By David Fiore, MD

Professor of Family Medicine, University of Nevada, Reno

Dr. Fiore reports no financial relationships relevant to this field of study.

SYNOPSIS: In this small study, non-opioid therapy (primarily acetaminophen and nonsteroidal anti-inflammatory drugs) was as effective as opioid therapy for chronic musculoskeletal pain with fewer medication-related side effects.

SOURCE: Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs. nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. JAMA 2018;319:872-882.

Chronic pain is a fact of life for many adults. In the early 2000s, in response to concerns that chronic noncancer pain was underestimated and undertreated, many organizations, including the CDC and The Joint Commission, released guidelines and recommendations suggesting that physicians assess and aggressively treat chronic pain.1 Unfortunately, this well-meaning focus on chronic pain, along with aggressive pharmaceutical marketing, has led to an explosion in the number of people on chronic opioid therapy and an associated epidemic of opioid abuse and overdoses. As summarized in the 2016 CDC guideline for prescribing opioids for chronic pain, approximately 11% of American adults experience chronic pain, with 3-4% of adults prescribed long-term opioid therapy.2 In its 2016 guideline on chronic pain, the American Pain Society stated that from 1980 to 2000, the proportion of office visits at which providers prescribed an opioid more than quadrupled, from 2% to 9% of all visits.3

Krebs et al examined the effectiveness of opioid and non-opioid therapy for chronic moderate-to-severe musculoskeletal (back, hip, or knee) pain. They evaluated pain relief in 240 VA patients (13% female, mean age 58.3 years) randomized to step-wise intervention based on either opioid or non-opioid therapy. Patients were recruited from 62 Minneapolis VA primary care clinics. The patients could participate in non-pharmacological therapies of their choosing (hence, a “pragmatic” study). Chronic pain was defined as pain nearly every day for six months or more, with moderate and severe defined by a score of ≥ 5 on the three-item pain intensity, enjoyment of life, and interference with general activity (PEG) scale (0-10).4 Patients in the two groups were similar at baseline regarding age, gender, pain intensity, depression, and several other measures. Notably, there was a higher percentage of patients in the non-opioid group who expressed an initial desire to be treated with opioids (37% vs. 21%). Patients in the opioid treatment group started on a short-acting opioid (morphine IR, hydrocodone/acetaminophen, or oxycodone IR) and advanced to sustained-release morphine or oxycodone, if needed. Step three was transdermal fentanyl. The maximum daily dose was 100 morphine-equivalent (ME) mg. In the non-opioid group, patients started on acetaminophen and/or a nonsteroidal anti-inflammatory drug. Step two added a neurologic agent (amitriptyline, nortriptyline, gabapentin) and topical therapy (capsaicin, lidocaine). Step three included drugs requiring a prior authorization in the VA system, such as pregabalin, duloxetine, and tramadol. Patients were assessed at three, six, nine, and 12 months.

There were no significant differences in pain-related function and slightly better pain relief in the non-opioid treatment group at nine and 12 months (no difference at three and six months). There were no differences in multiple secondary outcomes, but there were significantly more medication-related side effects in the opioid-based therapy group, but no differences in adverse outcomes or potential misuse measures.


This small, but well-designed pragmatic trial reinforces that we should not reach for opioid therapy initially for our patients suffering from chronic musculoskeletal pain. The lack of benefit of opioid therapy over non-opioid therapy was demonstrated at three, six, nine, and 12 months — a real strength of this study. Eleven percent of non-opioid patients received tramadol, which is a weak mu receptor agonist and is considered a weak synthetic opioid. Although it would have been helpful to see the results if these patients were removed from analysis, it is unlikely that the overall results would have changed. The fact that more patients in the non-opioid group initially preferred to be treated with opioids is reassuring in so much that this was not a self-selected group. Further, it’s encouraging to see that patients can obtain significant pain relief from non-opioid therapy, even when their expectation is that they need opioid therapy.

As we are pushed to decrease opioid prescribing for noncancer chronic pain, this study confirms that non-opioid therapy is appropriate for our patients requesting treatment of their chronic musculoskeletal pain. Unfortunately, since so many Americans already are on opioid therapy for these conditions, the next study should assess how to transition these patients from opioid to non-opioid treatment.


  1. Phillips DM. JCAHO pain management standards are unveiled. JAMA 2000;284:428-429.
  2. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. JAMA 2016;315:1624-1645.
  3. The American Pain Society, The American Academy of Pain Medicine. Guideline for the use of chronic opioid therapy in chronic noncancer pain: Evidence review. Available at: Accessed April 20, 2018.
  4. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med 2009;24:733-738.