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Puzzle Me This

By Graeme Stemp-Morlock Puzzle Me This VisualField / ISTOCKphoto.com What substance is supposed to have no effect but can make people feel better, has no chance for a big monetary payoff but is worth billions, and is used in virtually every rigorous clinical trial but has no single, universal formulation? The answer is the placebo. Hallmarks of good biomedical research, placebos are used throughout the world in double-blind, randomized controlled trials. A

By | February 1, 2011

Puzzle Me This

VisualField / ISTOCKphoto.com

What substance is supposed to have no effect but can make people feel better, has no chance for a big monetary payoff but is worth billions, and is used in virtually every rigorous clinical trial but has no single, universal formulation?

The answer is the placebo. Hallmarks of good biomedical research, placebos are used throughout the world in double-blind, randomized controlled trials. And recently, they’ve come under intense scrutiny.

Beatrice Golomb, an associate professor of family and preventive medicine at UC San Diego, has spent years thinking about the use of placebos in modern medicine. In a paper published in the Annals of Internal Medicine last October, she raises concerns that placebos are not regulated by the US Food and Drug Administration, yet can have a direct impact on whether a drug is considered effective or not.

In one classic case Golomb considers, researchers in the 1970s used olive oil as the placebo for a cardiovascular drug. Looking back, modern medical researchers realize that olive oil is anything but neutral in the cardiovascular system, and its use as a placebo likely jeopardized the results of the entire study.

Unfortunately, this is one of the few examples where this type of issue can be spotted, since, as Golomb points out, most placebo formulations are not reported. She analyzed more than 175 placebo-controlled trials published between January 2008 and December 2009 in the New England Journal of Medicine, the Lancet, the Annals of Internal Medicine, and the Journal of the American Medical Association to see if they listed placebo ingredients. In over 90% of the trials that used placebos in pill form, no formulation was mentioned. This “breaches basic scientific standards of rigor” and “compromises the foundation on which medical decisions are based, and on which the fate of lives may rest,” Golomb writes.

For its part, the FDA still views placebos as having no effect on either the body or the outcome of the trial, and correspondingly doesn’t seem to place too much emphasis on knowing the formulation of placebos used in different drug trials.

adam smigielski/ istockphoto.com

“Usually they tell us what’s in the placebo, so it’s not a secret,” says Robert Temple, director of the Office of Medical Policy at FDA’s Center for Drug Evaluation and Research. “But I can’t swear [they tell us] 100% of the time.”

Temple dismisses worries that placebo formulations should be made known more widely. “If it is one of the usual things—a little bit of lactose—we would not be worried about it, because everything has a little bit of lactose in it, and it won’t have any activity.”

But suspicion about the mysterious nature of placebos goes beyond just their composition. In the past ten years an increasing number of new drugs have been pulled from clinical trials because they were found to be no more effective than placebos, leading some to wonder if the placebo effect is strengthening. One of Golomb’s coauthors, McMaster University epidemiologist Murray Enkin, believes that drug trials against placebos aren’t a fair fight. “With a new drug, the implicit claim is that it is better than anything else, either more effective, or cheaper, or more stable,” says Enkin. “We should be comparing new drugs to the other best available drugs, not to something we think has no effect. And, if you can’t do that, at least you can be honest and say what it is you are comparing it to.”

Moreover, Jeremy Howick, researcher at Oxford University’s Centre for Evidence-Based Medicine in England, hopes that the whole practice of placebo use will be rethought. In some tests of antidepressants, he says, study participants are informed of side effects, such as dry mouth, during the consent process. If patients receive a pill and anticipate, and get, dry mouth, they might conclude that they have received the antidepressant, and therefore experience modified mood and reduced depression. Finding ingredients that can be safely added to placebos to mimic side effects of the drug being tested should be a major goal and would improve research, Howick says.

While changing the regulations on placebos could take years, University of Toronto researcher Robin Nunn hopes it could happen in his lifetime. Nunn harbors even more ambitious hopes that the use of placebos in clinical research will ultimately go the way of humoral medicine, phrenology, and bloodletting. After all, humoral medicine fooled the best medical minds for nearly two millennia before they realized that boiling down all of human biology to black bile, yellow bile, phlegm, and blood was just a trick of the mind—much like a placebo.

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Comments

Avatar of: Lon Jones

Lon Jones

Posts: 17

February 8, 2011

It would be nice if all placebos were really inactive. The FDA seems to be satisfied that they are.\n\nThe elephant in the room is that they work. They work because human beings can and do adapt, and even inactive substances can be read as a change in their environment to which the individual can adapt.\n\nInstead of making placebos unethical we ought to be using the hell out of them; they're a lot safer than most drugs; cheaper too.
Avatar of: N SUKUMAR

N SUKUMAR

Posts: 5

February 15, 2011

"Finding ingredients that can be safely added to placebos to mimic side effects of the drug being tested should be a major goal"? Sorry! This one does not have my vote. The major goal should be finding ingredients that can safely improve the therapeutic effects of the drug and reduce side effects, NOT finding new ways to make my hair fall off "safely"!\n
Avatar of: anonymous poster

anonymous poster

Posts: 17

February 25, 2011

If the placebo effect is purely psychosomatic, then it shouldn't occur in experimental animals. Thus, any control substance that can be shown to have a physiological effect when administered to animals, especially if this effect is pertinent to the claimed efficacy of the test drug, should not be considered a placebo.
Avatar of: Ellen Hunt

