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.

Percocet and Vicodin be gone (hopefully)

In light of my long-running antipathy toward the way acetominophen is currently used and regulated, this makes me very happy:

Panel Recommends Ban on 2 Popular Painkillers - NYTimes.com

By GARDINER HARRIS
Published: June 30, 2009

ADELPHI, Md. — A federal advisory panel voted narrowly on Tuesday to recommend a ban on Percocet and Vicodin, two of the most popular prescription painkillers in the world, because of their effects on the liver.
[....]

The agency is not required to [....] follow the recommendations of its advisory panels, but it usually does.

Unfortunately

But they voted 20 to 17 against limiting the number of pills allowed in each bottle, with members saying such a limit would probably have little effect and could hurt rural and poor patients. Bottles of 1,000 pills are often sold at discount chains.

‘We have no data to show that people who overdose shop at Costco,’ said Dr. Edward Covington, a panel member from the Cleveland Clinic Foundation.

IIRC, the problem is that their parents do. The patients who intentionally take handfuls of acetaminophen are usually teenage girls in initial and not-fully-serious suicide attempts. Few other countries allow the sort of bulk packaging we do.

Finally, I find this very hard to bellieve:

Still, some doctors predicted that the recommendation would put extra burdens on physicians and patients.

‘More people will be suffering from pain,’ said Dr. Sean Mackey, chief of pain management at Stanford University Medical School. ‘More people will be seeing their doctors more frequently and running up health care costs.’

The recommendation doesn't attempt to ban acetominophen. And, the 1,000 pill bottles are relatively cheap, so its hard to see too much of an increase in marginal cost if a patient will also have to buy the acetominophen OTC.

Moreover, why would more people go to the doctor because they have to get their oxycodone and acetominophen separately? Why would they go more frequently?

Indeed,

“It ties the doctor’s hands when you put the two drugs together,” said Dr. Scott M. Fishman, a professor of anesthesiology at the University of California, Davis, and a former president of the American Academy of Pain Medicine. “There’s no reason you can’t get the same effect by using them separately.” Dr. Fisher said the combinations were prescribed so often for the sake of convenience, but added, “When you’re using controlled substances, you want to err on the side of safety rather than convenience.”

Fingers crossed that the FDA will follow the recommendation....

Whose problem is the diversion of opioids?

Okay. In the last post I mentioned that I get annoyed when concerns about opioids being diverted pop up in discussions about when opioids are indicated treatments. It's not that I don't think diversion is an important concern in drug policy. It's just that I feel like it shouldn't be part of discussions of when opioids are good treatments.

Anyway, I was annoyed by not knowing I feel this way.* So, the following is some off-the-cuff noodling about when concerns are relevant in decisions about the use of opioid drugs. I'm not at all sure about how much of it I want to stand behind. But hopefully it might be useful for sparking some discussion.

*I remember someone once telling me that philosophy starts with a sense of wonder. I have since found that, for me, it usually starts with annoyance; it ends in wonder.

-------------

In general, I tend to think that the dangers of opioid diversion --opioids ending up outside of the patient's hands-- get too much weight in discussions of drug policy (although some recent statistics on overdose and death rates involving opioids are giving me some pause in my beliefs about the severity of diversion's harms).

But in addition to questions about how severe the consequences of diversion are, we also need to know whose problem it is. A comprehensive drug policy spans many different areas including, inter alia, the law in its criminal, civil, and regulatory forms; professional determinations of best clinical practices; and individual clinicians' decisions about how to treat individual patients. Thus we need to know whether preventing diversion should have the same importance for everyone involved in the prescription drug arena.

I'm going to suggest that preventing diversion can be a legitimate concern at the more general levels. And they may inform doctors practices in a general way. But, I suspect, the potential harms resulting from diversion should not factor into a doctor's decisions about what medications to prescribe a patient.

My claims here will rest on the supposition that a clinician's ethical responsibilities arise from her patient's individual welfare. Her professional obligation is not the promotion of the general welfare via her interactions with a certain individual. The clinician's responsibility is to alleviate her patient's suffering in the safest and most effective way available.

