When I published my first paper in clinical psychopharmacology in 1980 with a psychiatrist collaborator, the physician-patient relationship was still virtually sacrosanct. The Food and Drug Administration (FDA) regulated the research and marketing of drugs, and they did a pretty good job: it was the FDA that spared America from the thalidomide epidemic that swept Europe, for example. But with frightening hubris, narcs from the Drug Enforcement Administration (DEA), are now muscling into the practice of medicine. At this writing, politicians are preparing to launch what may turn into a witch hunt on the medical profession and the medical professionals at the FDA.
Specifically, the May 16, 2012, issue of Pharmalot reports that the Senate Finance Committee is cranking up to probe "an epidemic of accidental deaths and addiction resulting from the increased sale and use of powerful narcotic painkillers." The targets are drug manufacturers, physicians and patient advocacy groups.
The Centers for Disease Control (CDC) claims that, in 2008 alone, 15,000 people died from prescription opiate painkillers. To get some perspective on a number like this, Truthout spoke with one of most respected forensic pathologists in the country, Michael Baden MD. Dr. Baden, formerly chief medical examiner for the City of New York, currently serves as co-director of the New York State Police medico-legal investigation unit and has an active consulting practice. He has been pursuing his profession for 48 years.
Baden made several points. First, CDC statistics for mortality are predicated on poor data, namely death certificates. There are no uniform diagnostic standards for filling out death certificates and, indeed, the certificates themselves vary from jurisdiction to jurisdiction. The situation is all the more dismal because, in the US these days, only 5 percent of bodies are autopsied - the only definitive way to arrive at the cause of death. A corollary is that, absent an autopsy, we don't know how much drug - if any - is present in the body. Usually, Dr. Baden suggested, when the signer of the death certificate finds a bottle of an opiate, he or she then attributes the death to its contents.
What makes the CDC's reliance on death certificates even more problematic is that the signer of the death certificate in many jurisdictions need not even be a physician: he or she can be a non-physician coroner (generally an elective office), an emergency medical technician, an undertaker or even a cop. It is a pathetic fact that the CDC issues a 67-page manual that tells funeral directors how to fill out a death certificate.
Dr. Baden observed that a death may be caused by several factors and, indeed, most death certificates list a line for the putative primary cause and several lines for even more putative secondary causes. This applies with particular force to opiates, because most people are not junkies; they are taking opiates for an illness and that illness may be a primary or contributory cause of death ... but we'll never know without an autopsy. Of course, one can argue that, as one doctor said, the death certificates are the best we have. But so long as cops and undertakers can play pathologist and autopsies are the exception, the certificates' accuracy is problematic.
There is one cause of death from opiates that Baden considers very important, but which you can't identify from the CDC data: Suicide. Even if the signatory recognizes that they have a suicide on their hands, they often do not record it to spare the feelings of the dead person's loved ones. So, it just goes down as an opiate death, even though many suicides are accomplished with a potpourri of opiates, sleeping pills, anxiolytics and - to wash it all down - alcohol. Dr. Baden thinks that suicide is underestimated to a significant degree.
Just as the CDC statistics must be taken for what they are worth, the lethality of opiates requires examination. Not all opiates are equally toxic. Methadone heads the list: astonishingly, methadone is used not just for maintaining heroin addicts, but as an analgesic. Methadone is highly toxic to the heart; other commonly used opiates such as Percocet have been associated in some case series with changes in the electrocardiogram, but in this respect, they're far less dangerous than anti-psychotics like Geodon and Mellaril. Opiates become more toxic to the heart when combined with another drug that has the same effect - for example, Cipro, a widely used antibiotic. One revealing recent study found that most deaths from prescription opiates occurred when the patient was also taking methadone - though CDC statistics fail to reflect drug interactions. The opiate is usually fingered as the culprit.
