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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by zazenducke on September 12, 2012, at 16:59:51
Interesting article about an enantiomer of naloxone. Do you think people whose depression lessens on opiates would still feel relief if the pleasure producing effect was blocked and they were only recieving pain relief? Only testing in ratties of course.
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The study drug, (+)-naloxone, acts on glia, blocking a type of receptor called toll-like receptor 4 (TLR4), which is found on glial cells. Activation of this receptor appears to be important for both the pleasure and dependence-producing effects of opioids: when the receptor was blocked by (+)-naloxone, rodents didnt seek opioids or become tolerant to them. Blocking this receptor also enhanced opioids pain-relieving power.
But while giving (+)-naloxone to block TLR4 seemed to mitigate the development of opioid tolerance and withdrawal, mice that were bred to lack the TLR4 receptor altogether still experienced some withdrawal symptoms when opioids were stopped, suggesting that the function of the receptor doesnt fully account for opioid dependence.
Heres how the system may work: when exposed to opioid drugs like morphine, glial cells become active; in turn, they ramp up the activity of the neurons that respond to opioids, which are critical to pathways involved in pleasure and pain, explains Watkins. When this activity occurs in a pain pathway, glial activation amplifies pain. This counteracts what the opioid is trying to do for pain control, she says; morphine suppresses pain by acting on neurons, but it simultaneously enhances pain by activating glia. But since the morphine suppression is typically greater than the glial activation, the drug cuts pain overall.
Over time, with continue use of painkillers, however, glia become increasingly activated thats what reduces the drugs pain-relieving effect, producing tolerance and the need for larger and larger doses.
The same holds true for the neurons involved in opioid-related pleasure, according to Watkins; glial activation revs up the neurons, but now the neurons are in the reward pathway so you amplification of reward, she says. You can think of glia as volume controls. They can dial up pain. They can dial up drug reward.
And (+)-naloxone seems to turn glia down. Some types of chronic pain may in fact be caused by inflammation related to glia turning up pain circuits; earlier research by Watkins and colleagues has shown that (+)-naloxone can also counteract this type of pain, at least in rodents.
So far, (+)-naloxone has not been tested on humans. However, another drug that blocks TLR4 has undergone early stage clinical testing for use in addiction treatment to reduce withdrawal symptoms and block the opioid high. That drug, ibudilast, is already approved for other uses in Japan.
Potentially, ibudilast or a drug like (+)-naloxone could be added to prescription painkillers like OxyContin to increase pain relief, prevent the high and mitigate the development of tolerance and withdrawal upon cessation of use. Combinations are an interesting possibility, says Pasternak, adding that theres not enough data yet to know whether they would work.
Also, it is not clear whether preventing the high would hinder certain aspects of pain relief in humans. Subjective experiences of opioid use suggest that the high the relief of anxiety and sense of distance from the pain is not totally separate from the actual physical pain relief, and multiple previous efforts to dissociate the two have failed.
By itself, however, (+)-naloxone or a similar drug could be developed to treat chronic pain. We are trying to [raise the funds to] start a company to take this to clinical trials, says Watkins. There is a huge unmet need for effective therapies for chronic pain.
Of course, the long history of the quest for non-addictive opioids is one of repeated failure. Heroin was supposed to be a less addictive form of morphine, and OxyContin was supposed to be a less addictive pain reliever, too. But these new immune system connections are only just beginning to be explored and they may open up many new possibilities for relief.
Posted by brynb on September 13, 2012, at 22:40:59
In reply to Addiction Proof Pain killer, posted by zazenducke on September 12, 2012, at 16:59:51
> Interesting article about an enantiomer of naloxone. Do you think people whose depression lessens on opiates would still feel relief if the pleasure producing effect was blocked and they were only recieving pain relief? Only testing in ratties of course.
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Very interesting! I'm not great at sifting through all the neuroscience, but a doctor friend of mine who used to be a psych doc and addiction and pain med specialist (he's no longer practicing, he's a professional musician now) had told me that pain patients (be it physical or psychic pain) don't experience the same "high" that others would.He said that in his experience, the people who get the most "kick" out of opioids are people who are mostly not in chronic physical or mental pain. He said that pain meds affect "normals" and the painful VERY differently. For example, pain antagonizes the respiratory depression effect of high opioid doses, and dose can be raised almost geometrically per hour as long as acute pain exists.
