Darvocet decision a prelude a warm up for banning methadone?

Christian Sinclair over at Pallimed does some sleuthing into the FDA's rationale for pulling propoxyphene and comes away concerned:

He notes that

* Propoxyphene is a synthetic derivative of methadone.

* Methadone causes QT prolongation of questionable clinical significance in palliative care patients.

* QT prolongation is a risk factor for ventricular arrhythmias.

Combined with some FDA memo analysis (go read the post) he concludes

Well all this may be a whole lot of nothing but my real concern is that methadone may be a drug in the crosshairs of the FDA soon. It already has four strikes against it:

1) documented QT prolongation

2) stigma of heroin treatment programs

3) accelerating percent of all deaths related to opioids

4) methadone could be considered an orphan drug

This would be bad news indeed.

(Via: Pallimed: A Hospice & Palliative Medicine Blog: Are You Glad Darvocet Got Pulled by the FDA? Are You Sure?)

Meditation science

UCLA center
http://www.marc.ucla.edu/index.php?option=com_frontpage&Itemid=1

Physiological effects of meditation
http://www.noetic.org/research/medbiblio/index.htm
http://natural-meditation.org/ResearchedEffects.htm

Control over body temperature
http://www.hno.harvard.edu/gazette/2002/04.18/09-tummo.html
http://en.wikipedia.org/wiki/Tummo

Heat therapy for abdominal pain

Hot.

ScienceDaily (Jul. 5, 2006)The old wives’ tale that heat relieves abdominal pain, such as colic or menstrual pain, has been scientifically proven by a UCL (University
College London) scientist, who will present the findings today at the
Physiological Society’s annual conference hosted by UCL.

Dr Brian King, of the UCL Department of Physiology, led the research
that found the molecular basis for the long-standing theory that heat,
such as that from a hot-water bottle applied to the skin, provides
relief from internal pains, such as stomach aches, for up to an hour.
Dr King said: “The pain of colic, cystitis and period pain is caused
by a temporary reduction in blood flow to or over-distension of hollow
organs such as the bowel or uterus, causing local tissue damage and
activating pain receptors.

“The heat doesn’t just provide comfort and have a placebo effect –
it actually deactivates the pain at a molecular level in much the same
way as pharmaceutical painkillers work. We have discovered how this
molecular process works.”
If heat over 40 degrees Celsius is applied to the skin near to where
internal pain is felt, it switches on heat receptors located at the
site of injury. These heat receptors in turn block the effect of
chemical messengers that cause pain to be detected by the body.

The team found that the heat receptor, known as TRPV1, can block
P2X3 pain receptors. These pain receptors are activated by ATP, the
body’s source of energy, when it is released from damaged and dying
cells. By blocking the pain receptors, TRPV1 is able to stop the pain
being sensed by the body.

Dr King added: “The problem with heat is that it can only provide
temporary relief. The focus of future research will continue to be the
discovery and development of pain relief drugs that will block P2X3
pain receptors. Our research adds to a body of work showing that P2X3
receptors are key to the development of drugs that will alleviate
debilitating internal pain.”

Scientists made this discovery using recombinant DNA technology to
make both heat and pain receptor proteins in the same host cell and
watching the molecular interactions between the TRPV1 protein and the
P2X3 protein, switched on by capsaicin, the active ingredient in
chilli, and ATP, respectively.

Adapted from materials provided by University College London.
University College London (2006, July 5). Heat Halts Pain Inside The Body. ScienceDaily. Retrieved March 19, 2008, from http://www.sciencedaily.com­ /releases/2006/07/060705090603.htm

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: ""

List of Hospice & Palliative Medicine Blogs (Current & Inactive)

Some of you may find this useful:

Pallimed: A Hospice & Palliative Medicine Blog: *Updated* List of Hospice & Palliative Medicine Blogs (Current & Inactive): "

Palliative care for a patient with anorexia nervosa

Pallimed brings up a very hard case. I'm honestly not sure what I think about much of this:

Palliative care & eating disorders: "The International Journal of Eating Disorders has a case report and discussion of a patient with refractory anorexia nervosa who died receiving hospice care. This is one fascinating case report. The case, to summarize briefly, involved a young woman with a long history of anorexia nervosa, refractory to all attempts at treatment (including involuntary/forced treatment) who apparently also was not deemed a candidate for forced guardianship (the hospital's legal counsel advised she would not meet requirements to be declared incompetent).

This is how they describe the ethics committee's response to the case:

The committee’s members struggled to understand how one could die from a psychiatric illness (other than by suicide or unintentional overdose) and were not sure how to proceed. Although they could delineate the differences between acute mental health risks such as suicide, drug overdoses, psychosis or self-neglect, they had no points of reference regarding how to manage a patient who was chronically a danger to herself, unwilling to engage in further treatments, and unresponsive to all prior attempts to treat her involuntarily. The only examples the committee raised for comparison concerned drug users who received heart valve replacements, yet continued to use, knowing that such ongoing use would kill them. In such cases, if a high risk of ongoing subsequent IV drug use was suspected ahead of time, the decision was often made not to provide valve replacements, but there was no forced treatment.

