![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by lew on December 17, 2004, at 15:37:40
does anyone out there know of a good drug to use with opiates, that helps one from building such tolerance? Certainly there is nothing that I'm aware of that would completely prevent tolerence, but someone had posted a drug that was supposed to help and i didn't write it down. Also, maybe a natural remedy from a vitamin cottage? thanks
Posted by linkadge on December 17, 2004, at 16:06:05
In reply to diminishing tolerence to opiates, posted by lew on December 17, 2004, at 15:37:40
The amino acid phenlylalanine is used to make endorphens I believe. It is released when you exercise.
You could also try a TCA (such as amitryptaline) which have effects on the endorphen system.
Linkadge
Posted by SLS on December 17, 2004, at 16:25:47
In reply to diminishing tolerence to opiates, posted by lew on December 17, 2004, at 15:37:40
> does anyone out there know of a good drug to use with opiates, that helps one from building such tolerance? Certainly there is nothing that I'm aware of that would completely prevent tolerence, but someone had posted a drug that was supposed to help and i didn't write it down. Also, maybe a natural remedy from a vitamin cottage? thanks
There are studies in the medical literature on Medline that claim Namenda (memantine), a drug approved to treat Alzheimers, prevents and even reverses tolerance to opiates. I don't know if this is true only of the antinociceptive properties of opiates or if it would also include psychotropic effects.
- Scott
Posted by reefer on December 17, 2004, at 17:07:38
In reply to Re: diminishing tolerence to opiates, posted by SLS on December 17, 2004, at 16:25:47
Yes memantine works for preventing opiate tolerance. This is by blocking NMDA receptors. Another thing that works good for this is DXM (dextromethorphan) which also blocks NMDA receptors. I've only read about DXM + morphine so i'm not sure if it will work to block tolerance with other opioids. DXM is noramally a cough medication. Search google for +dxm +morphine and you will get loads of info on this.
Posted by JackD on December 18, 2004, at 4:26:46
In reply to diminishing tolerence to opiates, posted by lew on December 17, 2004, at 15:37:40
Linkadge, did you even bother to consider my previous posts? You quickly dismissed it because I didn't bother to "hold your hand" for you and post the URL's. FYI, YES, MEMANTINE HCL, AKA NAMENDA has been provent to slow the development of tolerance to opiates. It can potentially even reverse existing tolerance. Oh and yes this can be substantiated by perusing pubmed (.com). I can even attest to this from personal experience (hence my reason for POSTING not long ago). Lew, feel free to contact me for additional info. Up up, and away!
Posted by linkadge on December 18, 2004, at 9:44:42
In reply to LEW, please read this, posted by JackD on December 18, 2004, at 4:26:46
I don't know what you mean. I was not dismissing what you said. I understand that NMDA antagonists have effect, but so do the suggestions I offered.
You'll have to be more specific JackD.
Linkadge
Posted by lew on December 18, 2004, at 11:47:38
In reply to LEW, please read this, posted by JackD on December 18, 2004, at 4:26:46
How does one go about getting it from a doctor?
Posted by lew on December 18, 2004, at 12:32:46
In reply to LEW, please read this, posted by JackD on December 18, 2004, at 4:26:46
> Linkadge, did you even bother to consider my previous posts? You quickly dismissed it because I didn't bother to "hold your hand" for you and post the URL's. FYI, YES, MEMANTINE HCL, AKA NAMENDA has been provent to slow the development of tolerance to opiates. It can potentially even reverse existing tolerance. Oh and yes this can be substantiated by perusing pubmed (.com). I can even attest to this from personal experience (hence my reason for POSTING not long ago). Lew, feel free to contact me for additional info. Up up, and away!
