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News Author: Megan Brooks

CME Author: Désirée Lie, MD, MSEd

Results of a new study challenge the conventional notion that the safety profiles of different opioids are generally interchangeable, but instead show different risk profiles for the 5 most common opioids used for noncancer pain in older adults.

Perhaps of greatest concern, the researchers say, is the apparent increased risk for cardiovascular events observed after 6 months in codeine users and an increased risk for all-cause mortality after only 30 days in codeine and oxycodone users.

The study appears in the December 13/27 issue of Archives of Internal Medicine.

"This study's findings do not agree with a commonly held belief that all opioids are associated with similar risk," Daniel H. Solomon, MD, MPH, of Brigham and Women's Hospital, Boston, Massachusetts, and colleagues write.

The coauthors of an accompanying commentary say the study also "brings to light important data on serious safety issues related to opioid analgesic use in elderly patients." They call for a second-look at the widespread use of codeine in older patients.

Concerns of the Heart

On November 19, the US Food and Drug Administration (FDA) removed propoxyphene, sold under brand namesDarvon and Darvocet by Xanodyne Pharmaceuticals, from the US market, including generic and propoxyphene-containing products, after new data showed an increased risk for potentially serious, even fatal heart rhythm abnormalities.

In the current study, Dr. Solomon and colleagues compared safety-related risks of propoxyphene and 4 other opioids at equianalgesic dosages prescribed for noncancer pain in elderly Medicare patients. They propensity-matched 6275 subjects in each of the 5 opioid groups: codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride.

The use of propensity score–matched cohorts, the researchers say, "provides for well-balanced study cohorts" and is a key strength of the current study.

The researchers found that the risk for cardiovascular events was similar across opioid groups 30 days after initiation, but after 180 days of exposure it was elevated for codeine (rate ratio [RR], 1.62; 95% confidence interval [CI], 1.27 – 2.06), compared with the reference hydrocodone.

Similarly, propoxyphene showed a nonsignificant increase in cardiovascular toxicity at 30 days (RR, 1.17; 95% CI, 0.85 – 1.62), which persisted at 180 days (RR, 1.25; 95% CI, 1.00 – 1.57).

"Our analyses agree with the FDA action regarding [propoxyphene]," Dr. Solomon told Medscape Medical News. "However, our analyses also suggest that other opioids may be associated with cardiovascular toxicity." Although the FDA action was "silent" on other opioids, he added, they may "deserve similar attention."

All-cause mortality was also significantly elevated after 30 days of codeine and oxycodone use compared with hydrocodone use.

Table. All-Cause Mortality After 30 Days of Use

CI = confidence interval

A greater than 2-fold increased risk for all-cause mortality was also evident after 180 days for codeine and oxycodone. This may relate to the noted increase in cardiovascular events, at least with codeine, or other unmeasured confounding factors, the investigators say.

The study team notes that the "substantial" risks uncovered in this analysis "were not explained by the dosage being prescribed and did not vary across a range of sensitivity analyses."

They also noted a reduced risk for fracture after 30 days of exposure to tramadol (RR, 0.21; 95% CI, 0.16 – 0.28) and propoxyphene (RR, 0.54; 95% CI, 0.44 – 0.66), compared with hydrocodone.

The risk for gastrointestinal adverse effects did not differ across opioid groups.

Implications 'Significant'

In their commentary, William C. Becker, MD, and Patrick G. O'Connor, MD, MPH, of Yale University School of Medicine, New Haven, Connecticut, say there is a need to "reexamine the widespread use of codeine," which is often used as a middle-ground analgesic between nonopioids and more potent opioids.

"The untested but widespread assumption that codeine is safer from an addiction standpoint because of its lower potency may need to give way to these data demonstrating increased risk of cardiovascular events and all-cause mortality," they write.

The clinicians caution, however, that there really is no known unique effect of codeine that makes the increased cardiovascular risk biologically plausible. "We don't typically relate opioids as a class and codeine specifically to increased cardiovascular risk," Dr. O'Connor noted in an interview with Medscape Medical News.

"Certain opioids have been shown to cause some cardiovascular effects, such as prolonged QT interval, and propoxyphene was recently taken off the market for this reason," he explained.

Clearly, further research is needed, Dr. O'Connor said; in the meantime, he advised clinicians to use opioids wisely in elderly people. "If you do use them, you need to be sure they are indicated and then patients need to be monitored closely, and they should be used for the shortest duration as possible."

The study was supported by the Agency for Healthcare Research and Quality, US Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions about Effectiveness (DECIDE) program. Dr. Solomon discloses serving as an unpaid member of a Celecoxib Trial Executive Committee sponsored by Pfizer and also as an unpaid member of the Data Safety Monitoring Board for an analgesic trial sponsored by Pfizer. Dr. Becker and Dr. O'Connor have disclosed no relevant financial relationships.

Clinical Context

Despite warnings about the dangers of opioids, especially in older adults, there has been a 50% to 100% increase in opioid use in recent years. There is a commonly held belief that different opioids are associated with similar adverse effects, but little is known about these differences across types of opioids.

