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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 26. This is the beginning of the thread.
Posted by bulldog2 on April 10, 2010, at 11:52:22
I've seen this statement made on more than one occassion in reference to TCAs. Is there any scientific proof that any tca's have any influence on opioid receptors and which tca's would that be true for?
Posted by SLS on April 10, 2010, at 12:08:33
In reply to TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 11:52:22
> I've seen this statement made on more than one occassion in reference to TCAs. Is there any scientific proof that any tca's have any influence on opioid receptors and which tca's would that be true for?
I'll be interested to know more about this, too. I read that some TCAs inhibit activity at kappa opioid receptors. That would make sense, I guess, as stimulation of these receptors can produce dysphoria. Also, kappa antagonists produce behavioral changes in rats that resembled those of TCAs.
- Scott
Posted by bulldog2 on April 10, 2010, at 12:33:37
In reply to Re: TCA's With Opioid Actions?, posted by SLS on April 10, 2010, at 12:08:33
> > I've seen this statement made on more than one occassion in reference to TCAs. Is there any scientific proof that any tca's have any influence on opioid receptors and which tca's would that be true for?
>
> I'll be interested to know more about this, too. I read that some TCAs inhibit activity at kappa opioid receptors. That would make sense, I guess, as stimulation of these receptors can produce dysphoria. Also, kappa antagonists produce behavioral changes in rats that resembled those of TCAs.
>
>
> - ScottSomething about the tcas make them more effective than the ssris for moderate to severe depression. I guess tcas are more effective than the modern snris. I was wondering if the difference was activity opioid receptors? tcas seem to be the most effective of the ads for pain. Also there seems to be some evidence that the tcas moderate activity at the nmda receptor.I wonder what effect that has on the neurotransmitters.
Posted by Phillipa on April 10, 2010, at 12:47:25
In reply to Re: TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 12:33:37
cymbalta does relieve pain. Know from experience. Tca's huge weight gain issues for some. Phillipa
Posted by bulldog2 on April 10, 2010, at 13:11:40
In reply to Re: TCA's With Opioid Actions? » bulldog2, posted by Phillipa on April 10, 2010, at 12:47:25
> cymbalta does relieve pain. Know from experience. Tca's huge weight gain issues for some. Phillipa
I am using increased synthroid to deal with the weight issue and also watch what you eat. Climbing very slowly on elavil. 10 mg at a time and stay there for awhile. So far sides are manageable.
Personally if I was you I would give up on the drug option. You are to scared of the sides and I know you generally freak out after a day or two and stop. I was reading that patients who obsess with sides generally have failed drug trials. It's not a good or bad thing. It's just the way you are.
Posted by linkadge on April 10, 2010, at 16:19:11
In reply to TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 11:52:22
The TCA's have direct effect on opiate receptors: genererally, delta and kappa, with some mu interaction(?). The noradrenergic TCA's also have indirect effects on noradrenergic function. NRI's apparently prolong the effects of opiate ligands in some way.
Linkadge
Posted by linkadge on April 10, 2010, at 16:20:47
In reply to TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 11:52:22
Also, the TCA's activity is (in part) mediated by cannabanoid receptors. The TCA's elevate the activity of endocannabanoids. The ability of TCA's to supress stress induced cortisol secretion depends on an intact canabanoid system (namely CB1?)
Linkadge
Posted by linkadge on April 10, 2010, at 16:26:23
In reply to Re: TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 13:11:40
Yeah, like you mentioned the TCA's do have some (direct) NMDA antagonist effects. They are also sigma1 receptor agonists (especially imipramine) which elevates synaptic neurite outgrowth. Amitriptyline (in addition to these actions) is a direct agonist at TRKa and TRKb receptors. This activity promotes neurogenesis and induces neuroprotection.
Oh, also, the TCA's have some effect on monoamine oxidase. Generally, they exert stronger effects on MAO-b than MAO-a. I think trimipramine is also a dopamine reuptake inhibitor.