A rough analogy may help bring out this distinction between duties based in the promotion of the general welfare and duties based in the promotion of an individual's welfare. In an adversarial system of criminal justice like we have in the United States, the role of a defense attorney is to advocate for her clients interests as best she can. Even if she recognized that her client's conviction may benefit the public at large, she is obligated to ignore that fact in doing her job. This doesn't mean that the job of defense attorney is entirely removed from the enterprise of promoting the public good. It's that a system in which a party is assigned to look out only for the interests of the defendant is more likely to be better overall. (One major disanalogy here is that my supposition about the source of the doctor's duties need not appeal to claims about what would best promote the general welfare.)

If we a clinician's duties as tied her patient's welfare in this way, concerns about the welfare of others are thus (nearly always) irrelevant to decisions about what substances to prescribe her patient. This suggests that even though the clinician may foresee that others may be harmed through diversion if she prescribes an opioid to a patient, this possibility should have no weight in her decision about what to prescribe. Her duty arises from and is directed at the health of her patients, not the health of people in general.

Obviously, this has its limits. Massive harms to others may trump this obligation. And it may be that if two treatments were exactly equal in their efficacy and safety, then considerations of the general good or other effects on others may break the tie.

Nor does this mean that the doctor must completely ignore the possibility that the drug will be diverted. Other public entities' interests in preventing diversion are based in their obligation to protect public health overall. But given the source of her professional obligations, the clinician's concerns about diversion should be limited to its effects on her patient's health.

Clearly, a responsible clinician must be attuned to the possibility that the patient herself will divert the drug. But her vigilance is not demanded by the need to prevent harms to the recipients of the diversion. It comes from her responsibilities to the patient. The clinician's treatment decisions must be based on the supposition that the patient will comply with the prescribed regime. She cannot aim to promote an individual's welfare by prescribing her a substance that she believes that the patient will not take. Therefore, the belief that the patient will take the drug as prescribed is a necessary condition of justifiably prescribing an opioid.

Suppose that a patient is accompanied by a stoned adolescent whose T-shirt reads "I love drugs!" Does this necessary condition imply that she ought to take into consideration the likelihood that the son will divert the drugs?

The answer seems to be yes. She cannot prescribe a medication to benefit her patient if she believes that the patient won't take the drug because someone else will steal it. Of course, it's unlikely that the suspicion in this case would justify her refusing to prescribe an otherwise indicated opioid Much will hang on the strength of her conviction that the drug will be diverted. In the drug diverting adolescent case, the clinician may be required to put special emphasis on the need to keep control of the medication in counseling the patient. But as long as she can be satisfied that the patient will be reasonably vigilant, she will be justified in writing the prescription. Her uncertainty about the likelihood of diversion combined with the need to respect the patient's autonomy will set the bar for reasonable vigilance pretty low.

Cases in which she should altogether refuse to prescribe on these grounds will likely be rare. But they are easy to imagine. Suppose that a disabled patient is completely dependent on her caretaker for all of her medications. If the clinician was convinced that the caretaker would divert a significant portion of the prescribed opioid, then she should not write the prescription. Indeed, doing so would be tantamount to writing the prescription for the caretaker. Though, she may have some obligation to seek other ways of getting the indicated treatment to the patient (e.g., recommending at home nursing visits, and patient treatment).

What's important is the way concerns about diversion are figuring in here. A clinician should be cautious of diversion insofar as it would interfere with her patient's treatment. Her responsibilities do not depend on how the recipients of the diverted substance may be affected. Those dangers of diversion give her reason to, for example, keep her cabinets locked. But they should be irrelevant to her decisions about patients' treatments.

This is not to say that a comprehensive drug policy should not be concerned about the harms to non-patients who gain access to opioids through diversion. It is a fact that the availability of opioids in legitimate channels will involve some diversion and some non- patients will be harmed. While the clinician's responsibility is based in her individual patient's welfare, government policies are properly attuned to protecting welfare across the board. Thus entities (in the US) like the FDA, the Department of Justice and the DEA are justified in creating policies and enforcement practices which will minimize the amount of diversion.

But this picture of the clinician's obligations does create tension between the government's proper aims creating drug policy and the duties of clinicians. We should thus want a principled way of resolving these kinds of inevitable conflict. One possibility is that one set of considerations will always trump the other (that is, the first set is lexically prior to the other).

