Bluelight

Thread: Tramadol as an Antidepressant?

Page 1 of 2 12 LastLast
Results 1 to 25 of 41
  1. Collapse Details
    Tramadol as an Antidepressant? 
    #1
    I'm quite interested in researching new, or different, ways to treat clinical depression. While researching something completely different, I found this article at http://opioids.com/tramadol/index.html:

    Pharmacology of tramadol
    by
    Dayer P, Desmeules J, Collart L
    Service de Pharmacologie Clinique
    et Consultation de la Douleur,
    Hopital Cantonal Universitaire, Geneve, Suisse.
    Drugs 1997; 53 Suppl 2:18-24

    (+/-)-Tramadol is a synthetic analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.
    I'd like to highlight the following:

    This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level.
    and:

    (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol.
    The reuptake inhibition of both 5-HT and NA is extremely common amongst almost all antidepressants, mainly the former but the latter is receiving increasing attention as of late. Combined with the hypothesis that opioids may serve as potent antidepressants themselves, I'm curious as to how Tramadol might work as a antidepressant or if there have been any studies using it for this purpose. Due to the extremely low abuse potential and little (or no) issues of tolerance/dependence (especially when compared to many, more potent opioids), Tramadol may have great potential as an antidepressant. Thoughts?
     

  2. Collapse Details
     
    #2
    From http://opioids.com/tramadol/tramadol.html:

    Tramadol induces antidepressant-type effects in mice
    by
    Rojas-Corrales MO, Gibert-Rahola J, Mico JA
    Department of Neuroscience,
    Faculty of Medicine,
    University of Cadiz, Spain.
    Life Sci 1998; 63(12):PL175-80

    ABSTRACT

    Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibits preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.
    While it seems only NA was responsible for the A/D effects in mice, I'm having trouble believing that the effects of "the seotonoinergic or opioidergic" systems wouldn't provide additional A/D effects in humans.
     

  3. Collapse Details
     
    #3
    Opioids are never going to get used as antidepressants... not within my life-time anyway.... and I just have some gut feeling that it would be a bad idea... the politics, addiction and tolerance aside. Though I have a feeling tolerance would become insurmountable after a while....
     

  4. Collapse Details
    Re: Tramadol as an Antidepressant? 
    #4
    Originally posted by Dope_User
    Due to the extremely low abuse potential and little (or no) issues of tolerance/dependence
    ^^^
    Coming from someone with extensive experience with tramadol, these statements are complete bullshit coming from the pharm companies.

    Tramadol withdrawal, even with a 250mg a day habit, can be quite horrible and at times even worse than normal opiate withdrawal. Withdrawal symptoms are worse in some than others, but they WILL be seen with daily administration of doses in the 200mg area over the course of several weeks, let alone months as would likely be required with the use of tramadol as an anti-depressant.

    Tolerance certainly comes into play also, as anyone who has taken tramadol for several days in a row knows. Tolerance can usually be seen on the third or even second day of consecutive use. Long-term usage of the drug will result in your needing it in order to even get out of bed/feel "normal" in the morning, probably because of it's effect on noradrenaline(I think that's the right chem, not sure though, brain chemistry isn't really my thing). This applies to both moderate (200-300mg a day) and high dosages (400mg+).

    Tolerance and withdrawal will obviously be dose dependant, but it definately exists. There is also a great abuse potential potential for this substance in a percentage of people(what this percentage is, I have no idea, but I've found that IMPE roughly 50% love it and would abuse it with an infinite supply, and 50% don't like it and would never think to abuse it). For some reason, some get no rec value and some love it.

    My point is that of those who love it, many would abuse it, particularly if they were already depressed before getting the script.

    Tramadol is definately not a "safe, non-abuseable opiate alternative with no recreational value" as the pharm companies want you to believe.
     

