Thursday, December 26, 2013

No Needle, but the Damage was Done - A New Example of Suppression of Research about Adverse Effects of Prescription Narcotic Analgesics

This story feels personal, since as a physician who trained starting in the 1970s, figuring out how to manage patients who desperately wanted narcotics, whether to relieve pain, relieve addiction, or relieve financial distress has been a constant challenge.

Background  - Treating Pain while Avoiding "the Needle and the Damage Done"

Almost as soon as I started clinical training in medical school I came up against the problem of narcotics.  In the 1970s, narcotic addiction was a pressing problem that threw a dismal shadow over society..  In the hospital and emergency room we daily saw overdoses and the complications of narcotics addiction, including some particularly nasty infections like bacterial endocarditis,  While dealing with these, we tried to do our best to manage the severe pain of cancer and other relentless diseases with limited tools, narcotics being the most potent.

We knew that we should not let our bleak experiences with addiction to illicit narcotics prevent us from giving adequate pain medication to those with metastatic cancer.  However, it was never clear how to best to help people with chronic pain from diseases that were not so immediately deadly.  And whatever it took we wanted not to promote "the needle and the damage done."

Things did not become easier in the 1990s when we  incessantly heard about under-diagnosis and under-treatment of  pain, and how we should not be so afraid of addiction and other adverse effects when prescribing legal narcotics.  As we heard this, however, it seemed that more people with less well-defined chronic pain were coming to us seeking relief, sometimes while preoccupied with narcotics as the solution to their problems.  Yet many of these patients seemed at risk of addiction, appeared already addicted, or even appeared to be seeking drugs so they could sell them to others.

In my most recent clinical position, it seemed I was always dealing with new patients with years of obscure musculoskeletal pain who felt I was the miracle physician they were seeking, often specifically to prescribe something like Vicodin, Percodan, or Oxycontin.  When on weekend call I inevitably hear from some poor patient who had somehow run out of or lost an important medication, which turned out to be Vicodin, Percodan, or Oxycontin, and just needed a simple refill without the bother of actually seeing a doctor.  Etc, etc, etc.

How could I relieve real suffering without becoming the pusher man? 

The Over Promotion of Narcotic Pain Treatment  

Then the realization began to dawn that patients, doctors and society were being victimized by a new type of pusher man, this time dressed in a suit and working for an "ethical" drug company.  In the earlier days of Health Care Renewal, we first posted (in 2006) about allegations of deceptive and unethical promotion of fentanyl by Cephalon that lead to its overuse by patients beyond those with cancer who were its ostensible target population.  Then in 2007 came the spectacular case of guilty pleas by a subsidiary of Purdue Pharma and several of its executives for "misbranding" Oxycontin,  that is, promoting it far beyond any medically legitimate use in severe chronic pain.  Following that various investigations, well chronicled in the Milwaukee Journal Sentinel, showed how pharmaceutical companies employed deceptive marketing techniques, subverting medical education and research, and creating conflicted key opinion leaders and institutionally conflicted disease advocacy groups, to push more "legal" narcotics  For example, see the Journal Sentinel reports the subversion of :  medical schools and their faculty; .medical societies, disease advocacy groups, and foundations; and guideline writing panels.  In 2012, we posted about how a drug company paid key opinion leader admitted to second thoughts about his role promoting narcotics.

The realization that that overtreatment of chronic pain, now matter how sketchy, never mind the adverse effects of narcotics, was driven by greed and marketing did not make managing chronic pain and patients who wanted narcotics easier.

One strategy we used was to try to find drugs nearly as effective as narcotics (although we began to realize that narcotics are also notw as effective as we thought) but less addictive.  The latest story by the indefatigable John Fauber of the Milwaukee Journal-Sentinel suggests that strategy too was subverted.

 Suppression of Research about Addiction to Tramadol

One workaround I sometimes attempted was to prescribe tramadol (e.g., Ultram, Janssen), an opioid which was promoted as non-narcotic and non-addicting.  However, like many quick pharmaceutical solutions to difficult problems promoted in the last few years, that did not often seem to work as well as expected.  Now, per Mr Fauber, it appears that

the FDA failed to heed a key piece of research indicating tramadol had the potential to be abused when it first appeared on the U.S. market in 1995. The drug was not placed under the Controlled Substance Act.

Despite recent research affirming its abuse potential, restrictions on prescribing it are no more stringent than for Lipitor or Viagra.

The Controlled Substance Act places drugs into five progressively restrictive categories based on their abuse potential. At the top of the list are drugs such as heroin. At the other end are cough medicines with limited amounts of codeine.
In deciding tramadol need not be on the list, the FDA based its decision largely on research in which the drug was injected as well as reports from Europe, where it had been on the market for years, that showed very little abuse.

However, the agency also had unpublished research showing that when given to opioid abusers orally in high doses, rather than being injected, it produced opiate-like effects that were similar to those from oxycodone, the narcotic in OxyContin, one of the most abused drugs in America. 