I just started started taking effexor XR 37.5 and I have been on it for 6 days. But after reading some of the threads, now I'm scared to death and very confused. I am still on tramadol. I think that's the only thing that is helping, until I can get on my opiate therapy. I talked to my doctor about how the tramadol had helped me and brought in a notebook full of abstracts and threads from this post to help her understand that opiates really do help people that have been resistant to conventional AD. I got sent home with 3week supply of Effexor XR. I'm so frustrated. My gut instinct tells me to get on opiate therapy, along with memantine, the amino acid phenlylalanine, and a TCA (I'm thinking amitriptyline, because linkadge has suggested it). Any thoughts on how to get the memantine, because my doctor flat out refuses to even look at the info I brought in. She simply shuts me out and says "no". I know that opiates are the answer for me (no questions asked). But will asking for memantine put up a red flag to her. I hate to be dishonest, but I have to think of my state and the things I know will really help me, and she is so anti-opiate. I know I've got to get off this tramadol and get on something that won't hurt my liver (I know the tramadol isn't good, especially combined with effexor.) I have been lucky enough to find a place that offers opiates with less of the anelgesic stuff that my body doesn't need, so it save your liver. I have given up alcohol, and that's a huge bummer, because I'm so scared my liver is going to give out. Okay, so to consolidate, how do I get memantine, and is amitriptyline really the best choice? Oh, here's a little more confusion to add to the mix. I have extreme problems with anxiety and symptoms of OCD, all brought on by trauma. And I don't have insurance and I'm moving to LA in a couple of months. Please help! I know there are a lot of intelligent people on this sight. So please put on your Thinking Caps!! I really need your insight :) LEW
Posted by linkadge on December 18, 2004, at 15:55:39
In reply to Re: LEW, please read this, posted by lew on December 18, 2004, at 12:32:46
I hate to say it but you might have a very hard time convincing your docotor. The problem with having a mental illness is that even if you know what will help, nobody will take you seriously because they think you're sick (which you are).
Anyhow, I'm not disagreeing that opiates can bring considerable relief from depression, but I don't think we've found a way yet to use them continually for depression.
I was suicidally depressed about the time I got some teeth extracted. I was issued to take up to 180mg of codine which brought prompt and substantial relief from my depression. With a continual dose however, I was back to being suicidal in a month. The effects had quickly worn off, and not only was I still suicidal, but I had to go through an excruciating codiene withdrawl at the same time. This was probably the lowest moment of my life. Using opiates for depression is very risky buisness, and I hate to say that most doctors don't want to partake in it.
I hope you can find relief, but I also hope that you don't have to go through what I did.
Linkadge
Posted by JackD on December 18, 2004, at 23:13:27
In reply to Re: LEW, please read this, posted by linkadge on December 18, 2004, at 15:55:39
Sorry if I sounded condescending Linkadge, I was just annoyed because I had already gone out and tried to explain my insights into NMDA antagonists and nobody seemed to pay my posts any
mind. Anyway, addressing Lew, if you want to try memantine, have my doctor consult yours,
usually doctors need to be reassured that something has been attempted before going out on a
limb. They're scared to death over liability, and for good reason. You can also have your
doctor call Forest Laboratories and ask them about their current study using Namenda 40mg a day for depression. If that doesn't soften her up, then man, I'll ship you some of my memantine
myself damn it!Oh and by the way, I don't think, nor was I ever suggesting that, opiates are practical for
treating depression. HOWEVER, because the same systems activated by opiate drugs are linked to
depression causes me to consider any opiate-related drug as having potential to cure certain
depressions. Nevermind the specific details about my conjecture, I mean for God's sake, no one has anything even close to a proper perspective of how the brain behaves.What I'm getting at is that I don't personally believe you or anyone should use straight up
opiates to handle their depression. I guess it's like comparing extacy to paxil. Sorry it's
the best analogy I can think of right now, but here it is: one of MDMA's primary attributes is
its ability to cause a cascade release of serotonin (which by the way ultimately ends up
producing neurotoxicity for reasons I'd rather not discuss due to their irrelevance). Now
someone who feels especially drawn to this drug could infer that since the main mechanism of
MDMA is serotonin release, an SSRI would be the answer. That's logical enough and could be
true, but again what I'm getting at is that there's much more to the picture in this example
and than meets the eye. Ecstasy does so much more than make someone who is serotonin-deprived
satisfied, it triggers all sorts of other unecessary (and unhealthy) side-effects. Yes a
massive increase in serotonin levels is one of the actions of MDMA's, but this key component
MUST be isolated in an optimal treatment strategy for many reasons. For this far from perfect
example an SSRI could quite possibly be a much better, safer, and effective solution.Now in regards to direct opioid agonists, or should I say, the "pain-relieving pleasure pills
that are sometimes abused rather than admistered properly". one should seek a combination of
chemicals that specifically and discriminately alleviates their ailment. Alcohol affects GABA
and serotonin and the opiate system, but that doesn't mean it's a good answer for someone in
search of an antidepressant. Effexor, Tramadol, Remeron and Namenda are far more specific and
therefore far more practical for treating conditions that require treatment with something
targeting the opiate system. Give it a shot and see, maybe the opiate system is the key to
treating your problem.But please just make sure to follow my advice and use the right medications. Then maybe you
can explore other avenues and possibly even expand upon how you experience euthymia.P.S. I'm so so sorry if I come off sounding pompous with all the alliteration and big words,
it's just that it's finals week at my school and I've been writing papers for endless hours
with little sleep. The strange writing style you see is just subconscious reflex or rather
residue resulting from repeatedly rehearsing rhetoric and rhythme. Okay okay sorry, that one
was intentional, but hey, good luck to you Lew.
