Mind over Medicine: A New Look at The Placebo Effect
Studies of the effects of suggestion help researchers map basic brain pathways affecting pain, endurance and response to disease

October 30, 2008

Researchers usually consider placebo effects a nuisance because of their potential to distort patients’ responses to drugs in clinical trials. But recent studies of the effects have shown their potential power in the clinic and have provided insights into some of the brain’s most basic pathways.

“We are beginning to understand how words and rituals change brain chemistry and circuitry,” says Fabrizio Benedetti, a neuroscientist at the University of Turin who has been in the forefront of placebo research over the past decade. Such words, rituals, or pills with no medical value act as placebos when a patient accepts them as medicine or therapy. Any improvement patients show due to placebos is thought to be based on the power of suggestion.

The secret door to pain relief

Pain control is by far the best-studied application for placebo effects. “Placebo analgesia” works by tapping into a neural sensation-control system, based on expectations about the future, that allows us to endure a present painful situation—combat, for example—for the sake of an eventual, greater reward.

 It is only in the past two years that this connection between placebo expectations and the brain’s reward/punishment circuit has been confirmed. In July 2007, researchers led by David Scott, in the laboratory of John-Kar Zubieta at the University of Michigan, reported in the journal Neuron that placebo pain relief in volunteers was associated with activity in the same brain areas stimulated by an expected monetary reward—and that the strength of the response in both cases was modestly correlated.

Studies such as these suggest that the expectation of pain relief causes neurons in the reward/punishment circuit to pump the neurotransmitter dopamine into key brain areas such as the nucleus accumbens, stimulating the release of endogenous, morphine-like painkillers known as mu-opioids.

However, as both Zubieta’s and Benedetti’s groups have shown, individuals often vary considerably in their neurochemical responses and in their degrees of reported pain relief. In the Neuron study, some subjects experienced no significant placebo-effect pain relief. And a few even reported a worsening of pain, which researchers have termed the “nocebo” effect. The nocebo effect appears to be mediated by a separate, pain-associated neurotransmitter known as cholecystokinin (CCK). 

“Negative expectations induce anticipatory anxiety about the pain increase, and it is this anticipatory anxiety that triggers the activation of CCK receptors,” says Benedetti. He and his colleagues reported in 1995 that a CCK-blocking drug enhances the pain-relieving effect of a placebo, which suggests that CCK normally is present during placebo analgesia and counteracts that pain relief to a degree that depends largely on the patient’s anxiety level. Benedetti and others are investigating the possible use of CCK-blocking drugs for use in pain syndromes that may be worsened by anxiety.

Endogenous medicine?

The use of placebo-treated reference groups in clinical trials has become virtually mandatory over the past several decades, under the assumption that the placebo effect can modulate not just pain but any other disease. Moreover, recent international surveys suggest that many general practitioners deliberately use placebo-like medicines (such as antibiotics for colds) at least occasionally and informally, to calm anxious patients when their symptoms seem psychosomatic or are not serious enough to require expensive treatment. Yet some researchers have strongly challenged this assumption.

In 2001, two Danish researchers, Asbjørn Hróbjartsson and Peter Gøtzsche, published a review of 114 clinical trials in which placebo-treated groups could be compared with no-treatment groups. Their conclusion, which they repeated in an updated study published in 2004, was that the placebo effect appears to be insignificant against most diseases, and at best may affect only “subjective” outcomes such as pain.

Others have contended that the Hróbjartsson and Gøtzsche analyses were done in a way that effectively blurred the evidence for placebos’ real effects. But even proponents of the idea that placebos can be powerful concede that not every condition may be susceptible to them. “Placebos have never been shown to be effective against cancer growth, bleeding or trauma,” for example, Benedetti notes, though he adds that even in these conditions the possibility of placebo effects is worth studying.

In principle, there is still a lot of room for the use of placebos. A study by Benedetti and colleagues in 2001, for example, suggested that placebos could be used to reduce the doses of standard painkillers. In the study, postoperative patients were offered a standard opioid painkiller, buprenorphine, on demand for three days, along with an intravenous saline solution. Some patients were not told that the saline solution had a painkilling effect. Others were told that a test was being conducted and that the solution could contain either a placebo or painkiller. A third group was told, falsely, that the solution contained a potent painkiller. As a result, over the three days requests for buprenorphine were highest in the first group, about 20 percent lower in the middle group, and about 50 percent lower in the group that had been told they were receiving a potent painkiller—yet despite these widely differing doses, all three groups reported a net painkilling effect that was essentially the same.

