Study Design

How to Mitigate the Placebo Response in Analgesia Clinical Trials

The placebo effect can be problematic in analgesia clinical trials with a symptom-based approach, as placebo-related analgesic responses may occur and persist for some time in up to 60 percent of study participants.1 In chronic pain studies, it is generally assumed that the placebo effect accounts for approximately 30 percent of the analgesic response.2 The etiology of the placebo effect is multifactorial and includes an expectation of benefit, response bias, and psychological or cultural factors. Our first blog covered key considerations surrounding the use of placebo control in chronic pain studies. Here, we explore how trial designs and training programs may be used to help reduce the placebo effect in analgesia clinical trials.

Trial design

Incorporating a placebo run-in period in the study design is one approach for mitigating the placebo effect. During the placebo run-in period, all subjects are given a placebo but are characterized as using an active drug. Those patients who demonstrate a pre-specified level of improvement in their pain at the end of the run-in are classified as high placebo responders and discontinued from the trial. Unfortunately, a meta-analysis revealed that using a placebo run-in period did not lead to meaningful reductions in the placebo response or increase the odds of a positive study.3

An alternative approach that has been employed is a two-phase, sequential parallel comparison trial design. In the first phase, participants are randomized to either placebo or active treatment. Placebo non-responders move on to the second phase, where they are again randomized to either placebo or active treatment. The final analysis includes pooled data from both phases.

Other strategies include:

  • Selecting for drug responders
  • Making high variability in baseline pain reports a criterion for exclusion
  • Applying the assumption of additivity and subtracting the response in the placebo arm from the response in the active treatment arm to determine the effect of the investigational product

Training programs

Training programs can be used to target multiple factors that contribute to the placebo effect and can be aimed at both subjects and study staff to help reduce response biases.

Expectation of benefit. Subjects are more likely to report improvements in pain if they believe they have received an active drug rather than the placebo. Two meta-analyses have shown that measuring the expectations of subjects toward treatment is predictive of outcome.4 The key to mitigating expectation of benefit is dampening expectations. Special training programs have been developed to teach subjects how to neutralize their expectations and how to maximize the objectivity of their pain ratings.

Response bias. This type of bias occurs when a subject’s responses are skewed by what they think will please study staff. Subjects often build a rapport with staff over the course of a clinical trial, and they tend to believe that reports of pain improvement will be received more positively. Study staff may also contribute to response bias if they respond more favorably to reports of pain improvement.5Training programs designed for subjects and staff can help mitigate these biases. For subjects, these programs typically emphasize accuracy of reporting and proper, consistent use of pain assessment tools. For staff, training focuses on strategies for increasing neutrality in patient interactions and avoiding leading questions.

Psychological or cultural factors. These factors are highly variable and difficult to modify. However, attempts have been made to correlate certain psychological and cultural factors with the likelihood of placebo response so that adjustments can be applied during data analysis to measure the effect of the investigational product.

Key takeaway

A review of published chronic neuropathic pain trials found that placebo responses have become more pervasive, making it more challenging to definitively demonstrate treatment advantage.6 To optimize the likelihood of positive studies, sponsors must understand the causes of the placebo effect and design mitigation strategies accordingly.

To take a deeper dive into the nuances of placebo control in analgesia clinical trials, download our new white paper Placebo Considerations in Chronic Pain Studies.

Premier Research has performed more than 870 trials across nearly every type of pain and major class of analgesics, including every NSAID analgesic on the market today. Contact us to schedule a conversation with one of our experts and leverage our experience as you tackle the most innovative areas of analgesia research.


1 Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The importance of placebo effects in pain treatment and research. JAMA. 1994;271(20):1609-14.

2 Vachon-Presseau E, et al. Brain and psychological determinants of placebo pill response in chronic pain patients. Nat Commun 2018;9:3397.

3 Lee S, et al. Dose elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depress Anxiety 2004;19(1):10-19.

4 Vase L, Warolowska K. Pain, placebo, and test of treatment efficacy: a narrative review. Br J Anaesth 2019;123(2):e254-e262.

5 Kam-Hansen S, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med 2014;6(218):218ra5.

6 Tuttle AH, et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain 2015;156(12):2616-2626.