Science Translational Medicine

placebo-effect-one-a-day

Even when a medication works, half of its impact on a patient may be due to one aspect of the placebo effect: the positive message that a doctor provides when prescribing the treatment, according to a new study.

Researchers designed an elaborate study, in which 66 people suffering from migraine headaches were given either a placebo, or a common migraine drug called Maxalt. However, for each migraine attack the participants had during the study period, they were told something different. For example, they were told they were taking a placebo when they were actually taking Maxalt, or vice versa, and sometimes they were told the pill could be either Maxalt or a placebo.

The pain-relieving benefits of the migraine drug increased when patients were told they were taking an effective drug for the treatment of acute migraine. And when the identities of Maxalt tablets and placebo pills were switched, patients reported similar pain relief from placebo pills labeled as Maxalt as from Maxalt tablets labeled as a placebo, according to the study published January 8 in the journal Science Translational Medicine.

The results suggest that the information people have is as important as the effects of the drug in reducing pain, the researchers said.

“In many conditions, placebo effect is a big part of the effect of the drug,” said study researcher, Ted Kaptchuk, a professor of medicine at Harvard Medical School. In the new study, 50 percent of the drug’s effect could be attributed to the placebo effect, he said.

“Themore you give a positive message, the more a drug works. In this case, our message was just as important as the pharmacology of the drug,” Kaptchuk said.

In other words, patients may benefit from optimistic messages from their doctors, which may enhance the effectiveness of a good pharmaceutical, the researchers said.

“When doctors set patients’ expectations high, Maxalt [or, potentially, other migraine drugs] becomes more effective,” said study researcher Rami Burstein, a professor of anesthesia at Harvard Medical School. “Increased effectiveness means shorter migraine attacks and shorter migraine attacks mean that less medication is needed,” Burstein said.

However, physicians should be realistic when prescribing a treatment, Kaptchuk said.

“The medical community should consider what’s the positive message that is still accurate, and not an exaggeration that verges on deception,” he told LiveScience.

Migraine attacks are throbbing headaches, usually accompanied by nausea, vomiting and sensitivity to light and sound. The researchers decided to look at migraine, because it is a recurring condition, and responds well to medication, Kaptchuk said.

During the study, the participants had a total of 450 migraine attacks. Each time they were provided with one of the six available treatments: two were made with positive expectations (envelopes labeled “Maxalt”), two were made with negative expectations (envelopes labeled “placebo”), and two were made with neutral expectations (envelopes labeled “Maxalt or placebo”).

But within each of these conditions, the envelopes contained either the placebo or Maxalt. The patients then reported their pain experiences.

“When patients received Maxalt labeled as placebo, they were being treated by the medication — but without any positive expectation,” Burstein said.

For both placebo and Maxalt, patients reported great pain-relieving effects when the envelope was labeled “Maxalt.” This suggests that a positive message and a powerful medication are both important for effective clinical care, the researchers said.
The placebo effect is centered on the idea that a person’s expectations and beliefs drive changes in symptoms, even though they have received a sugar pill or a sham treatment with no effect. Knowing that they have received a placebo changes their expectations, which is expected to alter the placebo effect.

However, people in the study also reported pain relief even when they knew the pill they were receiving was a placebo, compared with no treatment at all.

This finding “contradicts the medical beliefs,” Kaptchuk said. “Because in medicine, we think you have to think it’s a real drug for placebo to work. But apparently, the body has memories, or an embodied awareness, which operates below the level of consciousness.”

One possible mechanism for this effect could be that the body is conditioned to react positively in medical situations, Kaptchuk said.

“We know from other studies that the symbols, the rituals and the words of medicine activate the brain to release neurotransmitters that change the experience of illness. It activates centers in the brain that modulate many symptoms like pain and nausea and fatigue,” he said.

http://www.livescience.com/42430-placebo-effect-half-of-drug-efficacy.html

sn-sleep

Hitting the wall in the middle of a busy work day is nothing unusual, and a caffeine jolt is all it takes to snap most of us back into action. But people with certain sleep disorders battle a powerful urge to doze throughout the day, even after sleeping 10 hours or more at night. For them, caffeine doesn’t touch the problem, and more potent prescription stimulants aren’t much better. Now, a study with a small group of patients suggests that their condition may have a surprising source: a naturally occurring compound that works on the brain much like the key ingredients in chill pills such as Valium and Xanax.