EKG changes have been seen in the therapeutic range for Percocet and Vicodin, however the FDA does not deem them sufficiently serious to include in the official prescribing literature as warnings, even for cardiac patients. The other major toxic effect of opiates is respiratory depression, but this effect only occurs in much higher doses and is the cause of death by suicide. Adding alcohol, in particular, potentiates the respiratory depression, and throwing in sleeping pills and sedatives doesn't help. Much is being made in the press of death by accidental overdose, but it seems likely that many of these cases are suicides. However, some patients escalate the dose on their own initiative, either because their pain is getting worse or because a small proportion of people on long-term therapy develop tolerance and the drug ceases to work. Unfortunately, people can develop tolerance to the analgesic effect of opiates, but not to its potentially lethal effect on the breathing center of the brain.
John D. Loeser's career spans 46 years as a neurosurgeon and pain specialist, most of that time at the University of Washington (UW). He has engaged in patient care, teaching, administration and research: plug his name into PubMed, the database of the National Library of Medicine, and the citations to his articles just come pouring out. Today, he is professor emeritus of neurological surgery and anesthesiology; from 1983 to 1997, he ran UW's Multidisciplinary Pain Center and he continues his pain research and teaching today. Loeser wears his laurels lightly, but he is a man of firm views.
Maria A. Sullivan MD, PhD is associate professor of clinical psychiatry at Columbia University and New York State Psychiatric Institute (NYSPI). She is both a psychiatrist and a psychologist and is board certified in addiction psychiatry and in adult psychiatry and neurology. In her daytime life, Dr. Sullivan is a researcher in substance abuse at NYPSI; in the evenings and Saturday, she maintains a private practice in psychopharmacology and psychotherapy. She holds several grants from the National Institute on Drug Abuse to study opiate dependence and detoxification. Dr. Sullivan is a young scientist, but her research impacts on almost every topic in this article. Like Dr. Loeser, she gave of her time both generously and authoritatively.
Loeser made it emphatically clear that he does not welcome the increasing "policing" of medicine by the DEA. Nor does he welcome the Senate hearings, "I hope the Senate doesn't cause trouble," he said in a voice that suggested he was pretty sure it would do exactly that. He believes that the proper body for regulating opiate prescribing practices is the FDA because its scientists possess the knowledge of pharmacology and medicine that DEA agents and politicians lack. Dr. Loeser serves on the board of directors of the American Chronic Pain Association, a 503(c) founded by Penny Cowan to help people with persistent pain issues with drug and nondrug modalities like meditation, physical therapy, biofeedback and acupuncture. Many of its 15,000 members are deeply troubled at the "politicizing of opiate prescribing," as Loeser put it.
Dr. Loeser told Truthout that there is indeed a problem with opiate prescribing. One statistic shows a 300 percent increase in prescription opiate sales and a corresponding increase in deaths. The deaths cluster in the higher dose range. Asked whether higher meant, for example, one 10/325 mg tablet of Percocet four times a day, he said yes, for some people that dose could be cardio-toxic. In fact, the FDA-approved package insert is more lenient, setting the approved upper limit at one 10/325 mg tablet every four hours. Dr. Loeser said that he would not sit in judgment on the dose a particular patient might need, provided the medication was prescribed appropriately. For example, many patients with cancer require substantially higher doses, or more powerful narcotics like Fentanyl. Dr. Loeser's criterion: "Is an opiate the best available treatment for this patient at this time?"
Dr. Loeser was very much interested in Dr. Baden's comments. He observed that the death certificates are all we have, and that a proportion of the CDC's 15,000 opiate deaths almost certainly can be attributed to physicians who prescribed inappropriately.
Feelgoods - physicians who derive their livelihood from writing prescriptions for controlled substances - are not the problem, he said - there aren't enough of them around to make a dent in the body count, and the average person in pain probably wouldn't know how to find one. Feelgoods are the province of junkies. A related and real problem, Dr. Sullivan told me, is diversion: one person gets a prescription for OxyContin, Percocet, or Vicodin and sells the pills at a profit. Most likely, the customers are junkies, but people in severe pain may obtain medication in this way if their doctors lack the knowledge - and empathy - to prescribe adequate pain medication.
Pain medicine specialists aren't the problem either. They are highly trained, board certified specialists who work with the patient's primary care physician or specialist (an oncologist or an orthopedist, for example) to solve tough pain problems. Yes, they prescribe opiates, but also nonsteroidal anti-inflammatory agents, muscle relaxants, Neurontin, cortisone injections, relaxation training and some use acupuncture.
