Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy Bulletin

AAFP CME Bulletin

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Disclosure Statements: It is the policy of the AAFP that all CME planning committee/faculty/authors/editors/staff disclose relationships with commercial entities upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest and, if identified, they are resolved prior to confirmation of participation. Only those participants who have no conflict of interest or who agree to an identified resolution process prior to their participation were involved in this CME activity.

Disclosures: Dr. Weiss, Dr. Melton, Ms. Gangel, Ms. Harden, and Mr. Carlson have returned disclosure forms indicating they have no financial interest in or affiliation with any commercial provider or providers of any commercial services discussed in this material.

This educational activity is supported through the AAFP’s in-cooperation-with agreement with the Collaborative for REMS Education (CO*RE), that received an independent educational grant from the ER/LA Opioid Analgesic REMS Program Companies (RPC). Please see www.er-la-opioidREMS.com(www.er-la-opioidREMS.com) for a list of the member companies.

This activity is designed to be fully compliant with the ER/LA Opioid Analgesic REMS education requirements issued by the U.S. Food and Drug Administration.

Toxicities and Drug Interactions

See Table 1(1 page PDF).

Sedation and Respiratory Depression

Most clinicians who prescribe opioid analgesics are aware that sedation occurs commonly with opioid use and that respiratory depression is the most serious adverse effect of opioid analgesics. Indeed, respiratory depression due to overdose was the likely cause in most of the approximately 16,000 opioid-related mortalities that occurred in the United States in 2010, the most recent year for which data are available.  The number of opioid-related overdose mortalities has nearly quadrupled since 1999.1  

With continued use of opioid analgesics, individuals develop tolerance to the sedative and respiratory depressive effects. However, concomitant use of drugs that act on the central nervous system--including alcohol, sedative-hypnotics, tricyclic antidepressants and, in particular, benzodiazepines2–can potentiate the sedative and respiratory depressive effects even in individuals who might otherwise be considered opioid tolerant. A similar effect can be seen occasionally when opioid analgesics are used concomitantly with, or within 2 weeks of discontinuing, monoamine oxidase inhibitors.3  Avoiding these substances while taking opioid analgesics will minimize the risk of opioid-induced sedation and respiratory depression.


Most clinicians are also aware that constipation is an adverse effect experienced by individuals using short- or long-acting opioid analgesics. The reported incidence of problems related to constipation in users of chronic opioid analgesics is shown to be as high as 29% in large population-based studies.4 Among the extended-release and long-acting (ER/LA) opioid analgesics, one older study found that the rate of constipation is higher with sustained-release morphine than with transdermal fentanyl.5 A more recent study that did not include morphine found the constipation rate (defined as no stools for more than 72 hours) was similar with transdermal fentanyl (22%)5 and transdermal buprenorphine (21%), but substantially lower, at 2%, with extended-release hydromorphone (Exalgo).6  

Opioid-induced constipation is typically managed by increasing intake of fluids and dietary fiber, plus use of both stool softeners and stimulant laxatives; stool softeners alone are often insufficient.7  Increasingly, however, the emphasis is on prevention of constipation rather than management, with institution of stool softeners and stimulant laxatives when opioid therapy is started, rather than after constipation develops.8

Decreased Effectiveness of Diuretics

Opioid analgesics induce release of antidiuretic hormone (ADH), which counteracts the effect of diuretic drugs. Although not often considered by clinicians, this effect may be important for patients with medical conditions that require diuretic therapy, such as heart failure.9

QT-Interval Prolongation

Methadone and high doses of transdermal buprenorphine (greater than 20 mcg/hr) are known to prolong the electrocardiographic QT interval, which in turn poses an increased risk of torsades de pointes, or torsades, ventricular tachycardia. Although either of these ER/LA drugs has the potential to induce torsades on its own, particularly at higher doses, the risk of torsades may be even greater when these opioid analgesics are taken in combination with other drugs that prolong the QT interval. Commonly prescribed drugs that prolong the QT interval and that have the strongest evidence for inducing torsades include azithromycin, clarithromycin, citalopram, and escitalopram.10  Clinicians can quickly identify drugs known to cause QT prolongation at http://www.crediblemeds.org(www.crediblemeds.org).