The SSRI's were initially lauded as the product of "rational" drug design - as if they identified "the" mechanism. The notion that the TCA's were working solely in their capacity as serotonin reuptake inhibitors in nonsense. I think between this post (and the one below) we have identified like 15 different antidepressant like targets of the TCA's. Better go back to the drawing board.
Linkadge
Posted by bulldog2 on April 10, 2010, at 17:25:22
In reply to Re: TCA's With Opioid Actions?, posted by linkadge on April 10, 2010, at 16:26:23
> Yeah, like you mentioned the TCA's do have some (direct) NMDA antagonist effects. They are also sigma1 receptor agonists (especially imipramine) which elevates synaptic neurite outgrowth. Amitriptyline (in addition to these actions) is a direct agonist at TRKa and TRKb receptors. This activity promotes neurogenesis and induces neuroprotection.
>
> Oh, also, the TCA's have some effect on monoamine oxidase. Generally, they exert stronger effects on MAO-b than MAO-a. I think trimipramine is also a dopamine reuptake inhibitor.
>
> The SSRI's were initially lauded as the product of "rational" drug design - as if they identified "the" mechanism. The notion that the TCA's were working solely in their capacity as serotonin reuptake inhibitors in nonsense. I think between this post (and the one below) we have identified like 15 different antidepressant like targets of the TCA's. Better go back to the drawing board.
>
>
> Linkadge
>
>
>I guess we all remember Peter Kramer's book "Listening to Prozac". Even if we weren't depressed but just a little bored we wanted Prozac. So everyone is now running to their GP and feeling depressed and so the flood begins. Definiltely some indoctrination going on to market the product. Recently met some friends who flew in, mother,daugher, father are on ads.
Now that we have such a safe product in that you can't die because of overdose there is a campaign to find depression in every nook and cranny. You have to wonder how much Eli Lilly knew or pushed the inappropriate diagnosis of depression for profit. After all the product was so safe compared to the dangerous and side effct riddled tcas and maois.So the success of the tcas in severe depression is the fact they are dirty and touch every corner of the brain or almost do.
Right now I'm looking for the best tca for both depression and pain. Need something that will work with percocet for both sciatica and severe hip arthritis (not the repaired hip). Is there a best tca for pain? Right now I find elavil better than nortriptyline for both pain and arthritis.
Posted by Justherself54 on April 10, 2010, at 18:45:08
In reply to Re: TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 17:25:22
I've just started clomipramine. I have fibromyalgia, Coccydynia and arthritis in my sacrum. The coccydynia pain has been very hard to tolerate. The most bizarre thing happened. After one dose at bedtime of clomipramine my coccydynia pain was gone. I'm still in shock.
I'm at a low dose and if I can tolerate it, I'll be increasing it next week. I feel quite a bit of sedation, but nothing like amitriptaline or nortriptaline, which knocked me out cold, even at very low doses.
I can't see the pain relief as being coincidence.
Thoughts anyone?
Posted by Phillipa on April 10, 2010, at 20:30:30
In reply to Re: TCA's With Opioid Actions?, posted by Justherself54 on April 10, 2010, at 18:45:08
Absolutely wonderfully amazing and it will continue!!!!! Love Phillipa
Posted by linkadge on April 11, 2010, at 6:37:01
In reply to Re: TCA's With Opioid Actions? » Justherself54, posted by Phillipa on April 10, 2010, at 20:30:30
on clomipramine I was able to go up to 75 mg no problem. Infact I almost wanted to go up after each dose (to be honest it gave me an initial buzz).
Amitriptyline is so sedating that I like taking it at night, I just regret it like hell the next morning.
