Efficacy of opioids versus placebo in chronic pain

Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials –  May 2018

Introduction: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated.

To evaluate opioids’ efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for μ-opioid receptor agonists performed for US Food and Drug Administration approval.  

Methods: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all μ-agonist opioids approved in the USA.

Results: Fifteen studies met criteria.

Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: −0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194).

There were minor benefits on physical function and no effect on mental function.

Conclusion: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials.

This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

This is opposite the conclusion reached in an earlier and much-misinterpreted study:

Krebs Study: Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain| Emergency Medicine | JAMA | The JAMA Network – The SPACE Randomized Clinical Trial – March 6, 2018

Erin E. Krebs, MD, MPH1,2; Amy Gravely, MA1; Sean Nugent, BA1; et al JAMA.

Key Points

Question  For patients with moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use, does opioid medication compared with nonopioid medication result in better pain-related function?

Findings  In this randomized clinical trial that included 240 patients, the use of opioid vs nonopioid medication therapy did not result in significantly better pain-related function over 12 months (3.4 vs 3.3 points on an 11-point scale at 12 months, respectively).

Meaning  This study does not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.

Well, that’s just plain wrong for so many other kinds of pain.

Even if opioids aren’t more effective for “moderate to severe chronic back pain or hip or knee osteoarthritis pain”, if the pain lasts for years, opioids with their fewer side effects in most people might be a better choice than NSAIDs, which will tear apart your gastric tissues.


Importance  Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain.

Objective  To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects.

Design, Setting, and Participants  

Pragmatic, 12-month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized


Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function.

Each intervention had its own prescribing strategy that included multiple medication options in 3 steps.

In the opioid group,

the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen.

For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug.

Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response.

This admits that this was far from a standardized trial.

Anyone’s pain will improve if they are treated with different medications that are adjusted to their particular bodies (genetics).

Main Outcomes and Measures  

The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale).

For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient-reported checklist; range, 0-19).


Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial.

  • Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, −0.5 to 0.7]).
  • Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]).
  • Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]).

Conclusions and Relevance

Treatment with opioids was not superior to treatment with nonopioid 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.

I previously posted two rebuttals to this conclusion:



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