In another study by Benedetti’s lab, placebo analgesia was measured more precisely, by comparing postoperative oral surgery patients’ reports of pain relief in two conditions. In the first condition, patients were given placebos described as powerful painkillers. In the second condition, patients were given morphine in secret, through a computer-controlled infusion pump—thus isolating morphine’s actual effect by removing the element of expectation. Benedetti and his colleagues found that in terms of pain relief, an overtly administered placebo was equivalent to about 6 mg to 8 mg of covertly administered morphine.

“When you inject a painkiller [overtly] there is no way to know whether it acts on pain pathways or rather on expectation pathways,” concludes Benedetti.

Relatively few studies of placebo have had the same kind of clinical relevance, but those that do suggest that the placebo effect can go well beyond pain relief. In trials of candidate drugs for Parkinson’s disease, for example, the placebo group often shows sustained improvements in symptoms compared to baseline disease levels. In 2001, Canadian researchers confirmed in a study published in Science that the administration of placebo to people with Parkinson’s disease caused a spike in dopamine levels like that seen when standard Parkinson’s drugs are given—and patients with a greater dopamine response were more likely to report a reduction in Parkinsonian motor symptoms.

Animal studies have shown that the immune system can be modulated via an unconscious kind of placebo effect, by first “conditioning” it with an immunologically active drug. In a 1999 study, National Cancer Institute researchers in Maryland found that a similar effect can be obtained in humans. Initially giving 31 volunteers interferon-gamma, a powerful immune stimulant, with polyethylene glycol as a placebo, they reduced the doses of interferon to zero over four weeks and found that the immune response was largely maintained by the placebo alone. Meanwhile a control group that received the same dwindling doses of interferon without placebo experienced the expected decay in immune response.

Hypnosis and placebo effects—what’s the difference?

Hypnosis also involves tapping into the nervous system through cognitive processes, and in the past 150 years or so it has seen a great deal of use for pain control and even surgical anesthesia. However, although hypnosis and the placebo effect both involve suggestion and might therefore be expected to stimulate pain control via the brain’s reward pathway, evidence suggests that they are separate phenomena. More than one study has demonstrated that naloxone, a drug that blocks opiate receptors in the brain and also blocks placebo pain relief, fails to block hypnotic pain relief. Other studies indicate that even when hypnotized subjects report an absence of pain during a pain stimulus, other physiological signs of pain are evident, which in turn suggests that hypnosis somehow specifically impairs the conscious perception of pain.

The future of placebo effect research

The pace of research into placebo and nocebo effects has been increasing, and as it does, the reasons for studying them—and worrying about their implications—seem to be multiplying. This past July, for example, Benedetti and his colleagues reported that a placebo could boost power and endurance in volunteers’ muscles as if they had been given high-dose caffeine—a result suggesting that a positive attitude can affect athletic performance. The researchers also showed that this muscle-boosting effect can be increased by a prior conditioning process, implying that learning mechanisms are important too—and also implying that athletes can get a “doping” effect without having any trace of banned chemicals in their blood.

Other research into placebo effects is driven by the fact that the variation in placebo/nocebo responses from person to person could explain much of the variation in how people respond to disease. Understanding why these response variations exist, and repairing or optimizing the circuits that control the response, could represent a new dimension in medicine.

Finally, researchers are beginning to focus on the fact that the essence of a placebo is not a pill or any other physical ingredient but, rather, information. “Many doctors and health care professionals effectively make use of the placebo response by treating patients with empathy, using healing rituals and verbal and nonverbal reinforcers that support the action of prescribed medication,” says Paul Enck, a specialist in psychosomatic medicine at the University of Tübingen in Germany and co-author of a review of the placebo effect in the July issue of the journal Neuron. “They may not even be aware, and they may not be happy if they become aware, that in so doing they utilize the placebo response for the patient’s benefit.”

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