Linkadge
Posted by ed_uk2010 on April 11, 2010, at 7:21:47
In reply to Re: TCA's With Opioid Actions?, posted by bulldog2 on April 10, 2010, at 17:25:22
Amitriptyline (Elavil) is believed to be one of the most effective TCAs for chronic pain. It's very widely used for this purpose. I don't believe that its efficacy in pain has much (if anything) to do with opioids, however. NE reuptake inhibition is thought to be an important mechanism. Its activity at sodium channels in the nervous system may also be relevent. Also, sleep is usually disturbed in patients with severe pain - amitriptyline can certainly help in this department. Nortriptyline is also effective for neuropathic pain. It may be slightly less effective than amitriptyline but generally better tolerated. Imipramine is another TCA which has been used for pain relief. It is considerably less sedating than amitriptyline, but may have similar efficacy. It hasn't received as much study for pain as amitriptyline.
> > Yeah, like you mentioned the TCA's do have some (direct) NMDA antagonist effects. They are also sigma1 receptor agonists (especially imipramine) which elevates synaptic neurite outgrowth. Amitriptyline (in addition to these actions) is a direct agonist at TRKa and TRKb receptors. This activity promotes neurogenesis and induces neuroprotection.
> >
> > Oh, also, the TCA's have some effect on monoamine oxidase. Generally, they exert stronger effects on MAO-b than MAO-a. I think trimipramine is also a dopamine reuptake inhibitor.
> >
> > The SSRI's were initially lauded as the product of "rational" drug design - as if they identified "the" mechanism. The notion that the TCA's were working solely in their capacity as serotonin reuptake inhibitors in nonsense. I think between this post (and the one below) we have identified like 15 different antidepressant like targets of the TCA's. Better go back to the drawing board.
> >
> >
> > Linkadge
> >
> >
> >
>
> I guess we all remember Peter Kramer's book "Listening to Prozac". Even if we weren't depressed but just a little bored we wanted Prozac. So everyone is now running to their GP and feeling depressed and so the flood begins. Definiltely some indoctrination going on to market the product. Recently met some friends who flew in, mother,daugher, father are on ads.
> Now that we have such a safe product in that you can't die because of overdose there is a campaign to find depression in every nook and cranny. You have to wonder how much Eli Lilly knew or pushed the inappropriate diagnosis of depression for profit. After all the product was so safe compared to the dangerous and side effct riddled tcas and maois.
>
> So the success of the tcas in severe depression is the fact they are dirty and touch every corner of the brain or almost do.
>
> Right now I'm looking for the best tca for both depression and pain. Need something that will work with percocet for both sciatica and severe hip arthritis (not the repaired hip). Is there a best tca for pain? Right now I find elavil better than nortriptyline for both pain and arthritis.
>
Posted by bulldog2 on April 11, 2010, at 8:40:50
In reply to Re: TCA's With Opioid Actions?, posted by Justherself54 on April 10, 2010, at 18:45:08
> I've just started clomipramine. I have fibromyalgia, Coccydynia and arthritis in my sacrum. The coccydynia pain has been very hard to tolerate. The most bizarre thing happened. After one dose at bedtime of clomipramine my coccydynia pain was gone. I'm still in shock.
>
> I'm at a low dose and if I can tolerate it, I'll be increasing it next week. I feel quite a bit of sedation, but nothing like amitriptaline or nortriptaline, which knocked me out cold, even at very low doses.
>
> I can't see the pain relief as being coincidence.
>
> Thoughts anyone?
>
>All I can say is wow! That's very impressive. I'm on 30 mg of elavil at bedtime but no pain relief but some boost in mood. Wake up feeling good. I have lumbar stenosis and right hip severe osteoarthritis. Back on the percocets which I didn't want to start again.
Sounds like I might try the clomipramine. What dose did this miracle occur at?
Posted by Justherself54 on April 11, 2010, at 10:56:29
In reply to Re: TCA's With Opioid Actions? » Justherself54, posted by bulldog2 on April 11, 2010, at 8:40:50
Hi Bulldog. I'm taking 50 mg. right now, then will try to increase it after speaking with my pdoc mid week.
I've only been on it for 3 days, and the pain has not returned. This morning I noticed my fibro pain and stiffness wasn't as bad either. I do feel very sedated however, but I'm hoping that will pass.