  5. Collapse Details
     
    #5
    Coming from someone with extensive experience with tramadol, these statements are complete bullshit coming from the pharm companies.
    NONE of this is from a pharmaceutical company - see references.

    There is also a great abuse potential potential for this substance in a percentage of people(what this percentage is, I have no idea, but I've found that IMPE roughly 50% love it and would abuse it with an infinite supply, and 50% don't like it and would never think to abuse it). For some reason, some get no rec value and some love it.
    I really have to disagree with this. Some abuse potential for Tramadol, definitely. "Great abuse potential," definitely not.

    "50% love it." Gotta disagree again, based on MPE it's more like 10% love it, and based on BL members, it's probably <5%...definitely no where near half.

    BilZ0r, I agree that opioids will most likely not be used any time soon (if ever) for depression. BUT, putting that aside, what do you think about Tramadol's potential as an antidepressant? HobbyIsBowling definitely would say it's impossible due to tolerance, but I personally (as well as a friend) took it for roughly a month for pain...it worked just as well on day 30 as day 1 and I NEVER abused it (and I LOVE my opioids, so I would have if I could have). If you still think tolerance would be a problem, what about for short term use (i.e. 4-6 weeks) following by a slow taper (another 2-4 weeks or longer if necessary)? I can't believe I just said that a 4 week taper would be necessary after 6 weeks of Tramadol use at theurapeutic doses.
     

  6. Collapse Details
     
    #6
    Originally posted by Dope_User
    NONE of this is from a pharmaceutical company - see references.



    I really have to disagree with this. Some abuse potential for Tramadol, definitely. "Great abuse potential," definitely not.

    "50% love it." Gotta disagree again, based on MPE it's more like 10% love it, and based on BL members, it's probably <5%...definitely no where near half.
    People who are experienced with opiates actually will be MUCH less likely to get any recreational effects from tramadol. This may partially explain why the general bluelight consensus is that tramadol is not recreational.

    Also, I'm willing to bet that you haven't seen nearly as many truly opiate(and drug in general) naive people take tramadol as I have. Roughly half of these people really got a good buzz from this stuff. This doesn't mean my anecdotal results are any more valid than yours(neither are at all scientifically valid), it's just what I've seen.

    My main point here is that tramadol can (and often does) go beyond just "stabilizing" your mood(the goal of any good anti-depressant), it actually gives some euphoria to many people even in moderate doses. Because of this, there is a potential for abuse. What a "great" potential for abuse is, I don't know, but I would wager that many depressed people would find small euphoria at lower doses and slowly(or not so slowly) increase their dosages as tolerance sets in.

    Now you will say "but I said I saw no tolerance, it effected my pain on day 30 the same as day 1" and this is actually right on with what I've seen when it comes to pain management. When it comes to tramadol's effect on mood and it's ability to cause euphoria, however, tolerance really does come into play. I'm not sure what the reason for this is. To clarify: If someone who gets buzzed from tramadol takes 200mg a day, it will probably work well for the pain on day #30, but this person will have lost most(or probably all) of the euphoria and positive effects on mood by this time. Again, this is only what I've seen.

    Ask anyone who gets a buzz off this stuff if they get the same euphoria on day #2 or day #3 of consecutive use(at any dose), and they'll tell you that the buzz leaves quickly with daily usage.

    The general idea is that some percentage of people (be it 5, 10, 50, or whatever) would probably abuse this substance, making it a poor anti-depressant candidate based on this factor alone. The FDA really hates approving abuseable anti-depressants nowadays.

    I guess what you are looking for is a discussion of tramadol's anti-depressant potential in those who don't receive any buzz from it. I don't see how we could possibly have a valid discussion about this, as it's not understood why some people get a buzz and some don't. Perhaps that is where this discussion should start, as opposed to jumping right into the "anti-depressant potential" discussion?

    Also of note: In males, tramadol lowers testosterone with daily usage(I don't have a source on this, but I *firmly* believe this is a fact). This is another factor that definately would need to be addressed, and another reason why tramadol would never be approved as an anti-depressant.
     

