The Pleitropic Effects of Volatile Anesthetics: Pain and Inhaled Agents?

Implications: There are well over 70 Million general anesthetics performed in the US each year, and the majority of these utilize one of four generally used inhaled anesthetic agents (Sevoflurane, Desflurane, Isoflurane and Halothane). How these drugs act to produce "unconsciousness" is largely unknown, but as the basic neurosciences have advanced, so too our understanding of these drugs and how they act to render people blissfully unaware. One of the more suprising and (therefore exciting to the capital markets) findings in the past decade has been that these drugs have myriad effects in addition to those that produce unconsciousness. A few of these such as conveyance of protection from ischemia are of such interest that huge industries are developing around them. A few are mere curiosities at present. This paper highlights one of those "effects" which may not be desirable. Worse, still, that effect, pain, is already the number one issue facing post-surgical patients.

Analysis: For nearly a century, our our understanding of how anesthetics worked to produce their effects (sleep, unawareness, relief from pain and blunting of natural reflexes) was centered around the idea that all of the drugs, no matter of what chemical shape or size, disrupted some single site in the brain (fat) and by virtue of that disruption; "caused" their effects. Our "endpoint" for those drugs was simple: essentially, looking, and acting as if one was just knocked out with a big hammer to the head. This 'immobility' and generally loss of consciousness was our metric for defining how drugs performed clinically. A key point, historically, was that these drugs came in various shapes and sized (chemically speaking), yet, somehow, ALL produced IDENTICAL effects. This is highly unusual for drugs where often one change in a single side-chain can alter the smell, or activity of compounds. Even more interesting, these agents did this "thing" in all organisms studied, from sea-snails to flys to humans.

What then to make of this PNAS article? (not the Newscientist summary-- the real thing:PNAS June 24, 2008 vol. 105, no. 25, pp8784-8789)

Well there are three main points to consider:

1. Inhaled Anesthetics (IA) have effects not related to their intended use of sleep and amnesia.
2. VA are not all equal.
2. Some VA actually have "effects" that are not desirable.

The key question to consider though is what do these three general findings portend for the capital markets?

First point. This finding is not novel. Since the mid to late 1980's there has been a trickle, then a steady flow of evidence that shows if one defines their "endpoints" more carefully, IA actually do other things besides just knock people out. In fact, many of these other effects have clear and evident clinical value-- such as the protection that IA offer to tissue in danger of becoming injured from lack of oxygen. We use these drugs for unconsciousness. But the first general point in this PNAS paper enters a robust corpus of evidence that points to a day not far off when one will use these drugs to selectively do something else, not at all related to sleep or awareness or unconsciousness. This finding then is welcome, and in accord with our expanding portfolio of knowledge.

Second point.This one is interesting. We have had glimmers of this finding over the past few years-- much of these data come at the molecular level and few from the more general "organism" level as shown in the PNAS paper. It has become generally accepted that IA act, somehow, to produce their effects by interacting with classes of ion channels in the central nervous system. We know with certainty that not all IA act at all targets equally well (example-- some work at glutamate receptors, some not so well, while many work very well at certain GABA channels). In addition, there is generally a clear distinction between liquid (IV) forms of anesthetics and the inhaled forms at a molecular level. So, that the PNAS paper shows a difference among IA Sevoflurane and Isoflurane adds to the evidence summarized above. So far, so good. What the PNAS paper adds to the mix is that they show that these molecular actions are relevent to an effect felt at the level of a whole organism (pain in mice). So, not only does Iso work at the ion channel under study while Sevo does not, but THAT Iso acts there is causally related to augmented pain experienced by the mouse (they argue). More on this below.

Third Point. This is the one making all the headlines. That IA given to humans, for the unstated but clear purpose of rendering sleep, unawareness and analgesia during surgery can actually produce an effect not related to this has been shown previously (pre-conditioning mentioned above). THAT such an effect can be counter-productive, and so explicity concerning in surgical patients, thats the essence of this PNAS paper. They show that because "pungent" or irritant agents seem are clinically repulsive (thats why we call them pungent...) AND that these agents act on these TRPA1 receptors in peripheral sensory neurons-- it is being argued that the TRPA1 actions of these agents CAUSE the noxious responses. The key evidence for this is that in mice lacking this TRPA1 receptor, the Isoflurane fails to cause this noxiousness. This noxiosness consists of inflammatory response and pain (in the case of an IV drug propofol).

So, what to make of this? Scientifically-- the paper is well written and the science is good. The receptor null mice help to make a compelling case that the TRPA1 receptor is important for the differences observed between happy and sad (less pain and more pain) mice. Three caveats as the capital markets try to digest this observation (however sound it may be).

a. Mice are not men, so to speak. Pain is a complex phenomenon which is more than the sum of its parts. The same toe stub on me, may not effect you at all, and some women labor and have babies without epidurals and some even with them, cannot bare the discomfort. We can discern none of this psychology in mice. Their behaviors are "surrogates" for pain in people-- mice cannot speak, so we really have no way of knowing.

b. similarly, that a drug can cause something to hurt-- does not mean that it equates with pain (lots of us have something that hurts us-- yet it is not painful). I use the word pain here to mean interfering with normal activities of daily living and function. Sure, maybe my biceps tendon hurts, and playing tennis makes it hurt more, but I still played tennis and the Nuprin still did the trick for me. So what if I played tennis and made it worse? The oral pain pills I take work just fine. So-- I ask-- what does it matter if Isoflurane makes swelling and/or pain worse?

c. which is the last point. Lets just say that a pain pill after surgery (call it Pain pill Jason) takes away 100 units of pain (arbitrary scale). Lets further assume that people that wake from surgery have a 50 unit pain score normally. Great, a single Jason and you are healed. Lets now say that by adding Isoflurane to the mix-- you get a score of 60 or 70 or 80, heck, lets almost double it to 90. Single pain pill still does the trick. Great. Double the pain, no change in therapy! Whats my point here? Well, that IA could cause pain is in complete agreement with everything we know about the pleitropy of these drugs. Its exciting to see more basic science work like this. BUT-- THIS PAPER WAS PUBLISHED IN A BASIC SCIENCE JOURNAL.

Its possible clinical relevance is fun to speculate on, but if it were more clinically relevant-- it would have been published in a clinical journal. This is excellent science, I need to be clear here. But extending this to clinical populations is premature and likely to cost some of you readers a fair bit of money. Besides the obvious that there are no alternatives to the drugs we use-- and no matter how much Baxter and Abbott may argue that this paper nails the case for using one drug versus another, that argument belies the reality that the cost of these drugs is so high that isoflurane will remain a key agent for years to come. It is not cost effective as of yet-- (no data) to dispose of Isoflurane. There are no newer agents in the pipeline. So-- this is NOT the paper to unseat Isoflurane from its low-cost, SAFE place in the medication chest of anesthesiologists.

In addition, until we do clinical trials to see just how much, and how, if at all, the pain among those given ISO versus SEVO differs, or how that inflammation matters-- this is all just fun and games. Maybe their pain doubles but it has NO effect on time to discharge, or post-op complications, or return to activities of daily living. Who cares, then, one could argue? Alternatively, that inflammation could be the horse loosed from the barn-- either way-- this is NOT the paper to make investment decisions on, unless you are a very, very young Angel or a very bored VC looking to play time horizons that border on generational.