I have to be able to work through through whatever side effects this med throws at me. The only thing I've taken for pain was Tylenol with codeine and it didn't completely block the pain. Now I feel like nothing was ever wrong with my back.
I'm supposed to see a surgeon next month to discuss removing my coccyx. This type of surgery can have all kinds of complications. If this med continues to block the pain..I'll keep my coccyx!
I'm still depressed as hell, but to finally have pain relief gives me hope that things can and will get better.
Posted by bulldog2 on April 11, 2010, at 12:17:33
In reply to Re: TCA's With Opioid Actions? » bulldog2, posted by Justherself54 on April 11, 2010, at 10:56:29
> Hi Bulldog. I'm taking 50 mg. right now, then will try to increase it after speaking with my pdoc mid week.
>
> I've only been on it for 3 days, and the pain has not returned. This morning I noticed my fibro pain and stiffness wasn't as bad either. I do feel very sedated however, but I'm hoping that will pass.
>
> I have to be able to work through through whatever side effects this med throws at me. The only thing I've taken for pain was Tylenol with codeine and it didn't completely block the pain. Now I feel like nothing was ever wrong with my back.
>
> I'm supposed to see a surgeon next month to discuss removing my coccyx. This type of surgery can have all kinds of complications. If this med continues to block the pain..I'll keep my coccyx!
>
> I'm still depressed as hell, but to finally have pain relief gives me hope that things can and will get better.
>Did you get any pain relief at 25 mg? How many days to get relief?
If I take 30 - 40mg of amitriptyline should I feel more or less sides on clomipramine? I fall asleep fine on the amitriptyline and don't feel sedated the next morning.My lumbar stenosis gives me sciatica like pain down the back of my legs. Worst in the morning. Also bad right hip pain. I had a hip replacement in Sept 2009 and that went well but I'm not ready for any operations. If the clomipramine works on the pain that would be great. I'm getting tolerant to the percocet when that worked well for a while.
Went back to your post. See you've only been on it 3 days. Give it time for depression as it can take several weeks for that.
So still did you start at 25 mg and did it work the first night? Seems like it only comes in capsules. I like to titrate slowly.
I think the chronic pain has something to do with my depression so a little pain relief would be a big plus! That coccyx surgery sounds brutal. I would try and avoid that.
Thanks
Bulldog2
Posted by hopefullynow on April 11, 2010, at 14:24:43
In reply to Re: TCA's With Opioid Actions? » Justherself54, posted by bulldog2 on April 11, 2010, at 12:17:33
Hy Bulldog,
I get pain relief at 25 mg clomi the next day at the beginning of treatment but it seems that the higher dose the greater analgesic effect.So maybe for acute pains one should target 75-100 mg/day.
You could titrate Anafranil (brand, made by Novartis), it comes in pills of 10 mg which have triangular form and 25 mg which are round.They're preety small, but with a razor you can cut them easily in half.
Compared to amitriptyline, clomi is more anticholinergic than antihistaminic and I found it easier to tolerate at comparable doses.I have a better tolerability to anticholinergics that to anti histamincs but overall, anafranil was easier to bear.
Posted by Justherself54 on April 11, 2010, at 14:52:19
In reply to Re: TCA's With Opioid Actions? » Justherself54, posted by bulldog2 on April 11, 2010, at 12:17:33
Hi Bulldog..my pdoc started me on 50 mg..probably to try to ramp up as quickly as we can, due to the severity of my depression. I took my first doseage three days ago, and woke up the next morning with no pain, so it basically was overnight. I still can't get over it.
The sedation is bothering me, but I know I have to give it time..and not be too hard on myself for being a sloth in my pj's.
I've always felt that my chronic pain fed my depression.
So here's hoping.
Posted by bulldog2 on April 11, 2010, at 14:54:10
In reply to Re: TCA's With Opioid Actions?, posted by hopefullynow on April 11, 2010, at 14:24:43
> Hy Bulldog,
>
> I get pain relief at 25 mg clomi the next day at the beginning of treatment but it seems that the higher dose the greater analgesic effect.So maybe for acute pains one should target 75-100 mg/day.
