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Issue 1, Volume 4
Addiction Medicine and Relapse Prevention
8 Articles in this Series
The Krebs SPACE Trial
Association of opioid prescriptions from dental clinicians for US adolescents and young adults with subsequent opioid and abuse
The influence of anxiety sensitivity on opioid use disorder treatment outcomes.
Draft Report on Pain Management Best Practices: Updates, Gaps, Inconsistencies, and Recommendations
The Addiction Patient
What the SUPPORT Act Means for Providers
Inside the NCASA Report: Ending the Opioid Crisis
The role of opioid prescription in incident opioid abuse and dependence among individuals which chronic non-cancer pain

The Krebs SPACE Trial

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

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 240were randomized.

INTERVENTIONS: 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.

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).

RESULTS: 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 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.1


This was a 12-month randomized trial from the Veterans Administration system, comparing pain and function in 240 patients (87% male) with “moderate-to-severe” OA-related back, knee or hip pain, who were treated with opioids or else with non-opioids (ie, NSAIDS, acetaminophen.) The conclusions were that there was no significant difference in function over the study period between the two groups, whereas improvement in pain level was significantly better in the nonopioid group, who also had significantly fewer medication side effects.

This study was widely publicized in the media as another example of the lack of efficacy in treating a very common type of pain, osteoarthritis-related chronic pain, and as support for encouraging clinicians to decrease their opioid prescribing. I do not believe that the study protocol or results support the conclusion.

What is most troubling in this paper, and unexpected in a study published in JAMA, is that very little information about the patients or about the medications and the doses they took is provided. The focus was on the outcomes in terms of pain level and adverse events, but there was no mention in the discussion, conclusions, or limitations about the specific medications and doses that these patients took. Discussions found in the media have also failed to address these issues and their relevance to appropriate conclusions.

The information provided in the paper about opioids and doses was:

  • Step 1 began with morphine IR, hydrocodone/acetaminophen, and oxycodone IR.
  • Step 2 was morphine sustained-action (SA) and oxycodone SA.
  • Step 3 was transdermal fentanyl.

"Opioids were titrated to a maximum daily dosage of 100 mg morphine equivalents”, “In each 90-day follow-up period, fewer than 15% of the patients in the opioid group had a mean dispensed dosage of ≥ 50 ME/day or more.” There is no information about which drugs and which formulations were actually used.

The printed paper did provide a link to a webpage where “supplementary content” about the opioid doses taken by the opioid group was listed. Specifically, eTable 8 reported that for patients treated with opioids, the mean daily opioid dose at 3 months was 21 mg ME; at 6 months 23 mg ME; at 9 months 21 mg ME; and at 12 months 21 mg ME. Also listed was the median morphine equivalent dose, which at 3, 6, 9, and 12 months was 19, 19, 18, and 12 mg ME, respectively. There was no mention of which opioids and whether they were immediate- or extended-release. These doses were so low that it is not surprising that there was no significant improvement. Had these very low doses been clear to all readers of this paper, the clear-cut conclusions of the study would surely have been dismissed. At the very least, the “Limitations” section discussion of the study should have included what was clearly the biggest limitation: the low opioid dose.

The printed paper provided very little information about other modalities with which the two groups were treated. A summary was provided online of the modalities used during the 1 year follow-up, which reported that 14% of the opioid group and 13% of the control group had mental health counseling, 17% of the opioid and 18% of the control group had personal training or supervised exercise therapy, 37% and 24% had physical therapy, 9% and 8% had epidurals or facet blocks, 29% and 22% had joint injections, 1% of each group had spine surgery, and 3% and 8% respectively had arthroscopy or joint replacement. There was no discussion of the role of these modalities in the paper.

Patients selected for this study had chronic back or hip or knee OA for at least 6 months and were being treated by a primary care provider. Prior treatment modalities were not identified.

Another problem with this report is that the patient population had specific limitations: those on long-term opioid therapy, those with physiological dependence due to ongoing opioid, and those using opioids and benzodiazepines, were all excluded. On the other hand, as stated, “patients with severe depression or post-traumatic stress disorder (PTSD) were not excluded because patients often receive opioids in practice.” But there was no mention of the need for behavioral health treatment for such patients along with medications. At baseline, a significant proportion of patients had mental health problems. These included 23% (opioid group) and 21% (non-opioid) had moderate depression, 11% of both groups had moderate anxiety, and 25% of each group had a positive PTSD screen. Yet only 14% of the opioid group and 13% of the control group had mental health counseling.

This study overall was not about a general population of patients with osteoarthritis and chronic pain, despite the misleading impression given in the abstract, which states, “Eligible patients had moderate to severe chronic pain or hip or knee osteoarthritis despite analgesic use.” In reality, patients whose prior analgesic use had included chronic opioid therapy were specifically excluded. The conclusion in the abstract stated: “Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months.” This statement is misleading, in that it should specify that this may be true for a population of patients who have not used chronic opioids for their OA-related pain and are then treated with only low doses of an opioid. 


We agree with Dr. Schneider’s assessment of the Krebs study. Although the authors did not show opioids were more harmful than non-opioids, they insinuated that a longer study would have borne that conclusion. Also, they tested opioid doses with an enriched sample of non-opioid responders in one group and an un-enriched sample in the opioid group, which skewed the outcome in favor of non-opioids.

The non-opioid group in this study had a higher incidence of supplementing with illicit drugs, but there was no clarification or speculation, as to why, and there was no delineation regarding urine drug monitoring frequency or outcomes.

Finally, for even a shred of applicability, the design should have included a cross-over in which all opioid patients received only non-opioids and all of the non-opioid patients received only opioids to see whether all subjects maintained similar pain levels on each arm of the study. Furthermore, Krebs failed to track chronic NSAID associated toxicities, such as elevated blood pressures, GERD, GI bleed, heart failure, or kidney dysfunction, and compare that against incidents of opioid-related toxicities, including but not limited to opioid-induced respiratory depression. These toxicities are exactly the reasons clinicians do not favor chronic daily NSAID use in patients with refractory low back pain.

Next Article:
Association of opioid prescriptions from dental clinicians for US adolescents and young adults with subsequent opioid and abuse
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