Blast from the past: Addiction fears and palliative care

 Recalled without comment...

November 25, 2003
The Delicate Balance Of Pain and Addiction
By BARRY MEIER

Over the past two decades, conflicting medical ideas have surfaced about narcotic painkillers, the drugs that Rush Limbaugh blames for his addiction while being treated for chronic back pain. And both of them, not surprisingly, have centered on the bottom-line question: just how great a risk of abuse and addiction do narcotics pose to pain patients?

Throughout much of the last century, doctors believed that large numbers of patients who used these drugs would become addicted to them. That incorrect view meant that cancer sufferers and other patients with serious pain were denied drugs that could have brought them relief.

But over the past decade, a very different viewpoint has emerged, one championed by doctors specializing in pain treatment and drug companies eager to broaden the market for such drugs. It held that these medications posed scant risk to pain patients, and some experts now believe that it also had unfortunate consequences because it caused, among other things, physicians to develop a false sense of security about these drugs.

''The pendulum went in two opposite directions,'' said Dr. Bradley S. Galer, group vice president for scientific affairs at Endo Pharmaceuticals, which manufactures two widely used narcotics, Percodan and Percocet. ''Luckily, now the pendulum is focusing where it should be, right in the middle.''

The reassessment of narcotic risk comes at a time of skyrocketing rates of misuse and abuse of such drugs. Medical experts agree that most pain patients can successfully use narcotics without consequences. But the same experts also say that much remains unknown about the number or types of chronic pain sufferers who will become addicted as a result of medical care, or ''iatrogenically'' addicted. The biggest risk appears to be to patients who have abused drugs or to those who have an underlying, undiagnosed vulnerability to abuse substances, a condition that may affect an estimated 3 to 14 percent of the population.

Dr. James Zacny, an associate professor at the University of Chicago and a leading narcotics researcher, said there was a dearth of data about the long-term risks that narcotics pose. ''We don't know a lot about the rate of iatrogenic addiction,'' he said.

It is not unusual for views about particular drugs and their hazards to change over time. But a look at the shift in medical thinking about the risk of addiction shows a struggle that was waged both as a guerrilla war among doctors and a high-powered drug industry initiative. It was also an effort that, while seeking a laudable goal, inaccurately portrayed science.

Modern views about the threat posed to patients by narcotics were shaped in the mid-1980's when pain treatment experts reported that cancer patients treated with such drugs did not exhibit the type of euphoria displayed by people who abused narcotics. That led some physicians to argue that strong, long-acting narcotics could also be used safely to treat patients with serious pain unrelated to cancer, like persistent back pain or nerve disorders.

One leader of this initiative, known as the ''pain management movement,'' was Dr. Russell Portenoy, who is now chairman of the pain medicine and palliative care department at Beth Israel Medical Center in New York. And soon Dr. Portenoy and others were pointing to studies that they said backed up their contention that the risk of powerful narcotics to pain patients was scant.

''There is a growing literature showing that these drugs can be used for a long time, with few side effects and that addiction and abuse are not a problem,'' Dr. Portenoy said in a 1993 interview with The New York Times.

Drug companies amplified that theme in materials sent to doctors and pharmacists. For example, Janssen Pharmaceutica, the producer of Duragesic, called the risk of addiction ''relatively rare'' in a package insert with the drug. Endo termed the risk ''very rare'' in presentations to hospital pharmacists. Purdue Pharma, the manufacturer of the powerful narcotic OxyContin, distributed a brochure to chronic pain patients called ''From One Pain Patient to Another,'' contending that it and similar drugs posed minimal risks.

''Some patients may be afraid of taking opioids because they are perceived as too strong or addictive,'' the brochure stated. ''But that is far from actual fact. Less than 1 percent of patients taking opioids actually become addicted.''

The trouble, however, was that studies that looked at the experience of pain patients who used long-acting narcotics for extended periods of time did not exist. So narcotics advocates like Dr. Portenoy and drug companies like Purdue Pharma had looked elsewhere, at surveys of patients whose use of narcotics was limited. And those reports were not always put into proper context.

A frequently cited survey of narcotics use, taken in 1980, found ''only four cases of addiction among 11,882 hospitalized patients.'' A director of that survey, Dr. Hershel Jick, an associate professor of medicine at Boston University, said his study did not follow patients after they left the hospital and did not address the risk of narcotics when they were prescribed in outpatient settings.