>
> You could titrate Anafranil (brand, made by Novartis), it comes in pills of 10 mg which have triangular form and 25 mg which are round.They're preety small, but with a razor you can cut them easily in half.
>
> Compared to amitriptyline, clomi is more anticholinergic than antihistaminic and I found it easier to tolerate at comparable doses.I have a better tolerability to anticholinergics that to anti histamincs but overall, anafranil was easier to bear.Thanks for the info..so if i'm on 30 mg of amitriptyline I might use 25 mg of clomipramine to start. I might ask my p-doc if I can get the 10 mg pills as that is how I like to titrate. First goal is to work up to 50 mg. From what I've read this med is potent at both se and ne. A doctor Gillman rates it as the best antidepressant. For me start low and proceed low is the best option.
Thanks again for the info.I have dog clomicalm at home. Unfortunately she has passed away. Dog clomicalm is Clomipramine. Capsules are 75 mg.
I don't know if my insurance would cover anafranil as they want generic. Any generic pills out there. they all seem to be capsules.
Bulldog2
Posted by conundrum on April 11, 2010, at 20:28:09
In reply to Re: TCA's With Opioid Actions?, posted by linkadge on April 10, 2010, at 16:26:23
What should the drawing board be? Maybe they should just create random safe molecules and see what effects they have on people. After all the antidepressant effects of the first generation of antidepressants were discovered by accident.
Posted by bulldog2 on April 12, 2010, at 9:21:09
In reply to Re: TCA's With Opioid Actions? » linkadge, posted by conundrum on April 11, 2010, at 20:28:09
The flaw was designing something based on a faulty hypothesis.
Before they go back to the drawing board they need to that what they are attempting to create is truely the answer.
Posted by linkadge on April 14, 2010, at 17:09:31
In reply to Re: TCA's With Opioid Actions? » bulldog2, posted by ed_uk2010 on April 11, 2010, at 7:21:47
Many of the TCA's are calcium channel blockers too, which have some effect on pain threshholds.
Linkadge
Posted by linkadge on April 14, 2010, at 17:11:38
In reply to Re: TCA's With Opioid Actions? » linkadge, posted by conundrum on April 11, 2010, at 20:28:09
>After all the antidepressant effects of the >first generation of antidepressants were >discovered by accident.
Exactly, and thats why this whole "rational drug design" approach is a bit of nonsense.
Linkadge
Posted by bulldog2 on April 14, 2010, at 17:25:40
In reply to Re: TCA's With Opioid Actions?, posted by linkadge on April 14, 2010, at 17:11:38
> >After all the antidepressant effects of the >first generation of antidepressants were >discovered by accident.
>
> Exactly, and thats why this whole "rational drug design" approach is a bit of nonsense.
>
> LinkadgeIf you thinking about it tweeking one neurotransmitter is a bit idiotic. Didn't any one forsee the eventual effect on dopamine and that ssris have the ability to almost act like a neuropletic drug. Perhaps it's effect on dopamine is what is flattening out people's emotions and effecting the limbic system. The long term effect on the brain may be far worse than the old tcas and maois.
If you plan on designing an antidepressant you better have the real answer and not some hopeful hypothesis. The so called dirty drugs are apparently what leads to their success in that they touch so many areas.
Reminds me of herbs. Sometimes once the so called active component is extracted you lose synergy.
Posted by linkadge on April 16, 2010, at 16:27:57
In reply to Re: TCA's With Opioid Actions?, posted by bulldog2 on April 14, 2010, at 17:25:40
This is it. I've heard some papers say that SJW (for instance) cannot possibly be effective cause it only inhibits the serotoinin transporter by 40-50%. Well true, but it affects dozens of other neurotransmitter transporters, receptor, and sinalling pathways.
Linkadge
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