Clinical Research: Phase 1 - Phase 4

The Placebo Problem, Part 3: Psychological Underpinnings

This is the third installment of our look at the increasingly high placebo response that is plaguing clinical trials in analgesia and psychiatry. Additional posts in the series can be accessed here.

Solutions to the placebo problem require an understanding of the underlying mechanisms. Broadly, research on contributors to the placebo response falls into two categories: psychological and neurobiological. This week, we’ll explore the former, taking a look at the theoretical constructs and empirical findings that contribute to the placebo response.

This, that, or both?
Historically, the best accepted psychological theory underlying the placebo response has been patient expectancy, where a patient’s belief that he or she will get better drives symptom improvement. This belief may be pre-existing as a result of the patient’s past experiences, or based on information from the current therapeutic environment gleaned prior to placebo administration.

Classical conditioning, too, has long been implicated in the placebo response, and is often viewed as an alternative to patient expectancy. According to the conditioning theory, a prior association between the therapeutic environment and the active drug produces a memory that causes the patient to respond to the environment as if it were the drug. Pavlov and his famous dogs provided one of the earliest demonstrations of this effect in 1927. He paired morphine, known to induce restlessness in dogs, with a bell, then later showed that the sound of the bell alone could recreate the animals’ restlessness.

More recently, a unified theory that marries the dual role of expectancy and conditioning, and which characterizes the placebo response more broadly as a learned phenomenon, has been presented. In this model, a combination of verbal, conditioned, and social observational cues trigger patient expectancy of symptom improvement that in turn drives central nervous system (CNS) responses.

Spoken and unspoken
The majority of research on the role of learned cues in the placebo effect has focused on placebo analgesia. Verbal cues, such as an explicit statement made by trial staff that a placebo is actually a potent analgesic, are always consciously perceived by the patient. In contrast, the patient may or may not be aware of the contextual elements of the therapeutic environment – for example, the clinician in a white coat or the specific characteristics of the treatment room – to which he or she becomes conditioned. However, research shows that while verbal and conditioned cues can each induce placebo relief from pain, itch, nausea, and fatigue on their own, pairing them together elicits the largest response.

Verbal and conditioned cues involve first-hand experiences; however, placebo analgesia can also be learned through social observation. For example, having study participants merely watch a video of a person reporting less pain following a placebo is enough to induce an effect in the observers.

New research is underway to examine the contributions of other psychological variables, such as motivation, empathy, anxiety, and attention, to the placebo response. Join us next week for the fourth installment of our Placebo Problem series, where we’ll dissect the extensive literature on the neurobiological mechanisms underlying the placebo response.

If you’d like to read more, the part 4 is available here.