The time-honored relationship between the drug rep and the doctor dates back decades. In the old days, a representative of the pharmaceutical industry would simply pay a visit to a doctor's office, bearing gifts: sandwiches, samples of Paxil, brochures, and in the headier days of "doctor detailing" — that's what industry calls these visits — tickets to professional sporting events and all-expense-paid tropical vacations. The drug reps are often young, attractive, scrubbed, well-coiffed and intensely personable, and as long as they don't come right out and ask the doctor to prescribe more of a certain drug so they can meet their quota, they remain welcome guests in most offices.

But over the course of the last decade or so, this awkward, ritualized dance has grown more complex — and for Big Pharma, far more effective.

Armed with literally billions of dollars in its PR war chest, the pharmaceutical industry has had an epiphany: Who's the best person to convey a marketing message to a doctor? The answer's easy: another doctor. After all, a drug rep has a flashing neon sign of a motive, and that is to secure prescriptions. But a doctor? An M.D. is concerned only with the disease and the means to treat the patient. For drug companies with the aforementioned means, that's more than enough.

We've never really known, in a monetary sense, just what the doctor-drug industry relationship entails — except that it includes money and, in some cases, lots of it. But over the course of the past year or so, seven of the world's biggest pharmaceutical companies have begun disclosing what they pay your doctor to consult and speak for them before gatherings of other physicians in hospitals, tony hotels and pricey restaurants. A provision of the health care reform bill (unless it's repealed) will require the entire industry to disclose their financial ties to our doctors by 2013.

ProPublica, a nonprofit organization dedicated to investigative journalism, didn't want to wait that long. Recently, the watchdog group assembled a searchable database combining the disclosures of the companies and linking them to individual doctors. For the first time, patients can search their doctors' names and find out which companies pay them and how much.

Before you pat the drug companies on the back for their laudable transparency, it's worth noting that collectively they've paid out more than $6 billion in settlements over the past few years — or about 20 percent of Tennessee's fiscal year 2011 budget — to avoid federal criminal prosecution. In nearly every case, it was found that the companies were paying doctors to promote non-FDA-approved, off-label uses for their drugs — a surefire way to boost market share and sales.

As part of their settlements, Pfizer, Merck, Eli Lilly, Johnson & Johnson, AstraZeneca, Cephalon and GlaxoSmithKline are now required to disclose payments made to physicians. Only three of the seven — Merck, Glaxo and AstraZeneca — had previous plans to begin disclosing this information. Regardless how it came to light, though, the information assembled by ProPublica makes for an illuminating document.

From the database — which covers 2009 and some of 2010, depending on the company — ProPublica culled 43 doctors who'd made $200,000 or more in the available disclosures. Perhaps it shouldn't be surprising that Tennessee had the most physicians on the list, with five topping the $200K mark.

Nor should it be surprising, perhaps, that three of those came from the Medical Mecca of the South, Nashville — where one in every 12 occupations is a health care job.

Of course, these disclosures represent but a slice of the pharmaceutical pie. And the numbers available depict just a year-and-a half snapshot. With some of the disclosures it's less. Nor does the list include pharmaceutical payments to nurse practitioners and physicians' assistants, or to doctors who speak at continuing medical education events sponsored by medical education companies — which are funded almost entirely by the pharmaceutical industry.

This is merely the tip of the iceberg. A New England Journal of Medicine article estimated that 94 percent of doctors have received some token of Big Pharma's esteem, whether it's a free lunch or payment for enrolling their patients in clinical trials, while nearly 30 percent have regular speaking and consulting gigs. Nevertheless, the very availability of the information is unprecedented.

So the Scene culled eight of the highest-paid Nashville doctors from the database. According to industry disclosures, they made anywhere from just above $40,000 to $240,000 during 2009 and 2010. Out of an abundance of caution, the Scene went to the source documents to double-check ProPublica's numbers. The companies don't make it easy: Sometimes last names are listed first; sometimes first names are listed first. Sometimes the name of the doctor's private practice is listed first.