The problem, said Loeser, is the "primary care docs" who know little about pain and bought into a "huge push" from drug companies to hand out pills, most notoriously OxyContin, for chronic conditions. It is well known that many doctors learn about new drugs from drug company sales reps, not respected journals like JAMA or the New England Journal of Medicine.
So, what's the right way? A careful history. A thorough examination and appropriate tests and radiology when indicated. An attempt to correct the cause of the pain. A trial of non-opiate pain medicine before resorting to opiates.
An important consideration depends upon whether the patient's pain is acute or chronic. Dr. Loeser told Truthout that opiates are actually underutilized by physicians and hospitals for treating acute conditions with adequate doses owing to the unfounded fear of getting patients hooked. Acute means 30 days or fewer on an opiate for situations such as postoperative pain, injuries healing, awaiting an operation or lab work, dental work, and so forth. Within a time frame of 30 days, a patient should have no trouble tapering off the opiate. One appalling example of undertreated pain is postoperative pain. In one national patient survey, Dr. Sullivan told Truthout, 47 percent of postoperative patients experienced moderate pain, while an astounding 33 percent experienced severe to extreme pain (Apfelbaum, 2003). Dr. Sullivan said that uncontrolled pain leads to adverse outcomes, especially in elderly patients who comprise a majority of postsurgical patients. For instance, pain-induced tachycardia (abnormally rapid heart beat) can cause a heart attack. Uncontrolled pain also increases the risk of delirium (Morrison, 2003), prolongs hospital stays and makes it difficult for the patient to resume a normal life. Human laboratory studies have shown that administering opiates does not precipitate an addiction in patients without a history of drug abuse (Corner et. al, 2010); such folks were found to use an opiate only when they felt pain.
Chronic pain is Dr. Loeser's special area of interest because it presents many treatment and research challenges. He was quick to take end-of-life pain off the table first: the physician should use however much of a powerful opiate is required. Back in 1998, Susan Anderson Fohr JD, MA, wrote with immense sensitivity and scholarship about the conundrum that adequate doses of opiates to alleviate pain might shorten life by depressing respiration and came down firmly on the side of giving the drugs (J Palliative Medicine 1998;1:315-28).
Dr. Loeser said, "We don't know why, but a subgroup of chronic pain patients doesn't respond to recognized treatment for their condition." This is the fraction that needs opiates and Dr. Loeser thinks it is small - certainly fewer than 50 percent of chronic patients. But as Dr. Loeser said, Big Pharma taught willing general practitioners and primary care providers that opiates were the answer to all pain symptoms. Such prescribing papers over symptoms (and complaints) and clears demanding pain patients out of the office. In an email that Dr. Loeser sent Truthout a few hours after our conversation, he added that "chronic pain patients are entitled to effective treatment. That is not a synonym for opioids [opiates]."
Dr. Loeser readily agreed with the statement that the majority of chronic pain patients who require opiates, sometimes for years, sometimes for life, use them responsibly, without jacking up the dose and continue to experience sustained relief. So, I asked why some people became junkies; why, specifically, that very first pill is "like discovering Heaven," a description I had encountered about a first drink in my research on alcoholism.
Dr. Loeser said that, just as there are a fraction of chronic patients, probably small, for whom therapy with opiates is appropriate, so there is another fraction, also probably small, for whom opiates are "a disaster." Dr. Loeser thinks the reason is genetic and pointed to the example of Native Americans, who disproportionately become disinhibited and violent on alcohol. The anti-opiate (or pro-pain) crowd that Dr. Loeser and many of his distinguished colleagues oppose would have us believe that every patient is a potential junkie. It simply is not so, any more than that every person who has a couple of drinks with dinner is a drunk.
The most widely used opiate pain killers are oxycodone, hydrocodone and OxyContin. The combination of oxycodone (which was synthesized in Germany in 1918) and acetaminophen (Tylenol) is known as Percocet and that is how oxycodone is generally prescribed. Similarly, the combination of hydrocodone and acetaminophen is called Vicodin. According to the authoritative Merck Manual, oxycodone is comparable to morphine and is indicated for moderate to severe pain; hydrocodone is comparable to codeine and is indicated for mild to moderate pain. Both drugs, according to "The Merck," should be taken every four hours and clinical experience is consistent with the time course of therapeutic blood levels. Combining the opiates with acetaminophen does not prolong their duration and the amount of acetaminophen in the tablets probably has a very modest effect at best, but the "piggyback" - two in one - drugs are certainly more expensive than the opiate tablets themselves.
