Creamed Brains on Toast

If you’re reading this, you probably know what it is to be constipated all the time. It goes together with the long-term use of opioids like, say, brains and toast (or peas and carrots, for you squeamish folks). A high-fiber diet helps. So does drinking enough fluids. Opioid users have to put a lot more effort into maintaining proper bowel health than most. Should you slip up and not get your daily fiber dose for a few days, all of a sudden your intestines have frozen shut and the only way to get them un-shut is to either go cold turkey (yeah, right!) until they un-freeze, or else use some kind of laxative to get the works moving again.

Only stimulant laxatives are really effective for opioid-induced constipation, because they directly stimulate (”irritate” is a better word for it) the intestinal walls to begin moving the contents contained within along more vigorously despite the opoids slowing them down. Laxatives with other mechanisms of action may work for some people sometimes, but the fundamental problem of opioid-induced constipation is the how much longer it takes for the intestinal contents to traverse the length of the colon. Say you take a stool softener (some stool softeners [e.g. docusate] also act as stimulant laxatives, but ignore them for the moment), or an osmotic laxative. You might have a nice, soft, stool sitting around up in there somewhere, but until the musculature of the large intestines gets a-pushin’ it’s not going anywhere. Unfortunately, stimulant laxatives used with any regularity (pardon the pun) are habit forming, making it so that you won’t be able to shit without the use of a laxative. [There appears to be growing consensus that long-term use of stimulant laxatives may not be as dangerous as previously thought. More on that in a separate post]

So it was with much interest that I read about a few peripherally-acting opioid antagonists. Outside of the central nervous system, the region of the body with the highest concentration of opioid receptors is the bowel. Since the analgesic effects of opioids are [almost] entirely centrally mediated, an opioid receptor antagonist that is incapable of crossing the blood-brain barrier should mitigate the bowel dysfunction that would otherwise occur without any effect on the desirable centrally-mediated opioid effects: analgesia, and the other effects that recreational opioid users are after. The idea of a peripheral opioid receptor ligand is nothing new; loperamide is a potent opioid receptor agonist available over the counter as Immodium(tm) because its ability to penetrate the blood-brain barrier (and therefore its “abuse potential”) is so low as to be negligible. It’s effective against all types of diarrhea, whatever the cause may be. And you can imagine the market for an OTC anti-diarrheal, when the alternative would be having to go to the doctor every time the shits hit.

Where opioid agonists are able to stop diarrhea caused by about anything, opioid antagonists have little to no effect on the bowel activity of non-dependent individuals. Simply giving someone who’s never taken any kind of opioid drug before naloxone or naltrexone won’t do much of anything to them. So the market potential of peripheral opioid receptor antagonists (hereafter PORAA) isn’t as large as that of peripheral opioid receptor agonists (which I shall refer to as PORA from here on out). There’re two ways to make a killing in the pharmaceutical industry: make some blockbuster lifestyle drug, something like viagra or claritin that moves huge numbers while it’s under patent protection, and hope something else like it comes down the pipeline before the patent runs out; or find some old, off-patent drug with a niche market, buy the rights from the current manufacturer, and jack the price up to obscene levels. That’s Ovation Pharmaceutical’s business plan in a nutshell. Instead of selling off-patent niche drugs, you can also develop new ones and get special perks provided by Congress to stimulate pharmaceutical companies to make so-called orphan drugs. PORAAs probably qualify as the latter, and so will probably command a huge price premium whenever they come on market, like how the new 5HT-3 antagonist antiemetics cost so many times more than the old D2 antagonists. They’re much more tolerable (no risk of dystonia!) and as effective, but their cost keeps them out of the hands of people who could benefit from them. I fear PORAAs may meet a similar fate.

The two peripheral opioid antagonists that have been studied the most are methylnaltrexone (which bears to naltrexone the same resemblance codeine does to morphine, i.e. a 3-methoxy group substituted for a 3-hydroxy group which has a quarternary piperidinic nitrogen substituted for a tertiary one), and alvimopan, which is totally synthetic and bears little resemblance to any other opioids on first glance. Clinically, they’re useful in the treatment of post-operative ileus, which is a condition where movement of intestinal contents basically stops for a while after surgery. Here’s a great review of what postoperative ileus is and how alvimopan works to prevent it. I don’t know much about methylnaltrexone, but am suspicious that it would be easily metabolized to naltrexone by the same pathway that codeine is metabolized to morphine [see above]. Free naltrexone is not something you want floating around your bloodstream without a good goddamn reason for it [but isn’t an issue with methylnaltrexone after all].

