SPACE

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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". JAMA. 2018. 319(9):872-882.
PubMed

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

Long term opioid therapy had been the main stay of chronic pain for many years. These strong medications have significant side effects, including the risk of dependence. With the rising rates of serious side effects and opioid related deaths this pragmatic trial compared opioid to non-opioid therapy for benefit pain and quality of life measures and tracked adverse outcomes. Including 240 patients randomized to receive escalating doses in a treat-to-target strategy, over 12 months there was no difference in pain-related function for opioid vs. non-opioid, 3.4 vs 3.3 points, respectively.

Adverse events in the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial treating patients with severe back or knee/hip osteoarthritic pain were more commonly seen in the opioid group (P = 0.03) but this may not have been clinically significant. There are several limitations in this trial: the generalizability may be limited due to the study population (Veteran population, mostly male, current opioid users excluded) and it relied on subjective reporting by the patients.

Guidelines

Canadian Guideline for opioid therapy and chronic non-cancer pain[1] adapted,

  1. Optimize nonopioid pharmacotherapy and nonpharmacologic therapy before trial of opioids
  2. For patients with persistent pain despite optimization and no history of substance misuse, consider a trial of opioids
  3. Avoid opioids in patients with active substance misuse
  4. Patients with active psychiatric disorder and persistent pain despite optimization, stabilize psychiatric disorder before trial of opioids
  5. Trial of opioids max dose should be restricting to less than 90 mg morphine equivalents daily
  6. Trial of opioids should be restricting to less than 50 mg morphine equivalents daily when initiating
  7. Patients with persistent pain or symptoms despite opioid therapy should have opioids rotated
  8. Patients should be tapered down to the lowest effective dose
  9. In patients unable to taper recommend multidisciplinary approach

Design

  • Single-center, blind outcome assessment, 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)[2]

Population

Inclusion Criteria

  • Back pain or knee or hip pain associated with osteoarthritis
  • current non-opioidanalgesic use
  • Nearly every day ≥6 months
  • ≥ 5 points on PEG scale[3]

Exclusion Criteria

  • Long term opioid treatment
  • contraindications to all drug classes in either group
  • conditions that could interfere with outcome assessment (e.g. life expectancy <12 months)

Baseline Characteristics

Opioid group displayed

  • Demographics: Mean age 56.8 years, 13% female, 88% Causation, 6% African descent, 6% other ethnicity, University education 24%
  • Employment: Employed 42%, Self-employed 6%, Retired 36%, other 16%
  • Back pain 65%, Hip/knee osteoarthritis pain 35%
  • Smoker 21%, Hazardous Ethanol use (AUDIT Score ≥8) 3%, Illicit drug use 7%
  • Mental Health: moderate depression 23%, Moderate anxiety 9%, PTSD 21%

Interventions

Step-wise apprach taken in both groups

  • 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-authoirzation in VA system (pregabalin, duloxetine, tramadol)

Outcomes

Comparisons are Opioid therapy vs. Non-opioid therapy at 12 months.

Primary Outcomes

Pain-Related Function BPI Score[2]
3.4 vs. 3.3 (Difference 0.1 [95% CI -0.5 to 0.7] P = 0.58)
Functional response (≥ 30% in BPI)
59.0% vs. 60.7% (Difference -1.7% [95% CI -14.4 to 11.0] P = 0.79)

Secondary Outcomes

Pain Intensity on BPI[2]
4.0 vs. 3.5 (Difference 0.5 [95% CI 0.0 to 1.0] P = 0.03)
Pain Intensity response (≥ 30% in BPI)
41.0% vs. 53.9% (Difference −12.8% [95% CI, −25.6 to 0.0] P = 0.05)
VR-12[4] Physical Health (score 0-100, lower=worse)
32.7 vs. 33.9 (Difference −1.3 [95% CI −3.8 to 1.3] P = 0.23)
VR-12 mental health (score 0-100, lower=worse)
51.2 vs. 50.4 (Difference 0.7 [95% CI −2.4 to 3.8] P = 0.04)
RMDQ-11[5] pain-related physical function (range, 0-11; higher score = worse)
5.8 vs. 5.9 (Difference −0.1 [95% CI −1.0 to 0.8] P = 0.47)
PHQ-8[6] depression symptoms (range, 0-24; higher score = worse)
4.3 vs. 4.5 (Difference −0.2 [95% CI −1.5 to 1.1] P = 0.13)
GAD-7[6] anxiety symptoms (range, 0-21; higher score = worse)
2.5 vs. 2.8 (Difference −0.4 [95% CI −1.4 to 0.7] P = 0.02)
PROMIS[7] sleep disturbance (range, 8-32; higher score = worse)
23.4 vs. 21.0 (Difference 2.3 [95% CI 0.1 to 4.6) P = 0.33)
MIDAS[8] headache disability (range, 0-270; higher score = worse)
3.7 vs. 3.2 (Difference −0.5 [95% CI −2.7 to 3.6] P = 0.82)
ASEX[9] sexual function (range, 5-30; higher score = worse)
17.9 vs. 19.0 (Difference −1.1 [95% CI −2.8 to 0.7) P = 0.49)
MFI[10] general fatigue (range 4-20; higher = worse)
12.5 vs. 12.0 (Difference 0.6 [95% CI −0.6 to 1.7] P = 0.68)
MFI mental fatigue (range 4-20; higher = worse)
9.2 vs. 9.3 (Difference 0.1 [95% CI −1.3 to 1.0] P = 0.39)
MFI physical fatigue (range 4-20; higher = worse)
12.4 vs. 11.8 (Difference 0.7 [95% CI −0.5 to 1.9] P = 0.73)
MFI reduced activity (range 4-20; higher = worse)
10.6 vs. 10.3 (Difference 0.3 [95% CI −1.0 to 1.5] P = 0.74)
MFI reduced motivation (range 4-20; higher = worse)
8.6 vs. 8.8 (Difference −0.2 [95% CI −0.7 to 1.6] P = 0.09)

Adverse Events

Medication-related symptom checklist (score 0-19, higher = worse)
1.8 vs. 0.9 (Difference 0.9 [95% CI 0.3 to 1.5] P = 0.03)
All-cause hospitalization, P = 0.94
0 = 83% vs. 83%
1 = 13% vs. 13%
≥2 = 5% vs. 4%
All-cause ED visit, P = 0.18
0 = 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%

Criticisms

  • Blinding not conducted
  • Patient self-reporting may by affected by bias
  • Generalizability limited due to VA population
  • Patients using opioids excluded

Funding

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

Further Reading

  1. Busse JW et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ 2017. 189:E659-E666.
  2. 2.0 2.1 2.2 Keller S et al. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain 2004. 20:309-18.
  3. Krebs EE et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med 2009. 24:733-8.
  4. Selim AJ et al. Updated U.S. population standard for the Veterans RAND 12-item Health Survey (VR-12). Qual Life Res 2009. 18:43-52.
  5. Stroud MW et al. Assessment of self-reported physical activity in patients with chronic pain: development of an abbreviated Roland-Morris disability scale. J Pain 2004. 5:257-63.
  6. 6.0 6.1 Kroenke K et al. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry 2010. 32:345-59.
  7. Yu L et al. Development of short forms from the PROMIS™ sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med 2011. 10:6-24.
  8. Stewart WF et al. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology 2001. 56:S20-8.
  9. McGahuey CA et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther 2000. 26:25-40.
  10. Smets EM et al. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995. 39:315-25.