This is how they presented what palliative care for anorexia nervosa would look like to the patient (italics mine):

If she chose to pursue treatment she would be assisted, but the staff would not force her into any involuntary placements or impose any treatment she did not want. There would be no weigh-ins, no calorie or exercise monitoring, no IM medications and no required therapy sessions. She would be offered outpatient therapy only as she felt desirable and necessary. Psychiatric medications would be prescribed as the patient deemed necessary to help manage depression, anxiety and insomnia. The patient would receive weekly visits from a palliative care nurse, who would work with her to manage her symptoms and keep her comfortable. The patient agreed to no further hospitalizations, but did not fully agree with the plan for ‘‘palliative care’’ since she did not believe she was going to die.

The patient basically continued her illness behaviors, got weaker/sicker, and was eventually enrolled in an inpatient hospice where she died.

Some observations.

1. AN is clearly at times a terminal illness, refractory to all attempts to reverse it.
2. In this case it was clear that the patient's life could have been prolonged although only with forced treatment. It was the opinion of her physicians that such forced treatment, while life-prolonging, would not 'cure' her AN (for some patients a trial, or many trials, of forced nutritional treatment along with psychiatric care gets them to the point at which they are willing to continue with voluntary treatment and can have a durable response; it was felt this would never happen with this patient). Thus the decision came down to trying to force further involuntary treatment vs. letting the disease run its natural course with her inevitably dying.
3. I found it interesting that they did not feel there was enough of a chance she'd be considered incompetent that they didn't even put her through the court process. Her statement that she did not think she would die (and it seems she continued that belief until the end, and persisted at least until she was enrolled in hospice in saying that she in fact wanted to live) seems to me to indicate such a fundamental lack of insight into her condition that I'm not sure I believe that. Granted, I'm not too familiar with criteria for declaring someone incompetent on psychiatric grounds, but I assume it has something to do with one's mental illness being such that one cannot even take in basic medical information.
4. That said, and even if she was legally stripped of her decision-making rights, for situations in which even involuntary treatment would not work long-term, is it right to force patients to do that? In this situation they concluded No, and made plans accordingly, which seemed to work as well as could be expected under the circumstances.

[A very interesting discussion follows in the rest. Definitely give it a read]

(Via Pallimed: A Hospice & Palliative Medicine Blog.)

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.]

Well, this sucks....

My 89 year old grandpa has graciously decided to allow me to put my several years of dilettantism with the pain sciences into practice. He's entered the hospital in pretty dire straights. I'm trying to help my parents be involved with decisions about his palliative care (without getting in the real clinicians way).

So, I'll be posting some reflections about his/my experiences with pain care, ethical issues, and other topics, as we go. I'm sure much of this will be naive; especially compared with many of your experiences and backgrounds. But perhaps I'll stumble across something interesting or useful to you.

Also, from time to time I'll probably be soliciting advice on where to find information on certain specialized topics. I'll really appreciate any help I can get.

Carnival of PAIN!!!!!

The always excellent and informative How to Cope with Pain carnival for January is up here. Check it out.

Efficacy of morphine

ScienceDaily (Feb. 3, 2008) — Opioids, such as morphine, are effective and widely used drugs for the control of pain.

However, tolerance to opioids can develop with repeated administration (that is, higher and higher doses of the drug are required to achieve the same level of pain relief).

Nonetheless, there is some evidence to suggest that tolerance to opiods does not develop when they are used to treat individuals with diseases that are accompanied by inflammation.

Support for this hypothesis has now been provided by Christian Zöllner and colleagues from Charité--Universitätsmedizin Berlin, Germany, who found that peripheral tolerance to morphine did not develop in the chronically inflamed paws of rats.

Furthermore, blocking the action of endogenous opioid compounds in the inflamed tissue enabled tolerance to morphine to develop.

These data indicated that under conditions of chronic pain, endogenous opioid compounds prevent morphine from causing tolerance, inferring that the use of peripherally acting opioids for the prolonged treatment of inflammatory diseases such as chronic arthritis, inflammatory neuropathy, and cancer is not necessarily accompanied by opioid tolerance.

Journal of Clinical Investigation (2008, February 3). Managing Chronic Pain: When Does Morphine Become Less Effective?. ScienceDaily. Retrieved February 6, 2008, from http://www.sciencedaily.com­ /releases/2008/02/080203101431.htm#

Coping with pain

This site (and its blog) has lots of good material for sufferers of chronic pain and their friends/families/et al.

How To Cope With Pain: A guide to coping with pain.

The author's philosopher husband also occasionally contributes some nice posts oriented toward laymen:

http://www.howtocopewithpain.org/blog/51/your-name-isnt-aristotle-youll-still-find-this-info-about-pain-and-your-brain-intriguing/
http://www.howtocopewithpain.org/blog/53/no-one-understands-your-pain-heres-the-philosophical-reason-why/

Snail venom: Yay

A bit old and a topic I've posted on before, but relevant:

Dr Jon-Paul Bingham, of Clarkson University, has an unusual note on his file at the local hospital in New York State.

