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    Preventing/reducing opiate tolerance 
    #1
    I stumbled across this while messing around on the US Patents website.

    Opioid analgesics remain the preferred therapy for the treatment of moderate to severe pain, and of many painful chronic diseases. However, the chronic use of opioid drugs produces tolerance to these drugs. Whereas tolerance develops to essentially all opioid effects at varying rates, an attenuated analgesic effect is the most devastating clinic consequence because it leads to dose escalation and inadequate pain control, and possibly drug dependence.

    Effective pain therapies directed to preventing opioid tolerance have long been sought. The success of developing such effective therapies requires a better understanding of the underlying tolerance mechanisms. Opioid receptor internalization, down-regulation, and uncoupling from G proteins (desensitization) all have been proposed as potential mechanisms. However, no consistent changes have been identified (Nestler, 1994; Nestler et al., 1997). A phenomena called "cAMP upregulation" has been proposed as a biochemical correlation for opioid tolerance (Sharma et al., 1975; Wang et al., 1994; Nestler, 1994). This theory was expanded when linked to the regulation of protein kinase A (PKA) and CREB activation in cellular model of opioid tolerance (Nestler, 1994; Nestler, 1997). However, studies with CREB mutant mice suggested that CREB may be a factor more important for opioid dependence (Maldonado et al., 1996; Blendy et al., 1998 ). Inhibition of PKA has produced an inconsistent effect on behavioral manifestations of opioid tolerance (e.g., Narita et al., 1995; Bilsky et al., 1996; Shen et al., 2000).

    Other studies found that blocking NMDA receptor antagonists could prevent the development of, or disrupt established, opioid tolerance (Trujillo et al., 1991; Mao et al., 1995). Central to these findings is increased intracellular Ca.sup.2+ levels resulting from NMDA receptor activation and other neuronal activation. Calcium ion (Ca.sup.2+) is used as a second messenger in neurons, leading to the activation various protein kinases, among them, Ca.sup.2+/phospholipids-dependent protein kinase (PKC) and Ca.sup.2+/calmodulin-dependent protein kinase II (CaMKII). PKC has been implicated in opioid tolerance (Coderre et al., 1994; Mao et al., 1995; Granados-Soto et al., 2000; Narita et al., 2001). Mice lacking PKC exhibited significantly reduced opioid tolerance (Zeitz et al., 2001). NMDA receptors are known to interact with CaMKII by Ca.sup.2+ influx and phosphorylation. It is unclear from these studies, however, whether CaMKII plays a role in the development and/or maintenance of opioid tolerance.

    The available opiate and opioid analgesics are derivatives of five chemical groups (i.e., phenanthrenes, phenylheptylamines, phenylpiperidines, morphinans, and benzomorphans). Pharmacologically, these opiates and nonopiates differ significantly in activity. Some are strong agonists (morphine), while others are moderate-to-mild agonists (codeine). In contrast, some opiate derivatives exhibit mixed agonist-antagonist activity (nalbuphine), whereas others are opiate antagonists (naloxone). Morphine is the prototype of the opiate and opioid analgesics, all of which have similar actions on the central nervous system.

    Morphine is an alkaloid chemically derived from opium papaver somniferum. Other drugs, such as heroin, are processed from morphine or codeine. Such opiates have been used both medically and nonmedically for centuries. By the early 19th century, morphine had been extracted in a pure form suitable for solution. With the introduction of the hypodermic needle, injection of a morphine solution became the common method of administration. Of the twenty alkaloids contained in opium, only codeine and morphine are still in widespread clinical use.

    The opiates are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system. Drugs of this group are used principally as analgesics, but possess numerous other useful properties. Morphine, for example, is used to relieve pain, induce sleep in the presence of pain, check diarrhea, suppress cough, ease dyspnea, and facilitate anesthesia.

    However, morphine also depresses respiration; increases the activity and tone of the smooth muscles of the gastrointestinal, biliary, and urinary tracts causing constipation, gallbladder spasm, and urinary retention; causes nausea and vomiting in some individuals; and can induce cutaneous pruritus. In addition, morphine and related compounds have other properties that tend to limit their usefulness.