But if anything, our doctors' ProPublica figures were low. Recently released Eli Lilly disclosures from the second quarter of 2010 available on the company's website hadn't been added to the database, giving a few of the doctors a significant bump.

In terms of credentials, these doctors run the gamut. There's the chairman of a local university's psychiatry department. There's a well-published clinician and former Fulbright scholar. And there are a few private-practice docs with no published work and few academic associations to burnish their curricula vitae. The Scene called all of them to discuss their relationships with pharmaceutical companies and the potential conflicts of interest that industry observers say they pose.

Almost half did not respond to repeated messages left for comment. But most of those who did speak with us were candid and forthcoming. Even if indirectly, they painted a vivid picture of the variability among doctors paid by Big Pharma — and how this $300 billion industry touches each and every one of us.

First of all, it would be useful to understand just what doctors are up against. According to some of the pharmaceutical industry's own numbers, there is one drug rep for every two to three doctors. Imagine how many drug reps come in and out of a doctor's office in a single week, vying for attention.

And they've done their homework. Before setting foot in a doctor's office, drug reps know how many patients he or she sees. They know what drugs the doctor prescribes and in what quantities. They know everything about the doctor's particular patient population. All of this information is available for purchase, of course. Pharmacies, Wal-Mart, your insurance company — all sell your information to third-party medical intelligence vendors such as IMS Health, which aggregate the numbers. And by information, we mean your body-mass index, your allergies, the prescription drugs you take, your last hospitalization, your zip code — everything but your name and address, a distinction that allows the vendor to remain kosher under the Health Insurance Portability and Privacy Act.

Even the American Medical Association gets a huge chunk of its yearly revenue from selling the information of its membership — specifically the Drug Enforcement Agency number that denotes an individual doctor. That number enables IMS Health to pair the prescription with the prescriber and the patient with the doctor, then to sell the whole package to Big Pharma. It's as close to omniscient as an industry can get without violating a whole host of federal laws.

As a result, drug companies know well what works and what doesn't. They can tell if prescriptions go up after bringing lunch to a doctor's office. They can tell if inviting a doctor to their speaker's lecture at Ruth's Chris Steakhouse (and picking up the tab while compensating them handsomely for their time) increases prescriptions — and it does, according to a number of studies in the Journal of the American Medical Association. Generally, JAMA researchers found that doctors who've been paid to speak for a pharmaceutical company or who have attended its promotional lectures are more likely to request that the specific company's drugs be added to the hospital formulary.

In fact, an internal Merck study obtained by the Wall Street Journal in 2005 showed the industry had quantified the "return on investment" of having a doctor speak for them down to the penny. According to the document, doctors who attended a promotional lecture led by another physician wrote an additional $623.55 in prescriptions of the Merck drug Vioxx — which has been voluntarily withdrawn from the market — than doctors who didn't attend. If the discussion was held in a more intimate venue over dinner, the figure rose to nearly $720.

If a drug rep led the discussion, on the other hand, the "return on investment" was far smaller. In pharmaceutical marketing, credibility is everything. Merck just put a price tag on it.

Dr. Terri Jerkins, a Nashville endocrinologist, takes issue with the perception that the money corrupts. Jerkins, who made $213,719 from her speaking engagements in 2009 and 2010, has relationships with five of the seven pharmaceutical companies currently disclosing physician payments — more than any of the top-paid docs in the country at the moment. She says she only speaks for drugs that she believes actually work. Being a solo practitioner, she says low Medicare reimbursement rates and high overhead make it tough to stay solvent. Speaking for drug companies pays the bills, she says.

"I'm not ashamed of it," Jerkins says. "All my patients know I lecture. I've got a waiting list six months long. If they're disturbed I lecture for pharmaceutical companies, bye. There are plenty of other people out there."

But patients could hardly be blamed for their fears, given the number of studies that suggest such interactions with Big Pharma influence which drugs doctors prescribe and how often. This worries the country's medical ethicists, who are unified in opposition to any unspoken quid pro quo — and to doctors acting as spokespeople, wittingly or not.

