Scientists at the University of Michigan found that giving placebos for pain treatment can cause the brain to release natural painkillers that actually diminish the unpleasant sensation and the associated stress.

    According to a study published in the August 24 issue of the

, nine out of the 14 participants’ brains responded to being told that they were receiving pain medication by releasing pain-fighting endorphins, even though all of the subjects were given placebos.

    “The effects of our own thinking are more pervasive and deeper than we even thought,” Tor Wagner, assistant professor of psychology at Columbia University, said in response to the study.

    The nine subjects who responded to the placebos reported that they felt a decrease in pain intensity and in the unpleasantness of the sensation, lead author Jon-Kar Zubieta explained. They also indicated a decrease in emotional responses to pain, including fear and irritability.

    In addition, Positron Emission Topography (PET) scans of the subjects showed that the brains of these nine reacted to the expectation of pain relief by releasing endorphins. This was observed in four different areas of the brain, according to Zubieta – the left dorsolateral prefrontal cortex, the pregenual rostral right anterior cingulated, the right anterior insular cortex and the left nucleus accumbens.

    These regions are also involved in other complex processes besides pain management, which may play a part in reducing the stress of pain, he explained.

    “Placebo effects are physiology, not just psychology,” Zubieta said.

    He described the reaction to placebos as graded, not black and white as is often indicated when the effect is observed in clinical trials. Zubieta indicated that future studies should try to determine the reasons for different levels of response to placebo such as emotional state, brain function and genetics.

    Zubieta thinks that understanding the placebo effect could help both scientists and doctors. First of all, it could aid clinical researchers in improving their interpretation of trial results. Alternatively, Wagner and Zubieta both suggested that pharma companies could develop a product that harnesses the placebo effect by targeting the brain pathways involved in this phenomenon.

    Additionally, physicians could maximize the impact of real drugs by using the mechanisms of the placebo effect to encourage their patient’s brains to provide additional relief, Zubieta said.

    Wagner believes understanding the placebo effect would change the way doctors interact with patients about the medicines they prescribe. He said these findings as contribute to a scientific dialog between doctors and sociologists concerning “how to think about pain, healing and health.”

    But Ted Kaptchuck, assistant professor at Harvard School of Medicine, said the clinical impact of understanding the placebo effect is “still a long way off.”

    Kaptchuck praised the Zubieta paper for tying several lines of enquiry together. But he said that more work needs to be done. He thinks that researchers should examine the placebo effect in patients with actual clinical problems. The Zubieta study used healthy volunteers and injected salt solution into their jaw muscles to cause pain. Kaptcuck also is interested in studying the placebo effect on subjects with long-term pain.

    He recently completed and submitted an 8-week study on the placebo effect in a clinical population. It has not been published yet.

Articles

Scientists at the University of Michigan found a brain mechanism that increases the release of pain-fighting endorphins when the subject was given a placebo. The implication? Better clinical trials, and maybe, new methods of pain relief, researchers say.

Placebo Effect: All in the Brain

A new test, approved by FDA on August 22, will help doctors set dosage levels for Pfizer’s Camptosar (irinotecan)-a chemotherapy drug used in the treatment of colorectal cancer. The test, the Invader Assay, developed by Wisconsin-based Third Wave Technologies, identifies a genetic mutation that causes the drug to be poorly metabolized, leading to serious toxic side effects. The company claims the Invader Assay is the first pharmacogenetic test approved by FDA for use as a companion diagnostic to a specific drug therapy.

The Third Wave detects a mutation in a gene called UGT1A1, which produces the enzyme UDP glucuronosyltransferase. The enzyme is involved in the metabolism of irinotecan, explained Howard McLeod, professor at Washington University School of Medicine. The enzyme attaches a molecule called glucuronide to the drug, making it more water soluble, so it is eliminated more rapidly from the body. This enzyme is also involved in eliminating other drugs and molecules such as estrogen and bilirubin, a by-product of breaking down hemoglobin, McLeod said.

