hepatic failure.[3] Aspirin and ibuprofen have their own inherent toxicities, including but not limited to possible gastrointestinal bleeding, kidney dysfunction, hypertension, etc.

When switching between different opioid preparations, a narcotic analgesic conversion calculator or equi-analgesic table may be used as a guide. A conversion calculator is available at Globalrph.com.[4] Equi-analgesic tables are readily available from multiple sources, including NovaPain[5] and the American Pain Society.[6]

However, many equi-analgesic tables provide different information, depending on the source and the manner in which equivalency was calculated. There are drawbacks to these equivalency tables, in part because many do not consider a recommended 15% dose reduction for opioid cross-tolerance.[1,2,7] Some resources actually recommend that a dose reduction of up to 50% is appropriate when switching from one opioid to an alternative.[7] Another common problem with conversion tables is that many are based on single doses rather than steady-state concentrations, so certain data will not apply to chronic opioid users.

Most opioid conversion tables fail to elucidate the potential problems when converting a patient to methadone from another opioid, or from another opioid to methadone. Methadone conversion requires careful consideration because of its long half-life and unusual pharmacokinetic profile compared with most other opioids. In addition, converting methadone to morphine, for example, is not bidirectional.[8,9] Consider that the half-life of methadone is 15-30 hours. When switching from an established dose of methadone to another opioid, we must consider that measurable methadone serum levels will be around for days. Therefore, when placing a patient on a new opioid, even with the discontinuation of methadone, both drugs are now readily available to the mu receptors, increasing the overall risk for opioid toxicity.[10] When newly converting a patient on methadone from another opioid, the equivalent dose conversion changes in a triphasic pattern[10]: For example, the ratio of morphine (or a morphine equivalent)

< 90 mg/day to methadone is 4:1; the ratio for morphine 90 mg/day - 300 mg/day is 8:1; and for morphine >

300 mg/day, the ratio is 12:1.[8,10]

Dosing opioids requires the clinician to account for a patient’s opioid history, physical tolerance, consideration of agents in mixed preparations, cross-tolerance, and conversion irregularities. It is always best to use caution when initiating and increasing opioid regimens.

The author wishes to acknowledge Michael S. Fox, student pharmacist, Albany College of Pharmacy, Albany, New York.

Jeffrey Fudin, BS, PharmD
Response from Jeffrey Fudin, BS, PharmD
Adjunct Associate Professor, Albany College of Pharmacy/Union University, Albany, New York; Clinical Pharmacy Specialist, Stratten VA Medical Center, Albany, New York


  1. National Guideline Clearinghouse. Pain Management Guideline. Available at http://www.guideline.gov/summary/summary.aspx?doc_id=9744&nbr=005217&string=opioid Accessed February 7, 2008.
  2. Purdue Pharma LP. Package insert: OxyContin. Available at http://www.pharma.com/PI/Prescription/Oxycontin.pdf Accessed February 7, 2008.
  3. Acetaminophen. Drug Products. [database on the Internet] Clinical Pharmacology. Tampa, Florida: Gold Standard. 2007.
  4. GlobalRPH. Narcotic Analgesic Converter. Available at http://www.globalrph.com/narcoticonv.htm Accessed February 7, 2008.
  5. NovaPain. Opioid Dosing Guidelines. Available at http://www.paindr.com/Perkins%20opioid%20dosing.pdf Accessed February 7, 2008.
  6. American Pain Society. Resources for the Clinician. Available at http://www.ampainsoc.org/links/clinician.htm Accessed February 7, 2008.
  7. Derby S, Chin J, Portenoy RK. Systemic opioid therapy for chronic cancer pain: practical guidelines for converting drugs and routes of administration. CNS Drugs. 1998;9:99-109.
  8. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer. 2001;9:73-83. Abstract
  9. Wolff K, Sanderson M, Hay AWM, Raistrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem. 1991;37:205-209. Abstract
  10. Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A, De Conno F. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998;16:3216-3221.

Provided by ArmMed Media