In 1995, the small drug company Purdue Pharma marketed a long-acting formulation of oxycodone under the brand name OxyContin. It came in a generous variety of strengths, and one capsule would maintain a reasonably constant blood level for 24 hours. At first, OxyContin seemed like an eminently practical and convenient pain killer: the patient didn't have to fear being awakened from sleep by pain when his Percocet wore off, nor did he have to worry about taking his pain killer every four hours lest the pain return - a relevant consideration for elderly, forgetful patients. However, OxyContin turned out to have a steep downside.
The time-delay chemistry was poorly conceived. The capsules could be chewed up and the contents ingested - one whole day's supply of oxycodone swimming to the brain in a single heavy hit. And aficionados of OxyContin soon found faster, more gratifying ways of experiencing the drug: snorting the powder; rubbing it in the gums; dissolving it in water and mainlining it.
Intentional abuse did not come to light right away, but another problem with OxyContin was apparently obvious to FDA medical officers, because it is reflected in the package insert. OxyContin was approved for moderate to severe pain in chronically ill patients who required round-the-clock pain medication. The latter stipulation is important because many patients with chronic pain have good days and bad days, in which case they might need only one or two Percocet, or perhaps even none at all. With OxyContin, on the other hand, the patient is exposed to a relentless 24-hour opiate assault. This increases the likelihood of developing tolerance and physical dependence. However, the voices of Purdue Pharma - its sales reps and tame doctors - claimed exactly the opposite in their pitches to the medical community. The general public was also educated in the benignity of OxyContin, creating a demand that translated into sales of $10.2 billion from 1995 to 2006. Within a few years of OxyContin's introduction, it was becoming clear that Purdue Pharma's spokespeople were lying in a big way about the safety of Purdue's only big seller. The United States attorney for the Western District of Virginia opened an investigation; four years later, in 2007, Purdue paid a fine of $600 million and three of its top executives shelled out $24.5 million to stay out of jail. Everybody had pleaded guilty to "misbranding," defined as lying or making claims not approved by the FDA, as reflected in the official labeling. To cap it off, the FDA required Purdue Pharma to come up with a new, long-acting formulation that is no more vulnerable to tampering than ordinary oxycodone tablets; such a product was approved by the FDA in April 2010.
When the FDA considers whether to approve a drug for marketing, it must balance a drug's safety against its efficacy. The FDA's medical officers review clinical trials and evaluate testimony from expert witnesses representing the manufacturer and other interested parties, pro and con. The noisiest con is Sidney M. Wolfe MD, formerly director of Ralph Nader's Health Research Group and now director of its umbrella organization, Public Citizen. Wolfe is a medical Luddite, who would weight the scales so heavily in favor of safety that we would get few effective new drugs. He is proud to be known as the FDA's nemesis and boasts that he killed 14 drugs. Wolfe and other activists like him seem to crave a world of perfect safety, but the reality is that the best a regulatory agency can do is predicate its decisions on the evidence in front of it. Wolfe berated the FDA in 2007 for failing to kick OxyContin off the market; instead, the FDA gave Purdue the opportunity to come up with a superior time-release drug. I would argue that this was the correct decision because a time-release opiate is a not-insignificant advance in managing pain for a small segment of the population, but Purdue's track record has been so sleazy that its marketing practices must be monitored closely. While it is perfectly proper for Wolfe to testify before the FDA as often as he wishes, it is another matter for him to testify in the House and Senate for the purpose of trying to get from the politicians what he can't get from the FDA. Truthout sought Wolfe's opinion on the forthcoming Senate Finance Committee hearings, but Wolfe refused to take a call on the issue.