    A patient with a specific mutation in the UGT1A1 gene will not be able to eliminate irinotecan as effectively as someone without this mutation, according to McLeod. Excessive blood levels of the drug can cause dramatic side effects leading to hospitalization or death. According to Camptosar’s label, approximately 10 percent of Americans have the mutation.

According to Rod Hise, spokesman for Third Wave Technologies, the test contains two synthetic fragments of DNA, capable of recognizing the mutation in UGT1A1. The fragments bind with DNA in the patient’s blood sample in a way that the two probes partially overlap each other, leaving a “flap” unattached. This overlapping structure is recognized by Third Wave Technologies’ proprietary enzyme, Cleavase, which cuts the flap of overlapping DNA that is not bound to the patient’s DNA. This small fragment then binds with another DNA probe, which is also recognized by Cleavase. When the structure is cut, it releases a fluorescent signal, indicating that the mutation is present.

Pharmacogenetic research is particularly important in cancer treatment, because chemotherapy has a narrow therapeutic window, according to Matthew Goetz, assistant professor of oncology at the Mayo Clinic in Rochester. He was the lead investigator on a study of pharmacogenetic testing for chemotherapy drugs that was presented at the American Society of Clinical Oncology meeting in May.

    Pharmacogenetic tests allow physicians to maximize the amount they know about their patient’s physiology and understand how best to treat them, McLeod explained.

“It’s a whole new way of looking at patients within all fields of medicine,” he said.

Goetz predicted that in five to ten years this type of testing would be common for a variety of drugs.

    McLeod was not certain that progress would be easy. He praised FDA for promoting the field of pharmacogenetic testing. But he criticized pharma companies and generics manufacturers for hesitating to embrace a more targeted, genetic approach to drug development.

An ingenious pharmacogenetic test from Third Wave Technologies tests for the presence of a genetic change that inhibits metabolism of irinotecan. Oncology specialists explain how it works, and why it matters.

FDA Approves Genetic Test to Customize Dosage for Pfizer Cancer Drug

After a day and a half of deliberations, a Texas jury found Merck & Co. liable in the 2001 death of 59-year-old Robert Ernst on August 19. His widow, Carol, was awarded $253 million, which will be reduced to $26 million in accordance with Texas law.

    Merck recently stated that it is willing to consider settling in specific cases, where the plaintiff took Vioxx for more than 18 months and had no additional risk of heart disease.

In the aftermath of the verdict, experts on both sides are saying that the presentation of scientific information was the key to Merck’s loss.

    “I thought this was a case where, because of causation issues, Merck actually had a pretty good shot at winning,” said Stephen Bainbridge, a professor of corporate law at the University of California Los Angeles.

    The heart of the issue is that Ernst took the drug for less than the 18 months that clinical studies identified as dangerous. In addition, his official cause of death was arrhythmia, which is not listed as one of the risks associated with Vioxx.

    “The most important part of that case is that the science seemed to have very little impact on the jurors,” said John Calfee, resident scholar at the American Enterprise Institute.

    Tom Dewey, partner at Dewey Pegno & Kramarsky LLP, suggested that the jurors either rejected or failed to understand all of the scientific defenses presented by Merck’s laywers.

    But Evan Schaeffer, a partner at Schaeffer and Lamere PC who is involved in prosecuting Vioxx cases on the Illinois and Missouri border, said that both sides presented valid science. The jury heard expert testimony backing both sides and decided that the plaintiff’s proof of causation was more powerful than the evidence presented by Merck scientists.

    For example, Schaeffer pointed to the testimony of the doctor who performed Ernst’s autopsy. She indicated that the arrhythmia could have been caused by a heart attack, which in turn was caused by a blood clot. Blood clots and heart attacks are associated with Vioxx’s risk profile.

    According to Schaeffer, the plaintiff’s lawyer, Mark Lanier, “presented a theory about causation that held together better.”

