Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials – Meske DS, Lawal OD, Elder H, Langberg V, Paillard F, Katz N – 19 December 2017

This is a study from almost a year ago that gives evidence that opioids ARE effective for our chronic pain. PROP manipulates the evidence to make it seem like opioids don’t work for us.

Introduction: 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.

The full article elaborates below:

Introduction In order to inform the ongoing controversy over whether there is evidence that opioids are efficacious for the treatment of chronic pain, we have gathered the randomized controlled trials required by the FDA for approval, and have performed a meta-analysis of their results. These trials are by regulatory expectation 3 months in duration. The free full-text article has a long sections on the Methods and Results Discussion The recent claims that opioids lack efficacy for chronic pain have created controversy among physicians, prescribers, regulators, scientists, and the general public regarding whether the benefits of opioid use outweigh the public health risks of abuse and other complications. Chou et al state “evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving pain” based on the opinion that studies of ≤1 year duration do not provide evidence of “long-term” efficacy. Clearly if there is no benefit then no amount of risk should be tolerated. This review was, therefore, performed in order to gather together the key evidence to facilitate understanding opioid efficacy within the paradigm of FDA studies required for approval, and to perform a meta-analysis in order to quantify opioid efficacy for chronic pain and assess consistency of effects across studies conducted for ≥3 months’ duration. This meta-analysis was limited to EERW-designed studies, since this design is by far the most commonly utilized for regulatory approval and therefore supports combinability. Several systematic reviews and meta-analyses regarding the efficacy of opioids in chronic pain have been published; however, these studies were published nearly a decade ago, and the more recent ones are not meta-analyses. Although most of these meta-analyses concluded that opioids were efficacious for the treatment of chronic non-cancer pain, a review specifically focused on studies designed for FDA approval (ie, of ≥3 months’ duration) for chronic pain has not been done. The EERW design provides an opportunity to evaluate both “effectiveness” (outcomes in the open-label titration phase) and

“efficacy” (outcomes in the randomized, double-blind, placebo-controlled phase). The present meta-analysis demonstrated the “effectiveness” of opioids since a majority of patients (63%) demonstrated a clinically meaningful response. The pharmacological efficacy of opioids for the treatment of chronic pain was evidenced by statistically significant differences between study drug and placebo in change in pain score from randomization to week 12 and in response rates. With regard to secondary endpoints, opioids were found to marginally improve physical function in the present meta-analysis. Therefore, the use of opioids alone to improve physical function is not supported by this review; whether opioids improve the effectiveness of rehabilitative treatments for chronic pain requires further study.

I can’t believe they are finding that easing pain doesn’t improve physical function. It implies that people don’t do more when they hurt less, and that doesn’t sound right to me.

From I’ve learned from all the reading I do for this blog, studies can be easily manipulated to create the desired conclusion, and we all know how badly a negative conclusion about opioids is wanted these days.

The PGASM measure allows subjects to aggregate multiple aspects of their experience, including pain relief,

improvement in physical and emotional function,

side effects, and

convenience, into a single measure. In the present meta-analysis, these measures were congruent with the primary finding that opioids are efficacious for the treatment of chronic non-cancer pain. It is worth noting that AE [Adverse Events] rates in the double-blind periods were similar between study drug and placebo, with dropouts due to AEs being higher in the drug group while dropouts due to loss of efficacy were higher in the placebo group. However, because patients with significant tolerability issues during the open-label titration phase are deliberately excluded from the randomized double-blind treatment phase, AE rates in the randomized double-blind treatment phase of EERW studies do not represent rates that would occur in prospective parallel clinical trials;

I cry foul! If they have been regularly excluding patients who are definitely a part of the cohort of people with chronic pain, this drastically distorts most opioid studies.

In a recent meta-analysis evaluating the efficacy of opioids for CLBP, the authors concluded that opioids provided “moderate short-term relief” but the effect is not clinically important. In that meta-analysis, Shaheed et al define “clinically important” arbitrarily as a group mean difference in pain or disability >20 points on a 0–100 scale.

Again, a deliberate (arbitrary only in narrow scientific terms) distortion of data to support the desired conclusion. It sickens me to see how science has been corrupted.

while clinical importance is more usefully viewed as a multidimensional concept that encompasses multiple factors including efficacy, safety, and availability of other treatments It is worth noting that the efficacy of opioids is at least as large as that of any other treatment for chronic pain. Thus, requiring a group mean difference of 20 points on a 0–100 pain scale would lead to a nihilistic conclusion that no pharmacological treatments for chronic pain are useful While the effectiveness of existing treatments for chronic pain leaves plenty of room for improvement, and considering that only a small minority of patients do not experience clinically meaningful treatment responses, discarding entirely all analgesics approved for chronic pain contradicts numerous treatment guidelines, international treatment guidelines, widespread patient experience, and the FDA approval process. These authors, as well as others, defined a 12-week treatment period as “short-term.” While 3 months is indeed short in comparison to the years patients may use opioid treatment for chronic pain, 3-month treatment periods are considered the regulatory standard for assessing long-term efficacy of a treatment in placebo-controlled clinical trials of chronic conditions. Indeed, the efficacy of all major drug and nondrug therapies for chronic pain is based on a similar body of evidence (ie, the number of studies and duration of those studies are similar for all chronic pain treatments). Thus, the body of evidence for the efficacy of opioids is similar in terms of duration of studies to that for other approved classes of analgesics. Finally, the inclusion of EERW studies in our meta-analysis allows a richer interpretation of “long-term” efficacy: the EERW design is utilized to assess the efficacy of treatment that has been administered for potentially lengthy periods of time prior to randomization. This design, also called the randomized discontinuation design, has been used in multiple therapeutic areas where it is important to determine whether patients responding to long-term open-label treatment are, in fact, responding to the pharmacological effects of the drug, or just the non-specific effects of treatment (such as the placebo response). Such studies have been performed for decades in oncology, depression, rheumatoid arthritis, cardiology, schizophrenia, and numerous other indications. Therefore, the superiority after randomization of active treatment over placebo among patients who have already demonstrated a longstanding response to open-label medication can be interpreted as long-term efficacy that is not due to a placebo effect or other non-specific factors. Conclusion This meta-analysis of FDA-required double-blind, randomized, placebo-controlled clinical trials of opioid analgesics for the treatment of chronic pain has shown that there is an ample evidence base supporting the efficacy of opioid analgesics for at least 3 months’ duration, a standard period for the evaluation of treatments for chronic pain and other chronic disorders. This evidence base is at least as large as that for any other class of analgesics, and analysis of responders demonstrates clinically meaningful improvements. We have not focused on the risks of opioids, nor the risk–benefit balance, and hope that our review at least characterizes the evidence base for efficacy in order to inform these important broader discussions.