Sunday, October 12, 2014

Placebos and Super Placebos: Medical Procedures and Drugs

The following is a good dictionary definition of the term “placebo.”

“a substance that is not medicine but is given to a patient who supposes it to be a medicine, either to appease a patient or as a control in an experiment”

The experiments referred to are generally clinical trials being run to determine the efficacy of a drug in treating a particular medical condition.  These trials are required to test medicines against a placebo because of the “placebo effect.”  If you give a sick person a pill and tell them it might make them feel better, there is a tendency for the person to feel as though they have improved even if the pill contained no medication at all.  This means that if you do give a person a specific medication she might feel better from this placebo effect rather from any actual medical change.  Consequently, medications are generally tested against placebos by giving a fraction of the patients a placebo and a fraction the actual medication.  The participants in these studies are aware that they may receive a placebo.

For this type of testing to work, the subjects cannot know whether they are given the actual medication or some inert substitute.  Generally, those performing the study will not know either in order to prevent inadvertent clues being provided to the subjects.  This process seems straightforward in principle, but it can be complicated in practice.

Aaron E. Carroll provided an interesting article in the New York Times that tells us that placebo effects are applicable to more than drug delivery: The Placebo Effect Doesn’t Apply Just to Pills.  Carroll provides examples where mock surgical procedures were performed in order to determine the existence of a placebo effect.

“At the turn of this century, arthroscopic surgery for osteoarthritis of the knee was common. Basically, surgeons would clean out the knee using arthroscopic devices. Another common procedure was lavage, in which a needle would inject saline into the knee to irrigate it. The thought was that these procedures would remove fragments of cartilage and calcium phosphate crystals that were causing inflammation. A number of studies had shown that people who had these procedures improved more than people who did not.”

A number of people were suspicious that these procedures might not actually be effective.  In 2002 a study was performed with the equivalent of a placebo control.

“A total of 180 patients who had osteoarthritis of the knee were randomly assigned (with their consent) to one of three groups. The first had a standard arthroscopic procedure, and the second had lavage. The third, however, had sham surgery. They had an incision, and a procedure was faked so that they didn’t know that they actually had nothing done. Then the incision was closed.”

The result was that those receiving the placebo treatment—the sham surgery—thought that they had improved as much as those who had actually received the procedures.

“The results were stunning. Those who had the actual procedures did no better than those who had the sham surgery. They all improved the same amount. The results were all in people’s heads.”

Carroll provides some additional examples where the efficacy of medical procedures turned out to be determined by a placebo effect.

“In 2005, a study was published in the Journal of the American College of Cardiology proving that percutaneous laser myocardial revascularization, in which a laser is threaded through blood vessels to cut tiny channels in the heart muscle, didn’t improve angina better than a placebo either.”

“A study published in 2003, without a sham placebo control, showed that vertebroplasty — treating back pain by injecting bone cement into fractured vertebrae — worked better than no procedure at all. From 2001 through 2005, the number of Medicare beneficiaries who underwent vertebroplasty each year almost doubled, from 45 to 87 per 100,000. Some of them had the procedure performed more than once because they failed to achieve relief. In 2009, not one but two placebo-controlled studies were published proving that vertebroplasty for osteoporotic vertebral fractures worked no better than faking the procedure.”

Carroll’s complaint is that introducing sham surgeries in order provide an assessment of the strength of a placebo effect is an approach that has been around for a long time, but it is too rarely used.  We subject a lot of patients to procedures of unproven validity and only think to verify them later, after the fact.

“Earlier this year, researchers published a systematic review of placebo controls in surgery. They searched the medical literature from its inception all the way through 2013. In all that time, they could find only 53 randomized controlled trials that included placebo surgery as one option. In more than half of them, though, the effect of sham surgery was equivalent to that of the actual procedure.”

One of the problems that arise with placebo controls in such studies is that subjects might be able to guess that they were recipients of the placebo and negate the effect.  Anesthesia and an actual incision would make that type of guess more difficult.  The use of sham surgeries might be referred to more accurately as utilizing an active placebo, or a super placebo.

Placebo effects are particularly important in evaluating medications targeting mental health issues.  They are very strong in these cases and can be subject to manipulation.  Marcia Angell provided an article in The New York Review that discusses the issues: The Epidemic ofMental Illness: Why?

Angell reports on the work of Irving Kirsch who published his findings in the book The Emperor’s New Drugs: Exploding the Antidepressant MythKirsch spent fifteen years trying to discover whether antidepressant drugs actually work.  His interest arose from a study of the effect of placebos.  In reviewing a large number of published clinical trials he discovered:

“Most such trials last for six to eight weeks, and during that time, patients tend to improve somewhat even without any treatment. But Kirsch found that placebos were three times as effective as no treatment. That didn’t particularly surprise him. What did surprise him was the fact that antidepressants were only marginally better than placebos. As judged by scales used to measure depression, placebos were 75 percent as effective as antidepressants.”

When drug companies perform clinical trials they don’t do just one.  Normally, they will do a number and they tend to promote publically those that make their product look good.  They often choose to bury those that do not make their product look good.  In a situation such as that involving antidepressants where efficacy appears marginal, one would really want to make sure that all the data was being evaluated.  As Angell points out:

“If two trials show that the drug is more effective than a placebo, the drug is generally approved. But companies may sponsor as many trials as they like, most of which could be negative—that is, fail to show effectiveness. All they need is two positive ones.”

