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: ""

Acetaminophen-Related Liver Damage May Be Prevented By Common Herbal Medicine

Perhaps I can slacken my anti-acetaminopen stance* a bit....

Acetaminophen-Related Liver Damage May Be Prevented By Common Herbal Medicine: "Acetaminophen-Related Liver Damage May Be Prevented By Common Herbal Medicine

A well-known Eastern medicine supplement may help avoid the most common cause of liver transplantation, according to a study by researchers at the Stanford University School of Medicine. The finding came as a surprise to the scientists, who used a number of advanced genetic and genomic techniques in mice to identify a molecular pathway that counters acetaminophen toxicity, which leads to liver failure.

'I didn't know anything about the substance that was necessary for the pathway's function, so I had to look it up,' said Gary Peltz, MD, PhD, professor of anesthesiology. 'My postdoctoral fellow, whose parents and other family members in Asia were taking this compound in their supplements, started laughing. He recognized it immediately.'

The molecule was S-methylmethionine, which had been marketed as an herbal medicine known as Vitamin U for treatment of the digestive system. It is highly abundant in many plants, including cabbage and wheat, and is routinely ingested by people. [...]

Peltz is the senior author of the research, which will be published online Nov. 18 in Genome Research. The experiments were conducted in Peltz's laboratory at Roche Palo Alto in Palo Alto, Calif., where Peltz worked before coming to Stanford in July 2008. He is continuing the research at Stanford. The first author of the paper, Hong-Hsing Liu, MD, PhD, is now a postdoctoral scholar in Peltz's Stanford lab.

Acetaminophen is a pain reliever present in many over-the-counter cold and flu medicines. It is broken down, or metabolized, in the body into byproducts - one of which can be very toxic to the liver. At normal, therapeutic levels, this byproduct is easily deactivated when it binds to a naturally occurring, protective molecule called glutathione. But the body's glutathione stores are finite, and are quickly depleted when the recommended doses of acetaminophen are exceeded.

Unfortunately, the prevalence of acetaminophen makes it easy to accidentally exceed the recommended levels, which can occur by dosing more frequently than indicated or by combining two or more acetaminophen-containing products. However, severe liver damage can occur at even two to three times the recommended dose (the maximum adult dose is 4 grams per day; toxic daily levels range from 7 to 10 grams).

'It's a huge public health problem,' said Peltz. 'It's particularly difficult for parents, who may not realize that acetaminophen is in so many pediatric medicines.' Acetaminophen overdose is the most common cause of liver transplantation in this country. The only effective antidote is an unpalatable compound called NAC that can induce nausea and vomiting, and must be administered as soon as possible after the overdose.

Peltz and his colleagues used 16 inbred strains of laboratory mice for their investigations. Most strains are susceptible to acetaminophen toxicity, but one is resistant. They compared how the drug is metabolized by the different strains and looked for variations in gene expression and changes in endogenous metabolites in response to acetaminophen administration. They identified 224 candidate genes that might explain the resistant strain's ability to ward off liver damage, and then plumbed computer databases to identify those involved in metabolizing acetaminophen's dangerous byproducts.

One, an enzyme called Bhmt2, fit the bill: It helped generate more glutathione, and its sequence varied between the resistant and non-resistant strains of mice. Bhmt2 works by converting the diet-derived molecule S-methylmethionine, or SMM, into methionine, which is subsequently converted in a series of steps into glutathione. The researchers confirmed the importance of the pathway by showing that SMM conferred protection against acetaminophen-induced liver toxicity only in strains of mice in which the Bhmt2 pathway was functional.

'By administering SMM, which is found in every flowering plant and vegetable, we were able to prevent a lot of the drug's toxic effect,' said Peltz. He and his colleagues are now working to set up clinical trials at Stanford to see whether it will have a similar effect in humans. In the meantime, though, he cautions against assuming that dosing oneself with SMM will protect against acetaminophen overdose.

'There are many pathways involved in the metabolism of this drug, and individuals' genetic backgrounds are tremendously variable. This is just one piece of the puzzle; we don't have the full answer,' he said. However, if subsequent studies are promising, Peltz envisions possibly a co-formulated drug containing both acetaminophen and SMM or using SMM as a routine dietary supplement."

*I don't doubt its usefulness for many conditions. What I don't like is how it's seen/promoted/prescribed as something benign by consumers/companies and drug stores/doctors.

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.

Coral for neuropathic pain

Not as cool as sea-snail venom, but still worth filing under 'cool things from the sea'

New Hope Of Relief For Neuropathic Pain: "New Hope Of Relief For Neuropathic Pain

A compound initially isolated from a soft coral (Capnella imbricata) collected at Green Island off Taiwan, could lead scientists to develop a new set of treatments for neuropathic pain - chronic pain that sometimes follows damage to the nervous system.
[....]

Recent research suggests inflammation in the nervous system is a major causative factor for this condition. Inflammation activates supporting cells, such as microglia and astrocytes, that surround the nerve cells. These activated cells release compounds called cytokines that can excite nerves carrying pain sensation (nociceptive pathways) and cause the person to experience mildly uncomfortable stimuli as very painful (hyperalgesia), or stimuli that would normally induce no discomfort at all as painful (allodynia). Thus, cold drafts or lightly brushing the skin can produce intense pain, severely affecting the person's quality of life.

[....]

Although the chemical they studied, capnellene, was originally isolated in 1974, it is only recently that scientists have started to appreciate its potential. Capnellene is interesting because its structure is very different from pain-relieving drugs currently in use. Initial experiments suggested that it may have pain-relieving properties. Working with Yen-Hsuan Jean MD, PhD and other colleagues, Dr Wen tested capnellene and a second very similar compound, in isolated microglial cells and in experimental models of the condition in rats.

They found that the compounds significantly reduced pain-related activities in isolated microglia, and that these compounds also significantly reversed hyperalgesic behaviour in the experimental rats.
"

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....

Heat and 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.

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

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#

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.

Sea snail toxins for chronic pain

Snails offer hope for pain sufferers

The humble but lethal sea snail may hold the key to a better life for thousands of chronic pain sufferers.

Researchers from the University of Queensland believe conotoxins contained in potentially deadly sea snail venom could be used to create a treatment to replace conventional pain relief drugs such as morphine.

Dr Jenny Ekberg said her research had shown the conotoxin could produce pain relief without side effects in animals.

However, the conotoxin is yet to be tested on humans and Dr Ekberg said it could be several years before the treatment was able to be produced in marketable quantities.

"It's working beautifully at the moment, we just have to learn to synthesize it properly so that we can get enough amounts to start chemical trials on humans," she said.

Dr Ekberg said the lack of side effects meant the conotoxin had the potential to completely revolutionise pain treatment for cancer patients and chronic and neuropathic pain sufferers.

"Unlike other anaesthetics, it's very specific against the pain and doesn't cause any side effects - it's the first time anyone has discovered anything like this," she said.

Conventional medicines such as morphine can cause a range of unpleasant side effects, including nausea, vision and movement defects and drowsiness.

These symptoms often rendered sufferers unable to work and could lead to depression and, in some cases, suicide, Dr Ekberg said.

"I've met people with this, it's really horrible ... neuropathic pain, which is caused by damaged nerves, not tissue, you have to live with forever," she said.

If the research proves successful Dr Ekberg hopes the treatment will allow sufferers to live normal lives and continue working.

She believed the treatment would initially be administered through hospitals but hoped patients would eventually be able to inject it themselves at home.

© 2006 AAP

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