EBQ:SPACE Trial

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

To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects in patients with moderate to severe chronic back or osteoarthritic hip/knee pain.

Bottom Line

In patients with severe back or hip/knee pain that weren't currently receiving opioid treatment, there was no difference between opioid vs. non-opioid treatment over 12 months with an escalating treatment-to-target approach. There may be more adverse events with opioid therapy.

Study Design

• Pragmatic, single-centre, open label, randomized trial
• N=240
  • Opioid (n=120)
  • Non-opioid (n=120)
• Setting: 62 American primary care clinicians affiliated with the Veterans Affairs
• Enrolment: June 2013 to December 2015
• Mean follow-up: 12 months
• Analysis: Intention-to-treat, masked outcome assessment.
• Primary Outcome: Improvement in pain-related function assessed with the Brief Pain Inventory (BPI)

Population Studied

Inclusion Criteria

• Back pain or knee or hip pain associated with osteoarthritis
• Pain occurring almost every day for ≥6 months despite non-opioid analgesic use
• Brief Pain Inventory (BPI) scale average pain ≥5 and BPI interference score ≥5

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

• 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 ≥8) 3%, illicit drug use in prior year 7%
• Mental Health: Moderate depression 23%, Moderate anxiety 9%, PTSD 21%

Interventions

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)

Outcomes/Results

Primary Outcomes

Outcome	Opioid Group	Non-opioid Group	Difference
Pain-related function BPI score 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

• 

  Brief Pain Inventory (BPI) over 12 months

• 

  Pain Interference over 12 months

Secondary Outcomes

There was no difference in a variety of secondary outcome measures, including pain intensity on BPI 4.0 vs. 3.5 (difference 0.5; 95% CI 0.0 to 1.0; P=0.03), and depression on PHQ-8 4.3 vs. 4.5 (difference −0.2; 95% CI −1.5 to 1.1; P=0.13).

Adverse events

• All-cause hospitalization, P = 0.94
  • None: 83% vs. 83%
  • 1: 13% vs. 13%
  • ≥2: 5% vs. 4%
• All-cause ED visit, P = 0.18
  • None: 50% vs. 61%
  • 1: 28% vs. 25%
  • ≥2: 22% vs. 14%
• Patients with Falls after enrollment, P = 0.19
  • 0: 53% vs. 53%
  • 1: 22% vs. 14%
  • ≥2: 25% vs. 33%

Discussion

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).

Criticism

• Unblinded
• Patient self-reporting is an area of bias
• The patients were veterans, and so this might limit the external validity
• Patients using opioids already were excluded
• The reported adverse events may not represent the highly concerning ones.

Funding

• Merit Review Award from the US Department of Veterans Affairs Health Services Research and Development Service

See Also

• Opioid Deprescribing