    For example, when morphine and related compounds are administered over a long time period, tolerance to the analgesic effect develops, and the dose then must be increased periodically to obtain equivalent pain relief. Eventually, tolerance and physical dependence develop, which, combined with euphoria, result in excessive use and addiction of those patients having susceptible personalities. For these reasons, morphine and its derivatives must be used only as directed by a physician (i.e., not in greater dose, more often, or longer than prescribed), and should not be used to treat pain when a different analgesic will suffice.

    Nevertheless, morphine remains the major drug for the treatment of moderate to severe pain (Foley, 1993). Opioids particularly are used to treat chronic painful conditions lacking a standard treatment, such as cancer pain, posttraumatic pain, postoperative pain, and neuropathic pain. However, opioid painkillers have significant adverse side effects like respiratory depression, nausea, vomiting, dizziness, sedation, mental clouding, constipation, urinary retention, and severe itching.

    These adverse side effects limit the usefulness of opioids, like morphine, as painkillers. Therefore, several companies are developing a new generation of opioid painkillers, but advances in neuroscience have not progressed a sufficient extent to provide a significant breakthrough. Typically, companies are using proprietary technology to reformulate opioid drugs, such as morphine, into branded painkillers with improved clinical benefits. To date, innovations in the field of opioid painkillers have largely focused on increasing the convenience of opioid drugs. For example, important advances have been made in opioid delivery, such as sustained release formulations and transmucosal delivery.

    CaMKII is a multifunctional calcium and calumodulin activated kinase, whose .alpha. and .beta. isoforms are abundant in the central nervous system. A vast amount of information is available for the interaction of CaMKII .alpha. isoform and NMDA receptor in longterm potentiation in hippocampal neurons, which is critical for learning and memory (e.g., Mayford et al., 1996). Glutamate can activate CaMKII through NMDA receptor and Ca.sup.2+ influx in cultured rat hippocampal neurons (Fukunaga et al., 1992). Calcium influx via NMDA receptors results in activation and Thr286 autophosphorylation of CaMKII (Strack et al., 1998; Strack et al., 2000). On the other hand, CaMKII phosphorylates and activates the NMDA receptor, and enhances Ca.sup.2+ influx through the channel (Kitamura et al., 1993).

    No direct information exists for the role of CaMKII or NMDA/CaMKII interaction in opioid tolerance. Indirectly, chronic opioid administration increases both the level (Lou et al., 1999) and activity (Nehmad et al., 1982) of calmodulin, as well as calmodulin mRNA levels (Niu et al., 2000). Cytosolic free Ca.sup.2+ also can be increased after treatment with opioids (Fields et al., 1997; Quillan et al., 2002). CaMKII also has been shown to phosphorylate and activate the cAMP response element binding protein (CREB) (Hokota et al., 2001). More direct evidence arose from the finding that CaMKII and .mu. opioid receptor (.mu.OR) are colocalized in the superficial layers of the spinal cord dorsal horn, an area critical for pain transmission (Bruggemann et al., 2000). The cloned pOR contains several consensus sites for phosphorylation by CaMKII (Mestek et al., 1995). Desensitization of .mu.OR was enhanced when CaMKII was overexpressed (Mestek et al., 1995; Koch et al., 1997). Recently, hippocampal, but not striatal, CaMKII was found to modulate opioid tolerance and dependence by affecting memory pathways (Fan et al., 1999; Lou et al., 1999). The role of spinal CaMKII in opioid tolerance is unknown.

    The present invention is directed to the discovery that some pharmacological actions of morphine can be modified by coadministration of an inhibitor of CaMKII, hereafter termed a "CaMKII inhibitor."
    and...

    SUMMARY OF THE INVENTION

    Opioid analgesics are a mainstay in the field of pain treatment. However, the use of opioids to treat chronic pain leads to development of drug tolerance. A method and/or composition that prevents and/or reverses opioid tolerance would provide improved pain control in a large population of patients inadequately treated with opioid analgesics alone.

    The present invention is directed to use of a CaMKII inhibitor in chronic pain therapy involving opiate analgesics, or administration of a CaMKII inhibitor to patients who develop a tolerance and/or addiction to opiate analgesics. Prevention or reversal of opiate tolerance by administration of a CaMKII inhibitor requires lower doses of opiate analgesics to treat pain, thus reducing the severity of various adverse side effects associated with high doses of opiate analgesics.