Posted by BradD on December 19, 2004, at 8:44:25
In reply to Re: LEW, please read this, posted by lew on December 18, 2004, at 12:32:46
LEW: where did you hear/read about Tramadol affecting liver? I've read that it doesn't hurt internal organs.
I also use Tramadol for my anxiety/slight depression - 400mg/day , every other day (if I use tramadol each day - it stops working). On the "other days" I use Xanax as an anti-depressant and to control anxiety - it doesn't work as well as Tramadol but still does the job rather well.Take care,
Brad
Posted by jerrympls on January 11, 2005, at 20:21:10
In reply to diminishing tolerence to opiates, posted by lew on December 17, 2004, at 15:37:40
> does anyone out there know of a good drug to use with opiates, that helps one from building such tolerance? Certainly there is nothing that I'm aware of that would completely prevent tolerence, but someone had posted a drug that was supposed to help and i didn't write it down. Also, maybe a natural remedy from a vitamin cottage? thanks
Lew-
My psychiatrist just started me on a trial of an opiate for my treatment resistnat depression. I took in a bunch of studies I found and he was open to the idea - but after he had done some research himself. Long story short, I started Oxycontin 10mg yesterday and hope that it works out. I am worried about tolerance and have done reasearch and found that dextromethorphan (an over the counter cough suppressant) has shown to reduce and even reverse opiate tolerance. I plan to investigate it more.
Jerry
Posted by JackD on January 12, 2005, at 11:32:54
In reply to Re: diminishing tolerence to opiates » lew, posted by jerrympls on January 11, 2005, at 20:21:10
Sigh... I seriously feel like some people on this board are incompetent or maybe just lazy or possibly just not computer savvy... I've posted numerous posts on this subject in hopes of helping SOMEONE, and they've all gone pretty much ignored (except by marketing reps). Anyway, here's some helpful stuff (in short, MEMANTINE, AKA Namenda, prevents and reverses tolerance safely, I can attest to it from personal experience, I won't even go into the dangers and messiness of DXM. Besides, what are you going to do, an acid-base extraction of cough syrup? Or just drink a few bottles, which you'd have to to get even close to enough DXM to work, with your meds). Also, I recommended against the use of a DIRECT opiate agonist for depression for what I thought were obvious reason, but anyway there's some abstracts I included here showing that antidepressants, some more than others, ultimately have significant impact on the opiate system and should be used instead of actual opiates. There's other useful info about the similarites of Tramadol and Effexor, and some other stuff that anyone with a decent understanding of pharmacology might hopefully find extremely useful. Gulp.. here goes:
------------"Pharmacological treatment of neuralgic and neuropathic pain."
McQuay HJ.
Nuffield Department of Anaesthetics, Oxford University, Abingdon.
The current pharmacological management of neuropathic pain with antidepressants, anticonvulsants, drugs with action on the autonomic nervous system, steroids, baclofen and naloxone is reviewed. The underlying clinical theme of relative opioid insensitivity of neuropathic pain is emphasized. Future pharmacological approaches in neuropathic pain are suggested on the basis of the mechanism of action of the current remedies. The problems of clinical trials in this area are discussed.
--------"Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline."