The condition is known as primary hypersomnia, and it differs from the better known sleep disorder narcolepsy in that patients tend to have more persistent daytime sleepiness instead of sudden “sleep attacks.” The unknown cause and lack of treatment for primary hypersomnia has long frustrated David Rye, a neurologist at Emory University in Atlanta. “A third of our patients are on disability,” he says, “and these are 20- and 30-year-old people.”

Rye and colleagues began the new study with a hunch about what was going on. Several drugs used to treat insomnia promote sleep by targeting receptors for GABA, a neurotransmitter that dampens neural activity. Rye hypothesized that his hypersomnia patients might have some unknown compound in their brains that does something similar, enhancing the activity of so-called GABAA receptors. To try to find this mystery compound, he and his colleagues performed spinal taps on 32 hypersomnia patients and collected cerebrospinal fluid (CSF), the liquid that bathes and insulates the brain and spinal cord. Then they added the patients’ CSF to cells genetically engineered to produce GABAA receptors, and looked for tiny electric currents that would indicate that the receptors had been activated.

In that first pass, nothing happened. However, when the researchers added the CSF and a bit of GABA to the cells, they saw an electrical response that was nearly twice as big as that caused by GABA alone. All of this suggests that the patients’ CSF doesn’t activate GABAA receptors directly, but it does make the receptors almost twice as sensitive to GABA, the researchers report today in Science Translational Medicine. This effect is similar to that of drugs called benzodiazepines, the active ingredients in antianxiety drugs such as Valium. It did not occur when the researchers treated the cells with CSF from people with normal sleep patterns.

Follow-up experiments suggested that the soporific compound in the patients’ CSF is a peptide or small protein, presumably made by the brain, but otherwise its identity remains a mystery.

The idea that endogenous benzodiazepinelike compounds could cause hypersomnia was proposed in the early 1990s by Elio Lugaresi, a pioneering Italian sleep clinician, says Clifford Saper, a neuroscientist at Harvard Medical School in Boston. But several of Lugaresi’s patients later turned out to be taking benzodiazepines, which undermined his argument, and the idea fell out of favor. Saper says the new work makes a “pretty strong case.”

Based on these results, Rye and his colleagues designed a pilot study with seven patients using a drug called flumazenil, which counteracts benzodiazepines and is often used to treat people who overdose on those drugs. After an injection of flumazenil, the patients improved to near-normal levels on several measures of alertness and vigilance, the researchers report. Rye says these effects lasted up to a couple hours.

In hopes of longer-lasting benefits, the researchers persuaded the pharmaceutical company Hoffmann-La Roche, which makes the drug, to donate a powdered form that can be incorporated into dissolvable tablets taken under the tongue and a cream applied to the skin. One 30-something patient has been taking these formulations for 4 years and has improved dramatically, the researchers report in the paper. She has resumed her career as an attorney, from which her hypersomnia had forced her to take a leave of absence.

The findings are “certainly provocative,” Saper says, although they’ll have to be replicated in a larger, double-blind trial to be truly convincing.

Even so, says Phyllis Zee, a neurologist at Northwestern University in Evanston, Illinois: “This gives us a new window into thinking about treatments” for primary hypersomnia. “These patients don’t respond well to stimulants,” Zee says, so a better strategy may be to inhibit the sleep-promoting effects of GABA—or as Rye puts it, releasing the parking brake instead of pressing the accelerator.

The next steps are clear, Rye says: Identify the mystery compound, figure out a faster way to detect it, and conduct a larger clinical trial to test the benefits of flumazenil. However, the researchers first need someone to fund such a study. So far, Rye says, they’ve gotten no takers.

http://news.sciencemag.org/sciencenow/2012/11/putting-themselves-to-sleep.html

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Category: Science Translational Medicine

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