The benefits of practical clinical trials over traditional randomized clinical trials for opioid management

KEYWORDS:

• Chronic pain
• opioids
• practical clinical trials
• randomized clinical trials
• analgesics

Chronic pain has been defined as ‘pain that persists beyond normal tissue healing time, which is assumed to be 3 months (IASP)’. Chronic pain may occur in the context of numerous diseases and syndromes. Opioids are the most important analgesic drugs and are widely used with many indications, including acute postoperative pain, injury or trauma, chronic non-cancer pain, and cancer pain [1]. Although opioid analgesics are widely used for the treatment of chronic pain, their use is still controversial, because treatments with opioids delivered today are lacking clear evidence of effectiveness. Although evidence is limited, expert groups have recommended that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic non-cancer pain [2]. Indeed, opioids are associated with potentially serious problems, including opioid-related adverse effects and potential abuse. An opioid epidemic has developed in the United States because of over-prescribing in patients with non-cancer pain. Thus, safe and effective chronic opioid therapy for chronic non-cancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion [3].

Decision makers in health care are increasingly interested in using high-quality scientific evidence to support clinical and health policy choices. However, the quality of available scientific evidence regarding the use of opioids has been often found to be inadequate. The widespread gaps in evidence-based knowledge suggest that systematic flaws exist in the production of scientific evidence, in part because there is no consistent effort to conduct clinical trials designed to meet the needs of decision makers.

The traditional randomized clinical trials (RCTs) are recognized to provide the highest quality information on efficacy and safety of the use of opioids for chronic pain. These studies, also named explanatory trials, often form the foundation for decision-making strategies as well as drug approval of regulatory authorities. To ensure that the findings can be attributed to the treatment proposed, some approaches are commonly employed. Randomization in comparison studies, for example, minimizes the risk that subject differences will contribute to different outcome among the arms receiving different treatments. Blinding to group allocation may prevent bias in management and evaluation. Potential confounders, such as comorbidities, concomitant medications or disease severity, are reduced by the study design. Of interest, a treatment that fails to work is unlikely to be efficacious in general practice, with an asymmetric interference.

However, a treatment that is effective or safe in RCT may not be in general practice. Traditional RCTs in chronic pain are slow and expensive, and results cannot often be implemented easily in clinical practice. Findings can be difficult to translate into the real world because treatments are given to carefully selected populations in ideal conditions. Indeed, the purpose of comparative effectiveness research is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care. Thus, the real-world experience may be different and the proscriptive nature of RCTs may limit the degree to which the results can be generalized.

Practical clinical trials can bridge the gap between research and clinical care as they compare two or more treatments under conditions in which they would be applied in practice [4]. Practical or pragmatic clinical trials (PCTs) are those for which the hypothesis and study design are developed specifically to answer the questions faced by decision makers. PCTs select clinically relevant alternative interventions to compare, include a diverse population of study participants, recruit participants from heterogeneous practice settings, and collect data on a broad range of health outcomes. Although PCTs may have less power to detect a clinical effect, they provide data to increase generalizability to clinical practice settings, demonstrate improvement of health outcomes and cost-effectiveness, establish evidence-based guidelines, and enhance their adoption in clinical practice [5]. Thus, while explanatory trials confirm a physiological or clinical hypothesis, PCTs may inform a clinical or policy decision by providing evidence for adoption of the intervention into the real-world clinical practice. A typical example of pragmatic trial has been recently published. Data from this randomized study showed that pain-related function over 12 months was not superior with opioids in comparison with non-opioid medications [6]. The flexibility and the treat to target approach reflected what commonly occurs in clinical practice.

However, the sample size required to assess safety outcomes may be too great to make PCT of long-term use feasible. Long-term studies are really difficult to carry out. Of concern, FDA requires just 3 month follow-up for regulatory approval and pharmaceutical companies do not have interest to support trials of longer duration. Other approaches are needed to assess opioid effectiveness and safety.

Controversies have emerged to weight limitations of systematic reviews and dearth of pragmatic effectiveness trials. In general, explanatory trials are focused on the question, ‘Can this intervention work under ideal conditions?,’ whereas PCTs seek to answer the question, ‘Does this intervention work under usual conditions’ [7,8]. To improve the performance of PCTs, it has been introduced a tool, named Pragmatic–Explanatory Continuum Indicator Summary (PRECIS), to provide a scoring system of the pragmatic features of a trial. Suggested items included the recruitment of investigators and participants, setting, the treatment with flexibility in delivery and adherence, the nature of follow-up, and the analysis of outcomes [9].

Increasing the supply of PCTs in pain research and specifically in opioid use in chronic non-cancer pain, is dependent on the development of criteria to establish priorities for these studies, on facilitation of appropriate infrastructures to conduct clinical research, on more interest by health care decision makers, other than an adequate economic support for these studies. Because PCTs focus on widely used treatments, there are concerns on the degree to which patients’ enrollment may add risk above the inherent risks of the treatments themselves. Thus, it is important to distinguish the incremental risks of the research from the inherent risks of the clinical situation in order to determine whether a study is of minimal risk [10]. Involvement of stakeholders in PCTs can help ensure that regulatory policies and practices are sustainable and able to support patient, clinician, healthcare system, and societal priorities. Clinical and health policy decision makers are the principal subjects who can make these changes.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a co-investigator on a grant to the research institute where they work for FDA-mandated post-marketing surveillance studies of long-acting opioids funding by a consortium of drug companies.

Additional information

Funding

This paper was not funded.