Hamon M, Gozlan H, Bourgoin S, Benoliel JJ, Mauborgne A, Taquet H, Cesselin F, Mico JA.
The central mechanism responsible for the potentiation by antidepressant drugs of analgesia induced by morphine, was explored by measuring the levels of various neuropeptides (met-enkephalin, leu-enkephalin, dynorphin, substance P and cholecystokinin-like materials) and the density of delta and mu opioid binding sites in the spinal cord of rats treated for 14 days with amoxapine (10 mg/kg i.p., daily) or amitriptyline (10 mg/kg i.p., daily). Similar measurements were made in the hypothalamus and cerebral cortex for comparison. Chronic treatment with amoxapine or amitriptyline did not affect the levels of dynorphin, substance P and cholecystokinin, but markedly enhanced the levels of leu-enkephalin in the three structures examined. The levels of met-enkephalin were also increased after treatment with amitriptyline but only in the spinal cord and hypothalamus. No changes in opioid receptors were found in the cerebral cortex, but the densities of delta and mu opioid binding sites were increased in the spinal cord, and decreased in the hypothalamus of rats treated with amoxapine or amitriptyline. These changes induced by antidepressants in opioidergic markers at the spinal level might account for the potentiation of the action of morphine in amoxapine- or amitriptyline-treated rats. In addition, the observed alterations in the same markers in the hypothalamus could be associated with changes induced by antidepressants in neuroendocrine regulation.
------------
"Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system."
Botney M, Fields HL.
Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.
------------------
"Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain."
Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, Rondelli I, Chamiot-Clerc P, Simonato M, Barbieri M.
Research and Development Department, Chiesi Farmaceutici SpA, Parma, Italy. [email protected]
N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.
------------
"Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal."
Maldonado C, Cauli O, Rodriguez-Arias M, Aguilar MA, Minarro J.
Area de Psicobiologia, Facultad de Psicologia, Universitat de Valencia, Aptdo. 22109, 46071 Valencia, Spain.
"Adaptive changes in neural systems due to chronic opiate exposure are related to the neural plasticity phenomenon, NMDA receptors being implicated in these processes, e.g. tolerance, dependence or withdrawal. In this work, we investigated the effect of two non-competitive NMDA antagonists, memantine and MK-801, in motivational (Conditioned Place Aversion paradigm, CPA) and physical aspects of morphine withdrawal. After the induction of morphine dependence, animals in which the CPA was studied, received memantine (5 and 10 mg/kg) or MK-801 (0.3-0.006 mg/kg) either during the acquisition (conditioning) or expression (test) phase of this procedure. Both drugs were capable of inhibiting conditioned aversion when administered in any phase. In a second experiment, the effects of these drugs were evaluated in the intensity of the physical signs of withdrawal, only memantine administration being efficient. In addition to these studies, the intensity of morphine dependence was investigated under the blockade of NMDA receptors, i.e. morphine was co-administered with memantine or MK-801. These animals did not develop CPA and present less intensity in the physical signs of morphine withdrawal. Our results support the idea that NMDA receptors are involved in the behavioural changes and therefore in the neural adaptations produced by repeated morphine administration.
------------
"Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval."
Belozertseva IV, Dravolina OA, Neznanova ON, Danysz W, Bespalov AY.
Laboratory of Behavioural Pharmacology, Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, 6/8 Leo Tolstoy St., 197089, St. Petersburg, Russia.
