The REAL Future of Partial Agonist Treatment— Pharma are you Listening?

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980’s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)
Hi ——,
(private chit chat that would bore everyone)
Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.
The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.
The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.
The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.
Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.
A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.
Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?
I figured you’re the person to ask!
Thanks ——–
Jeff

3 thoughts on “The REAL Future of Partial Agonist Treatment— Pharma are you Listening?”

  1. 15-30mg every 4 hours is nothing compared to what I used to take… On Suboxone for 10-months. I assume that my liver is repaired since I don’t drink… Is that safe to think? The poisoned feeling from too much Acetaminophen is not missed at all!

  2. Just a question….
    I am on 6mg Subutex/day (just plain old generic buprenorphine) and recently had an emergency appendectomy. I had no analgesia problems at all. Dilaudid 2mg IV in the ER worked for the pain (which REALLY surprised me since I was on the Bupe) and afterwards I was given Dilaudid for pain until I requested to be switched back to Subutex about 24 hours after the surgery. Obviously this contrasts with: “The second problem with the high ceiling/tolerance level is that surgery is a hassle. People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.” I never went on oral pain meds after the surgery. Just right back to the Subutex.
    Some hx…
    I have been on the Subutex about 4 months because I became physically dependent on opiates while being treated for chronic pain associated with ankylosing spondylitis ( I can’t take NSAIDs due to GI bleeding). The opiates eventually quit working for me. I could not get on a stable dose due to tolerance issues. I was at OxyContin 80mg 3x/day and increasing quickly before I was yanked off of them CT by military docs (I was seeing a civilian Pain Specialist) and accused of being an addict by them (something I do not believe I am). Interestingly enough, I had only minor WD symptoms once forced to go CT off the Oxy. My WD symptoms felt like a mild hangover. But mentally, I soon found myself in an absolutely crippling, hellish, and suicidal depression. I suffered that way for 2-3 months before I was placed on Subutex. The Subutex completely erased all of my depression and brought me back to feeling normal immediately.
    My lack of WD’s is certainly unusual, but is anything else in your opinion as a doc who deals with addicts and Sub patients?
    Thanks…

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