The Almost Discovery Of Anesthesia : NPR

Here's an NPR story on the discovery of nitrous oxide. The transcript and podcast are here:

No, Thank You; We Like Pain: The Almost Discovery Of Anesthesia : NPR

Today's Quantified Self practitioners take note, you've got nothing on young Humphry Davy.

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.

TENS confusion

Given that TENS was part of the discovery of the gate-control theory 40 years ago, it really would be nice if its implications for the distinction between nociception and pain had seeped in. This is from a press release on Science Daily:

Widely used device for pain therapy not recommended for chronic low back pain A new guideline issued by the American Academy of Neurology finds that transcutaneous electric nerve stimulation (TENS), a widely used pain therapy involving a portable device, is not recommended to treat chronic low-back pain that has persisted for three months or longer because research shows it is not effective.... TENS can be effective in treating diabetic nerve pain, also called diabetic neuropathy, but more and better research is needed to compare TENS to other treatments for this type of pain. Research on TENS for chronic low-back pain has produced conflicting results. For the guideline, the authors reviewed all of the evidence for low-back pain lasting three months or longer. Acute low-back pain was not studied. The studies to date show that TENS does not help with chronic low-back pain.

So far so good. But then in the nickel summary of what TENS is they write:

With TENS, a portable, pocket-sized unit applies a mild electrical current to the nerves through electrodes. TENS has been used for pain relief in various disorders for years. Researchers do not know how TENS may provide relief for pain. One theory is that nerves can only carry one signal at a time. The TENS stimulation may confuse the brain and block the real pain signal from getting through.

How about:

Neural signals reporting injury have to pass through a gate in the spine in order to be transmitted to the brain and cause pain. The electric impulse from TENS closes the gate.

That's still inaccurate. But it at least avoids framing the phenomenon as the system stopping the pain before it gets to the brain. Getting people used to distinguishing between nociception and pain is a small but important step in a better public understanding of analgesia and chronic pain conditions.

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.

Regional blocks better for Cesarean sections

Medical News Today
For Cesarean Section, Regional Blocks Prove Superior To General Anesthesia
30 Apr 2009

General anesthesia (GA) is associated with an increased risk of infant intubation and low Apgar scores, relative to regional anesthesia. An analysis of 50,806 cesarean deliveries, published in the open access journal BMC Medicine, strongly supports guidelines that regional anesthesia is to be preferred over GA for most cesarean sections.

Charles Algert, from the Kolling Institute at the Royal North Shore Hospital, Sydney, was part of a team of researchers who studied births in the state of New South Wales, Australia, between 1998 and 2004. He said, "We have shown that general anesthesia poses significant risks to the neonate of both resuscitation requiring intubation and of a poor Apgar score at 5 minutes. The greatest relative risk of both adverse outcomes occurred in low-risk, planned, repeat cesarean deliveries under GA, but the greatest excess in risk attributable to GA was for emergency deliveries for fetal distress where the infant would already have been compromised to some extent".

Although current guidelines recommend regional blocks, GA was still used for 12.6% of cesareans across NSW in 2006. According to the NHS Maternity Statistics, 8.7% of cesarean sections in England in 2006-2007 were performed using GA. It is generally presumed that any harm caused by GA is short-lasting, with most studies focusing on resuscitation and the Apgar score at one minute. According to Algert, however, this may not be the case, "The increased rates of neonatal intubation after GA shown in this study represent harm in and of itself, and the persistence of low 5-minute Apgar scores suggests that deleterious effects may last longer than the immediate aftermath of delivery".

The authors conclude, "Clinicians considering the use of GA for a cesarean delivery should be aware of these possible consequences for the infant, for both planned and emergency sections".

Regional block versus general anaesthesia for caesarean section and neonatal outcomes: a population-based study
Charles S Algert, Jennifer R Bowen, Warwick B Giles, Greg E Knoblanche, Samantha L Lain and Christine L Roberts
BMC Medicine (in press)
Article available at journal website: http://www.biomedcentral.com/bmcmed/

Source:
Graeme Baldwin
BioMed Central

Article URL: http://www.medicalnewstoday.com/articles/148091.php

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#

Capsaicin undermines the effectiveness of vaginal self-stimulation

Following on the present theme of the analgesic effects of vaginal selt-stimulation:

Inverse relationship between intensity of vaginal self-stimulation-produced analgesia and level of chronic intake of a dietary source of capsaicin
Beverly Whipple, Margarita Martinez-Gomez, Laura Oliva-Zarate, Pablo Pacheco, and Barry R. Komisaruk
Abstract: Women who chronically ingest a diet rich in capsaicin, the pungent ingredient in hot chili peppers, showed a significantly lower magnitude of analgesia in response to vaginal self-stimulation than women with relatively low or medium levels of ingestion. Vaginal self-stimulation-produced analgesia was quantified by measuring (on the hand) pain detection thresholds, pain tolerance thresholds and tactile thresholds. Whereas vaginal self-stimulation produced a 32.6–43.8% increase in pain detection and pain tolerance thresholds in the low chili diet group, it produced only a 2.3–7.3% increase in these measures in the high chili diet group. The medium chili diet group showed an intermediate effect on the pain thresholds. Tactile thresholds were not increased by the vaginal self-stimulation. Baseline (no stimulation) pain thresholds did not differ significantly among the three groups. These findings are consistent with earlier studies in laboratory rats, in which capsaicin administered neonatally abolished vaginal stimulation-produced analgesia, but did not affect baseline pain thresholds to mechanostimulation.

LInk

Categories: Analgesia, Gender, Sex_pain, Vaginal_stimulation