Caution Urged in Prescribing Long-Acting Opioids


"Avoid long-acting opioids whenever possible," says a physician who linked a higher risk of mortality to long-acting opioids used for chronic pain.

A new study shows that chronic pain patients who are prescribed long-acting opioids have an increased risk of death as compared to patients who are prescribed other medications used to control pain.

The study, published in the June 14 issue of JAMA, found that patients being treated for chronic pain with long-acting opioids had a 64% increased risk of death for any reason as compared to patients prescribed an analgesic anticonvulsant or a low-dose cyclic antidepressant. They also found a 65% increased risk of cardiovascular disease in the study cohort.

“More than two-thirds of the excess deaths were due to causes other than unintentional overdose. Of these, more than one-half were cardiovascular deaths,” the researchers wrote.  [[{"type":"media","view_mode":"media_crop","fid":"49660","attributes":{"alt":"(©Burlingham/","class":"media-image media-image-right","id":"media_crop_6164760009191","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6015","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"(©Burlingham/","typeof":"foaf:Image"}}]]

The study is based on a 12-year analysis of prescriptions for Tennessee Medicaid patients who were treated for moderate to severe chronic pain with either long-acting opioids or non-opioid medications, such as an analgesic anticonvulsant or a low-dose cyclic antidepressant. The patients were being treated for back pain (75%), other musculoskeletal pain (63%) and abdominal pain (18%).

The analysis included 22,912 new prescriptions for long-acting opioids and an equal number of prescriptions in the control group. Most patients, 60%, were women with a mean age of 48 years.

Patients in the study group were prescribed sustained release morphine, controlled release oxycodone, transdermal fentanyl and methadone. Patients in the control group were prescribed anticonvulsants indicated for chronic pain (gabapentin, pregabalin, carbamazepine) or low-dose cyclic antidepressants.

Long-acting opioids have been widely recommended for non-cancer pain. Gabapentin and pregabalin are indicated for neuropathic pain and fibromyalgia while low-dose cyclic antidepressants are indicated for chronic back pain, neuropathic pain and fibromyalgia.

Led by Wayne A. Ray, Ph.D., of Vanderbilt University School of Medicine in Tennessee, researchers sought to answer three questions:  (1) Did total mortality differ between the two groups? (2) What was the relative risk of deaths outside of the hospital? (3) Were there differences in the risk of death?

The findings as reported in JAMA:

-  Total mortality:  Researchers followed patients in the long-acting opioid group for an average of 176 days in which 185 deaths were reported. By comparison, the control group was followed for an average of 128 days in which 87 deaths were reported. The hazard ratio for death from any cause was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths per 10,000 person years (95%CI, 28.2-120.7).

-  Out-of-hospital deaths:  154 in the long-acting opioids group and 60 deaths in the control group (hazard ratio, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years.

-  For out-of-hospital deaths, other than unintentional overdose (120 long-acting opioid, 53 control deaths), the hazard ratio was 1.72 (95%CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95%CI, 15.7-91.4) per 10,000 person-years.

-  The hazard ratio for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95%CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95%CI, 4.6-65.3) per 10 000 person-years. The increased risk of cardiovascular deaths could be related to adverse respiratory effects of long-acting opioids, the researchers wrote.

-  The hazard ratio during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95%CI, 2.27-7.63) with a risk difference of 200 excess deaths (95%CI, 80-420) per 10,000 person-years.

-  For low doses (≤60mg of morphine or its equivalent) the hazard ratio was 1.54 (95%CI, 1.01-2.34) and the risk difference was 51 (95%CI, 1-126) per 10,000 person-years. For high doses (>60 mg morphine or its equivalent) the HR was 1.94 (95% CI, 1.40-2.70) and the risk difference was 111 (95%CI, 47-200) per 10,000 person-years.

More than 96% of patients in the study cohort filled a prescription for a short-acting opioid in the prior year, and 68% had a current prescription for these drugs at the beginning of follow-up.

These findings should be considered when assessing the pros and cons of potential treatments for patients, the authors wrote. ““Nevertheless, for some individual patients, the therapeutic benefits from long-acting opioid therapy may outweigh the modest increase in mortality risk. As the CDC guidelines indicate, all prescribing decisions must be based on an evaluation of the source and severity of the patient’s pain and a discussion of the known risks and realistic benefits of opioid therapy,” they wrote.

The researchers caution against prescribing long-term acting opioids.

"The take-home message for patients with the kinds of pain we studied is to avoid long-acting opioids whenever possible. This is consistent with recent Centers for Disease Control and Prevention guidelines. This advice is particularly important for patients with high risk for cardiovascular disease, such as those with diabetes or a prior heart attack," Dr. Ray said in news release issued by Vanderbilt University.




Ray WA, Chung CP, Murray KT, Hall K, Stein M. “Prescription of Long-Acting Opioids and Mortality in Patients with Noncancer Pain.” JAMA. 2016; 315:2415-2423. doi:10.1001/jama.2016.7789

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