Oops.  Here is more detail about the suppressed research,

Tramadol was first introduced in Germany in 1977.

Data from Germany had suggested it was only about one-tenth as potent as morphine when injected. Other data showed that after years of use in Germany and other countries there was very little abuse of the drug.

However, in the early 1990s, researchers at Johns Hopkins University did a study in which high doses of the drug were given orally to opioid abusers. Taken that way, tramadol acted much differently than when injected.

At very high doses it produced opiate-like effects that were similar to high-dose oxycodone.

Taken by mouth, the drug is transformed in the liver to a metabolite known as M1, which is able to attach to and activate opioid receptors in the brain. It is M1 that is believed to produce the desirable, opiate-like effect.

In 1994, Ortho-McNeil, part of the R.W. Johnson Pharmaceutical Research Institute of Johnson & Johnson, sought approval from the FDA to sell its brand-name version of the drug, Ultram, in the United States.

The Johns Hopkins study never was published, but the company said it was provided to the FDA.

Also, oops.  The FDA decided not to list the drug as a controlled substance, realized more thought might be needed in the future, but did not appear too worried about who would be doing the thinking.  

That was when the FDA allowed Ortho-McNeil to fund its own committee, separate from the FDA, that would monitor the country for problems with the drug.

While it was called an 'independent steering committee,' Ortho-McNeil paid for the group's work and also paid consulting fees to its members.

Sidney Schnoll, a former member of the committee, said he could not remember how much the committee members were paid. In total, the program cost Ortho-McNeil about $15 million a year, said Schnoll, now an executive with Pinney Associates, a Bethesda, Md., company that works with drug and opioid companies.

'There was absolutely nothing independent about this group,' said Andrew Kolodny, a New York addiction specialist and advocate of tighter controls on opioids.

From early on, Ortho-McNeil's marketing plan for tramadol meant keeping it off the list of controlled substances where it would have difficulty competing against other narcotic painkillers such as Tylenol 3 and Tylenol 4, Schnoll said in a 2009 interview. Both Tylenol products contain codeine and are schedule 3 drugs.

The Schnoll interview was done by two professors, one from the University of Florida and one from Rensselaer Polytechnic Institute in New York, as part of a project at University of Michigan Substance Abuse Center.

'There were equally good products that were cheaper on the market,' Schnoll said, according to a transcript of the interview. 'So they really wouldn't have much of the market. They wanted to see if it would be possible to get the drug onto the market as a non-controlled substance.'

After a decade, the eight-member Ortho-McNeil committee dissolved itself in December 2005, without ever having recommended that tramadol be put under the Controlled Substances Act.

Oops, again.  Meanwhile, the adverse effects of tramadol were becoming more apparent.

An analysis by the Journal Sentinel and MedPage Today found that tramadol use is up dramatically since 2008, the earliest year for which data is available. It rose from 25 million prescriptions that year to nearly 40 million in 2012, according to data from IMS Health, a market research firm.

In 2011, the drug was linked to 20,000 emergency department visits around the country. In Florida alone, there were 379 overdose deaths involving tramadol that year, up from 106 in 2003, according to the DEA.

In Milwaukee County, 20 people died of a drug overdose involving tramadol from 2010 through October 2013, according records from the Medical Examiner's Office. In most of those cases, tramadol was one of several opioids that had been taken.

Final oops.  Perhaps no needles were involved, but the damage was being done.  

Summary - Goddam the Pusher Man

The over-promotion of addictive narcotics for pain relief has become an instructive example of deceptive and unethical practices used by commercial health care firms seeking revenue no matter what it takes to get it.  Just the latest article on tramadol illustrated the use of paid key opinion leaders and more broadly, the creation of conflicted medical academics for marketing objectives (here, apparently, obfuscating the dangers of the product); the suppression of clinical research (for the same reason); and at least raised the possibility of regulatory capture.  It seems unlikely that whoever made the decisions to use the tactics worried about adverse effects including loss of the integrity of research, subversion of academic medicine, ;undermining medical decision making, and obviously most importantly direct harm to patients.  (I would note that the decision makers appeared to be working for Johnson and Johnson, a company which seems to have a growing history of questionable behavior.)  

Health care professionals should at least learn that the pusher man does not always look like a character out of Easy Rider.


Steve Lucas said...

Being of the same age and growing up in a town with Big U I watched as bright young people were pulled into the world of drugs, always with the caveat that it was ok since it was no worse than prescription medication. Today I shudder at the head long rush to legalize many substances for “recreational” use that are anything but recreational.

I have watched as a 90 year old woman was given Oxy for pain, only to discover later that she was self medicating to achieve an altered state to escape her life situation.

I have watched the bright young people of my youth turn into doctor dependent drug addicted shells who have thrown away their potential and settled for a life of mediocrity.

Today we dress up all the problems, and all the medications into marketing sound bites, while ignoring the reality of the loss of countless people’s potential, to support an industry that is only interested in financial gain.

Steve Lucas

Anonymous said...

The addiction epidemic was wrought gy greedy pharma and well paid physician promoters.