  7. Collapse Details
     
    #7
    Hobby, very good points...but I'm trying to just focus on the potential as an antidepressant essentially IGNORING abuse potential or likelihood of FDA approval as an A/D, etc.
     

  8. Collapse Details
     
    #8
    When people are given opiates clinically, they very often get dysphoria.
     

  9. Collapse Details
     
    #9
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    I have tried tramadol and I certainly think that it is not addictive, though it could be a link in the drugs ladder eventually leading to the 'hard' drugs etc. It is only moreish in the sense of wanting more, but if I dont get it - it's not like I am going to rob houses for it etc. I personally dont rate it that highly but I definately think of it more than just a toilet flush job.

    Also I cant see this drug getting put into the same class of drugs as Zoloft or Paxil. If you want it, just say that the repetitive tasks you have to perform at work give you lower back pain.
     

  10. Collapse Details
     
    #10
    When I happened to get hold of some tramadol 100mg tablets I certainly did like them and enjoyed the slight buzz. But I found them particularly good as an instant-acting antidepressant. Same is true for slow-release 100mg Valoron N (tilidine + naloxone). Modest, oral doses of opioids have great potenital as antidepressants for me. I used the Valoron for several months at 100 - 200mg/day with good success. When my supplies finished, withdrawals were clearly present, but bearable. I should add that I was never a hardcore opioid user or addicted to opioids.

    Sometimes I consider making a supply of a potent legal opioid for the treatment of my depression. Being a chemist, this would be rather easy for me. But I'm really afraid that things might get out of hand and I slide into a real serious addiction.

    There are some more recent publications which indicate that selective delta opioid agonists show antidepressant activity in animal experiments. They might be a better choice, and withdrawals are believed to be much milder than from mu opioids. Mitragynine from Kratom is a delta opioid agonist.
     

  11. Collapse Details
     
    #11
    the Affinity (pKi) of mitragynine for the mu, kappa and delta opioid receptors are 8.14 ▒ 0.28, 7.22 ▒ 0.21 and 5.96 ▒ 0.22 respectively or 7.2nM, 60nM and 1.1ÁM.

    So Mitragynine is 10 times more selective for Mu-OR; at least according to

    Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S.
    Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands.
    J Med Chem. 2002 Apr 25;45(9):1949-56.
     

  12. Collapse Details
     
    #12
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    Being a chemist by profession, synthesis of a drug molecule is not a barrier. Working inside of the law though is quite difficult since trying to find pharmacologically interesting compounds that are within teh constructs of the legal framework is actually restrictive in terms of the success rate. 3-chlorotramadol could possibly knock off some of the opoid virtues of tramadol whilst perhaps (theoretically speaking) increasing ratios of binding to monoaminergic receptors. However the neurotoxicity of such a said compound is a dark and unexplored in humans.

    Check out this patent for some open-chain tramadol analogues:

    http://patft.uspto.gov/netacgi/nph-P...l+AND+tramadol

    This will at least answer some pharmacological queries but only wrt pain relief. There are some rather colorful methods of isomer separation employing the cheap L-tartaric acid. A detailed survery of the literature will reveal this to the reader at the level of depth that is required.

    -Smyth
    Last edited by Smyth; 22-02-2005 at 12:20.
     

  13. Collapse Details
     
    #13
    So Mitragynine is 10 times more selective for Mu-OR
    Maybe it's a mu antagonist? But seriously, without EC50 values the pKi doesn't say too much. In vivo the effects of mitragynine seem to be mediated at least in part by delta agonism:

    Life Sci. 1998;62(16):1371-8.

    Identification of opioid receptor subtypes in antinociceptive actions of supraspinally-administered mitragynine in mice.

    Thongpradichote S, Matsumoto K, Tohda M, Takayama H, Aimi N, Sakai S, Watanabe H.