To see the implications of a lexical ordering of these considerations suppose that the paramount consideration in shaping drug policy was ensuring clinicians' abilities to carry out their duties to their patients. This would have implications for how we decide conflicts. Such a partial lexical ordering would entail that the protection of access to safe and effective drugs cannot be trumped by considerations about diversion. More generally, this might mean that any proposed policy that would promote the general good could be vetoed if it unreasonably affected the ability of clinicians to treat their patients.

This ordering of concerns would be unlikely to undermine reasonable restrictions on the use and prescription of opioids. For example, this is compatible with a well regulated and organized system for inventory control in the manufacturing, shipping, and distribution of opioids. The same is true for methods of verifying the legitimacy of prescriptions and the identity of patients. But some apparently relatively mild restrictions on prescribing ability may not be compatible with this set of drug policy priorities.

For example, the FDA is presently considering requiring all clinicians who prescribe powerful long-acting opioids to have a special certification. Many general practice clinicians who currently prescribe such medications may be unwilling to go through the hassle of obtaining and maintaining the certification. If the certification process was unduly difficult, many clinicians would be unable to prescribe the medications that they thought were best indicated for their patients conditions. Such a regulation would likely decrease the number of deaths from diversion. But no matter how many diversion related deaths would be prevented, it should be rejected if we believe that the clinician's abilities to treat their patients should always trump any other consideration.

So, in sum, here's what I've suggested: If we think about the source and nature of clinicians' professional obligations in a particular way, then concerns about diversion should not play a role in determining whether to prescribe an opioid (outside of diversion undermining the treatment regime). Direct focus on preventing diversion is instead the job of regulatory agencies whose mission is the common public good.

I haven't given any argument in favor of the further idea that concerns about diversion should always be subordinated to clinicians ability to prescribe opioids as they see fit. Though I am definitely attracted to this view. We can leave that a subject for another post.

Opioids often preferable to NSAID's in the elderly

This is important.

The NYT reports that in light of findings that

[in elderly patients] The risks of Nsaids include ulcers and gastrointestinal bleeding and, with some drugs, an increased risk of heart attacks or strokes. The drugs do not interact well with medicines for heart failure and other conditions, and may increase high blood pressure and affect kidney function, experts said.

The American Geriatrics Society

removed those everyday medicines, called Nsaids, for nonsteroidal anti-inflammatory drugs, from the list of drugs recommended for frail elderly adults with persistent pain. The panel said the painkillers should be used “rarely” in that population, “with extreme caution” and only in “highly selected individuals.”
[....]
“We’ve come out a little strong at this point in time about the risks of Nsaids in older people,” said Dr. Bruce Ferrell, a professor of geriatrics at U.C.L.A. who is chairman of the panel. “We hate to throw the baby out with the bathwater — they do work for some people — but it is fairly high risk when these drugs are given in moderate to high doses, especially when given over time.

“It looks like patients would be safer on opioids than on high doses of Nsaids for long periods of time,” he continued

Link (My italics; I've interpolated the order of the paragraphs)

Editorial comment: I'm unhappy that the reporter chose to use this quote in emphasizing that opioids have their own dangers:

“We’re seeing huge increases nationwide of reports about the misuse and diversion of prescription drugs and related deaths,” said Dr. Roger Chou, a pain expert who was not involved in writing the guidelines for the elderly but directed the clinical guidelines program for the American Pain Society. “The concerns about opioids are very real.”

Diversion of opioids is a real problem. But it really annoys me to see it used as a counterpoint in discussions of their clinical usefulness.

I almost feel like these claims are saying something like: Advil might kill Grandma, but we might not want to give her a safer treatment because her grandson might steal it and kill himself.' (I don't think the reporter or Dr. Chou intended it this way --that's just how I take it)

Update: I was bothered by not knowing why the stuff about diversion annoys me so much. So I've posted some very rough thoughts here.

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.)

BLEG: Opiates and renal failure

Hi all,

As I mentioned, I'm suddenly in the position of helping coordinate my grandpa's palliative care. Since I'm not a clinician, I need to get up to speed on some of the pharmacology so that I can have meaningful discussions with the real doctors.

Thus I'd really appreciate it if you could point me in the right direction toward any resources on treating acute pain in patients with severe renal impairment/failure.