The actual time-course of morphine antinociception is shorter than what would be predicted from its elimination kinetics, suggesting the presence of an acute tolerance phenomenon. Since antagonists acting at NMDA subtype of glutamate receptors were repeatedly shown to prolong acute morphine antinociception, acute tolerance may be attributed to hyperactivity of NMDA receptors. The ability of various site-selective NMDA receptor antagonists to affect morphine antinociception (tail-flick test) was assessed in mice 30 and 120 min after acute morphine challenge. Competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene) (SDZ EAA 494; 0.1-1 mg/kg), low-affinity channel blockers 1-amino-3,5-dimethyl adamantane (memantine) (1-10 mg/kg) and 1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride (MRZ 2/579) (1-10 mg/kg), glycine site antagonists 5-nitro-6,7-dichloro-1, 4-dihydro-2,3-quinoxalinedione (ACEA-1021) (5 or 10 mg/kg) and 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaliono(4, 5-b)quinoline-5-oxide choline salt (MRZ 2/576) (1-10 mg/kg) were administered intraperitoneally (i.p.) 15 or 30 min prior to the tail-flick test (i.e., interval between injections of morphine and NMDA receptor antagonist was either 0-15 or 90-105 min). ACEA-1021, MRZ 2/576 and to the lesser extent, memantine and MRZ 2/579 enhanced morphine antinociception when tests were conducted 120 but not 30 min post-morphine. D-CPPene potentiated morphine antinociception irrespective of the interval between morphine administration and the tail-flick test. The results suggest that NMDA receptor antagonists may restore analgesic activity of morphine in acutely tolerant mice.
------------"Non-selective opioid receptor antagonism of the antidepressant-like effect of venlafaxine in the forced swimming test in mice."
Berrocoso E, Rojas-Corrales MO, Mico JA.
Pharmacology and Neuroscience Research Group (PAI-510), Department of Neuroscience (Pharmacology and Psychiatry), Faculty of Medicine, University of Cadiz, Plaza Falla, 9, 11003 Cadiz, Spain.
The opioid system has been implicated in mood disorders as well as in the mechanism of action of antidepressants. Since the opioid component in venlafaxine (VLX) is still a matter of discussion, we investigated the role of opioid receptors in the antidepressant-like effect of VLX in the forced swimming test in mice. The non-selective opiate antagonist naloxone at high dose (2 mg/kg, s.c.) antagonized the effect of VLX. In contrast, beta-funaltrexamine (40 mg/kg, s.c.), which preferentially blocks mu(1)/mu(2) opioid receptors, naloxonazine (35 mg/kg, s.c.), a selective mu(1) opioid antagonist, naltrindole (10 mg/kg, s.c.), a selective delta opioid antagonist, and Nor-binaltorphimine (10 mg/kg, s.c.), which selectively blocks kappa-opioid receptors, were all ineffective. Thus, although apparently mediated by the opioid system, the behavioural effect of VLX does not involve specific opioid receptors.
---------
"Pharmacotherapy for neuropathic pain caused by injury to the afferent nerve fibers"
[Article in Dutch]
Weber WE.
Academisch Ziekenhuis, afd. Neurologie, Postbus 5800, 6202 AZ Maastricht.
Phantom pain, a form of neuropathic pain, is caused by damage to somatosensible afferent nerve fibres in the peripheral or central nervous system. Often, the pain cannot be satisfactorily treated with nonsteroidal anti-inflammatory drugs. Dependent on the underlying mechanism the pain is treated with either antidepressants (for more or less continuous pain) or anti-epileptics (for paroxysmal pain). Of the antidepressants, the tricyclic antidepressants are the best studied and most prescribed. The activity of new drugs, such as the selective serotonin reuptake inhibitor paroxetine as well as venlafaxine, has yet to be clearly shown. Of the anti-epileptics, carbamazepine and phenytoin are the most prescribed. New drugs which provide greater pain relief than the placebo are oxcarbazepine, gabapentine and lamotrigine. Other effective drugs for phantom pain are: gamma-butyric acid agonists (baclofen), opiates (morphine preparations with a regulated release; phentanyl patch), the N-methyl-D-aspartate receptor antagonist amantadine, transdermally administered clonidine and locally applied lidocaine.
---------"The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways."
Schreiber S, Getslev V, Weizman A, Pick CG.
Department of Psychiatry C, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
Moclobemide is an antidepressant which affects the monoaminergic neurotransmitter system through a reversible inhibition of monoamine oxidase (MAO), preferentially type A. We examined the antinociceptive effects of moclobemide alone and in conjunction with specific opioid, adrenergic and serotonergic antagonists, using the mouse-tail flick test. Intraperitoneal moclobemide produced a dose-dependent antinociceptive effect with an ED50 of 69.1 mg/kg. Tests with selective antagonists yielded positive results only for yohimbine (P < 0.001), implying a noradrenergic mechanism of action in the moclobemide antinociceptive effect. This was confirmed by the coadministration of moclobemide with inactive doses of prototype agonists of the opioid, adrenergic and serotonergic systems. Only clonidine, an alpha2 agonist, significantly shifted (8-fold) the dose response curve of moclobemide. We conclude that there is a selective involvement of the alpha2 adrenergic pathways in the moclobemide-induced antinociceptive effect and a lesser involvement (if any) of the opioid, serotonergic and alpha1 adrenergic mechanisms. More research is needed to establish a possible role for moclobemide in pain management.