Changes in Opioid Levels With Cytochrome Enzyme Inhibitors

Several ER/LA opioid analgesics are metabolized in the liver by cytochrome enzyme systems. The levels of these opioid analgesics can increase when they are taken simultaneously with drugs that inhibit those cytochrome enzymes. 

In particular, methadone levels can increase when taken simultaneously with drugs that inhibit cytochrome P450 enzyme systems. Although many drugs inhibit cytochrome P450, some of the more commonly prescribed drugs with this effect include antidepressants (including bupropion, fluoxetine, and paroxetine), cimetidine, acyclovir, duloxetine (Cymbalta), fluoroquinolone antibiotics, ketoconazole, several protease inhibitors (indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir]), proton pump inhibitors, verapamil, and diltiazem.11 Buprenorphine, fentanyl, and oxycodone levels can increase when taken simultaneously with drugs that inhibit cytochrome P3A4 (a subtype of the P450 system). Commonly prescribed drugs that inhibit P3A4 inhibitors include cimetidine, diltiazem, protease inhibitors, fluconazole, ketoconazole, and verapamil. Grapefruit juice is also a P3A4 inhibitor.11

Conversely, the levels of several opioid analgesics can decrease when they are taken with drugs that stimulate cytochrome enzymes involved in opioid metabolism, both cytochrome P450 and subtype P3A4. Levels of buprenorphine, fentanyl, methadone, and oxycodone may decrease when patients simultaneously use cytochrome inducers that include carbamazepine, isoniazid, tobacco, rifampin, and St. John’s wort (Hypericum perforatum).11

Prescribing Considerations for Specific Extended-Release/Long-Acting Opioid Analgesics


Because the sedative and respiratory depressive effects of ER/LA opioid analgesics are so potent, some ER/LA formulations should not be used by individuals who are intolerant to these effects. Tolerance typically develops after taking an opioid for 1 week or more at a morphine-equivalent dose of 60 mg/day.

Other ER/LA agents can be used in patients who are intolerant, but only at low doses. Still others should not be used, regardless of dose, in patients who have never received opioid analgesics.

Transdermal fentanyl and extended-release hydromorphone are the two ER/LA opioid analgesics that should not be used by patients who are intolerant. These drugs, regardless of the dose, are specifically contraindicated in such patients.3 For other ER/LA opioid analgesics, although not specifically contraindicated in patients who are intolerant, there are limits to the strength of individual doses and total daily doses. Notably, those strengths and doses can vary with different brands and formulations of the same drug. For example, when prescribing extended-release morphine under the brand names of MS Contin and Kadian, the patient must be opioid tolerant to receive doses of 100 mg or more.3  For the brand name Avinza extended-release morphine, the corresponding dose is 90 mg.3 Clinicians should check the dosing and tolerance requirements for the various ER/LA opioid analgesics before prescribing (see Table 2(4 page PDF)).

Finally, two oral ER/LA agents should not be used as a first opioid (ie, by patients who have never taken opioid analgesics), regardless of the dose. These two agents are extended-release morphine under the brand names of Kadian and MS Contin.3

Concerns With Oral Administration

Oral ER/LA opioid analgesics must be swallowed whole. Breaking, crushing, or chewing these pills is dangerous because doing so can cause a rapid release of the opioid into the circulation, resulting in respiratory depression and death.

There is, however, an exception for patients who are unable to swallow ER/LA opioid pills. For these patients, there are three ER/LA formulations available in capsule formulation that can be opened and the contents either administered through a feeding tube or sprinkled onto food (applesauce is recommended). If taken with applesauce, it is important to swallow without chewing to avoid breaking the sprinkled pellets, and the mouth should be rinsed with water after ingesting the applesauce to assure that all contents have been swallowed.12 The three ER/LA opioid analgesics that can be administered in this way are morphine sulfate under the brand names of Avinza, Embeda, and Kadian.3

Concerns With Transdermal Administration

Fentanyl and buprenorphine are available in transdermal formulations. When these transdermal ER/LA opioid analgesics are prescribed, patients should be made aware of several important safety concerns.

First, patches should never be cut or torn before use. Doing so could lead to rapid release of opioid through the skin into the circulation with resultant overdose.