    “I’m sure Merck lawyers had reasons for presenting the way that they did,” Schaeffer said. “But definitely one of the conclusions that could be reached is that the plaintiff had a better way of presenting evidence.”

    In future trials, Merck will have to break the science down into more simple components, suggested Dewey.

    “The science here was very good for Merck. If you are Merck you need to be able to communicate that very clearly, very simply and repeatedly,” Dewey said. “That’s a very hard thing to do, but it’s do-able.”

Another problem in Merck’s defense, Dewey noted, was that witnesses for the company seemed unprepared to respond to internal documents that were used by the plaintiff in cross examination.

    “You have to have a playbook for dealing with unhelpful internal documents,” he said.

    Calfee indicated that for Merck to win future cases, it would have to prove that internal documents addressing risks are a normal part of day-to-day communications at a pharma company. He suggested Merck should have two witnesses who testify that expressing doubt in internal communication is standard – one from inside the company and one external expert in corporate culture.

Merck lost the suit because the jurors were angry with the company, according to Calfee.

    “The jury seemed to be working backwards,” he said, explaining his belief that they used their anger to arrive at the verdict rather than causation.

    Lanier managed to shift the focus from causation to the fact that Merck aggressively market a product that was at some point associated with increased risks, Bainbridge explained. The jury bought into the idea that the company knew of Vioxx’s risks and failed to disclose them, he said.

    Schaeffer indicated that although causation will vary from trial to trial, the case against Merck’s marketing tactics and the argument that the company knew of risks long before it warned the public would be similar.

    In order to win in the future, Bainbridge believes the company needs to confront this tactic and convince the jury to look past it in order to focus on causation, he said.

    Merck needs to create thematic development throughout the next trial, Dewey suggested. The company should present a strong case for what they stand for and the commitment to science and integrity that once brought then the nickname St. Merck, he continued.

    “None of that story seemed to come out,” he said

Dewey believes that the results of the Texas trial will have an impact on the way other pharma companies handle product liability trials.

    “You have to be troubled by this verdict,” he said.

    Bainbridge predicted that the verdict could discourage pharma companies from developing new drugs.

    “We may see an effect here of pharma companies becoming even more risk averse in terms of developing new drugs,” he said. “This may create an incentive to focus on one or two new drugs.”

    But Schaeffer disagreed. Fen Phen litigation cost Wyeth a lot of money but that company still has a healthy pipeline, he claimed.

    Bainbridge also expressed concern that Merck shareholders could file lawsuits.

    “It wouldn’t surprise me if somebody sued,” he said.

    Dewey indicated that shareholder suits related to the drop in stock price after Merck pulled Vioxx from the market are already out there. He said it is possible that more could be filed on the basis of an allegedly unsatisfactory defense, but he thought it unlikely.

    Bill Lerach, partner at Lerach, Coughlin, Stoia, Geller, Rudman and Robbins LLP, is representing a pending derivative suit against Merck alleging directors and officers’ misconduct. He predicted that the results of suits like the Ernst trial could impact the results of shareholder and derivative suits.

    Shareholder suits have already impacted Merck’s insurance premiums, according to industry experts. An underwriter at a multinational insurance company said that a $25 million dollar claim resulted in Merck having to change its policy with his company to cover only non-indemnifiable claims against directors and officers. Continuing its previous plan would have increased Merck’s premiums by almost 100 percent. He indicated that premiums for other Cox-2 manufacturers have also gone up as a result of this type of liability.

    But University of Connecticut law professor, Tom Baker, said that this increase was unlikely to influence the impact premiums for the industry as a whole.

Legal experts play Monday-morning quarterback with Merck's first Vioxx loss. The lessons, they say: learn to present science better, pay attention to jury emotion and, oh yes, worry about shareholder lawsuits.

Pharmaceutical Executive-08-30-2005

Placebo Effect: All in the Brain

FDA Approves Genetic Test to Customize Dosage for Pfizer Cancer Drug

Merck Found Liable in First Vioxx Trial