The placebo problem Big Pharma's desperate to solve - Page 3

By Steve Silberman| 14 September 2009
The placebo problem Big Pharma's desparate to solve Photo: Nick Veasey
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The main objections to more widespread placebo use in clinical practice are ethical, but the solutions to these conundrums can be surprisingly simple. Investigators told volunteers in one placebo study that the pills they were taking were "known to significantly reduce pain in some patients". And the researchers weren't lying.

These new findings tell us that the body's response to certain types of medication is in constant flux, affected by expectations of treatment, conditioning, beliefs and social cues.

Moreover, a pill's shape, size, branding and price all influence its effects on the body. Soothing blue capsules make more effective tranquilisers than angry red ones, except among Italian men, for whom the colour blue is associated with their national football team - Forza Azzurri!

But why would the placebo effect seem to be getting stronger worldwide? Part of the answer may be found in the drug industry's success in marketing its products. Potential trial volunteers in the US have been deluged with ads for prescription medications since 1997, when the FDA amended its policy on direct- to-consumer advertising. The secret of running an effective campaign, Saatchi & Saatchi's Jim Joseph told a trade journal last year, is associating a particular brand-name medication with other aspects of life that promote peace of mind: "Is it time with your children? Is it a good book curled up on the couch? Is it your favourite television show? Is it a little purple pill that helps you get rid of acid reflux?" By evoking such uplifting associations, researchers say, the ads set up the kind of expectations that induce a formidable placebo response.

The success of those ads in selling blockbuster drugs like antidepressants and statins also pushed US trials offshore as therapeutic virgins - potential volunteers who were not already medicated with one or another drug - became harder to find. The contractors that manage trials for Big Pharma have moved aggressively into Africa, India, China and the former Soviet Union. In these places, however, cultural dynamics can boost the placebo response in other ways. Doctors in these countries are paid to fill up trial rosters quickly, which may motivate them to recruit patients with milder forms of illness that yield more readily to placebo treatment. Furthermore, a patient's hope of getting better and expectation of expert care - the primary placebo triggers in the brain - are particularly acute in societies where volunteers are clamouring to gain access to the most basic forms of medicine. "The quality of care that placebo patients get in trials is far superior to the best insurance you get in America," says psychiatrist Arif Khan, principal investigator in hundreds of trials for companies like Pfizer and Bristol- Myers Squibb. "It's basically luxury care."

Big Pharma faces additional problems in beating placebo when it comes to psychiatric drugs. One is to accurately define the nature of mental illness. The litmus test of drug efficancy in antidepressant trials is a questionnaire called the Hamilton Depression Rating Scale. The HAM-D was created nearly 50 years ago based on a study of major depressive disorder in patients confined to asylums. Few trial volunteers now suffer from that level of illness. In fact, many experts are starting to wonder if what drug companies now call depression is even the same disease that the HAM-D was designed to diagnose.

Existing tests also may not be appropriate for diagnosing disorders like social anxiety and premenstrual dysphoria - the very types of chronic, fuzzily defined conditions that the drug industry started targeting in the 90s, when the placebo problem began escalating. The neurological foundation of these illnesses is still being debated, making it even harder for drug companies to come up with effective treatments.

What all of these disorders have in common, however, is that they engage the higher cortical centres that generate beliefs and expectations, interpret social cues and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson's and many other ailments that respond robustly to placebo treatment. To avoid investing in failure, researchers say, pharmaceutical companies will need to adopt new ways of vetting drugs that route around the brain's own centralised network for healing .

Ten years and billions of R&D dollars after William Potter first sounded the alarm about the placebo effect, his message has finally got through. In the spring, Potter, who is now a VP at Merck, helped rev up a massive data-gathering effort called the Placebo Response Drug Trials Survey.

Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data - including blood and DNA samples - to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi- Aventis, Johnson & Johnson and other major firms are funding the study, and the laborious process of scrubbing volunteers' names and other personal information from the database is about to begin.

For Potter, who used to ride along with his father on house calls in Indiana, the significance of the survey goes beyond Big Pharma finally admitting it has a placebo problem. It also marks the twilight of an era when the drug industry was confident that its products were strong enough to cure illness by themselves. "To really do the best for your patients," he says, "you want the best placebo response plus the best drug response."

The pharma crisis has also finally brought together the two parallel streams of placebo research - academic and industrial. Pfizer has asked Fabrizio Benedetti to help the company figure out why two of its pain drugs keep failing. Ted Kaptchuk is developing ways to distinguish drug response more clearly from placebo response. Both are exploring trial models that treat the placebo effect as more than just statistical noise competing with the active drug.

Ironically, Big Pharma's attempt to dominate the central nervous system has ended up revealing how powerful the brain really is. The placebo response doesn't care if the catalyst for healing is a triumph of pharmacology, a compassionate therapist, or a syringe of salt water. All it requires is a reasonable expectation of getting better. That's potent medicine.

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