Second, exposure to heat can increase release and absorption of opioid analgesics from transdermal formulations, resulting in inadvertent overdose. Heat exposure can involve external heat, such as occurs in saunas, hot tubs, or hot baths; with use of heat lamps, electric blankets, or heating pads; or even with prolonged sun exposure. Heat exposure with increased opioid absorption also can occur during strenuous exercise or with a fever. Febrile patients using transdermal opioid analgesics should be monitored for signs and symptoms of increased opioid effect.13-16

Third, caution should be exercised in caring for the application site. For adults, the patch should be applied on the chest, side of the waist, or upper arm, ideally in a place without hair. If hair is unavoidable, it should be clipped as close to the skin as possible but not shaved because shaving-induced trauma to the skin can result in increased drug absorption. The application site should be kept clean by washing with water only; no other substances should be used, including soaps, lotions, oils, or alcohol. The site of application should be rotated. That is, the same site should not be used for two consecutive applications, and the used patch should always be removed before, not after, applying a new one.16

Concerns About Pharmacokinetics and Pharmacodynamics

Finally, the basic pharmacokinetics and pharmacodynamics of opioid analgesics are important considerations. Indeed, it is often the failure to consider these factors that can result in unintentional overdose. For example, because opioids undergo biotransformation in the liver, impaired hepatic function may result in slow clearance and increased opioid levels, particularly with long-acting agents. Some opioid analgesics, such as morphine and hydromorphone, undergo renal clearance so impaired kidney function, even the common age-associated decline in kidney function, might result in accumulation of these drugs. Older adults may be particularly sensitive to opioid effects, such as experiencing increased sedation even when taking opioid analgesics at recommended doses. Thus, when prescribing opioid analgesics, clinicians should be familiar with the specific modes of metabolism and excretion for the drug being considered, and consider the needs and comorbidities of individual patients.

Copyright © 2013. American Academy of Family Physicians. All rights reserved. Reuse of this material is prohibited without the express written consent of the AAFP. Please contact copyrights@aafp.org.


1.  Centers for Disease Control and Prevention. CDC Newsroom. Opioids drive continued increase in drug overdose deaths. Feb 20, 2013. Available at http://www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.html(www.cdc.gov).

2.  Onali P, Dedonia S, Olians MC. Direct agonist activity of tricyclic antidepressants at distinct opioid receptor subtypes. J Pharmacol Exp Ther. 2010;332(1):256-265.

3.  US Food and Drug Administration. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. Available at http://www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf(www.fda.gov).

4.  Takemoto ML, Fernandes RA, Almeida GR, et al. Health care resource use and costs in opioid-treated patients with and without constipation in Brazil. Value Health. 2011;14(5 Suppl 1):S78-81.

5.  Allan L, Hays H, Jensen NH, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001;322(7295):1154-1158.

6.  Wirz S, Wittmann M, Schenk M, et al. Gastrointestinal symptoms under opioid therapy: a prospective comparison of oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine. Eur J Pain. 2009;13(7):737-743.

7.  Walters JB, Montagnini M. Current concepts in the management of opioid-induced constipation. J Opioid Manag. 2010;6(6):435-444.

8.  Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2010;8(9):1046-1086.

9.  Vuong C, Van Uum SH, O’Dell LE, et al. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31(1):98-132.

10.  Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce torsades de pointes. Available at http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm(www.azcert.org).

11.  Indiana University School of Medicine, Division of Clinical Pharmacology. P450 drug interaction table: abbreviated “clinically relevant” table. Available at http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx(medicine.iupui.edu).

12.  US Food and Drug Administration. Medication guides for ER/LA opioids. Available at http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM312000.pdf(www.fda.gov).

13.  In brief: heat and transdermal fentanyl. Med Lett Drugs Ther. 2009;51(1318):64. 

14.  Sindali K, Sherry K, Sen S, et al. Life-threatening coma and full-thickness sunburn in a patient treated with transdermal fentanyl patches. J Med Case Rep. 2012;6(1):220.

15.  US Food and Drug Administration. Medication guide: Butrans (buprenorphine) Transdermal System, CIII. Available at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM219146.pdf(www.fda.gov).

16.  US Food and Drug Administration. Patient information: Duragesic (Fentanyl transdermal system.) Available at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm125846.pdf(www.fda.gov).

Websites accessed May 2013.