One physician who isn't the least bit shy about his views is Andrew Kolodny, the chair of psychiatry at Maimonides Medical Center in Brooklyn, New York. He is also the head of an innocuous-sounding organization called Physicians for Responsible Opioid Prescribing (PROP). At the mention of Kolodny's name, Dr. Loeser laughed: "Kolodny occupies the far end of the spectrum" of the anti-opiate fringe, and he added, "He believes nobody should have opiates unless they're about to die." And if you want opiates from Kolodny, you'd better be dying of cancer.
Kolodny was the subject of a puff-piece interview in Pharmalot (May 16, 2012), where he betrayed an abysmal ignorance of pharmacology, and Pharmalot failed to ask for documentation of his more outré assertions, such as this one: "There's increasing evidence that opioids are neither safe nor effective for the majority of people with non-cancer pain." Kolodny seems to be afraid that even cancer patients were in danger of getting too much relief, as he told Pharmalot: "To increase use of opiates for cancer care, Purdue paid thought leaders to encourage prescribing more opioids." Cancer pain is the most important indication for OxyContin.
And how does Dr. Kolodny feel about the upcoming Senate probe of, among other people, fellow physicians and advocacy groups for people with pain issues? "I'm thrilled this is finally happening," he said. "Some of the people who played a role in creating this mess should be punished" (Pharmalot, May 8, 2012). And what about the FDA? Kolodny condemned the FDA for having "no teeth" because it declined to impose Draconian restrictions on opiate prescribing after hearing testimony from pain specialists and patients with chronic pain who required opiates for relief.
Jane C. Ballantyne MD, professor of anesthesiology and pain management at the University of Washington and the director of the Pain Management Residency Training Program, as well as a member of PROP, shared some of her thoughts with me in an exchange of emails. I asked her if she thought cancer was the only indication for opiates. Her reply: "Cancer only is a little too narrow, but pain should be severe and intractable (in other words, failed all attempts with non-opioid and non-medical treatments) before opioids are used." I asked Dr. Ballantyne whether she thought the FDA, not the DEA or Capitol Hill, is the appropriate agency to regulate opiate prescribing. Her reply: "The FDA has not heeded early warning signs that prescription opioid abuse is becoming a public health problem in the US, so I do not agree that the FDA alone has been or can be effective." Ballantyne also contravened the view that opiates are being underprescribed for acute pain, the evidence notwithstanding. She insists that opiates are "grossly overutilized" and reiterates that they should only be utilized for pain that is "severe and intractable." This is a physician with responsibility for training future doctors in pain management. And her PROP leader's voice has inspired some very unhealthy comments, like this one from Original Industry Insider in the pages of Pharmalot: "Maybe if we let them go cold turkey in a basement shooting gallery and puke their guts out for three days, the addiction problem might change for the better."
There is no doubt that opiates are addictive, but to what degree? In her email, Dr. Ballantyne wrote: "... opioids are much more addictive than alcohol, which puts opioid users at higher risk than alcohol users." In the authoritative Schatzberg, Cole and DeBattista "Manual of Clinical Psychopharmacology." the very first sentence under "Alcohol" reads, "Ethyl alcohol is a short-acting sedative drug that produces withdrawal syndromes similar to those caused by barbiturates." Few clinical situations are worse than the barbiturate withdrawal syndrome, which is a medical emergency that can cause death if not aggressively treated. Alcohol withdrawal, too, requires prompt and aggressive treatment with a drug like Librium, for without it, the patients' anxiety will go over into agitation and he or she may develop delirium tremens and perhaps have one or more seizures.
By contrast, the opiate withdrawal syndrome is generally rather mild and easy to treat. As Schatzberg et al write, the syndrome, if untreated, is self-limiting, peaks at two to three days and resolves within about ten days.
But an untreated syndrome is no fun. Withdrawal symptoms include anxiety, insomnia, sweating, chills, muscle cramps, anorexia, diarrhea, nausea and vomiting. There may be an increase in pulse, blood pressure, breathing rate and temperature. In the old days - not that long ago, actually - "dope fiends" were treated "cold turkey," as Original Industry Insider proposes.
