The real – and growing – effects of fake pills

Most of us think of a placebo as a simple psychological trick – a fake pill might give us hope, but it produces no real effects.

Yet, recent research has shown an increase in the placebo response over the past couple of decades. Just last week, the results of a new study published in the journal Pain suggest that a placebo can have real, even profound, physical benefits.

People with chronic lower back pain were recruited to participate in research at a public hospital in Lisbon, Portugal. First, they filled out questionnaires describing the intensity of their pain and their degree of disability.

The researchers randomly assigned the patients to two groups. One continued with treatment as usual: the nonsteroidal anti-inflammatory drugs (NSAIDs) they were currently taking to prevent pain. The other group received their usual pain drugs as well as placebo pills in a typical prescription medicine bottle. They were told that a placebo pill contained no medication, and the bottle’s label read “Placebo pills. Take 2 pills twice a day.”

“We were very careful about making sure that they understood that there was nothing in the pill that could affect pain,” said Irving Kirsch, senior author of the study and a professor at Harvard Medical School.

After three weeks, both groups filled out a second questionnaire about their pain. On average, the pain medication group experienced a 9% reduction in usual pain, a 16% reduction in maximum pain and no reduction in disability.

By contrast, the placebo group averaged a 30% reduction in both usual and maximum pain, while reporting nearly the same reduction, 29%, in disability.

Ritual and response

“We know that placebos are effective, and we have learned a lot about how they work,” Kirsch said. He explained how all of us have learned to associate the ritual of taking a medication with the effects of the medication, “just as Pavlov’s dogs had learned to associate the sound of a bell with food.”

These rituals can help activate our natural capacity to control pain. An added “sense of hope” allowed the patients to achieve greater relief beyond the medications they were already taking, he said.

Though the study has obvious limitations – it included only 83 patients and a short study period that did not take long-term effects into account – this is not the first time Kirsch has demonstrated a significant placebo effect in circumstances in which patients knowingly take fake pills.

A study published two years ago came to nearly the same conclusion. For this three-week study, Kirsch and his colleagues divided 80 people with irritable bowel syndrome into two groups. One group received no treatment, while the other group was given sugar pills and instructions to take them twice a day. Once again, Kirsch and his colleagues made it absolutely clear the pills had no active ingredient and printed “placebo” on the bottle.

At the end of the study period, nearly twice as many patients in the placebo group reported reduced symptoms as in the control group. According to Kirsch, the level of relief experienced by the placebo group equals that of patients taking the most powerful IBS drugs during past clinical trials for those medications.

Increasing placebo response

Psychology is at work in every clinical trial. The placebo effect is taking place for both the patients who receive a placebo as well as those who receive a real drug, according to Jeffrey Mogil, a professor in the department of psychology at McGill University.

Mogil recently researched whether the placebo responses in randomized control trials of pain drugs had increased over the years. The study was inspired by speculation among scientists that clinical trial participants were reporting greater responses to placebos.

“This is something that people were sort of whispering about at meetings,” he said.

So he and his McGill colleagues analyzed the results of 84 clinical trials conducted around the world between 1990 and 2013. Over the years, participants who received placebos in chronic pain studies reported greater improvements over time.

By 2013, placebo participants were reporting, on average, a 30% decrease in pain up from an average of about 18% in the 1990s.

Another finding: Americans were the main driver of this effect. In the US and nowhere else, trials had become longer (from an average of four weeks in 1990 to 12 weeks in 2013) and larger (from an average of 50 patients or fewer in 1990 to more than 700 patients in 2013).

“I think what’s driving this is contract research organizations,” Mogil said, explaining that these businesses did not exist at the beginning of the study period and now are increasingly doing clinical trials for pharmaceutical companies. According to Mogil, there may be something about a trial run by a contract research organization that produces a bigger placebo response.

“Frankly, I think they have a reason to be nicer to the participants in a clinical trial than your standard research nurse in a hospital does, and maybe that actually makes people better,” Mogil said, adding that the reason the US is an outlier is still unknown.

The boost in placebo response over time may not seem like a problem, but keep in mind that if placebo participants report greater improvements, it becomes more difficult to demonstrate the effectiveness of a drug. This affects whether pain-relief drugs get approved by the Food and Drug Administration, which takes into account how well a new drug stacks up against a placebo.

Notably, participants who received the actual drugs during these 84 clinical trials did not report increasingly positive results over time. Comparatively, then, drugs produced about 27% more pain relief than placebo in 1996 and slipped to just under 9% more pain relief by 2013, the study results indicated.

An unrelated Northwestern University study, published Thursday in the journal PLOS Biology, suggests the tendency to respond to placebos can be seen in MRI scans of the brain. The researchers found the brains of placebo responders with chronic pain share information differently than the brains of non-responders.

“The amount of information sharing for the right midfrontal gyrus was twice as large in placebo responders versus non responders,” said Apkar V. Apkarian, lead author of the study and a professor of physiology. Importantly, this result was replicated in a second investigation, he noted.

Placebos through time

The placebo effect is not only well-known, it is a phenomenon that has been put to good use for some time.

Doctors have long given demanding patients useless pills or ointments, according to Robert Jutte, a professor at the Institute for the History of Medicine in Germany. Usually, these pills were not “pure” placebos; instead, they were mostly mild medicines deemed powerless or largely ineffective in treating a condition. But the patient’s expectations are satisfied: No one wants to go home empty-handed.

Anesthesiologist Henry K. Beecher is given credit for developing the “double-blind trial,” in which patients are divided into groups that receive either the real drug or a placebo, without patients or doctors knowing who received what.

In a paper published in 1955, Beecher suggested that a placebo will have a real therapeutic effect in about 35% of cases. He also explained that his complex double-blind ruse was necessary during tests of new treatments to control the psychological variables at play.

Psychology is at work in every clinical trial. There is a placebo effect for both the patient who receives a placebo and the one who receives a real drug, according to Jeffrey Mogil, a professor in the department of psychology at McGill University. Our hopes and expectations color our experience, whether we take a placebo or a drug, he suggests.

The price of that placebo

The strength of placebo response is also influenced by other factors, including the form in which it is given and its price tag.

For instance, placebo shots work better than placebo pills, one team of Harvard researchers says. In six clinical trial studies, participants who were given placebo injections showed more of a response than those given placebo pills. The researchers believe their results are intriguing even if the underlying studies have some methodological flaws.

An unrelated University of Cincinnati study investigated how a patient’s assessment of the value of a placebo might influence their response.

“I was inspired by the marked improvement patients with Parkinson’s disease derive from unproven but costly interventions,” said Dr. Alberto J. Espay, lead author of the study and associate professor of neurology.

Espay’s study included 12 participants with moderately advanced Parkinson’s. First, the patients received one placebo in the form of a saline solution injection, and then they received a second identical placebo. Although the second shot was a duplicate of the first, the researchers referred to one as “expensive” and the other as “cheap.”

As most of us would guess, the placebo perceived by patients to be more expensive worked better than its seemingly lower-cost equivalent. “Perceptions of cost are capable of altering the placebo response,” concluded Espay and his co-researchers.