This is an observational study using healthcare utilization data for Medicare beneficiaries to examine the adverse events profile of 5 different opioids prescribed for nonmalignant pain in older adults.

Study Highlights

• Included were Medicare beneficiaries from 2 US states who qualified for pharmacy assistance between 1996 and 2005 who had filled at least 1 prescription for an opioid for nonmalignant pain and who demonstrated consistent healthcare system use in the past year.
• Excluded were those with a cancer diagnosis within 1 year, those who had filled a prescription for a nonsteroidal anti-inflammatory drug within 1 year, or those who had evidence of hospice or nursing home care within 1 year.
• Participants were matched for 5 common opioids used for nonmalignant pain: hydrocodone bitartrate, codeine phosphate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride.
• Healthcare utilization data, including diagnosis and procedure codes and claims data, were used to examine the association between opioid use and adverse events.
• A propensity score was constructed from baseline covariates based on claims data.
• Adverse events of interest included cardiovascular events, all-cause mortality, fractures, gastrointestinal tract bleeding or bowel obstruction, and any hospitalization related to the adverse event.
• Data on opioid exposure included drug dosage, drug name, and days of supply.
• Participants were defined as being exposed to opioids from the day after dispensing through 7 days after the last available dose.
• Incidence RRs were calculated for follow-up of 30 and 180 days for each adverse outcome.
• 541,867 beneficiaries with drug benefits who had evidence of any opioid use during the study period were considered, and 143,482 met inclusion criteria for analysis.
• 6275 participants were matched in each of the 5 opioid groups.
• The groups had a mean age of 79 years, 80.9% were women, and 91.0% were white.
• The mean number of comorbid conditions was 1.7.
• The mean number of hospital stays was slightly higher for oxycodone users vs other opioid users.
• The median supply of opioids was for 2 to 6 weeks, and some participants received opioids for many months.
• Hydrocodone was used as the reference exposure, and RRs calculated across all opioids for the 30- and 180-day analyses.
• The risk for cardiovascular adverse events was similar across all opioids for the 30-day analysis.
• However, in the 180-day analysis, the risk was elevated for codeine use (RR, 1.62; 95% CI, 1.27 - 2.06).
• Risk for all-cause mortality was elevated only after 30 days for oxycodone users (RR, 2.43; 95% CI, 1.47 - 4.00) and codeine users (RR, 2.05; 95% CI, 1.22 - 3.45).
• The risk for fracture was lower in the first 30 days for tramadol (RR, 0.21; 95% CI, 0.16 - 0.28) and propoxyphene users (RR, 0.54; 95% CI, 0.44 - 0.66).
• Gastrointestinal tract safety did not differ across the opioid groups for the different intervals.
• There was no gradient of risk across dosages of opioids.
• In further subanalyses, no differences were detected by other variables.
• The authors concluded that the opioids examined were not similar for adverse effects, increased mortality risk was associated with oxycodone and codeine use, and fracture risk was reduced for tramadol and propoxyphene use.
• They recommended that consideration be given to these differential adverse effects of opioids when prescribing them.

Clinical Implications

• In older persons, codeine use after 30 days is associated with increased cardiovascular morbidity, and use of oxycodone and codeine after 30 days is associated with increased all-cause mortality risk.
• In older persons, use of tramadol and propoxyphene for 30 days is associated with reduced fracture risk vs hydrocodone use.

CME Test

A 79-year-old woman requires an opioid for nonmalignant pain control. Which of the following opioids should be avoided because of an increased risk for cardiovascular morbidity and all-cause mortality within the first 30 days of use?

1.Tramadol
2.Codeine

3.Propoxyphene

4.Hydrocodone

In the patient from Question #1, which of the following opioids should be considered first if fracture risk reduction is a primary goal?

1.Hydrocodone

2.Tramadol

3.Codeine

4.Oxycodone

解答：

1.A 79-year-old woman requires an opioid for nonmalignant pain control. Which of the following opioids should be avoided because of an increased risk for cardiovascular morbidity and all-cause mortality within the first 30 days of use?
Answer: Codeine 
In this healthcare utilization study by Solomon and colleagues, the risk for cardiovascular adverse events was similar across all opioids for the 30-day analysis. However, in the 180-day analysis, the risk was elevated for codeine use (RR, 1.62; 95% CI, 1.27 - 2.06). Risk for all-cause mortality was elevated only after 30 days for oxycodone users (RR, 2.43; 95% CI, 1.47 - 4.00) and codeine users (RR, 2.05; 95% CI, 1.22 - 3.45).

2.In the patient from Question #1, which of the following opioids should be considered first if fracture risk reduction is a primary goal?
Answer: Tramadol 
The risk for fracture was lower in the first 30 days for tramadol (RR, 0.21; 95% CI, 0.16 - 0.28) and propoxyphene users (RR, 0.54; 95% CI, 0.44 - 0.66). Gastrointestinal tract safety did not differ across the opioid groups for the different intervals.