In another case, advocates of increased narcotics use also misstated a study's results. It involved a study of chronic headache sufferers conducted at the Diamond Headache Clinic in Chicago that some pain care specialists repeatedly claimed had found only ''three problem cases'' among some 2,000 patients.

While the Diamond Headache Clinic did treat 2,369 patients in the study period, just 62 were studied because they met the criteria of having used painkillers alone or in combination with barbiturates for six months before entering the clinic. And the report's findings were far different from the way they were characterized by narcotics advocates. It concluded, ''There is a danger of dependency and abuse in patients with chronic headaches.''

Dr. Seymour Diamond, the clinic's director, said in a recent interview that neither pain experts nor narcotics manufacturers like Purdue Pharma who cited his study contacted him to discuss how they planned to use it. And he added that he believed that it was mischaracterized.

''It distorts the picture and it clearly underplays the risks,'' Dr. Diamond said.

In a recent interview, Dr. Portenoy said he now had misgivings about how he and other pain specialist used the research. He said that he had not intended to mischaracterize it or to mislead fellow doctors, but that he had tried to counter claims that overplayed the risk of addiction. Still, he and others acknowledge, the campaign by pain specialists and drug companies has had consequences.

''In our zeal to improve access to opioids and relieve patient suffering, pain specialists have understated the problem, drawing faulty conclusions from very limited data,'' Dr. Steven D. Passik, a pain management expert wrote in a 2001 letter published in The Journal of Pain and Symptom Management. ''In effect, we have told primary care doctors and other prescribers that the risk was so low they essentially could ignore the possibility of addiction.''

Today, some narcotics manufacturers like Endo have changed or are changing the way they present abuse and addiction information. For example, Purdue Pharma, while maintaining the accuracy of its past position, now states in patient information that it does ''not know how often patients with continuing (chronic) pain become addicted to narcotics but the risk has been reported to be small.'' Ligand Pharmaceuticals, which manufactures a time-released form of morphine under the brand name Avinza, makes a similar statement.

For its part, a spokeswoman for the federal Food and Drug Administration, Kathleen K. Quinn, said the agency believed that ''the risk of addiction to chronic pain patients treated with narcotic analgesics has not been well studied and is not well characterized.''

In a letter to The New York Times, Purdue stated that it had found no cases of iatrogenic addiction in a recently completed long-term study of chronic pain patients suffering from osteoarthritis, diabetes and low pain back. Purdue did not identify where it planned to submit the study for publication although the company said it involved an older group of patients whose average age was 55.

Such results are encouraging. But several pain experts said that the full risks of narcotics will not be fully known until these drugs are tested in a wide range of pain patients of different ages and conditions.

''You may have a study telling how uncommon these problems are in patients over 50,'' Dr. Portenoy said. ''But what does that tell you about the risks to younger patients or those patients who walk into a doctor's office with a history of substance abuse or psychological problems.''


Link

The most obnoxious email my hand surgeon has ever received

I managed to badly break my thumb during judo last week. I'm having surgery to repair it this Friday. After spending all this time learning about pain/pain medicine, I've learned just enough about drugs to be dangerous. Today, that danger has manifested in what I'm guessing is the most obnoxious email my hand surgeon has ever received from a patient.

For your enjoyment:

Dear [Dr's assistant],

....The pharmacy has a prescription of Darvocet for me. But, I'd actually like to avoid both the propoxyphene and APAP in Darvocet. I'd appreciate it if you could ask Dr. xxxxxx to cancel that prescription and write me one for something different. He might find the following useful:

The Vicodin prescription [which I had been written for the initial pain of the injury] worked fine. Still, I had forgotten that there is some evidence of an interaction between acetaminophen and xxxxxx. See, for example, [3]. So I'd prefer something without APAP. It's not a big deal, but I'd prefer to keep on the safe side.

I'd prefer to avoid anything containing propoxyphene for two reasons. First, it's somewhat contraindicated with xxxxxxx (propoxyphene can potentiate the xxxxxxxxxx). Second, there are some concerns about its cardiotoxic metabolites. See [1] and [2]. I know it's a tiny risk. But, again, I'd prefer to stay on the safe side wherever possible.

To make things just a bit more complicated: I don't think anything with straight codeine will be very useful. I'm fairly certain that both my mother and my sister are poor metabolizes, so I don't want to trust my CYP2D6's any more than I have to. Moreover, according to Cochrane Reviews [7], with a NNT=12, codeine just doesn't seem very trustworthy.

Finally, just in case this is relevant, I'd prefer to use the narcotics to hit the acute pain hard for 1-2 days and then get off of them as quickly as possible. There seems to be evidence that early aggressive treatment helps cut the overall duration of post surgical pain and, more important to me, reduce the risk of chronic pain (see, e.g., [4], [5], [6], [8]). Thus I'd prefer very few doses of something strong to more of something weaker.

These are just some very weak preferences based on my rudimentary understanding of pain management protocols. I trust your judgment completely.

Thanks
Adam

References
[1] http://www.citizen.org/publications/publicationredirect.cfm?ID=7420

[2]http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm170268.htm

[3] Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther. 1984; 35:480-486.

[4] Leibeskind, J. C. (1991). "Pain Can Kill." Pain 44: 3-4.

[5] Merskey, H. (1999). Pain and Psychological Medicine. Textbook of Pain. P. D. Wall and R. Melzack. Edinburgh, Churchill Livingstone: 929-949.

[6] Harman, K. (2000). "Neuroplasticitiy and the Development of Chronic Pain." Physiotherapy Canada 52(64-71).

[7] Derry, S., R. A. Moore, et al. (2010) "Single dose oral codeine, as a single agent, for acute postoperative pain in adults." Cochrane Database of Systematic Reviews DOI: 10.1002/14651858.CD008099.pub2.

[8] Kehlet, H., T. S. Jensen, et al. (2006). "Persistent postsurgical pain: risk factors and prevention." Lancet 367(9522): 1618-1625.
Acute postoperative pain is followed by persistent pain in 10-50% of individuals after common operations, such as groin hernia repair, breast and thoracic surgery, leg amputation, and coronary artery bypass surgery. Since chronic pain can be severe in about 2-10% of these patients, persistent postsurgical pain represents a major, largely unrecognised clinical problem. Iatrogenic neuropathic pain is probably the most important cause of long-term postsurgical pain. Consequently, surgical techniques that avoid nerve damage should be applied whenever possible. Also, the effect of aggressive, early therapy for postoperative pain should be investigated, since the intensity of acute postoperative pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop chronic pain. Based on information about the molecular mechanisms that affect changes to the peripheral and central nervous system in neuropathic pain, several opportunities exist for multimodal pharmacological intervention. Here, we outline strategies for identification of patients at risk and for prevention and possible treatment of this important entity of chronic pain.

Does Morphine Stimulate Cancer Growth?

No.

GeriPal does yeoman's work in explaining why

Does Morphine Stimulate Cancer Growth? | GeriPal - A Geriatrics and Palliative Care Blog: ""

Antidepressants, CYP2D6, and opioid metabolism

Awhile back I posted this bleg for more information about the interaction between antidepressants and codeine. Peter Nelson emailed me asking whether I had found out anything else. I hadn't, so he did some research of his own which he has kindly agreed to allow me to share.

Take it away, Peter:

[Usual disclaimer: Neither he nor I are medical professionals. Don't take this as medical advice, et cetera.]

Since emailing you I’ve been studying the research literature and it’s crystal clear that codeine will not have any analgesic properties for people either genetically lacking CYP2D6 (6-10% of caucasians, other %’s for other ethnic groups) or who are taking a drug that blocks it.
Many antidepressants, including fluoxetine, paroxetine and bupropion are strong inhibitors of it, as are many other drugs including various antiarrhythmics, antifungals, cancer drugs, etc.

The story on the other synthetic opioids doesn’t look too good either. CYP2D6 plays a critical role in the metabolism of hydrocodone, oxycodone, and tramadol but they have more complex metabolic pathways and even now there are details that remain to be elucidated.

Hydrocodone itself has little affinity for the μ opioid (pain) receptors so it has to get metabolized the main clinically-active metabolite is assumed to be hydromorphone because it’s a known painkiller with a high affinity for the μ opioid receptors. And lack of CYP2D6 blocks that process. That part is clear, but there are unanswered questions.

For example in Kaplan et al, (Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability J Pharmacol Exp Ther. 1997 Apr;281(1):103-8) subjects’ subjective perception of the effects of hydrocodone were unrelated to hydromorphone conversion. Heiskanen et al, (Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther. 1998 Dec;64(6):603-11. ) performed a similar experiment involving oxycodone with similar results.
But critically, neither experiment looked at pain tolerance. Also Otton et al, (CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone - SV - Clin Pharmacol Ther - 01-NOV-1993; 54(5):) performed an experiment similar to Kaplan’s but did find that subjects responded in ways consisten with hydromorphone conversion (again, no pain test).

Based on what we think we know about hydrocodone (i.e., that the active metabolite is hydromorphone), Otton’s results make more sense. But both hydrocodone and oxycodone still have work left to do elucidating the effects of some of the other metabolites that are currently thought to be inactive.

And Heiskanen’s results also make sense because oxycodone – the parent compound - actually appears to have a nontrivial affinity for μ receptors itself, and furthermore some of its other metabolites such as noroxycodone, which may be mediated by a different enzyme – CYP2C19 - may also have high binding affinity. (Lalovic et al, Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004 Apr;32(4):447-54. )
In other words oxycodone may work fine as an analgesic for CYP2D6 impaired patients. BUT that doesn’t mean oxycodone gets us off the hook - instead it appears to have a nastier hook: The oxymorhone is far more readily cleared than the parent compound oxycodone. So without CYP2D6 oxycodone accumulates, potentially becoming toxic or fatal.
Two studies underscore that risk: Jannetto, et al, Pharmacogenomics as molecular autopsy for postmortem forensic toxicology; genotyping cytochrome P450 2D6 for oxycodone cases. J Anal Toxicol 2002; 26:438–447 and Drummer et al, A study of deaths involving oxycodone. J Forensic Sci 1994; 39:1069–1075.

The real bottom lines are these:

1. Work remains to be done in elucidating both the pharmacokinetics and clinical effects of various metabolites for all of the synthetic opioids.

2. As far as I could tell, there seem to be no human studies evaluating analgesic properties of synthetic opioids for patients who either lack the gene for CYP2D6 or for whom CYP2D6 is blocked by a drug-drug interaction.

3. Drug-drug interactions of this type will become more common as the population becomes older and as we use a greater variety of drugs. As it is, bupropion. paroxetine and fluoxetine (all potent CYP2D6 blockers) accounted for roughly 50 million prescriptions in the US alone last year. Other CYP2D6 blockers account for millions more.

4. I’ve spoken to several physicians about this and they all expressed worry and concern that they feel unsure how to do pain management for CYP2D6-impaired patients, especially in postoperative or fracture cases where OTC drugs aren’t enough and the “nuclear options” like fentanyl or methadone (both of which work regardless of CYP2D6) would be overkill and dangerous.

Visit Peter's blog at http://blog.pnart.com/. Thanks again!

A role for glial cell-targeting treatments for pain?

The Psychology of Pain blog links to an interesting new study from CU-Boulder. I don't want to steal too much of his post, so here's a tease:

Under normal circumstances glial cells are thought to be like housekeepers, said Watkins. They essentially clean up debris and provide support for neurons.

But, like Gremlins, they have a nasty side too

[the researchers] believe they have figured out how morphine affects glial cells and neurons. 'We've found that different receptors are involved in how morphine suppresses pain through its actions on neurons versus how morphine activates glial cells,' Watkins said. 'What this means is that you should be able to separate the suppressive effects of morphine -- its pain-reducing effects through its action on neurons -- from all of its bad effects when it excites glial cells.'

(Via Psychology of Pain.)

Methadone prescribers' network

The astonishing recent rise in opioid overdoses (many involving methadone) has finally forced me to agree that our (at least in the US) opioid policies and practices need some revision. Thus this expansion of a program available to buprenorphine prescribers seems welcome.

A New Service For Health Care Providers Who Prescribe Methadone To Treat Chronic Pain Or Opioid Addiction: "
A new service for health care providers prescribing methadone to treat chronic pain or opioid addiction -- the Physician Clinical Support System for Methadone (PCCS-M) -- opens this week with a mechanism to connect prescribers of methadone with experienced clinicians for one-to-one mentoring regarding the use of this medication.

Methadone is an inexpensive opioid medication that has several unique properties that make it particularly well suited to the treatment of chronic pain or opioid addiction, but it also has side effects and the potential for overdose and requires specific information for its proper use.

The new service is one in a number of federally-funded projects that address the need within the nation's health care system to provide safe and effective care of patients with chronic pain and opioid addiction while, at the same time, protecting the public from prescription drug abuse and diversion of medications. Using this new service, prescribers can contact a mentor, a knowledgeable colleague, by phone or e-mail with specific questions about the use of methadone for treating chronic pain or opioid addiction.

Source: American Society of Addiction Medicine "

As a general rule, I think drug policy should (strongly) promote the responsible clinician's ability to prescribe opioids as she sees fit . So, insofar as this sort of program can help stem diversion and accidental overdose, I'd much rather see more of these than more restrictive drug policies.