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Study: Krebs 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. PMID: 29509867. DOI. Full Text.

Clinical Question

In patients with moderate to severe chronic back or osteoarthritic hip/knee pain, despite analgesic use, does opioid compared to non-opioid medication therapy result in better pain-related function?

Bottom Line

In patients with severe back or hip/knee pain not currently receiving opioid therapy, there was no difference between opioid vs. non-opioid therapy used in an escalating treat-to-target approach over 12 months but there may be more adverse events associated with opioid therapy.

Major Points

Opioids became widely prescribed for chronic pain starting in the 1990s, largely driven by intensive marketing strategies by pharmaceutical companies like Purdue (led by the Sackler family).[1] Increasing availability of highly abusable opioids has been identified as a major driver of the opioid epidemic. In the US alone, overdose deaths grew from 17,000/year in 1999 to 70,000/year in 2017.[2] Despite the widespread prescription of opioids, their efficacy for chronic pain was unknown.

Published in 2018, the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial randomized 240 VA ambulatory patients with moderate to severe chronic musculoskeletal pain (back, hip, or knee) on analgesics to opioid or non-opioid pain management strategies (e.g., NSAIDs, gabapentin, TCAs). At 12 months, overall pain was similar in each group, except a lower pain intensity in the non-opioid group and more adverse events in the opioid group. Given the male-predominant VA population, the trial's generalizability is somewhat limited. However, it provides initial evidence against the routine use of opioids for chronic musculoskeletal pain.


As of June 2019, no guidelines have been published that reflect the results of this trial.

Study Design

  • Single-center, open label, randomized trial
  • N=240
    • Opioid (n=120)
    • Non-opioid (n=120)
  • Setting: 62 American primary care clinicians affiliated with the Veterans Affairs
  • Enrollment: June 2013 to December 2015
  • Mean follow-up: 12 months
  • Analysis: Intention-to-treat
  • Primary Outcome: Improvement in pain-related function assessed with the Brief Pain Inventory (BPI)[3]

Population Studied

Inclusion Criteria

  • Back pain or knee or hip pain associated with osteoarthritis not receiving opioids
  • Pain occurring almost every day for โ‰ฅ6 months despite analgesic use
  • Brief Pain Inventory (BPI) scale average pain โ‰ฅ5 and BPI interference score โ‰ฅ5

Exclusion Criteria

  • Severe mental illnesses
  • Moderate severe cognitive function
  • Planned surgery to address pain in the next year
  • Long term opioid treatment
  • Contraindications to study medications
  • Life expectancy <12 months

Baseline Characteristics

From the opioid group.

  • Demographics: Mean age 57 years, 13% female, 88% white, 6% black, 6% other ethnicity, higher education 24%
  • Employment: Employed 42%, self-employed 6%, retired 36%
  • Pain eligibility: Back pain 65%, Hip/knee osteoarthritis pain 35%
  • Smoker 21%, hazardous alcohol use (AUDIT Score โ‰ฅ8) 3%, illicit drug use in prior year 7%
  • Mental Health: Moderate depression 23%, Moderate anxiety 9%, PTSD 21%


Participants were randomized to a group in and received stepwise approach to management of pain:

  • Opioid Group - Titrated to maximum of 100 morphine-equivalent mg:
  1. Morphine IR, hydrocodone/acetaminophen, oxycodone IR
  2. Morphine sustained release, oxycodone sustained release
  3. Transdermal fentanyl
  • Non-opioid
  1. Acetaminophen and NSAIDs
  2. Adjuvant oral medications (nortriptyline, amitriptyline, gabapentin), topical analgesics (capsaicin, lidocaine)
  3. Drugs requiring pre-authorization in VA system (pregabalin, duloxetine, tramadol)


Comparisons are opioid therapy vs. non-opioid therapy at 12 months.

Primary Outcomes

Outcome Opioid Group Non-opioid Group Difference
Pain-related function BPI score[3]
out of 10 points, higher indicating worse function.
3.4 3.3 difference 0.1; 95% CI -0.5 to 0.7; P=0.58
Medication-related symptom checklist
out of 19 points, higher indicates worse result.
1.8 0.9 difference 0.9; 95% CI 0.3 to 1.5; P=0.03

