Primary Literature Review: Effect of Opioid vs Non-opioid Medications on Pain-Related Function in Patients with Chronic Back Pain or Hip or Knee Osteoarthritis Pain – The SPACE Randomized Clinical Trial

Logane Kiehnau, Pharm.D., Allina Health

Background: Despite an increasing number of opioid-related deaths and limited efficacy, opioids have become a common treatment for musculoskeletal pain. Opioid prescribing for treating chronic pain is discouraged by many institutions given the high risk/benefit ratio, and there is evidence that non-opioid alternatives can be equally effective.

Objective:  This randomized clinical trial aimed to compare opioid therapy vs non-opioid therapy over 12 months for primary care patients suffering from chronic back pain or hip or knee osteoarthritis pain of at least moderate intensity despite analgesic therapy. The hypothesis was that opioids, compared with non-opioids, would result in better pain management and more adverse events.

Design:  The primacy outcome was pain-related function. In order to maintain the most realistic approach, a variety of patients from primary care (total of 240) were included. Therapies were delivered at varying doses and with flexibility in medication selection based on a stepwise methodology detailed below. All patients were allowed to seek out non-pharmacological options as well.  Treatments were adjusted within treatment groups according to participant response. Participants had to be suffering from chronic pain defined as a duration of 6 months or greater. Patients were recruited from 62 Minneapolis Veteran’s Affairs (VA) primary care clinicians from June 2013 to December 2015.

Patients in the opioid group started with immediate release (IR) opioids. Step one was morphine IR, hydrocodone/acetaminophen, and oxycodone IR. Step 2 was sustained action (SA) morphine and oxycodone SA. Step three was transdermal fentanyl. Single opioid regimens were preferred but patients were allowed to use combination of SA and IR opioids if necessary. Opioids were not titrated to doses greater than 100 morphine equivalents (ME) mg. Lower doses were used if adequate pain relief was achieved.

In the non-opioid group, the first step was acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Step two included nortriptyline, amitriptyline, gabapentin, topical capsaicin or lidocaine. The third step involved pregabalin, tramadol, and duloxetine.

Results: Of the 265 enrolled patients, 25 withdrew before to randomization mostly due to concerns with substance abuse, or lack of interest in the study.  As a result, 240 were randomized (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. In total, 120 patients were enrolled in each arm of the study. There was no reported difference in pain-related function between the two groups over 12 months ( P = 0.58). Pain intensity was significantly better in non-opioid group (P = 0.03). The most common treatment in the non-opioid group was non steroidal antiinflammatory agents. Health related quality of life was not significantly different between the groups. The opioid group experienced significantly more medication related symptoms (overall P = 0.03). There was no difference in adverse outcomes or misuse between the groups.

Conclusion: Among patients with chronic back pain or hip or knee osteoarthritis pain, there was no significant difference in pain-related function between treatments with opioids compared with non-opioids over 12 months.

Key Point: Opioids are not more effective than non-opioid pain medications when treating chronic back pain or hip and knee osteoarthritis pain, but do pose significantly higher risks.


Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs non-opioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain. The SPACE Randomized Clinical Trial. JAMA. 2018;319(9):872–882. doi:10.1001/jama.2018.0899