--------“Psychobiological Mechanisms of Resilience and Vulnerability: Inplications for Successful Adaptation to Extreme Stress”
by Dennis S. Charney (Am J Pschiatry 161:195-216, February 2004
Subjects with major depression are hyperresponsive to amphetamine such that the severity of depression in major depression was highly correlated with the rewarding effects of amphetamine. The mechanism may be depletion of synaptic dopamine with up-regulation of dopamine receptors (154, 155). Increasing dopamine function in the nucleus accumbens, the orbital frontal cortex, and the ventral tegmental area and NMDA receptor blockade in the nucleus accumbens and the medial prefrontal cortex may enhance sensitivity to reward. Therefore, psychostimulants, dopamine reuptake inhibitors, monoxamine oxidase-B inhibitors (selegiline), the dopamine receptor agonists (pramipexole), and NMDA receptor antagonists (memantine) may be useful for treating anhedonia and hopelessness resulting from traumatic stress exposure.
--------
"Effects of Chronic Tramadol on Pre- and Post-Synaptic Measures of Monoamine Functionby Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA.
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and The Royal London School of Medicine and Dentistry,
Royal London Hospital, Whitechapel, UK.
J Psychopharmacol 2001 Sep;15(3):147-53ABSTRACT
The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphe (DRN) or median raphe (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology. "-------
"Venlafaxine-tramadol similarities"
by
Markowitz JS, Patrick KS
Department of Pharmacy Practice,
Institute of Psychiatry,
Medical University of South Carolina,
Charleston 29425-0810, USA.
Med Hypotheses 1998 Aug; 51(2):167-8ABSTRACT
Venlafaxine and tramadol are relatively new compounds indicated for the treatment of depression and pain, respectively. These agents share a number of molecular and pharmacological features that may allow for broader and overlapping therapeutic indications for both drugs. Additionally, certain patient populations with coexisting depression and pain syndromes could potentially be treated with a single agent.---------
"The antinociceptive effect of tramadol-venlafaxine combination on the paw withdrawal threshold in a rat model of neuropathic pain."
Uyar M, Onal A, Uyar M, Dogru A, Soykan N.
Pain Clinic, Department of Anesthesiology, Bornova, Izmir, Turkey. [email protected]
The combination of venlafaxine and tramadol was compared with the single use of these agents to investigate the antinociceptive effect on paw withdrawal latency (PWL) to paw pressure in rats with neuropathic pain. Rats were divided into 4 groups: group 1 received saline (0.2 ml i.p.); group 2 received venlafaxine (22 mg/kg i.p.); group 3 received tramadol (20 mg/kg i.p.); and group 4 received venlafaxine + tramadol. No statistically significant changes were observed in the saline and venlafaxine groups with respect to PWL in the lesioned paw. However, tramadol produced a significant antinociceptive effect on the lesioned paw at 30 min compared with the saline and venlafaxine groups. A more potent antinociceptive effect was observed in the tramadol + venlafaxine group, beginning at 60 min and lasting for 1 h. The combination of venlafaxine + tramadol was more effective in increasing the pain threshold in this animal model of neuropathic pain than either of these drugs administered alone. (c) 2003 Prous Science. All rights reserved.
----------
"Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?"
Schreiber S, Bleich A, Pick CG.
Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Israel.
The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies as far as mild to moderate depression is involved. However, it seems that some antidepressants are more effective than others in the treatment of severe types of depression (i.e., delusional depression and refractory depression). Following studies regarding the antinociceptive mechanisms of various antidepressants, we speculate that the involvement of the opioid system in the antidepressants' mechanism of action may be necessary, in order to prove effective in the treatment of severe depression. Among the antidepressants of the newer generations, that involvement occurs only with venlafaxine (a presynaptic drug which blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine) and with mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-auto- and hetero-adrenoreceptors). When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.