    Department of Pharmacology, Research Institute for Wakan-Yaka (Oriental Medicines), Toyama Medical and Pharmaceutical University, Sugitani, Japan.

    Mitragynine (MG), a major alkaloidal constituent extracted from the plant Mitragyna speciosa Korth, is known to exert an opioid-like activity. Our previous study showed the involvement of opioid systems in the antinociceptive activity of MG in the tail-pinch and hot-plate tests in mice. In the present study, to clarify the opioid receptor subtypes involved in the antinociceptive action of MG, we investigated the effects of selective antagonists for mu-, delta- and kappa- opioid receptors on antinociception caused by the intracerebroventricular (i.c.v.) injection of MG in the tail-pinch and hot-plate tests in mice. The coadministration of a selective mu-opioid antagonist, cyprodime (1-10 microg, i.c.v.) and the pretreatment with a selective mu1-opioid antagonist naloxonazine (1-3 microg, i.c.v.) significantly antagonized the antinociceptive activities of MG (10 microg, i.c.v.) and morphine (MOR, 3 microg, i.c.v.) in the tail-pinch and hot-plate tests. Naltrindole (1-5 ng, i.c.v.), a selective delta-opioid antagonist, also blocked the effects of MG (10 microg, i.c.v.) without affecting MOR (3 microg, i.c.v.) antinociception. Nor-binaltorphimine, a selective kappa-opioid antagonist, significantly attenuated MG (10 microg, i.c.v.) antinociception in the tail-pinch test but not in the hot-plate test at the dose (1 microg, i.c.v.) that antagonized the antinociceptive effects of the selective kappa-opioid agonist U50,488H in both tests, while it had no effect on MOR antinociception in either tests. These results suggest that antinociception caused by i.c.v. MG is dominantly mediated by mu- and delta-opioid receptor subtypes, and that the selectivity of MG for the supraspinal opioid receptor subtypes differs from that of MOR in mice.

    PMID: 9585164
     

  14. Collapse Details
     
    #14
    Working inside of the law though is quite difficult since trying to find pharmacologically interesting compounds that are within teh constructs of the legal framework is actually restrictive in terms of the success rate.
    That only seems so to the amateur

    The structural diversity of, for example, opioid agonists, is amazing. There are even steroids, such as SC17599, which are mu opioids. Not that I would want to synthesize that one...

    But tramadol and analogues are particular indeed because they combine opioid agonistic and monoamine reuptake inhibitory properties. B 777-81 {4-(p-aminophenoxy)-1-methyl-4-phenylpiperidine, US 4333942} seems to have similar mixed opioid/antidepressant properties, but off hand I can't think of any other. Of course the synthesis of B 777-81 carries the risk of inadvertently making the neurotoxic MPTP as a byproduct.
     

  15. Collapse Details
     
    #15
    But tramadol and analogues are particular indeed because they combine opioid agonistic and monoamine reuptake inhibitory properties. B 777-81 {4-(p-aminophenoxy)-1-methyl-4-phenylpiperidine, US 4333942} seems to have similar mixed opioid/antidepressant properties, but off hand I can't think of any other.
    3-chlorotramadol could possibly knock off some of the opoid virtues of tramadol whilst perhaps (theoretically speaking) increasing ratios of binding to monoaminergic receptors.
    While Tramadol might not be the best option for an opioid antidepressant, from these quotes it seems as though an analogue could have much more potential. For the time being, let's ignore possible neurotoxicity of such analogues and the possibility of accidentally synthesizing neurotoxic byproducts (MPTP) on accident.
     

  16. Collapse Details
     
    #16
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    On a more social level I picked up my first copy of Shulgin 7 years ago. Since that time I have moved away from hallucinogenics and plain stimulants. I am now more interested in compounds with mixed analgesia and antidepressant effects. A racemic or otherwise enantiomerically pure version of syn 3-chloro-tramadol is the best that I can currently muster utilizing readily available starting materials and popular attractive synthetic protocol.