Ellen Hunt

Posts: 74

February 25, 2011

Controlling using parallel animal studies as proposed by "anonymous" to show the placebo is not itself effective physiologically is also a good step, and in the scheme of things, a minor cost in the world of human clinical trials. The best thing about it is that for pharmaceutical manufacturers, it could prevent them from incorrectly throwing away a worthwhile compound. Even if it happens only 1 in 100 trials, that will be well worth the extra effort. \n\nAdditionally, I would point out that every lymph node is innervated and we don't know much at all about why. Clearly, the nervous system has some interaction, but what?
Avatar of: Carrie Elsass

Carrie Elsass

Posts: 2

February 25, 2011

In the case of the Gardisil cervical cancer vaccine, aluminum was used in the placebo. When no more significant side effects were reported with this "placebo", one has to wonder if the inclusion of this adjuvant in the placebo was by design to get the drug approved?
Avatar of: Richard Patrock

Richard Patrock

Posts: 52

February 25, 2011

Even pesticides are field-tested against other pesticides to determine a champion. The western medical establishment firmly believes in its own magic while all the while denouncing the 'pseudo-science' of alternative or 'competitive' medicine. Why not show that the latest 'Flimflamique' is 2x as effective as lactose' instead of simply being equally effective as a generic' drug; what is the point of only pulling out one cheap rabbit from a hat when you can report two very expensive chinchillas?
Avatar of: anonymous poster

anonymous poster

Posts: 18

February 25, 2011

That placebo constituents should be dsiclosed as Golomb suggests makes perfect sense. The elimination of them (per Nunn) is patent nonsense. Give 100 people a pill and tell them that it usually causes mild distress and then give another 100 people the same pill and tell them it is just a "sugar pill." If you think you have the same types of responses, you don't know the clinic or human beings. The lesssons of controlled clinical trials has been learned over and over again. Golomb makes a good point, but the thread thereafter is irrational and contradicted by years of experience.
Avatar of: Steven Brenner

Steven Brenner

Posts: 14

February 25, 2011

The placebo effect can be blocked by opiate receptor blockers, a study which blocked the placebo effect would probably actually be a better study, since placebo effect may have strong, if not overwhelming effects, especially when pediatric studies are performed. That may be the reason a lot of drugs are not approved for children. \nProbably, unless the placebo effect is blocked, the results are essentially "Ignorance is bliss."\n Probably for a true assessment of a drug effect, opiate blockers should be utilized on both arms of the study, both the active and placebo arms. \n The placebo effect may be due to release or generation of endogenous endorphins, or essentially centrally acting opiate like substances. Endogenous cannaboids also probably play an active roll, considering the widespread distribution of cannaboid receptors throughout the central nervous system.
Avatar of: Lon Jones

Lon Jones

Posts: 17

February 26, 2011

The function of placebos in clinical trials is to eliminate the individual's adaptation to either the suggestions of the physician or the environment of the trial; we need to know that it is the drug and not the individual that is active. Conflating the placebo with an active drug misses the point.\n\nIn this process we are eliminating, controlling for, the adaptation that is a significant part of being alive. All living things adapt. It would be nice if humans were the mechanical contrivances the medical world wished they were, but they are not. Rather than making placebo use unethical we ought to be telling our patients about the activity of a variety of supplements and let them see how they adapt. That would be human medicine.\n
Avatar of: anonymous poster

anonymous poster

Posts: 2

February 27, 2011

The "placebo effect" is part of ALL therapy results, including successful medications. The point of using placeboes is to discover if the medication or intervention is any stronger than the placebo effect by itself. The mere act of seeking medical services provides a sense of relief and, therefore, there is the beginning of the placebo effect. If the service providers come across as effective and knowlegeable, the placebo effect is enhanced. If the providers appear hopeful and encouraging and seem to anticipate sucess, the placebo effect is further enhanced. THAT is the main reason that these studies have to be "double-blind": so the providers don't treat the subjects differently\nand thus unduly influence the outcome.
Avatar of: Dov Henis

Dov Henis

Posts: 97

February 28, 2011

\nPavlov?s Smile\nApril 6, 2010\n\n\nA. ?Junk food junkies, round two?\nhttp://www.sciencenews.org/view/generic/id/57772/title/Junk_food_junkies%2C_round_two\nLaura Sanders follows up on a story first reported from the Society for Neuroscience?s 2009 meeting.\n\nB. From ?Phantom Limbs, Pavlov And Genes Lifehood?\nhttp://www.the-scientist.com/community/posts/list/220/122.page#4127\n\n?So why did Pavlov smile in 2008?\n\nPavlov demonstrated effecting placebo phenomena in multicelled organisms by manipulation of their drives-reactions. Now placebo and imagination phenomena are demonstrated also in the primal life organisms, in the genes and genomes of multicelled organisms, in our primal first stratum and second stratum base organisms. A very good reason to smile.\n\nNow an interesting chain is exposed to our view, the Genes-Virtual-Reality Chain, a most intriguing cultural evolution chain extending from the genesis of our genes to nowadays, throughout life, a virtual reality existence, and by virtual reality phenomena, exploitations and manipulations.?\n\nDov Henis\n(Comments From The 22nd Century)\n03.2010 Updated Life Manifest\nhttp://www.the-scientist.com/community/posts/list/54.page#5065\n
Avatar of: anonymous poster

anonymous poster

Posts: 13

March 2, 2011

I'll have some of what Dov had.

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