"I think what I'd ask them is, 'Do you think your opinion is getting influenced by taking all this money?' says Ellen Wright Clayton, a physician and attorney who teaches biomedical ethics at Vanderbilt. "And they're gonna say no. And the answer is: Of course it is."

To be clear, it's not as if the lecturer is getting up on the dais and making a snake-oil come-on for the wonders of Vioxx or Avandia — two hotly promoted drugs that did not exactly prove to be the greatest panaceas known to man. Doctors are educated sophisticates, not tent-show rubes — which is why peer-to-peer promotion works so well.

"They're talking to me, I'm talking to them," said Dr. Amanda Sparks-Bushnell, a psychiatrist and head of The Sparks Clinic near Centennial Medical Center. "It's a scientific exchange."

That exchange has been beneficial for Sparks-Bushnell. During 2009 and 2010, she made nearly $127,000 from Pfizer and especially Eli Lilly in speaking and consulting fees, the companies' disclosures indicate. She's also spoken for Sepracor, Wyeth and other companies, she says, which currently aren't required to disclose payments to physicians. Speaking for different companies, she believes, keeps her impartial.

"I think the appearance of that is important and not having all your eggs in one basket," Sparks-Bushnell says.

Sparks-Bushnell was first approached by a drug rep who informed her that she'd been chosen as a "key opinion leader," the industry's term for a cutting-edge medical luminary. She attended company speaker training, where she says she was brought up to speed on current research and federal guidelines for doctors who belong to industry speaker bureaus — one of the closest relationships a doctor can have with Big Pharma.

Why she was singled out as an opinion leader in the community isn't immediately clear. The industry often targets up-and-comers with academic appointments and published research. Yet Sparks-Bushnell admits she hasn't taken part in any clinical trials, and a search of the U.S. National Library of Medicine database doesn't turn up any medical journal articles under her byline. So why, then, was she chosen?

According to Dr. Adriane Fugh-Berman, a Georgetown University School of Medicine professor and director of PharmedOut, a research and education project examining the influence Big Pharma has on doctors, the industry chooses its speakers in a few ways. It might target a psychiatrist like Sparks-Bushnell with a bustling practice. The industry spends more money paying psychiatrists to speak than it does specialists in any other field, because psychiatry relies so heavily on prescription drugs.

As for the training given to those speakers, Fugh-Berman argues that it's little more than promotional indoctrination.

"They invite hundreds of doctors to speaker training, and they pay them hundreds at a nice resort, but it's not really speaker training," she says. "It's paying you to memorize marketing messages and thinking, 'I'm going to be one of the [key opinion leaders].' But what happens is, your own prescribing goes up."

It doesn't hurt if the doctors who hear their lectures prescribe more too. After attending speaker training, Sparks-Bushnell says she most often speaks to small groups of doctors, nurses and physician assistants at their offices and over dinner. For these talks, a speaker can make anywhere from $500 to $1,000. Sparks-Bushnell says she's there to discuss current research and the treatment of disease, not just to promote the drug developed by the company that sponsors the dinner.

But in a 2006 piece in The Atlantic written by Dr. Carl Elliott, a professor at the University of Minnesota's Center for Biomedical Ethics, a drug rep confided that if a speaker "didn't write (a bunch of prescriptions), he wouldn't speak." It's worth noting that nobody gets a continuing medical education credit — courses that are supposed to keep physicians current in their specialty — for attending such gatherings, though they do generally get paid.

No one — neither the speaker nor the attendee — thinks of it as unadulterated industry shilling. To Sparks-Bushnell, it's education: a chance for colleagues to share information on the latest treatments. To Fugh-Berman, that's the insidious part.

"Everything has to be camouflaged," Fugh-Berman says. "The bribes have to be camouflaged. The promotion has to look like education, even if you're not getting the CME credit."

The line between continuing medical education and promotion is already sometimes hard to discern. Dr. Jon Draud is the medical director of the psychiatry department and addiction medicine services at Baptist Hospital and Middle Tennessee Medical Center, according to his bio. He's also the highest-paid industry speaker in Nashville, making just over $240,000 during 2009 and 2010, the industry disclosures say.

