Clinical Research: Phase 1 - Phase 4

The Placebo Problem, Part 1: Overview

For hundreds of years, the medical community has known that the mere act of receiving treatment, even if it’s just a sugar pill, can improve a patient’s symptoms. Therefore, in order to ensure that the effects of an experimental treatment are real, most randomized controlled trials (RCTs) include a placebo arm.

Placebos are most often pharmacologically inactive pills that mimic the physical characteristics of the study drug, but they can also take the form of inert medical devices, sham surgeries, and fake acupuncture. The placebo effect is broader than just patient improvement in response to this inactive treatment; it encompasses the patient’s response to the entire therapeutic context in which treatment is administered.

Details matter
There is actually not one single placebo effect, but many, all of which come together to produce symptom improvement through mind-brain responses to treatment context. Psychosocial factors such as expecting to get better, rituals of care, active engagement in treatment, and even the mere act of taking a pill can all contribute to the placebo response. Research has also shown that how the placebo is administered is just as important as what is administered. The type of placebo, the color and dosing regimen of pills, and how caring the physician acts can all influence the magnitude of the response.

Although the placebo effect was once thought to be an irrelevant and illegitimate nuisance, it is now a field of research in its own right. Multiple brain systems and neurotransmitters underlie the many components of the placebo effect, and a growing body of literature has shown that it improves health in a number of very real ways. The placebo effect doesn’t cure – it won’t shrink a tumor or heal a broken bone – but it can relieve chemotherapy-induced nausea and diminish chronic pain. It can also produce changes in physiological functions such as heart rate, blood pressure, lung function, and gastric motility, and can even lead to improved survival rates in some diseases. In general, the placebo response is most effective at relieving pain and improving depression, anxiety, and fatigue – all conditions in which symptoms are self-reported and psychological distress plays a significant role.

Placebo…uh oh
In an RCT, the true effects of the experimental treatment are those that are above and beyond the placebo response. But there is an inherent problem in this design: the bigger the placebo response, the harder it is to show that an experimental treatment is effective. Ultimately, these reduced drug-placebo differences result in a higher likelihood of a negative trial outcome despite drug effectiveness. Such late stage trial failures come at a great financial cost to pharmaceutical companies and can lead to an erroneous abandonment of viable drugs.

Indeed, a large placebo response has been the downfall of a number of major clinical trials with solid preclinical and prior clinical evidence of efficacy. In an analysis of 52 antidepressant trials that examined the relationship between placebo response magnitude and trial outcome, trials with a low placebo response fared much better than those with a high placebo response. In high placebo response trials, only 20 percent of treatment arms achieved significance, compared to 75 percent in low placebo response trials.

The magnitude of the placebo response has also been deemed the biggest contributor to trial outcome in neuropathic pain, and a high placebo response is thought to be partially to blame for the fact that more than nine out of ten late-stage trials of treatments for neuropathic and cancer pain have failed over the last decade.

Even more alarming is the fact that the placebo response is growing over time, especially in analgesic, antipsychotic, and antidepressant trials. Strangely, this increasing effect seems to be specific to the U.S., at least for trials of neuropathic pain.

Continue on to part two. In the coming weeks, we’ll be examining issues surrounding the placebo response and its rise in more detail. Our Placebo Problem series will first explore how and why the placebo effect is growing over time. We’ll then turn to the psychological and neurobiological mechanisms that are responsible for its effects. Next, we’ll look at how the placebo effect can be accurately measured in studies and the latest research on strategies to reduce it. Finally, we’ll discuss some the placebo’s opposite, the nocebo effect, where the brain’s response to treatment context negatively impacts health, as well as some ethical considerations of placebo use.