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"Serotonin and noradrenaline reuptake inhibitors in animal models of pain."
Mochizucki D.
Asahi Kasei Pharma, Chiyoda-Ku, Tokyo, Japan. [email protected]
Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline and serotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathic pain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone. 2004 John Wiley & Sons, Ltd.
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"Treatment of pain syndromes with venlafaxine."
Grothe DR, Scheckner B, Albano D.
Global Medical Communications, Neuroscience, Wyeth Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.
Major depressive disorder (MDD) and anxiety disorders such as generalized anxiety disorder (GAD) are often accompanied by chronic painful symptoms. Examples of such symptoms are backache, headache, gastrointestinal pain, and joint pain. In addition, pain generally not associated with major depression or an anxiety disorder, such as peripheral neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia), cancer pain, and fibromyalgia, can be challenging for primary care providers to treat. Antidepressants that block reuptake of both serotonin and norepinephrine, such as the tricyclic antidepressants (e.g., amitriptyline), have been used to treat pain syndromes in patients with or without comorbid MDD or GAD. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has been safe and effective in animal models, healthy human volunteers, and patients for treatment of various pain syndromes. The use of venlafaxine for treatment of pain associated with MDD or GAD, neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome is reviewed. Currently, no antidepressants, including venlafaxine, are approved for the treatment of chronic pain syndromes. Additional randomized, controlled trials are necessary to fully elucidate the role of venlafaxine in the treatment of chronic pain.
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"Synergistic antinociceptive effect of amitriptyline and morphine in the rat orofacial formalin test."
Luccarini P, Perrier L, Degoulange C, Gaydier AM, Dallel R.
Institut Universitaire de Technologie Genie Biologique, Universie d' Auvergne-Clermont I, Les Cezeaux, Aubiere, France.
BACKGROUND: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats. METHODS: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline. RESULTS: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. CONCLUSIONS: The current study suggests that systemic amitriptyline and morphine synergistically inhibit cutaneous orofacial inflammatory pain in rats.
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http://www.clinicaltrials.gov/show/NCT00040261
Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants.
Memantine (Akatinol memantine), an agent that is approved in Germany for dementia syndrome, Parkinson's disease has significant antiglutamatergic and neuroprotective properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential efficacy of memantine, an agent which reduces glutamatergic output via open-channel block of the NMDA receptor-associated ion channel. Most importantly, memantine only blocks the channel during periods of abnormal, excessive activity, and leaves relatively spared normal neurotransmission. This finding is the basis for the minimal side effect profile displayed by memantine.
Posted by jerrympls on January 12, 2005, at 18:56:29
In reply to PLEASE READ!!! --------------------------, posted by JackD on January 12, 2005, at 11:32:54
Jack -
Can you explain more about the "messiness" of dextromethorphan and why it takes a huge amount to cause any effect?
I'm wondering if my doc has been willing to prescribe an opiate for my depression that he'll be open to prescribing memantine?
Thanks for all the info too!!
Jerry
Posted by Dr. Bob on January 12, 2005, at 19:23:23
In reply to PLEASE READ!!! --------------------------, posted by JackD on January 12, 2005, at 11:32:54
> I seriously feel like some people on this board are incompetent or maybe just lazy or possibly just not computer savvy...
Please don't post anything that could lead others to feel put down.
If you or others have questions about this or about posting policies in general, or are interested in alternative ways of expressing yourself, please see the FAQ:
http://www.dr-bob.org/babble/faq.html#civil
Follow-ups regarding these issues should be redirected to Psycho-Babble Administration. They, as well as replies to the above post, should of course themselves be civil.
Thanks,
Bob
Posted by JackD on January 12, 2005, at 20:31:05
In reply to Re: PLEASE be civil » JackD, posted by Dr. Bob on January 12, 2005, at 19:23:23
I didn't mean to sound condescending, and if so, I apologize to anyone who misinterpreted. Why would I be putting down people I'm trying to help? Too much is lost in translation.
I did a lot of work to compile that list of abstracts by the way, and well, that was exactly my point, that it actually wasn't all that hard at all. So I just want to nudge people into trying it themselves, it's not as intimidating as it can seem (scouring the internet for data).