    Q: Guess what tramadol and cocaine have in common.

    A: They both are made in the laboratory via the mannich condensation rxn.

    The 3,4-dichloro-tramadol analog is also a lucrative possibility. Here though a more expensive fractional crystalization technique would get employed to get at the more 'opiophilic' enantiomer directly. Dont forget that enantioselective reactions are happening all over the shop in nature. The chemist should feel no shame in delivering such measures.
    Last edited by Smyth; 22-02-2005 at 22:47.
     

  17. Collapse Details
     
    #17
    I just remembered another one: the dextro-rotatory isomer of the opioid propiram is said to also have psychostimulant effects: US 3594477.
     

  18. Collapse Details
     
    #18
    Of course it's an agonist, that paper you copied and pasted shows its an agonist... several articles and abstracts have shown mu-specific effects, with nM potency....
    Last edited by BilZ0r; 23-02-2005 at 07:02.
     

  19. Collapse Details
     
    #19
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    Right down the bottom in this patent you can compare/contrast tramadol and M1's effects on various receptors:

    http://patft.uspto.gov/netacgi/nph-P...ol&RS=Tramadol

    Buschmann is the master in this area. See US 6,828,345 for the most cutting edge discovery to be patented.

    I still hold my candle on (R,R) 3-chlorotramadol as my contribution to this area. I am going to have to take a look at patents on Bupropion AKA Wellbutrin to pack some punch into this theoretical breakthrough.
     

  20. Collapse Details
     
    #20
    Symth, what comparison are you trying to make between your tramadol analogue and bupropion?
     

  21. Collapse Details
     
    #21
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    Well they both share the 3-chlorophenyl group. I am not necessarily saying this idea will work, or it is destined to failure. However tramadol does induce seizures at doses >400mg. This is a real hefty dose for someone who is using sparingly. But once you develop a tolerance this amount can very easily be digested within a 24hr time frame.
     

  22. Collapse Details
     
    #22
    There's something they have in common, lowering of the seizure threshold or actually causing seizures. I believe 450 mg / day is the highest recommended dose of bupropion while 400 mg /day is the highest rec. dose of tramadol. I'd like to hear more about your idea.
     

  23. Collapse Details
     
    #23
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    It is just an idea for R&D although I cant say for sure to what extent this infringement on existing work will be a success.

    The scope is really open ended but the intent of the project is directed toward enantioselectivity. Enantioselective separation of tramadol has been patented several times already. It seems evident that a racemic mixture works best although the threat of seizure remains.

    It could turn out that (S,S)-4-chlorophenyl-tramadol could serve a positive role as a stimulant that shares similarities with cocaine. This idea may not be suitable grounds for a patent but it might be adequate grounds for sale of a potential RC. At this stage in development I just dont know
    Attached Images Attached Images
     

  24. Collapse Details
     
    #24
    Tramadol surely is a "unique" opioid but I'm curious about the mechanism of action that would give your theoretical (S,S)-4-chlorophenyl-tramadol stimulant properties. Also, could you please elaborate on what similarities it may share with cocaine? I'm just curious as to why you said cocaine as opposed to another stimulant, such as an amphetamine. Are you suggesting that it would have potent stimulant properties and a short duration like cocaine?
     

  25. Collapse Details
     
    #25
    Bluelighter Smyth's Avatar
    Join Date
    Nov 2004
    Location
    England
    Posts
    2,205
    I'm afraid i'll have to cry wolf on this whole project. It was an idea that occured to me at work. However since I have had time to drag up related patents I have reached the conclusion that this idea does not hold its water.

    However, from closer scrutinization of previous work it does appear that appropriately 2-substituted phenyl radicals do possess anti-depressant effects. Find the reference in the above aforementioned patent.

    -Smyth
     

Page 1 of 2 12 LastLast

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •