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

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!

Redheads need more drugs

Huh.

The Pain of Being a Redhead - Well Blog - NYTimes.com:
A growing body of research shows that people with red hair need larger doses of anesthesia and often are resistant to local pain blockers like Novocaine. As a result, redheads tend to be particularly nervous about dental procedures and are twice as likely to avoid going to the dentist as people with other hair colors, according to new research published in The Journal of the American Dental Association.

Researchers believe redheads are more sensitive to pain because of a mutation in a gene that affects hair color. In people with brown, black and blond hair, the gene, for the melanocortin-1 receptor, produces melanin. But a mutation in the MC1R gene results in the production of a substance called pheomelanin that results in red hair and fair skin.

The MC1R gene belongs to a family of receptors that include pain receptors in the brain, and as a result, a mutation in the gene appears to influence the body’s sensitivity to pain. A 2004 study showed that redheads require, on average, about 20 percent more general anesthesia than people with dark hair or blond coloring. And in 2005, researchers found that redheads are more resistant to the effects of local anesthesia, such as the numbing drugs used by dentists.
[....]

It's also nice to hear that the research came from taking this sort of common experience seriously, rather than simply dismissing it:

Dr. Daniel I. Sessler, an anesthesiologist and chairman of the department of outcomes research at the Cleveland Clinic, said he began studying hair color after hearing so many colleagues speculate about redheads requiring more anesthesia.

‘The reason we studied redheads in the beginning, it was essentially an urban legend in the anesthesia community saying redheads were difficult to anesthetize,’ Dr. Sessler said. ‘This was so intriguing we went ahead and studied it. Redheads really do require more anesthesia, and by a clinically important amount.’

If I had red hair, I would bring a copy of the paper with me to the dentist/doctor to help them take my needs seriously.*

*Just as I would, for example, show literature on the usefulness of pre-incision lidocaine in lowering post-surgicial pain to my surgeon.

I might also post articles on the problems with using morphine in patients with kidney problems on the wall by an elderly relative's hospital bed.

More drugs, please: Italian edition

May I have your attention please?

Ahem.

STOP DENYING CANCER PATIENTS THE MEDICINE THEY NEED.

Thank you for your attention

Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study Group.: "

Br J Cancer. 2009 Apr 28;
Apolone G, Corli O, Caraceni A, Negri E, Deandrea S, Montanari M, Greco MT

Most patients with advanced or metastatic cancer experience pain and despite several guidelines, undertreatment is well documented. A multicenter, open-label, prospective, non-randomised study was launched in Italy in 2006 to evaluate the epidemiology, patterns and quality of pain care of cancer patients. To assess the adequacy of analgesic care, we used a standardised measure, the pain management index (PMI), that compares the most potent analgesic prescribed for a patient with the reported level of the worst pain of that patient together with a selected list of clinical indicators. A total of 110 centres recruited 1801 valid cases. 61% of cases were received a WHO-level III opioid; 25.3% were classified as potentially undertreated, with wide variation (9.8-55.3%) according to the variables describing patients, centres and pattern of care. After adjustment with a multivariable logistic regression model, type of recruiting centre, receiving adjuvant therapy or not and type of patient recruited (new or already on follow-up) had a significant association with undertreatment. Non-compliance with the predefined set of clinical indicators was generally high, ranging from 41 to 76%. Despite intrinsic limitations of the PMI that may be considered as an indicator of the poor quality of cancer pain care, results suggest that the recourse to WHO third-level drugs still seems delayed in a substantial percentage of patients. This delay is probably related to several factors affecting practice in participating centres and suggests that the quality of cancer pain management in Italy deserves specific attention and interventions aimed at improving patients' outcomes.British Journal of Cancer advance online publication, 28 April 2009; doi:10.1038/sj.bjc.6605053 www.bjcancer.com."

(Via HubMed - pain.)