Alivmopan looks like it’s on track to hit the US market sometime soon. The Adolor Corporation (great name, btw) is marketing it as Entereg(R). With any luck, it will become widely available for anyone on any kind of long-term opioid therapy, be it for pain or otherwise.

Two things make me wonder, though:

• What is alvimopan’s affinity for opioid receptors? This is significant for people on buprenorphine maintenance because of buprenorphine’s extremely high affinity for the same receptors. Naloxone only partially reverses the effects of buprenorphine when administered in overdose because its affinity is lower than that of buprenorphine. Similarly, if alvimopan can’t out-compete buprenorphine for gut opioid receptors, its usefulness in buprenorphine users will be limited.
• What happens if someone who is already dependent on opioids takes a peripherally acting opioid antagonist? Will it be like what happens when they take a centrally-active opioid antagonist (e.g. naloxone), only the instant withdrawal is limited to the gut? If so, would that necessarily be a bad thing? The sensation of having one’s bowels finally, suddenly, come back to life is nothing that anyone needs to go through more than is absolutely necessary. But would it be so bad if it weren’t accompanied by the rest of the (centrally-mediated) withdrawal syndrome? My hunch is that it’d be like a bad case of traveller’s diarrhea for 24-48 hours followed by the kind of “regularity” you once took for granted. There’s only one way to find out for sure.

There’s a lot there to digest, if you’ll excuse the pun. But this is an approach to treating opioid-related constipation that hasn’t really been looked at anywhere before in any depth.

If your comments take a while to appear, it’s because they’re moderated. If I’m incommunicado for a while like I was this last week, they won’t show up. It’s nothing personal! (unless you’re a raging dick or trying to 53..!! ch3.,  4p v!4gr..,’;a or something)

Here’s a couple of posts I’m working on at the moment. They’re creeping along steadily for the most part:

• A novel solution to the perennial problem of opioid connoisseurs the world over (as long as they’re in dope for a while) — constipation. For some people, a high-fiber diet and plenty of H₂O suffices to keep their bowels operating as they ought. Others (including yours truly) have trouble eating right consistently enough to get their colons in gear. For some, all the fiber in the world isn’t enough to get unplugged to their satisfaction. Stimulant laxatives used occasionally are useful in inducing defecation by a local irritant effect on the bowel wall and will, in sufficient doses, get almost anyone shittin’ again. Used regularly, they lead to laxative dependence and changes in the structure and pigmentation of the colon into which I won’t enter here. But there is another way…to be continued!
• The politics of high-dose buprenorphine maintenance therapy and some notes on the differences between clinical trials of HDBMT and clinical practice.
• A FAQ on the rectal administration of drugs, as soon as I can figure out the FAQ-making software I’ve got.

Instead of spending a week putzing around southwestern VA and writing the aforementioned posts, I decided to go poke around what counts as North Carolina’s “God’s Country” (even though everyone knows the real God’s Country is in western/southwestern VA and southern W-by-god-VA, and encompasses the VA blue ridge west through the Alleghenies until the Cumberland Plateau and coal country) to see what’s there. It’s plenty lovely, but the sheer amount of development and crowding in most of the attractions I went to see (and in the off-season, at that) took away from my enjoyment of the place. And there’s something else that I can’t put my finger on that just isn’t as divinely inspired about that piece of the Appalachians as compared to my beloved Alleghenies.

That’s why I’ve been neglecting you some more, dear readers! One of these days I’ll begin to post more than excuses and let me tell you it’s going to be awesome d00d!!11 — or something like it.

I apologize for the delay in getting this page up and rolling. I attend school full-time, and my schedule doesn’t permit me much opportunity to post these days. Having finally exceeded Giganews’s 5 gb/month d/l limit yesterday, my access to alt.drugs.hard is gone for a day. It’s just the kick in the butt, dear reader, that I needed to start posting some things I’ve been meaning to post for a while. Spring Break is coming soon, and instead of going to May-hee-ko or Panama City to get puked on by idiot frat boys, or even NYC or Montreal to get some dog food and watch my friends puke from it (the good kind of puking!), I’ll be sitting around SW Virginia, sober, alone, and catching up on my posting here. The things I do for you, dear public! (BTW, dear public, does anyone know how to keep track of how many people visit here? Your input is much obliged.)

Also, this is my first time operating any blogging software more complicated than livejournal, so the quality and complexity of the layout and posts may remain crude for a while. Anyone out there with experience operating WordPress: I could use whatever tips or tricks you have to offer.

this is my new home on the world wide intarnets!!!11 i’m new to this software so bear with me as i figure out wtf i’m doing. i’d like for this to become my repository for thoughts drug-related. we’ll see how it develops. wish me luck!