Draud often lectures before a much broader audience than your average dinnertime promotion. He did not respond to repeated messages requesting comment, but a cursory Web search indicates — along with the Pharma speaker bureaus he belongs to — that he also speaks at continuing medical education functions for CME LLC., an education company funded by a who's who of pharmaceutical-industry players. Not coincidentally, that roster includes every company he speaks for.

It's quite common for companies that provide continuing medical education to choose speakers from a list supplied by the industry. According to testimony before the U.S. Senate Committee on Aging, some 90 percent of the funding for those companies comes from pharmaceutical providers. And because the industry money is delivered through a CME company, Draud does not have to disclose these payments, known as "honoraria."

"It's not just the money. It's not just the amount of the money," Fugh-Berman says. "It is part of a very multifaceted, very far-reaching, octopus-like campaign that includes every source of medical information physicians depend on." (It should be noted that Fugh-Berman is a paid expert witness on behalf of plaintiffs in litigation regarding pharmaceutical marketing practices.)

In 2007, the research firm Integrated Medical Systems estimated the drug industry was spending $20 billion a year to cultivate relationships with doctors. The National Institute of Medicine recently recommended that interaction between doctors and industry be curtailed — accepting gifts, meals and drug samples; making industry-funded and –controlled presentations — and to examine ways to provide industry-free CME. Harvard has forbidden its faculty from joining industry speaker bureaus. Vanderbilt toughened its conflict of interest policy in 2009, banning the acceptance of gifts, though it doesn't ban speaking and consulting for the pharmaceutical industry.

Already realizing the subtle influence Big Pharma has on what is supposed to be objective medical education, a handful of academic hospitals, medical schools and medical centers have banned or drastically reduced industry-sponsored CME: University of Michigan Medical School, Memorial Sloan-Kettering Cancer Center, East Carolina University's Brody School of Medicine and Kaiser Permanente's mid-Atlantic region.

But the CME-industry relationship is so firmly cemented that when Fugh-Berman gave a CME lecture to a hospital's assembled doctors on Big Pharma's influence, one incredulous cardiologist asked, "How did you get in here?"

"We responded, quite honestly, that the department coordinator thought we were drug reps," Fugh-Berman recalls. "And we paid for lunch."

The second method in thought-leader making is to identify the rising stars whose research is consistent with the marketing message a company has for a specific drug. If a promising young doctor's research centers on the impact a healthy diet, exercise and certain vitamins have on Alzheimer's, for example, it's unlikely this doctor will be chosen to become a member of a pharmaceutical company's speaker bureau.

But if a psychiatrist says that he or she is seeing promising results in Alzheimer's patients treated with the anti-psychotic drug Seroquel, then the drug's maker, AstraZeneca, might make an overture. Seroquel isn't approved by the FDA to treat Alzheimer's, so AstraZeneca can't say it works that way. But a psychiatrist can. And to back the psychiatrist up, AstraZeneca might provide him with a few low-quality studies that say taking Seroquel is more effective in the treatment of Alzheimer's than taking nothing at all.

The next step might be to publish an article written by an AstraZeneca employee under that psychiatrist's name, based on a study the good doctor didn't conduct. It's called "ghost writing," and according to Fugh-Berman, it's all too common. In truth, all of this actually happened with Seroquel, and AstraZeneca paid a $520 million settlement to avoid criminal prosecution in April.

Even for discerning doctors, it can be almost impossible sometimes to spot the marketing angle when a drug company comes calling with a proposition. Take the cervical cancer vaccine Gardasil. Long before the FDA approved its use, you may remember a TV commercial that looked like a public service message, in which women on the street expressed shock when told of the prevalence of human papillomavirus (i.e., genital warts) and its connection to cervical cancer.

That commercial was the cornerstone of the "Tell Someone" campaign. Its backer was Merck, the HPV vaccine's patent holder. With FDA approval pending, Merck was only allowed to publicize the disease, not the vaccine. So if Merck approached an up-and-coming clinician studying the link between cervical cancer and HPV — asking the doctor to speak on the subject long before it planned to bring its vaccine before the FDA — that doctor might think, "Why not?" After all, it's only education: a public service, even. And yet the doctor unwittingly became a part of Merck's pre-release marketing strategy, selling the disease to create a customer base for its eventual treatment.