Here's an example of the sort of information I'm looking for:

After reading through a bunch of journals early this morning, it seems like there's pretty good reason to not give people with severe renal impairment/failure morphine or hydromorphone. Two of the metabolites don't clear very well and can build up to cause coma or respiratory failure (in fact, at least one of the dangerous metabolites --6MG I think-- doesn't really affect pain, so the danger well outlasts the analgesic effect of the dose).

Codeine is probably even worse. The evidence with oxycodone isn't entirely clear; fentanyl is probably okay. But methadone seems to be all around pretty safe.

These are just my impressions from a bunch of journal articles. But I feel like I can now intelligibly ask his doctors whether they might consider trying methadone instead of giving him morphine for breakthrough pains and then giving him nothing (occasionally APAP) for very long periods. I don't want to second-guess their judgment, but I do want to be able to understand the treatment options....

I'll appreciate anything you can recommend.

Thanks again.

[also, sorry that these posts are pretty sloppy. I'm posting from my phone outside the hospital.]

Pharmacology bleg

I have a request for any of you who know about the pharmacology of antidepressants. I have a friend who is taking Wellbutrin (bupropion) for smoking and codeine for chronic pain. I'm curious whether the combination may be attenuating the effect of the codeine and thus whether he should talk to his doctor about changing the codeine dose or switching medications.

Here's why: Codeine itself isn't really an analgesic. It is a substrate of a polymorphic P450 enzyme CYP2D6, and is metabolized to the more potent drug morphine. Some SSRI's like fluoxetine inhibit CYP2D6 activity. Thus combining prozac with codeine can attenuate its effects (see below).

What I'd like to know is whether bupropion might have the same effect on codeine metabolism. But I can't find anything directly on the topic.

From this chart of the various enzymes involved, it looks like that might be the case. But then I found this in the Wikipedia entry on buproprion

As bupropion is metabolized to hydroxybupropion by CYP2B6, drug interactions with CYP2B6 inhibitors (paroxetine, sertraline, fluoxetine metabolite norfluoxetine, diazepam, clopidogrel, orphenadrine and others) are possible. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers (carbamazepine, clotrimazole, rifampicin, ritonavir, St John's Wort and others).

Hydroxybupropion (but not bupropion) inhibits CYP2D6 and is a substrate of that enzyme. Significant increase of the concentration of some drugs metabolized by CYP2D6 (venlafaxine, desipramine and dextromethorphan, but not fluoxetine or paroxetine) when taken with bupropion has been observed.

So I need your help. Can anyone point me in the direction of studies on bupropion and codeine? Or maybe just explain this in a way I can understand?

--
For your enjoyment, here are a few studies of fluoxetine and codeine that I came across in looking for an answer.

Inhibition by fluoxetine of cytochrome P450 2D6 activity.
Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM
Clin Pharmacol Ther. 1993 Apr ; 53(4): 401-9

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 mumol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O-demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O-demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O-demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Treatment of codeine dependence with inhibitors of cytochrome P450 2D6.
Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK
J Clin Psychopharmacol. 2002 Jun ; 22(3): 326-9

Codeine is O-demethylated by cytochrome P450 2D6 (CYP2D6) to form the more potent drug morphine, accounting for much of codeine's analgesic and dependence-producing properties. Because morphine production can be decreased by inhibition of CYP2D6, the authors hypothesized that CYP2D6 inhibition could be used to treat codeine dependence. A randomized, double-blind, placebo-controlled trial was conducted. All patients received brief behavioral therapy. Two weeks of baseline monitoring were followed by 8 weeks of daily treatment with fluoxetine or quinidine (two potent CYP2D6 inhibitors) or placebo. Thirty patients were assessed (all white, age 40 + 12 years using 127 + 79 mg/day of codeine [mean + SD]), and 17 entered treatment. Eight patients remained in the study by treatment week 8. Quinidine > fluoxetine > placebo inhibited CYP2D6 as reflected in the change of the O-demethylation of dextromethorphan, a specific CYP2D6 probe. At treatment week 8, placebo, quinidine, and fluoxetine reduced mean daily codeine intake by 57%, 56%, and 51% of baseline intake respectively; there was no difference among treatment groups. In this small sample, CYP2D6 inhibitors did not appear to have a useful role in the treatment of codeine dependence.