Opioids No Better than Nonopioids in Treatment of Chronic Back, Osteoarthritis Pain

Monday, August 20, 2018

R.L. Wynn

Among patients with chronic back pain or hip or knee osteoarthritis pain, treatment with opioids did not result in any significantly better pain-related function compared with treatment with nonopioid medications over 12 months in a recent study. In addition, opioids caused significantly more medication-related adverse symptoms than nonopioid medications. Over all, opioids did not demonstrate any advantage to potentially outweigh their greater risk of harms.

According to the authors of the study, prior systematic reviews identified no randomized trials of opioid therapy that reported long-term pain, function, or quality-of-life outcomes. This Minneapolis Veterans Administration (VA) trial was a prospective, pragmatic, randomized trial that compared the effectiveness of opioid therapy to nonopioid medication over 12 months for primary care patients with chronic back pain or hip or knee osteoarthritis pain of at least moderate severity despite analgesic use.

The study can be accessed at: Krebs EE, 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 randomize clinical trial.” JAMA 2018 Mar 6; 319(9): 872-882.

Study Design and Participants

Study authors were from the Minneapolis Veterans Affairs Health Care System, University of Minnesota Medical School and Indiana University School of Medicine. It was funded by the U.S. Department of Veterans Affairs Health Services. 

The working hypotheses were that opioid compared with nonopioid medications would result in better pain-related function, better reduction in pain intensity, and more adverse effects.

The uniqueness of this trial was in its pragmatic approach and design. Drug interventions were delivered with flexibility in medication selection and dosage. Patients were allowed to participate in nonpharmacologic pain therapies outside of the study and encouraged to complete outcome assessments regardless of their participation in the active interventions.

Eligible patients had chronic back pain or hip or knee osteoarthritis pain that was moderate-to-severe despite analgesic use. Patients were recruited from 62 Minneapolis VA primary care clinicians from June 2013 to December 2015. Of 265 patients originally enrolled, 25 withdrew, and 240 were included in testing.

Medication Regimens and Strategy

Medications were delivered by a pharmacist. Follow-up visits occurred every 1 to 3 months. Visits were conducted in person at 6 and 12 months whenever possible, and otherwise by telephone. 

Opioid Regimens

Patients in this group started taking immediate-release opioids in the following regimen:

  • Step 1: morphine, hydrocodone/acetaminophen, or oxycodone
  • Step 2: morphine sustained-action or oxycodone sustained-action
  • Step 3: transdermal fentanyl

Single opioid therapy was preferred, but dual therapy with a scheduled sustained-action opioid, and as needed, immediate-release opioid was considered based on patient needs and preferences.

Nonopioid Regimens

Patients in the nonopioid medication group were given the following regimen:

  • Step 1: acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID)
  • Step 2: adjuvant oral drugs such as nortriptyline, amitriptyline, and gabapentin and topical analgesics, which included capsaicin and lidocaine
  • Step 3: drugs requiring VA clinic authorization (i.e., pregabalin and duloxetine) and tramadol

All patients were initially prescribed a Step 1 drug. Subsequent changes included titrating, replacing, and adding medications.

Outcomes and Measures

The Brief Pain Inventory interference scale was used to measure the primary outcome of pain-related function over 12 months. The main secondary outcome was pain intensity using the Brief Pain Inventory severity scale. For both scales, a range of 0 to 10 was used as the measure, with higher scores equal to a worse function or worse pain intensity. According to the authors, based on prior studies, a one-point improvement was clinically important.

The primary adverse outcome was a patient-reported checklist of 19 medication-related symptoms. 

Adverse Events

At each assessment, patients reported new hospitalizations, emergency department visits, and falls. Investigators determined whether these events were analgesic-related.

Opioid misuse was defined as the use of prescription opioids in a manner other than as prescribed. The study used medical record surveillance for evidence of doctor shopping, diversion, substance use disorder, or death. Authors also checked the state prescription monitoring program website at each visit and as needed.


Initially, 240 patients qualified for the study. Follow-up numbers were:

  • 3 months: 106 opioid group, 115 nonopioid group
  • 6 months: 116 in each group
  • 9 months: 108 in each group
  • 12 months: 117 in each group

Patient breakdown:

  • Mean age was 58.3 years (range 21 to 80 years)
  • 32 patients were women (13%)
  • 156 patients had back pain (65%)
  • 84 had hip or knee osteoarthritis pain (35%)

Relative to treatment preferences, in the opioid group:

  • 72 patients (60%) had no preference
  • 25 patients preferred opioids

In the nonopioid group:

  • 51 patients (43%) had no preference
  • 44 patients (37%) preferred opioids

Relative to pain-related function, there was no significant differences between the two groups over 12 months. The mean scores were 3.4 in opioid group and 3.3 in nonopioid group.

Relative to pain intensity, there was significantly less pain in the nonopioid group over 12 months. The mean scores were 4 in opioid group and 3.5 in the nonopioid group. According to the authors, the difference of 0.5 units was significant. 

Additional results:

  • Functional response of > 30% improvement occurred in 69 patients (59%) in the opioid group vs 71 patients (60.7%) in the nonopioid group
  • Pain intensity response > 30% improvement occurred in 48 patients (41%) in the opioid group vs 63 patients (53.9%) in the nonopioid group
  • Health-related quality of life did not significantly differ between the two groups
  • Only anxiety significantly differed between groups, with less anxiety in the opioid group

Relative to adverse outcomes, the opioid group had significantly more medication-related symptoms over 12 months than the nonopioid group. There were no significant differences in adverse outcomes or potential misuse measures. Two hospitalization or ED visit events were determined to be analgesic-related (one hospitalization in the nonopioid group and one ED visit in the opioid group). No deaths, “doctor-shopping,” or opioid use disorder diagnoses were detected.

Authors’ Summary

The authors commented that among patients with chronic back pain or hip or knee osteoarthritis pain, treatment with opioids did not demonstrate any advantage over nonopioid medications that could potentially outweigh their greater risk of harms.

The authors point out the pragmatic design of this study in that reassessment and adjustment of medications is likely necessary for effective pharmacologic treatment of chronic pain. They refer to an earlier report by Chou, et al, which assessed pharmacologic therapies in which individual medications were evaluated compared to placebo in controlled studies. That report showed that individual medications are effective for only a minority of patients with chronic pain. 

The Chou, et al, study by was performed to review current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain. The protocol reviewed Ovid MEDLINE, Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and reference lists. The study selection included randomized trials that reported pain, function, or harm of systemic medications versus placebo or other intervention. One investigator abstracted the data and a second verified accuracy. Two investigators independently assessed study quality.

Relative to opioids versus acetaminophen or NSAIDS, the review by Chou, et al, found the following:

  • For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain. Opioid trials were not designed to assess serious harms
  • For acetaminophen, evidence found that it was ineffective for acute low back pain
  • For NSAIDs, evidence showed that these drugs had smaller benefits for chronic low back pain than previously observed

The Minneapolis VA study was somewhat consistent relative to opioids with the Chou study: The Chou study found modest effects of opioids in treating back pain, while the VA study found that opioids did not provide any advantage over nonopioids in treating chronic pain. Differences occurred relative to acetaminophen effectiveness. Unlike the Chou study however, which found no effect by acetaminophen, the VA study incorporated a protocol that included adjustment and titration of dosing if necessary.

Both studies showed, however, that opioids are probably not the answer to the pharmacologic treatment of hip or knee osteoarthritis pain and chronic low back pain. 

Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.

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