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Re: Paradoxical Reactions and Inverse Agonists » Quintal

Posted by Larry Hoover on August 28, 2007, at 19:35:00

In reply to Paradoxical Reactions and Inverse Agonists, posted by Quintal on August 17, 2007, at 18:10:45

I've been struggling to answer posts that I've been interested in answering.....this one took me a while to find again.

> I've noticed for a while now that as I've built up tolerance to codeine, after each dose it actually seems to be *causing* pain.

That sounds familiar to me.

> It reminds me of those ill-defined aches and pains, like currents running through the body, that one gets on high doses of GHB.

I'm unfamiliar with that, though.

> Also, there is a mild pain in my back and shoulders. Last night I felt ill after taking my usual dose, so much so that I feared I'd accidentally taken an overdose. A great heaviness descended upon me, accompanied by a wave of sickness, leaving me feeling weak and faint. I'm starting to wonder if I have a bleeding ulcer which the ibuprofen has re-opened now my stomach acid is back on?

I experienced a blend of withdrawal and overdose symptoms from oxycodone, after a period of stable use.

> Anyway, today I felt much better when I got up so I didn't want to take any codeine in case it made me ill again. I've been fine all day without it - no pain or withdrawal symptoms at all. Yesterday I felt ill all day with it - pain despite taking a larger dose than the day before and a horrible malaise, which is the opposite of the usual effect it has on me. The day before, I ran out of codeine and I felt ill all day without it, withdrawal symptoms and awful aches and pains. So what's going on? I think Larry Hoover once had a similar experience with an opiate, so I'd be interested to hear what happened there.

Yes, I certainly did. And my pain doctor denied that the drug was at the heart of it. I was using Oxycontin (sustained release oxycodone) t.i.d. (three times a day), because the drug did not last 12 hours in my body, as it was supposed to. Rather than bridging with I.R. oxycodone (as Percocet), I was switched from b.i.d. to t.i.d., and was stable at about 100 mg/day. I began to experience signs of sympathetic activation, including sweats and faints and panic attacks. These would occur at roughly the mid-point between doses. I also began to experience abdominal cramping, enhanced pain, insomnia, and other signs of withdrawal, despite remaining at this stable dose (that had worked for a lengthy period of time). I lost so much weight (60 lbs.) that they did exhaustive testing for cancer, yet no one would attribute my suffering to the oxycodone.

I was told that withdrawal from the drug would necessitate my enrolling in a methadone program, which would exclude me from my habitual medical supports. Instead of receiving my drugs at monthly intervals, I would be require to go out daily, and travel to another city, to receive methadone. I was too ill, and unable to manage all that driving due to pain, to even consider that option.....so I did the withdrawal at home, alone. I've never been sicker in my life. Not even close.

Anyway, my experience entering into withdrawl confirmed my intuitive understanding of what was happening; I had been in withdrawal, despite maintaining stable dosing of sustained release drug. Although my doctors wouldn't support my interpretation, they certainly validated the outcome. After withdrawal, the adverse symptoms went away.

I found some anecdotal reports of identical experiences on the net, or I feared I'd have lost my mind, thinking myself uniquely f*cked up. There is one doctor who published an account of this syndrome, and called it "downhill spiral syndrome", but it's not much accepted. I think that you can only use opiates for some finite period, and after that, your body finds some way to reject them.

> I'm also thinking about the article I posted a week or so ago on benzodiazepine withdrawal, where the receptors can become locked into the inverse agonist configuration and thereby cause the opposite effect of the drug. I haven't examined that theory carefully, and it may just apply to people suffering lingering withdrawal symptoms after the drug has been discontinued, and therefore be irrelevant to this, but I wonder if there is a technical explanation for this phenomenon?

Whoa, I'm been rather verbal, eh? This is the point I wanted to address, in fact. You might want to consider epigenetics, sometimes epigenomics. Prefix taken from the Greek that means "on, upon, at, by, near, over, on top of, toward, against, among." In other words, genes subject to the environment they occupy. We've already identified a number of genetic "switches", molecular changes in the DNA or its immediate environment, that turn genes on or off. These include methylation, histone complexes (proteins that wrap the DNA), and RNA that serves one purpose, to bind to and regulate DNA. Some of these effects even are capable of being passed along to the next generation (some experiments have shown grandparent to grandchild transfer), so the once ridiculed alternative to natural selection proposed by Lamarck, that the giraffe passed on its long neck by reaching for branches might yet have some validity.....Here's a recent study in rats, that hit the news: http://www.world-science.net/othernews/070814_obesity.htm

Your genes might be switched to different positions, Quintal. You might have been changed by using the drug for as long as you have.

That said, I do use small doses of oxycodone, when I cannot stand the pain. I just cannot foresee myself using it the way I once did. I use it with trepidation, and with some reserve.

> Maybe the best thing to do is taper off to regain tolerance?

It worked that way for me. I was too scared to take any for a good four months, after I went through that hell.

> I'm thinking of substituting it with Parnate and Xanax for a month or so. I have some Parnate left over from my prescription last October and it's mildly dopaminergic so might take up the slack in my dopamine system. One batch goes off at the end of this month so I need to get it used up anyway and now would be a good time. I also need to stay away from the ibuprofen (in Nurofen Plus) as it cant be good for my poor stomach any more. I actually felt something wobbling around in there today, a fleshy mass of some sort. Not nice, but I'm not going back to the doctor unless it flares up again.
>
> Q

Ibuprofen is not usually associated with stomach problems, although chronic use can do you in. Buffering it with food is possibly all you need to do.

Lar

 

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URL: http://www.dr-bob.org/babble/20070824/msgs/779383.html