Here are some good starting points (aside from searching google or this board):
www.pubmed.com
xxx(ignore the hedonism/philosophizing, it's still got tons of useful links)
P.S. Man it's tough crack smiles sometimes ;)
Posted by JackD on January 12, 2005, at 20:51:08
In reply to Re: PLEASE READ!!! -------------------------- » JackD, posted by jerrympls on January 12, 2005, at 18:56:29
Well I'd like to encourage people to look up information themselves about this topic, since I've put out quite a bit.
Basically, DXM's pharmacological properties (for example its half-life or its competitive NMDA blockade which possibly make it neurotoxic), the whopping dose you need for effect and it's legal inavailability in a workable purified form make it highly impractical. It's an ingredient in cough syrup like Robitussin for other properties it possesses (cough suppression). Other NMDA antagonists include Ketamine and Phencyclidine (PCP)... need I say more?
Posted by jerrympls on January 12, 2005, at 21:17:16
In reply to Just miscommunication..., posted by JackD on January 12, 2005, at 20:31:05
> I didn't mean to sound condescending, and if so, I apologize to anyone who misinterpreted. Why would I be putting down people I'm trying to help? Too much is lost in translation.
>
> I did a lot of work to compile that list of abstracts by the way, and well, that was exactly my point, that it actually wasn't all that hard at all. So I just want to nudge people into trying it themselves, it's not as intimidating as it can seem (scouring the internet for data).
>
> Here are some good starting points (aside from searching google or this board):
>
> www.pubmed.com
> www.biopsychiatry.com
>
> (ignore the hedonism/philosophizing, it's still got tons of useful links)
>
> P.S. Man it's tough crack smiles sometimes ;)Jack - I do a lot of research on the web and use those sources you listed quite frequently. But I'm always in search of stuff that I don't have and haven't found that others have....so thanks for sharing your info.
Jerry
Posted by jerrympls on January 12, 2005, at 21:21:21
In reply to Re: PLEASE READ!!! --------------------------, posted by JackD on January 12, 2005, at 20:51:08
Thanks for the encouragement - but what's wrong with asking someone about something they already know??? I looked at a lot of abstracts regarding DXM and they never mentioned its apparent neurotoxicity. From what I've reasearched it's a viable option. But when I found you post saying it's NOT a good idea to use - I thought I'd ask you why. Is it too much to ask to answer someone's question? Geeesh.
Posted by Willyee on January 12, 2005, at 23:22:11
In reply to PLEASE READ!!! --------------------------, posted by JackD on January 12, 2005, at 11:32:54
Jack,thanks for the informative posts,people are different,and present things different i found the way you presented the information fine.
I cant speak for everyone,but my depression,anxiety etc keeps my brain at a semi-functional level,certain times i can read information,and take it in,however most times its hard for me,i cant explain it exactly,sorta a sohrt attention span or something,but the anxiety makes it hard to really take in and understand information that is in any way the slightest complex.
So i hope im not asking much,but from all the information you provided,do you have any recomenations from it on a substance that might possably ehnace the effectiness of the medication,or prevent tolerance to it.Thanks!
Posted by JackD on January 13, 2005, at 2:58:46
In reply to Re: PLEASE READ!!! -------------------------- » JackD, posted by jerrympls on January 12, 2005, at 21:21:21
Sorry Jerry, it's hard to get across my "tone" through the internet. I really wasn't trying to sound obnoxious, it's just my residual sarcasm/playfulness from how I talk in person. Look at that DXM link I posted, it talks about some of the neurotoxic potentials of DXM, as do the other ones! Take care.
Posted by Dr. Bob on January 13, 2005, at 16:59:19
In reply to Just miscommunication..., posted by JackD on January 12, 2005, at 20:31:05
> xxx
Please don't post links to pages that (link to pages that) explain how to produce medication yourself.
If you or others have questions about this or about posting policies in general, please see the FAQ:
http://www.dr-bob.org/babble/faq.html#illegal
Follow-ups regarding these issues should be redirected to Psycho-Babble Administration.
Thanks,
Bob
This is the end of the thread.
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