The placebo response: a hot topic for pain researchers?

The role of the placebo effect has become a focus in pain research due to its potential to reduce separation between the drug and control arms, and so influence the outcome in randomised controlled trials (RCTs).¹ In clinical trials of analgesics, failure to demonstrate benefit over placebo has been a common finding over the past years.² Many potentially effective analgesic compounds have been discarded in early drug development due to a lack of statistically significant reductions in pain reports in RCTs.² For example, in the past 10 years it has been estimated that over 90% of candidate drugs in development for neuropathic and cancer pain have been discontinued after failing to show superiority compared with placebo.³

Placebo responses and symptom relief: from expectation to measurable biological effects

Although medical understanding of placebo responses is still far from complete, it is known that for certain conditions, especially those with subjective symptoms, patients receiving placebos may report similar health benefits to participants taking effective drugs.⁴ Placebos have measurable effects on many symptoms, including pain, depression, fatigue, and other perceptions of bodily dysfunction.⁴ Several interlinked neuropsychological and neurophysiologic mechanisms driving symptom improvements in response to placebo are recognised:⁵

Priming and expectation: the patient believes that a particular intervention will provide benefit/relief. This expectation for the positive outcome seems to play a key role in placebo-related benefit, along with other factors such as optimism and social conditioning, and may produce a medium-sized benefit. Effects on brain activity: Functional imaging studies have confirmed that the placebo response of pain relief can be measured as neural activity documented in cortical areas directly associated with pain Inhibition.

Altered biochemical activity: Studies demonstrate that some placebo mechanisms operate by altering the activity of both cholecystokinin (CCK) and endogenous opioids. Other pain regulating pathways, for example involving dopamine and cannabinoid signalling, may also be involved in placebo responses. The growing body of evidence demonstrating objective physiologic responses to placebo (in terms of measurable alterations in brain and biochemical activity) indicates that improvement in symptoms is a genuine effect, rather than simply spontaneous remission, normal symptom fluctuation, or regression to the mean.⁶ Are patients’ rising expectations for new pain medicines influencing trial outcomes?

A retrospective analysis of data from 84 published RCTs of drugs for the treatment of chronic neuropathic pain found that the placebo response (in terms of a reduction in pain) has grown over time: from an average of about 18% in the 1990s to an average of 30% by 2013.¹ In contrast, the drug response remained stable, leading to a diminished treatment advantage. The authors attributed the increased placebo response to differences in the execution of trials within the US over this period – in particular, the growth in study size (from on average 50 patients per study in 1990, to over 700 per study in 2013), study duration (from on average 4 weeks per study in 1990 to 12 weeks in 2013) and the introduction of contract research organisations, whose clinical trialists may have provided more one-to-one support to patients than they would have received through routine care in primary/secondary care. These changes in trial format may enhance participants’ expectations of the treatment’s effectiveness.⁷ Similarly, exposure to direct-to-consumer advertising for medicines in the US may increase people’s expectations of the benefits of drugs, and has been proposed as a possible reason why the trend of a rising placebo response was observed in US neuropathic pain trials.³

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