“This practice greatly biases the medical literature, medical education, and treatment decisions.”

Unfortunately, the FDA allows drug companies to treat all results as proprietary data that can be withheld from the public.  Kirsch’s next step was to look at the broader set of data held by the FDA using the freedom of information path to gain access.  He examined data on six drugs: Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor.

“Altogether, there were forty-two trials of the six drugs. Most of them were negative. Overall, placebos were 82 percent as effective as the drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely used score of symptoms of depression. The average difference between drug and placebo was only 1.8 points on the HAM-D, a difference that, while statistically significant, was clinically meaningless. The results were much the same for all six drugs: they were all equally unimpressive. Yet because the positive studies were extensively publicized, while the negative ones were hidden, the public and the medical profession came to believe that these drugs were highly effective antidepressants.”

Kirsch took advantage of other studies that indicated drugs that had no relation to the treatment of depression performed as well as the antidepressants on subjects.  What these various drugs had in common was the fact that they produced side effects in those who took them.  Kirsch suspected that it was the presence of side effects that was critical.  A fraction of the subjects receiving a placebo in a clinical trial might be concluding that the absence of a side effect was evidence that they had received a placebo, thus limiting the validity of the trial’s results.

“To further investigate whether side effects bias responses, Kirsch looked at some trials that employed ‘active’ placebos instead of inert ones. An active placebo is one that itself produces side effects, such as atropine—a drug that selectively blocks the action of certain types of nerve fibers. Although not an antidepressant, atropine causes, among other things, a noticeably dry mouth. In trials using atropine as the placebo, there was no difference between the antidepressant and the active placebo. Everyone had side effects of one type or another, and everyone reported the same level of improvement. Kirsch reported a number of other odd findings in clinical trials of antidepressants, including the fact that there is no dose-response curve—that is, high doses worked no better than low ones—which is extremely unlikely for truly effective drugs.”

Kirsch is not the only investigator to take the trouble to look at all the data, not just that publicized by the drug companies, and conclude that antidepressants work no better than a placebo.  Such a conclusion poses ethical and medical problems for those who prescribe such drugs.  Daniel J. Carlat is a psychiatrist who addresses these issues in his book Unhinged: The Trouble with Psychiatry - ADoctor's Revelations about a Profession in Crisis.

Carlat does not seem to be aware of Kirsch’s work, but he is familiar with a similar effort by the psychiatrist Erick Turner that came to the same conclusion. 

“Eventually, Turner and his colleagues tracked down the fate of all the research that had been submitted to the FDA about twelve newer antidepressants approved from 1987 to 2004.  This included all the SSRIs, both of the dual reuptake inhibitors (Effexor and Cymbalta), and several other antidepressants, such as Wellbutrin, Remeron, and serzone.”

Carlat defines the problem he faces as a psychiatrist:

“If I relied on the published medical literature for information (and what else can I rely on), it would appear that 94 percent of all antidepressant trials were positive.  But if I had access to all the suppressed data, I would see that the truth is that only about half—51 percent—of trials are positive.  Turner calls this the ‘dirty little secret’ of the psychiatric world.”

Carlat recognizes that Turners findings suggest that antidepressant drugs are acting as no more than a placebo—an expensive and dangerous placebo.  He deals with this by concluding that the clinical trials run by the drug companies are irrelevant to the “real” depression patients he sees.

“Companies have found by experience that if they want to be sure their drug outperforms a placebo, they have to be very picky about which patients are allowed into the study.”

He describes a study by Mark Zimmerman, a psychiatrist at Brown University, who applied the exclusions that drug companies usually apply to subjects for clinical studies and concluded that only 8.3 percent of a population 346 patients who showed up at a hospital for treatment of depression would have qualified for a clinical study.  This allowed Carlat to draw the following conclusion:

“The bottom line is that antidepressant research studies are not generalizable to real patients, meaning that few of their results, whether positive or negative, are reliable indicators of what would happen to your mood on antidepressants.”

Given this, Carlat decides that he and other psychiatrists are the best judges of the efficacy of prescribing antidepressants.  And even though most, or perhaps all, of the effect of the drugs might be due to a placebo effect, they believe it is still appropriate to prescribe them.

“….if you ask any psychiatrist in clinical practice, including me, whether antidepressants work for their patients, you will hear an unambiguous ‘yes.’  We see people getting better all the time.  True, much of the response is due to the placebo effect, but it would be deceptive for me to prescribe a sugar pill to my patients while telling them that it is a real medication.  So I am stuck with prescribing active psychotropic drugs in order to activate the placebo, with the main disadvantage being that such drugs have far more side effects.”

What this discussion should make clear is that placebo effects are strong.  Perhaps that is why witch doctors managed to stay in business for so long.

Placebo effects are important but not well understood.  Their existence suggests that the brain has means to either accentuate or alleviate feelings of pain and discomfort.  Placebo effects can often compete with surgery and powerful drugs in controlling symptoms.  Given that, it is disturbing that no one seems to be interested in discovering ways to activate them that do not involve surgeries and powerful drugs. 

Unfortunately, to understand the medical industry it is necessary to follow the money.  There are fortunes to be made in delivering drugs and procedures.  The interest is more in eliminating placebo effects because they interfere with business plans. 

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