If he is admitted unconscious, they are to check to see whether he has been harpooned by a deadly snail.

Every week, he milks lethal marine molluscs called cone shells for their venom, using a condom, barbecue tongs and a fish. If anything goes wrong, though, it is no laughing matter.

Cone shells look like a seaside souvenir from the tropics. You find them in places like the Great Barrier Reef or Hawaii. The shells themselves are sometimes two to three inches long, often with striking patterns which make them collectable.

These snails will produce millions of changes in their toxins that they use to kill their prey
Dr Jon-Paul Bingham, Clarkson University
The snails inside are not all poisonous but the fish-eating ones are right up there with snakes and scorpions in the danger stakes. If you get stung by one of them, there will be enough venom in your system to kill up to 15 people; but it is not entirely hopeless.

"Get on a life support system. There have been cases where people have survived," Jon-Paul says helpfully.

Biological 'kit bag'

It is quite an overkill for a little marine animal whose usual dinner is no bigger than a goldfish, but what grips scientists is not the potency of its venom but the complexity.

Cone snail (Clarkson)
On a par with snakes and scorpions
"These snails will produce millions of changes in their toxins that they use to kill their prey," Jon-Paul tells the BBC Radio 4 programme Danger! Venomous Snails.

"If they don't make these changes, they can be at an evolutionary disadvantage, so the snails have become good pharmaceutical chemists. It is these compounds that we are trying to harness to use as specific medicines."

One of these compounds is already at work. Just over a year ago, the US Federal Drug Agency approved the first of a new type of painkiller - Prialt® - which can work in cases where ordinary drugs fail. The drug has also been approved for use in Europe.

It blocks a particular channel in nerves which communicates pain signals to the brain. The original toxin behind the drug was discovered in the lab of Professor Baldomero Olivera, at the University of Utah, and he's excited about the future.

In close-up: The cone snail's harpoon
"There's an explosion of data about neuroscience and what can go wrong," he says.

"We'd like to understand and affect many different molecules in the normal brain. Using very specific toxins that wipe out the function of just one thing in the nervous system, lets us do that.

"We see applications in epilepsy, stroke and cardiovascular conditions. Some are in development and one has reached clinical trials."

Just the beginning

Another way of stopping strokes and heart attacks is to cut down on smoking. Snail toxins might help here, too.

Professor Bruce Livett, of the University of Melbourne, Australia, is looking at how they affect the nicotinic receptor - the very thing that gets a hit when you puff on a cigarette.

A drug to inhibit that might help you stop smoking, but this research is already tackling severe pain in diabetic patients.

Some species are threatened because of the actions of collectors
There could even be applications in Alzheimer's or Parkinson's disease, says Bruce, but one thing bothers him: we should take time to get to know the snail, not just its venom.

"There's a whole world of invertebrate biology out there far more advanced than our own mammalian biology," he says.

That is where Jon-Paul Bingham's work has been important. By developing his way of milking the snails, Jon-Paul keeps the animals alive in his lab and learns more about them.

He does not need to dissect the "goose that lays the golden egg" to study its venom. He analyses their venoms and then synthesises the compounds he finds for further work.

His hope is to set up a library of venoms to help other researchers get access to this field. He sees potential for snail toxins to be used in everything from agriculture to anti-fouling paints against marine worms.

Cone shells research appears to be advancing much more quickly than your average snail.

Danger! Venomous Snails was broadcast on BBC Radio 4 on Monday 27 March. It can still be heard at the Listen again page.

Link

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.

Meditation resources

As we've seen here before, meditation can be an effective component to treating many types of chronic pain. From a new friend, here are some nice resources:

http://www.marc.ucla.edu/ Mindful Awareness Research Center at UCLA; Podcast resources

www.mbsr.mass.edu: Mindfulness Based Stress Reduction; CD and book resources

www.contemplativeprayer: Christian Based Contemplative Prayer Information

www.contemplativemind.org: Introduction to a range of contemplative practices

Period pain

Fyi

Ibuprofen beats acetaminophen for period pain

NEW YORK (Reuters Health) - Although both ibuprofen and acetaminophen reduce menstrual pain, ibuprofen appears to have more potent effects, according to investigators from the West Virginia University School of Medicine, Morgantown.

Although ibuprofen is accepted as an effective treatment for painful periods, or dysmenorrhea, Drs. M. Yusoff Dawood and Firyal S. Khan-Dawood note in the American Journal of Obstetrics and Gynecology, there is still controversy about the usefulness of acetaminophen. Acetaminophen, the active ingredient in Tylenol, is known as paracetamol in several countries.

To investigate further, the duo conducted a small trial involving 12 women with dysmenorrhea who were given three different treatments in random order for three different periods: 1000 milligrams of acetaminophen, 400 milligrams of ibuprofen, or an inactive placebo, four times daily for three days.

The women rated the active medications as being more effective than placebo. "However," Dr. Dawood told Reuters Health, "it appears that ibuprofen has a greater effect and patients also preferred it."

SOURCE: American Journal of Obstetrics and Gynecology, January 2007

Link