Opioid v. Nonopioid Medications in Patients with Chronic Pain

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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 Randomized Clinical Trial". JAMA. 2018. 319(9):872-882.
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Clinical Question

In adults with chronic pain disorders (e.g. osteoarthritis, back pain), do non-opioid medications compared to opioids decrease pain and improve quality of life?

Bottom Line

Treatment with opioids was not superior to treatment with non-opioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.

Major Points

The purpose of this study is to compare opioid medications and non-opioid medications when treating long term chronic pain. Long-term opioid therapy has become a very common and standard treatment in managing chronic musculoskeletal pain despite a lack of quality data.¹ Consequentially, opioid overdose death rates have increased², bringing up the question of whether or not opioid therapy is an appropriate treatment of chronic musculoskeletal pain without sufficient evidence of benefit for the patient. Currently, the CDC guidelines discourage the use of opioids for chronic pain.³

In this double blinded randomized control trial, 240 patients with a prior-month electronic health record diagnosis of back or lower extremity pain were randomized using a computer program to receive either an opioid based therapy or a non-opioid based therapy. There was no significant difference in the primary outcome, pain related function, in the span of 12 months (P-value=0.58). However, over 12 months, the major secondary outcome, pain intensity, was significantly reduced in the non-opioid group compared to opioid group (P-value=0.03). Adverse medication reactions were significantly more common in opioid group compared to non-opioid group (P-value=0.03).

A specific meta-analysis within the article looked at trials using large doses of opioids for chronic back pain and denoted that the benefits were too small to be clinically significant.⁴ Another meta-analysis within the article looked at the effects the dosage of opioids had on musculoskeletal pain in older adults and found there to be no association.⁴ While the study had several advantages including “high study retention” due to the “flexibility of treatments in assigned groups” and the utilization of intention to treat analysis, there was a major limitation-reporting bias. Overall, when assessing the primary outcome of this study, the use of opioids was not better than non-opioid medications at reducing pain over a 12 month period. Therefore, the results from this trial do not support use of opioids for moderate to severe chronic pain.¹


CDC Guidelines³: Non-pharmacologic interventions and non-opioid pharmacologic therapy is preferred for chronic pain. Only consider opioid therapy when the benefits for pain and function would outweigh risk of harm of opioid therapy. If opioid is determined to be best option, use IR instead of ER products. If opioid is initiated, use lowest effective dose.


- Pragmatic randomized trial - N=240 - Experimental arm (n=120) - Standard (n=120) - Setting: Veterans Affairs primary care clinics - Enrollment: 2013-2015 - Mean follow-up: 12 months - Analysis: ITT - Primary outcome: pain-related function, assessed with the 7-item Brief Pain Interference Scale (BPI)


Inclusion Criteria

Chronic back pain or hip or knee osteoarthritis that was moderate or severe. (Chronic pain defined as pain every day for 6 months or more, moderate-severe pain defined as score >5 on the 3-item pain intensity, interference with enjoyment of life, interference with general activity (PEG) scale (0-10).)

Exclusion Criteria

Patients on long term opioid therapy were excluded. Contraindications to all drug classes in either group, including class level opioid contraindications (active substance abuse disorder). Conditions that could interfere with outcome assessment (ex: life expectancy <12 months).

Baseline Characteristics

Opioid Group: - Age: Mean-57 years old - Female: 13% - Race: 88% Caucasian, 6% African American, 6% other - Education: Greater than or equal to 4-year degree: 24% - Employment: Employed for wages: 42%, self-employed: 6%, retired: 36%, other: 16% - Primary pain diagnosis: Back pain: 65%, hip, knee or osteoarthritis pain: 35% - Substance use assessment: Current smoker: 21%, hazardous alcohol use: 3%, illicit drug use: 7% - Mental health measures: Moderate depression: 23%, Moderate anxiety: 9%, Positive PTSD screen: 21% - Pre-randomization group preference: No preference: 60%, opioid medications: 21%, non-opioid medications: 19% - Pre-randomization perceptions of treatment groups: opioid effectiveness: 2.1%, opioid safety: 2.5%, non-opioid effectiveness: 2.7%, non-opioid safety: 2.7% - Expectations for improvement: 1.8%


In both groups, patients received structured symptom monitoring, and a treat-to-target approach to medication management delivered mostly by one pharmacist.


Primary Outcomes

There was no significant difference in pain-related function between the 2 groups over 12 months (overall P = .58). At 12 months, mean BPI interference was 3.4 in the opioid group (SD, 2.5) vs 3.3 in the non-opioid group (SD, 2.6); difference, 0.1 (95% CI, −0.5 to 0.7).

Secondary Outcomes

Pain intensity was significantly better in the non-opioid group over 12 months (overall P = .03). At 12 months, mean BPI severity was 4.0 in the opioid group (SD, 2.0) vs 3.5 in the non-opioid group (SD, 1.9); difference, 0.5 (95% CI, 0.0 to 1.0).

Subgroup Analysis

Post hoc tests for interaction of primary pain diagnosis by treatment group on pain outcomes were not statistically significant.

The subgroups analyzed included those suffering from back pain and hip or knee osteoarthritis pain.

Adverse Events

No significant differences in adverse outcomes or potential misuse were reported. Two hospitalization visits were determined “analgesic-related”: “1 hospitalization in the nonopioid group and 1 ED visit in the opioid group. No deaths, “doctor-shopping” (going from doctor to doctor), diversion, or opioid use disorder diagnoses were detected”.


- Complexity of interventions precluded masking of patients - Primary outcomes are patient reported, results are subject to reporting bias that would likely favor opioids - Imbalance in pre-randomization treatment, effect of imbalance would favor opioids - Study was conducted in VA clinics so patient characteristics differ from the general population, most notably in sex - Patients with physiological opioid dependence due to ongoing use were excluded so results do not apply to this population


This trial was funded by the Merit Review Award (I01-HX-000671) from the US Department of Veterans Affairs Health Services Research and Development Service.

Further Reading

1. Reuben DB, Alvanzo AA, Ashikaga T, et al. National Institutes of Health Pathways to Prevention Workshop:The role of opioids in the treatment of chronic pain. Ann Intern Med. 2015;162 (4): 295-300. 2. Department of Veterans Affairs/Department of Defense. Management of opioid therapy for chronic pain. https://www.healthquality.va.gov/guidelines/Pain/cot/VADoDOTCPG022717.pdf. Accessed May 1, 2018. 3. National Guideline Clearinghouse (NGC). Guideline summary: CDC guideline for prescribing opioids for chronic pain — United States, 2016. [Internet]. Agency for Healthcare Research and Quality (AHRQ); 2016 Mar 18. 4. 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.