The messaging is similar for a doctor who belongs to a drug company's speaker bureau. It's the doctor's job to sell the disease. The drug rep sells the drug. Let's say a doctor's published paper touts a certain class of diabetes drug known by the acronym TZD as a potential method of diabetes prevention, instead of diet and exercise. And if Glaxo is already selling billions of dollars' worth of just such a drug — called Avandia — you have a match made in heaven.

Dr. Hal Roseman is a Nashville forensic cardiologist. The aforementioned TZD paper is his, published in the Journal of Managed Care Pharmacy and based on the proceedings of a symposium funded with an unrestricted educational grant from — you guessed it — Glaxo. Roseman is a member of Glaxo's speaker bureau, the company that pays most of his disclosed speaking fees; by our tally, he's the second highest-paid speaker in Nashville. A search of the national medical research database yielded no other published work under his name. Though he doesn't lack a medical pedigree — a degree from Yale and a fellowship at Brown and Massachusetts General Hospital — he has no current affiliation with any academic institutions.

That hasn't kept his profile low. If you followed the Senate Finance Committee hearings on Avandia back in January, you may remember him testifying on behalf of the drug, now linked to heart disease in diabetic patients. The Scene asked him if it was possible that the more than $240,000 he's made in speaker fees in the past year or so could cloud his judgment.

"If you have a drug that's shown benefit, you need an opportunity to make that known and propagate that knowledge and improve the branding consciousness of that particular drug," Roseman says. "Educational programs take place in order to help doctors do that. And I can tell you as a national speaker who's, from what I understand, one of the most paid — I'm not proud of it and I presume that's why you're calling me — but I speak predominately about disease state."

At the Senate Finance hearing, however, Roseman gave a PowerPoint presentation titled, "In Defense of Avandia," and one couldn't help but wonder if Glaxo was compensating him for his time and travel to Washington, D.C.

"I still am convinced that, number one, the absolute risk for myocardial infarction (heart attack), if it exists for Avandia, is low." Roseman tells the Scene, referring to the once-popular diabetes drug. "Number two, unlike some of my academic colleagues who would not go on the public record, they admit that the FDA based its decision on observational data and not randomized-, clinical-trial data."

While this may be true, during the hearing he went on to present five reasons why Avandia shouldn't be taken off the market. He cited data in a few Glaxo-funded studies he said pointed to an insignificant risk of heart disease. Here's the problem with that: As early as 1999, a University of North Carolina professor warned that Avandia could cause cardiovascular problems. Glaxo effectively silenced him by complaining to his superiors and threatening a lawsuit, according to testimony before the Senate committee.

In 2000, an internal Glaxo report obtained by investigators noted that Avandia raised the level of a kind of bad cholesterol and a particular blood enzyme. Taken together, they could cause serious heart problems for diabetes patients already prone to cardiovascular disease. A Glaxo executive made the call to squelch the data, internal Glaxo communiqués indicate.

There was worse to come. In 2006, Glaxo provided a meta-analysis — a kind of statistical analysis that combines the results of a number of different studies — to the FDA and the European Medicines Agency that pointed to increased heart risk due to the drug. But the FDA never made the analysis public. Then, in 2007, a clinical researcher at the Cleveland Clinic named Dr. Steven Nissen conducted a meta-analysis very similar to the one Glaxo had conducted the year before. He arrived at roughly the same result, which was in part based on Glaxo's own studies. In a supreme irony, the only reason Nissen obtained those studies was because Glaxo was forced to make them public. That came after Eliot Spitzer, then New York state attorney general, found the pharmaceutical giant had suppressed data that showed children who used its popular anti-anxiety/depression drug Paxil experienced an increase in suicidal tendencies.

"To a great extent, the numbers are the numbers. The Nissen analysis is very similar to our own," wrote one Glaxo consultant in an internal memo requisitioned by the Senate committee.

