Long after cancer has left the body, many survivors say that one particular symptom refuses to go away: fatigue. Few treatments are available, and the most effective come with side-effect warnings that include panic, psychosis and heart failure. But in a new pilot study, researchers at UAB have found a surprisingly effective therapy: paper pills.

The pills are made of cellulose, to be precise, although their contents have no "active ingredient," pharmacologically speaking. As the researchers told participants right up front, they are simply placebos – inert pills.

In a paper published in Scientific Reports, however, the UAB investigators found that cancer survivors who knowingly took these placebo pills reported significant benefits: a 29 percent improvement in fatigue severity, and a 39 percent improvement in fatigue-disrupted quality of life. "And they still had benefits three weeks out" – that is, after they stopped taking the placebo pills – "which hasn't been shown before," says Kevin Fontaine, PhD, chair of the Department of Health Behavior in the UAB School of Public Health, who co-authored the paper.

"That caused the most excitement about our results in the placebo community," adds Teri Hoenemeyer, PhD, a scientist and director of Education and Supportive Services at the UAB Comprehensive Cancer Center. The research was carried out as an extension of Hoenemeyer's dissertation project for her doctorate in health behavior.

"Patients and survivors report that fatigue is the most distressing symptom they experience after a cancer diagnosis. It's even more distressing to them than other symptoms like nausea or pain." In a new UAB study, however, participants who took placebo pills reported a 29 percent improvement in fatigue severity and a 39 percent improvement in fatigue-disrupted quality of life.

First in cancer

This is the latest in a series of studies of "open-label" placebos – placebos given to participants who are expressly told that the pills have no active ingredients. The leader in this field is Harvard Medical School Professor Ted Kaptchuk, director of the Harvard-wide Program in Placebo Studies and the Therapeutic Encounter. Kaptchuk, who was a co-author on the current UAB study, has shown that open-label placebos can bring relief to patients dealing with conditions for which there are few effective treatments, including irritable bowel syndrome, chronic low-back pain and migraine headache.

UAB's study is the first to apply this concept to cancer survivors. But it is a natural fit, considering that so many survivors struggle with fatigue – and clinicians struggle to find ways to help them, Hoenemeyer notes. "The majority of patients receiving treatment for cancer experience moderate-to-severe fatigue, and for 30 to 50 percent of those patients, the fatigue can extend out to 10 years post-treatment," she says. "Patients and survivors report that fatigue is the most distressing symptom they experience after a cancer diagnosis. It's even more distressing to them than other symptoms like nausea or pain."

Study participants received pills just like these, clearly labeled with their (inactive) ingredients.

Placebo power

The study involved 74 cancer survivors, with a range of different cancer types, who had completed treatment 6 months to 10 years prior to enrollment. Each reported at least moderate fatigue (four or higher on a 10-point scale). Half were randomized to treatment as usual. The other half were asked to take two cellulose pills, twice per day, for three weeks.

"We explained to the study participants how we thought it might work – through conditioning," Hoenemeyer says. "For instance, through conditioning patients learn that by taking a pill, or even making a phone call to the doctor, they begin to feel better. That's because once a patient becomes engaged in their care, they begin to pay more attention to how they feel and factors that might impact that, like fatigue and stress or anxiety. For some, it's an automatic response."

"Think of watching a horror film," Fontaine adds. "You know it isn't real, but your body still reacts. There's a physiological response: your heart beats faster and you break into a sweat. There could be something similar going on through your positive association with taking a pill, even though it's non-conscious."

At the beginning of the study, the researchers asked participants what they thought about the odds of success. They were surprised to find that the responses didn't correlate to the eventual study outcomes. "It did not matter what they thought about placebos," Hoenemeyer says. "Some people who thought it wouldn't do anything had a good response; others who believed it would help didn't have a response."

Finding a "placebo response gene" could help target placebo therapy to those most likely to benefit. It would also be of great interest to industry.

Seeking genetic links

One possibility is that genetic factors could lead some people to benefit. Kaptchuk's research at Harvard has identified several genes that are associated with positive placebo response. In the UAB study, the researchers obtained samples from participants to see if they could replicate those results. They are analyzing that data now.

Finding a "placebo response gene" could help target placebo therapy to those most likely to benefit. It would also be of great interest to industry. "Drug companies would love to screen these people out," says Fontaine. "In studies evaluating drugs to treat pain, it is common for about 30 to 40 percent of the people on placebo to report a significant reduction in pain. If you can enroll study participants who will not respond to the placebo, the effects of the drug will look more impressive."

Funding difficulties

Although placebo research has implications for improved patient care and clear economic potential, the lack of a clear mechanism to explain the effects of placebos leaves many in the scientific field uneasy. "Several years ago, we received a perfect score on a placebo grant submitted to the National Institutes of Health, but it wasn't funded because they said that 'the study moves us too far away from what we understand about placebo effects,'" Fontaine says. "Since that time, we've submitted several other placebo grants, but it's been hard to overcome the skepticism of reviewers. We hope that the results of this study with cancer survivors, combined with the application of emerging technologies related to genetics and neuroimaging to investigate potential mechanisms, will appeal to reviewers and funding agencies. However, I'm realistic. We are swimming against the tide with this type of research, so, it may well be that the only way to advance this work will be through philanthropy."

Using placebos to help patients avoid the addictive problems of opioid pills for pain is an area with promise.

Future directions: opioids and telemedicine

Another area of future research for Fontaine and Hoenemeyer involves "dose extension." "I'm very interested in the idea of pairing a drug with a placebo," Fontaine notes. "Then over time reducing the dose of the drug while maintaining or increasing the dose of the placebo pills and seeing if you can still get the same effect."

Using placebos to help patients avoid the addictive problems of opioid pills for pain is an area with promise, Fontaine says. Another candidate for placebo research are immunosuppressive drugs with strong side effects, such as HIV medicines. "One short-term study paired a placebo with an immunosuppressive drug, and the participants still had immunosuppression, even though they eventually were only taking the placebo," Fontaine says.

"We're also excited about doing this through telemedicine," Fontaine adds. "UAB is developing a large telemedicine system, and the Alabama Department of Public Health has a robust system already. Does it make a difference if you offer placebos through telemedicine instead of in person? We'd like to know."