Secondary Outcomes

Efficacy Outcomes

Pain intensity on BPI
4.0 vs. 3.5 (difference 0.5; 95% CI 0.0 to 1.0; P=0.03)
VR-12 scores[4]
Out of 100 points, lower indicates worse reported symptoms.
Physical health: 32.7 vs. 33.9 (difference โˆ’1.3; 95% CI โˆ’3.8 to 1.3; P=0.23)
Mental health: 51.2 vs. 50.4 (difference 0.7; 95% CI โˆ’2.4 to 3.8; P=0.40)
RMDQ-11[5] pain-related physical function
Out of 11 points, higher indicates worse function.
5.8 vs. 5.9 (difference โˆ’0.1; 95% CI โˆ’1.0 to 0.8; P=0.47)
PHQ-8[6] depression symptoms
Out of 24, higher indicates worse depressive symptoms.
4.3 vs. 4.5 (difference โˆ’0.2; 95% CI โˆ’1.5 to 1.1; P=0.13)
GAD-7[6] anxiety symptoms
Out of 21, higher indicates worse anxiety symptoms.
2.5 vs. 2.8 (difference โˆ’0.4; 95% CI โˆ’1.4 to 0.7; P=0.02)
PROMIS[7] sleep disturbance
Out of 32; higher indicates worse sleep disturbance.
23.4 vs. 21.0 (difference 2.3; 95% CI 0.1 to 4.6; P=0.33)
MIDAS[8] headache disability
Out of 270; higher indicates worse headache.
3.7 vs. 3.2 (difference โˆ’0.5; 95% CI โˆ’2.7 to 3.6; P=0.82)
ASEX[9] sexual function
Out of 30; higher indicates worse sexual function.
17.9 vs. 19.0 (difference โˆ’1.1; 95% CI โˆ’2.8 to 0.7; P=0.49)
Out of 20; higher indicates worse fatigue, activity, or motivation.
General fatigue: 12.5 vs. 12.0 (difference 0.6; 95% CI โˆ’0.6 to 1.7; P=0.68)
Mental fatigue: 9.2 vs. 9.3 (difference 0.1; 95% CI โˆ’1.3 to 1.0; P=0.39)
Physical fatigue: 12.4 vs. 11.8 (difference 0.7; 95% CI โˆ’0.5 to 1.9; P=0.73)
Reduced activity: 10.6 vs. 10.3 (difference 0.3; 95% CI โˆ’1.0 to 1.5; P=0.74)
Reduced motivation: 8.6 vs. 8.8 (difference โˆ’0.2; 95% CI โˆ’0.7 to 1.6; P = 0.09)

Adverse events

  • All-cause hospitalization, P = 0.94
    • None: 83% vs. 83%
    • 1: 13% vs. 13%
    • โ‰ฅ2: 5% vs. 4%
  • All-cause ED visit, P = 0.18
    • None: 50% vs. 61%
    • 1: 28% vs. 25%
    • โ‰ฅ2: 22% vs. 14%
  • Patients with Falls after enrollment, P = 0.19
    • 0: 53% vs. 53%
    • 1: 22% vs. 14%
    • โ‰ฅ2: 25% vs. 33%


This is a landmark study published in 2018 by Krebs et al - the SPACE study. It was a pragmatic randomised controlled trial comparing opioid versus non opioid analgesics for 12 months in primary care. Participants were 240 VA patients with moderate to severe chronic back pain or knee/hip OA, and not on opioids. The mean pain intensity initially was 5.4 in both arms. Pain scores at 1 year was worse in the opioid arm (4.0) than non opioid (3.5) (P=0.034). There was no difference in pain interference, and adverse effects were worse in opioid group (P=0.03).


  • Not blinded
  • Patient self-reporting may by affected by bias
  • Generalizability limited due to VA population and unclear[11]
  • Reported adverse events may not represent highly concerning ones[12]
  • Patients using opioids excluded


  • Merit Review Award (I01-HX-000671) from the US Department of Veterans Affairs Health Services Research and Development Service

See Also


  1. โ†‘ Dyer. OxyContin maker stops marketing opioids, as report details payments to advocacy groups. BMJ (Clinical research ed.) 2018. 360:k791. PMID: 29459379. DOI.
  2. โ†‘ Overdose Death Rates page on the NIDA/NIH website. Accessed 2019-06-27.
  3. โ†‘ 3.0 3.1 Keller et al.. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. The Clinical journal of pain 2004. 20:309-18. PMID: 15322437. DOI.
  4. โ†‘ Selim et al.. Updated U.S. population standard for the Veterans RAND 12-item Health Survey (VR-12). Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 2009. 18:43-52. PMID: 19051059. DOI.
  5. โ†‘ Stroud et al.. Assessment of self-reported physical activity in patients with chronic pain: development of an abbreviated Roland-Morris disability scale. The journal of pain 2004. 5:257-63. PMID: 15219257. DOI.
  6. โ†‘ 6.0 6.1 Kroenke et al.. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. General hospital psychiatry 2010. 32:345-59. PMID: 20633738. DOI.
  7. โ†‘ Yu et al.. Development of short forms from the PROMISโ„ข sleep disturbance and Sleep-Related Impairment item banks. Behavioral sleep medicine 2011. 10:6-24. PMID: 22250775. DOI. Full Text.
  8. โ†‘ Stewart et al.. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology 2001. 56:S20-8. PMID: 11294956. DOI.
  9. โ†‘ McGahuey et al.. The Arizona Sexual Experience Scale (ASEX): reliability and validity. Journal of sex & marital therapy 2000. 26:25-40. PMID: 10693114. DOI.
  10. โ†‘ Smets et al.. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of psychosomatic research 1995. 39:315-25. PMID: 7636775. DOI.
  11. โ†‘ Wang & Macaulay. Opioids vs Nonopioids for Chronic Back, Hip, or Knee Pain. JAMA 2018. 320:506-507. PMID: 30088003. DOI.
  12. โ†‘ Singh et al.. Opioids vs Nonopioids for Chronic Back, Hip, or Knee Pain. JAMA 2018. 320:508. PMID: 30088001. DOI.