Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments

Abstract

Introduction:In the field of pain research, clinical trials may randomize over 500 subjects and include more than 150 sites spanning over a dozen countries.Methods:This review examines the ethical considerations affecting clinical trial design, execution, and analysis of trials for chronic pain. The Belmont Report has been the touchstone for human studies protection efforts since 1979. Commissioned by the U.S. government in response to ethical failures in medical research, such as the Tuskegee Syphilis Study, the report emphasizes 3 basic principles: respect for persons, beneficence, and justice. Trial design and sample size have important ethical implications.Conclusions:Measures to enhance trial transparency and combat publication and many other types of bias should be implemented.

Recruitment and retention for chronic pain clinical trials: a narrative review

“… 55 A balancing act exists, however, between providing sufficient rescue relief to retain participants in a study, but not so much that data noise invalidates the treatment effect estimate 55 or contributes to false-negative results. 115 In a study of patients with fibromyalgia, 72% said that allowing only acetaminophen for breakthrough pain in a clinical trial was a “very poor” idea. 64 Although use of NSAIDs was later allowed in the control arm of that study, this option may still prove unacceptable to some prospective participants and could result in lower enrollment and more participant withdrawals.…”

“…Likewise, the design decision to remove early on those patients with a high placebo response (in an effort to improve assay sensitivity) could have a significant negative impact on recruitment, 38 in addition to reducing translatability to clinical practice. 39,119,126 Investigators should consider that although there may be ethical considerations regarding placebo treatment when potentially effective treatments are available, 38,115 increased use of rescue medication in the placebo group vs the drug treatment group may in itself provide evidence of a stronger response to the investigational drug. 54 One solution, used in the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial, is to replace the placebo with some other form of pain treatment and compare the 2 groups.…”

Clinical outcome assessment in clinical trials of chronic pain treatments

“…Systematic monitoring of rescue medication use and concomitant use of pain treatments during the course of a chronic pain clinical trial is necessary for appropriately interpreting trial results and is recommended as a core outcome measure by IMMPACT. 37 As noted by Rowbotham and McDermott 122 in their article in this supplement, pain relief derived from rescue medication can reduce assay sensitivity. Therefore, the amount (dose), date taken, and reason for the rescue medication use (ie, to differentiate relieving pain for the condition being investigated or some other reason such as a transient headache or dental pain) should be systematically recorded (ideally at the time the medication is taken).…”

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants

“…These include the responsibilities of investigators and the importance of informed consent, as well as institutional and national regulations for study review and approval. Rowbotham and McDermott 12 begin part I of the ACTTION Guide by discussing several important ethical considerations involving clinical trials of pain treatments. Although these RCTs share numerous ethical considerations with clinical trials in many other medical conditions, there are also unique challenges; for example, rescue pain treatments should be provided for patients with unacceptable levels of pain, but doing so has the potential to reduce the study's ability to show a difference between the active and the placebo or sham intervention.…”