The Nocebo Effect: The Flip Side of Medicine’s Placebos

The Nocebo Effect: The Flip Side of Medicines Placebos

If any pill has been shown undeniably to work in clinical trials, it is the sugar pill, along with its close cousin, the sham treatment. The placebo, as such inert and cost-free remedies are known, can relieve depression as well as Prozac, ease discomfort as well as acupuncture and reduce disability and back pain as well as a widely used vertebral surgery that costs up to $5,000.

That the effect of bogus treatments is real has long been known, but the mechanism behind them is still largely a scientific mystery. The standard explanation is that we are just fooling ourselves. In Latin, placebo means “I shall please,” which suggests that the placebo effect is just a fleeting mind trick — that the mere suggestion of pharmacologically induced pain relief humors the body into temporary recovery. In trials, every drug response is in fact assumed to be at least partially due to the placebo effect. But the confounding thing about the benefits of the placebo is that the effect is often not beneficial at all.

Consider the negative placebo response, called the nocebo effect. A nocebo response occurs when the suggestion of a negative effect of an intervention leads to an actual negative outcome. When doctors tell patients that a medical procedure will be extremely painful, for example, they tend to experience significantly more pain than patients who weren’t similarly warned. And in double-blind clinical trials of antidepressants, even those participants receiving a sugar pill report side effects like gastrointestinal discomfort if investigators have warned them at the outset that those effects are likely.

It’s possible that the nocebo response is easily explained: in the antidepressant trials, maybe some patients — given that they already tended toward depression and anxiety — worried so much about the doctor’s cautions that their stomach released enough acids to cause pain. That would make sense except that the range of possible nocebo responses stretches far beyond stomachache . In a new paper published in the journal Pain, researchers found that clinical-trial participants have reported a wide variety of nocebo-fueled medical complaints, including burning sensations outside the stomach, sleepiness, fatigue, vomiting, weakness and even taste disturbances, tinnitus and upper-respiratory-tract infection. What’s more, these nocebo complaints aren’t random; they tend to be specific to the type of drug that patients believe they may be taking.

The Pain study, which was led by Italian neuroscientist Martina Amanzio, reviewed 73 clinical trials conducted between 1988 and 2007. All the previously published trials pitted potential antimigraine medications against sugar pills. The medications included nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen ; triptans, which include Imitrex; and anticonvulsant drugs like Topamax. Those three categories of drugs carry different adverse effects: NSAIDs, for instance, often cause stomach problems; anticonvulsants can cause paresthesia and memory impairment. Interestingly, patients who took sugar pills tended to report nocebo problems consistent with whatever drug they thought they might have swallowed. No one who thought they could be taking an NSAID or triptan reported memory problems or tingling, but some who thought they might have taken anticonvulsants did. Likewise, only placebo groups in the NSAID trials reported side effects like stomach upset and dry mouth.

Exactly why the placebo and nocebo responses arise is a puzzle, but a fascinating article in Wired magazine noted earlier this year that the positive placebo response to drugs has increased during clinical trials over the past few years. The article speculated that drug advertising — which exploded after 1997, when the Food and Drug Administration began allowing direct-to-consumer ads — has led us to expect more from drugs. Those expectations, in turn, have made us feel better just for popping a pill.

But the Pain study found that date of publication had no effect on the side effects reported: the placebo and nocebo responses were just as robust before 1997 as after. That leaves scientists still looking for an answer. The Wired story suggested that the act of merely doing something good for yourself may stimulate the body’s “endogenous health-care system,” perhaps by inhibiting stress hormones. But that wouldn’t explain why the same act might lead to phantom nocebo aches and pains.

A final question: What happens now that more of us are onto the placebo/nocebo problem Will our expectations adjust to reality Who knows “The placebo is a trickster,” says Ted Kaptchuk, a placebo expert at Harvard Medical School. “We still don’t understand how it works.” But Kaptchuk says it’s possible to defeat placebo benefits and overcome nocebo problems simply by being aware of them. Mind, in other words, over mind.

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