Except for a patient who has been treated with an opiate for only a few days or a week - for something like dentistry, some types of post-op pain, injuries etc. - it is best to taper the dose down gradually at the rate of 10 percent per day. Addicts - that is, people who have pushed their dose well above the therapeutic range - or people who are hooked on heroin - not only require more aggressive detoxification, but need measures to keep them out of drug trouble in the future. Dr. Sullivan told Truthout that opiate detoxification can be accomplished on an inpatient or outpatient basis using buprenorphine, a synthetic opiate with which Dr. Sullivan has done extensive research, for just one injection daily to mitigate the withdrawal syndrome. This is augmented with anxiolytics like clonazepam and with sleeping medication. Dr. Sullivan notes that clonidine, a blood-pressure-lowering medication, is a useful addition to the treatment regimen. Probably the reason is that clonidine can relieve the "physical" symptoms of withdrawal, such as anxiety, tremor, palpitations, sweating and so forth. But after detox has been accomplished, the relapse rates are extremely high and medication support in the post-detox period is essential. Dr. Sullivan has just completed a study of long-acting, injectable naltrexone, a drug that blocks the opiate receptor, to see whether it promotes abstinence. The idea is that, with naltrexone bound to the receptor and rendering it "silent," opiate drugs can't exert their euphoriant effect. Dr. Sullivan found that naltrexone substantially increases the rates of abstinence - as much as 60 percent at six months, a figure that is much better than methadone maintenance.
Junkies don't find methadone as pleasant as heroin, and besides, methadone is very toxic to the heart. For those who just can't hack it without an opiate, the answer may be buprenorphine. Dr. Sullivan explains that heroin addicts much prefer it to methadone: it's not as addictive as heroin and it's legal.
This article invites several conclusions:
1. Narcs and politicians are not qualified to meddle in the practice of medicine because, as Dr. Loeser put it, they don't know enough. By contrast, the medical officers at the FDA are specialists in various categories of drugs; they have the expertise to draw evidence-based conclusions from the available data. It follows that the regulation of drugs must be the province of the FDA, not the DEA or Capitol Hill
2. No worthwhile purpose is served with hysterical rhetoric about an "epidemic" of prescription opiate abuse because, as Dr. Baden explained, the CDC's conclusions are predicated on dubious data. It is unquestionably true that, in recent years, there has been an upward trend in opiate prescribing and a parallel trend in deaths from these pain killers. However:
a. Opiates are underutilized for people with acute pain;
b. Opiates are inappropriately overprescribed for chronic pain, mainly by primary care providers who use these drugs as a Band-Aid to cover symptoms instead of seeking and treating the cause of the pain, although an unknown fraction of chronic patients are going to require long-term or permanent opiate therapy;
c. The only predictable consequence of policing and politicizing the prescribing practices of physicians will be to intimidate them, thereby depriving patients with real pain issues of the medications they need; it follows that physicians and patients must join forces and kick back hard at those would diminish the role of the FDA as the only appropriate regulatory agency for drugs and challenge the heated rhetoric, errors and misrepresentations of PROP and it members;
d. The overwhelming majority of patients on opiates for chronic pain use their medication responsibly. As Drs. Loeser and Sullivan attest, that unknown but small fraction of patients who get hooked from their first dose probably have a genetic deficit;
3. It is essential to get Big Pharma out of the lucrative racket of "educating" physicians by reps and complicit doctors. Dr. Sullivan drew Truthout's attention to evidence-based guidelines for the appropriate prescribing of opiates, and continuing medical education credits could be offered by medical societies to doctors who master these guidelines;
4. Perhaps most important, the politicians should increase the FDA's budget, and the medical Luddites should eschew pronouncements on matters for which they evince a major paucity of knowledge.
Special thanks to Michael J. Tria, formerly a biochemist with the Nassau County Department of Health, for inspiring me to write this article and invaluable help in researching reference material. He declined a co-authorship on the grounds that he didn't do enough. He's wrong.
Editor's note: Andrew Kolodny denies allegations made about him in this article. He writes: "The article states that I believe opioids should only be prescribed to people who are dying from cancer. This is completely false. In my clinical practice, I frequently prescribe opioids to people who don’t have cancer. I have many patients who can attest to this fact....Never have I stated that opioids should only be used for dying patients." You can read Kolodny's response in the comments below.