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Fast Fact and Concept #001; Once-Daily Oral Morphine Formulations

First Author: Drew A. Rosielle, MD

Background
In recent years two once-a-day long acting oral morphine formulations have been introduced in the U.S.: Kadian and Avinza. These formulations have unique properties which are important for their safe and effective use. To prevent confusion due to similar generic names, this Fast Fact will use trade-names for Kadian and Avinza, and “ER-morphine” to describe extended-release formulations which are usually dosed q12 hours (e.g. MS Contin).

Kadian capsules contain tiny granules of morphine layered with an inert polymer which releases morphine slowly within the gastrointestinal tract. Its tmax (time to maximum serum levels after consumption) of ~9.5 hours is the longest of any long-acting morphine preparation. For example, most ER-morphine products have a tmax of 2-3 hours. Despite this, some patients do seem to require q12 hour dosing, although for most, q24 hour dosing is adequate.

Avinza capsules contain tiny granules which are a mixture of immediate-release and delayed-release morphine such that therapeutic serum levels are achieved rapidly (~1/2 hour) and then maintained for 24 hours. In its steady-state there is essentially no peak-trough phenomenon. Avinza contains fumarate, limiting total daily doses to 1600mg to prevent fumaric acid toxicity. Alcohol, including alcohol-containing medications, cannot be taken with Avinza as this can lead to a rapid dissolution of the granules and release of morphine.

Clinical Use Head-to-head studies of Kadian and Avinza with ER-morphine confirm that they should be used as if they were bioequivalent (e.g. ER-morphine 45mg q12 hours = 90mg qday of Avinza). No studies have shown that either is safer, more effective, or has fewer side effects than ER-morphine. Theoretically, patients will have less end-of-dose failure (“rebound” pain due to serum morphine levels dropping prior to a patient’s next scheduled dose) with these longer-acting preparations, but this effect has not been shown to be clinically meaningful in trials. Because of their long duration of action, dose titration should not be more frequently than every 2 days.

Both Avinza and Kadian capsules can be opened and the granules sprinkled onto applesauce for patients who have trouble swallowing pills. Care should be given that the granules are not chewed, crushed, or dissolved. Kadian granules can also be suspended in water and administered down a large bore (≥16F) gastrostomy tube (the pellets become lodged in smaller tubes which include most nasogastric tubes). Neither of these dosing techniques is safe with ER-morphine or ER-oxycodone. It is not clear whether administering Avinza down a gastrostomy tube is safe; this has not been described in the literature, nor is it part of its manufacturer’s prescribing information. The average wholesale price of a month’s supply of 60mg daily of either formulation is approximately $200—roughly double that of generic ER-morphine.

Recommendations Avinza and Kadian are the only long-acting oral morphine products that can be used with individuals who cannot swallow pills (or for people with gastrostomy tubes in the case of Kadian). Their expense and lack of superiority to other long-acting oral opioid formulations limits recommending their use beyond this indication.

References
1. Broomhead A, Kerr R, Tester W, et al. Comparison of once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain. J Pain Symptom Manage. 1997;14:63-73.
2. Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage. 2002;23:278-291.
3. Collins SL, Faura CC, Moore A, McQuay HJ. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage. 1998;16:355-402.
4. Gourlay GK. Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine. Clin Pharmacokinet. 1998;35:173-190.
5. Jones R, Hale E, Talomsin L, Phillips R. Kapanol™ capsules. Pellet formulation provides alternative methods of administration of sustained-release morphine sulfate. Clin Drug Invest. 1996;12:88-93.
6. Portenoy RK, Sciberras A, Eliot L, et al. Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza™, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain. J Pain Symptom Mange. 2002;23:292-300.
7. Avinza Prescribing Information, Ligand Corporation. Available at: http://www.ligand.com/pdf/AVINZAPI.pdf
8. Kadian Prescribing Information, Alpharma Inc. Available at: http://www.kadian.com/pages/getfile.aspx?id=1C6197AB-8F83-43E7-B239-D4615293989B

Fast Facts are edited by David E. Weissman, MD; Palliative Care Center, Medical College of Wisconsin. For comments/questions write to: dweissma@mail.mcw.edu. The complete set of Fast Facts are available at EPERC: www.eperc.mcw.edu

Copyright/Referencing Information : Users are free to download and distribute Fast Facts for educational purposes only. Rosielle D. Fast Fact and Concept #166 Once daily oral morphine. October 2006. End-of-Life Physician Education Resource Center End-of-Life Palliative Education Resource Center www.eperc.mcw.edu.

Disclaimer: Fast Facts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

Creation Date: October 2006

Format: Self-Study Guide Books

Purpose: Self-Study Guide, Teaching

Educational Objective: Fast Fact

ACGME Competencies: Medical Knowledge, Patient Care

Keyword(s): Addiction, Chronic non-malignant pain, Controlled substance regulations, Pain, Pain assessment, Pain treatment

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