Publicly, however, Glaxo came out swinging. The company trashed Nissen's analysis and pointed to its own long-term studies as more reliable, much as Roseman did in his testimony before the committee. The first two studies were panned in a New England Journal of Medicine editorial, which said these "industry-sponsored trials do not represent compelling science."

Furthermore, the Glaxo study released specifically to undermine Nissen's, called RECORD, was eviscerated by an FDA scientist who said he found dozens of instances where trial participants suffered heart problems that weren't included in the tally, skewing the results. In most cases, rather than sully the outcome Glaxo hoped for, these participants were simply jettisoned from the trial.

More recent analysis of Avandia by the FDA indicates that as many as 100,000 heart attacks were caused by the drug. Its use was severely restricted by the FDA in September, and it was banned entirely in Europe. Roseman maintains that the risk of heart attack with Avandia is "statistically insignificant."

On paper, Dr. Rahn K. Bailey is an ideal industry speaker. Unlike Sparks-Bushnell, Roseman and Draud, he's listed as the author of a number of peer-reviewed studies. He's chairman of the psychiatry and behavioral sciences department at Meharry, the country's pre-eminent historically black medical college. Dr. Bailey said he would need to check with the school's communications department before commenting, but did not respond by press time. Available disclosures indicate he speaks and consults almost exclusively for Eli Lilly and made more than $120,000 during 2009 and the first half of 2010.

Bailey is the only doctor the Scene has encountered who holds a significant position in academia and is also paid more than $100,000 by Big Pharma. Meharry, for its part, "discourage(s) the receipt of honoraria tied to pharmaceutical products."

Dr. Jan Brandes is another speaker who fits the mold of what one imagines is a sought-after sort — a former clinical instructor of neurology at Vanderbilt, a Fulbright scholar and well-published researcher who specializes in migraines and is on the board of the National Headache Foundation. Brandes spoke candidly with the Scene about her relationship with Big Pharma. Disclosures indicate she was paid $111,150 by Glaxo during the last half of 2009 and the first half of 2010.

Brandes didn't attend company speaker training, however. Her involvement with the drugs she speaks about comes from participation in clinical trials, she says, and she's been the lead investigator for a number of them.

"It's my view that if you do not have direct involvement in a trial and you don't really know the data, you shouldn't be [lecturing about the drug]," Brandes said. This way, she says, speakers know for sure that the treatments they talk about are empirically proven. Case in point: Botox. There were indications that the foe of frown lines could be very effective in the treatment of migraines, and Brandes was an investigator for the trial. When the data didn't shore up the conclusion, Brandes said its maker, Allergan, changed the study's endpoint — essentially lowering the bar and expectations for Botox rather than continuing the original trial goals, which would be considered the ethical move.

Put off, Brandes bailed on the trial. Nevertheless, the FDA approved using Botox for treating migraines in October. But in September, Allergan paid $600 million to settle charges that it was promoting Botox to doctors for off-label uses and paying kickbacks to those who prescribed it for the treatment of cerebral palsy and chronic migraine before FDA approval.

Considering how entwined Big Pharma and our physicians have become, it comes as little surprise that a poll of 1,250 people conducted by the Consumer Reports National Research Center found that 75 percent of adults said they were concerned about the quality of care they would receive from a doctor who takes $25,000 or less from drug companies.

Brandes says her patients know about her relationship with the industry because many of them participate in clinical trials, but she believes patients should talk it over with their doctors. "I think anything that creates an element of mistrust between a physician and patients should always be addressed," she says.

One thing is certain: By 2014, pharmaceuticals will be a $400 billion industry, IMS Health reports say. According to a study in the journal PLoS Medicine, Big Pharma will spend about 25 percent of the sales dollar on promotion, and so-called key opinion leaders will be on the receiving end of about a third of that.

Meanwhile, the pharmaceutical companies are mandated to serve their shareholders' best interests. Physicians are charged to look out for their patients' best interests. As troubling examples from Big Pharma's recent history show, profits and patients occasionally represent opposing interests. Jan Brandes takes a thoughtful tack.

"If [the money] is influencing people in an undue way," Brandes says, "maybe we should stop it."

Email editor@nashvillescene.com.