So basically, in theory, or at least in my friend's opinion, it should still be effective despite not producing euphoric effects.
I take Tramadol (hardly an "opiate" but a weak opioid nonetheless). I never get "high" or euphoric from it, just a brightening in mood and motivating effect.
Thought I'd chime in and add my two cents.
-b
Posted by jono_in_adelaide on September 15, 2012, at 4:09:56
In reply to Re: Addiction Proof Pain killer » zazenducke, posted by brynb on September 13, 2012, at 22:40:59
I'd agree with what your doctor friend said, based on my experience..... after surgery, i was prescribed injections of Omnopon, and while they releived the pain extremely well, I found them most unplesant, i hated that stoned drugged feeling, so that after 2 shots, I asked if i could just have ibuprofen by mouth
Posted by jono_in_adelaide on September 15, 2012, at 17:25:47
In reply to Re: Addiction Proof Pain killer, posted by jono_in_adelaide on September 15, 2012, at 4:09:56
but, that cant be the whole story, as one heres of people who are in genuian pain whos use spirals out of control - Betty Ford being an examply..... I guess some people are born addiction prone and others arnt
Posted by brynb on September 16, 2012, at 12:55:18
In reply to Re: Addiction Proof Pain killer, posted by jono_in_adelaide on September 15, 2012, at 17:25:47
> but, that cant be the whole story, as one heres of people who are in genuian pain whos use spirals out of control - Betty Ford being an examply..... I guess some people are born addiction prone and others arnt
True. I'm definitely (unfortunately) in that category. I had quite a few years of intense substance abuse which pretty much stemmed from depression/anxiety and trying to self-medicate. Again, though, for those of us who do become abusers or addicts, I believe it very often stems from the desire to annihilate some type of pain (physical or psychic), and we tend to chase any euphoria or high as it's so remarkably different from our "normal," baseline existence.
There's a distinct difference between dependence and addiction, too, though. Many pain patients are dependent. When I was abusing pills and illegal substances, I was both dependent AND addicted. Still, I believe addiction is more a behavioral issue, not a disease issue as 12-step programs and similar disease models present. That's, of course, a different discussion.
Posted by jono_in_adelaide on September 16, 2012, at 17:55:49
In reply to Re: Addiction Proof Pain killer » jono_in_adelaide, posted by brynb on September 16, 2012, at 12:55:18
Yeah, I am mildly dependant on my Xanax (mild withdrawl symptoms if i cat the dose in half) but not addicted.
Re the addiction proof painkiller, i thought they had come close with tramadol - the abuse rate was lower than for codeine, the mildest traditional narcotic, and only slightly higher than for naproxen, a non narcotic, yet it is a stronger painkiller than codeine.
I think LA tramadol deserves to be more widely used in chronic pain states
Posted by brynb on September 16, 2012, at 18:31:27
In reply to Re: Addiction Proof Pain killer, posted by jono_in_adelaide on September 16, 2012, at 17:55:49
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> I think LA tramadol deserves to be more widely used in chronic pain statesYes, definitely! Tramadol actually helps my mood a ton, and I never go above 100 mg. I'm fearful to take anything beyond my prescribed dose as I'm also on Lexapro and don't want to risk serotonin syndrome or seizures. (My typical dose is 50 mg, and I only go above that when I absolutely need to.) The idea that it's addictive at all is a HUGE joke to me. I have a very "addictive personality" and I'm never tempted by Tramadol. I can (and have) stop it at anytime.
I'm the first to attest to the horrors of drug dependence and addiction. At my worst, I was using lots of pills and illegal stuff. With benzos, I was taking up to 200 mg of Valium a day. I had a really hard time functioning without the pills, and a miserable time withdrawing from drugs in general. Benzo withdrawal is absolute, pure hell. Period. I'm clean and fine now (and have been for a couple of years) and all too aware of the fragility of my brain chemistry and how easily my depression is affected.
I could go on forever about addiction, our (the US's) ridiculous approach to it, and the misconception that pain meds are inherently bad! But only because I've been there, and I know firsthand.
-b
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