    Accordingly, one aspect of the present invention is to provide a composition comprising a CaMKII inhibitor for use in treating pain in combination with an opiate analgesic, e.g., morphine.

    The present invention also is directed to a method of reducing, reversing, or preventing tolerance to an opiate analgesic in an individual undergoing an opiate analgesic therapy by administering a CaMKII inhibitor to the individual. In the absence of an administered dose of a CaMKII inhibitor, the opiate analgesic dose would have to be increased over time to achieve the same pain-reducing effect. Administration of a CaMKII inhibitor allows the opiate analgesic to be administered at a constant, or reduced, dose to achieve a desired pain treatment. Administration of a CaMKII inhibitor to a patient who already developed tolerance to the opiate analgesic restores the effectiveness of a low dose of opiate analgesics. The constant or reduced amount of opiate analgesic required to provide a desired pain-reducing effect thus reduces the severity of various adverse side effects associated with opiate analgesic treatment, and reduces the possibility of opiate analgesic dependence.

    The present invention also provides a method for improved pain treatment. In particular, the present invention is directed to methods of administering an opiate analgesic and a CaMKII inhibitor to prevent and/or treat chronic pain. More particularly, the present invention is directed to compositions containing an opiate analgesic, like morphine, and a CaMKII inhibitor, and to use of an opiate analgesic and a CaMKII inhibitor, administered simultaneously or sequentially, in methods of treating pain, and reducing, reversing, and preventing opiate analgesic tolerance and dependence.

    An important aspect of the present invention, therefore, is to provide a method and composition for preventing or treating pain, while reducing the occurrence or severity of adverse side effects associated with opiate analgesic treatment.

    Another aspect of the present invention is to reduce the problem of dependence and addiction associated with present opiate analgesics used to treat pain by administration of a therapeutically effective amount of a CaMKII inhibitor to an individual undergoing opiate analgesic treatment.

    Still another aspect of the present invention is to provide a method of reducing or reversing opiate analgesic tolerance in an individual undergoing an opiate analgesic therapy by administering a therapeutically effective amount of a CaMKII inhibitor to the individual.
    Now, besides this I only know of a few other ways to actively reduce/prevent opiate tolerance.
    1. ultra low antagonist dosing (naloxone, etc)
    2. CCK inhibitors (Proglumide which builds up its own tolerance)
    3. NMDA antagonist (d-methadone, etc)


    SO, do you know of any other ways to prevent/reduce tolerance? (feel free to include sources!)

    Do you have any hands on experience doing it?


    Here is a link to the patent. That's where I got the quotes from. There is a bunch of other interesting information(tests they performed, etc) there.
     

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    #2
    OOOO IF I ONLY KNEW lol. 200mg of oxy to get high is unconventional (right word for this meaning?
     

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    #3
    Thank you for posting. I have no ways to prevent/reduce tolerance but will be watching the replies.
     

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    #4
    DXM and other NMDA receptor antagonists, empirically, there is indeed a modest tolerance reversal with daily DXM intake at low doses. Also, DXM coadministration with opioids causes potentiation that is most likely due to DXM's tolerance reversing abilities. It is also a delta opioid agonist so that may play a role as well.
     

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    #5
    thanks, im having me mum go get me a bottle of dxm only robo.
     

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    #6
    btw im just doing this for pain relief purposes not getting high
     

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    #7
    Other NMDA antagonists:
    • Ketamine
    • PCP
    • Nitrous
    • DXM(mentioned earlier)
    • d-methadone
    • dextropropoxyphene
    • ketobemidone


    I'm not sure about the strength of each... Anyone know of a non-psychoactive one?


    Come on, no one has anything to add to this topic?
     

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    #8
    Bluelighter jasoncrest's Avatar
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    Quote Originally Posted by phrozen
    Now, besides this I only know of a few other ways to actively reduce/prevent opiate tolerance.
    1. ultra low antagonist dosing (naloxone, etc)
    2. CCK inhibitors (Proglumide which builds up its own tolerance)
    3. NMDA antagonist (d-methadone, etc)


    SO, do you know of any other ways to prevent/reduce tolerance? (feel free to include sources!)
    Besides the tolerance-preventing solutions you listed, there are also Opioids with delta antagonist and/or kappa antagonist properties that have been shown to cause a much slower onset of tolerance....
    Mu mixed agonists/antagonists also cause less tolerance I think.....
     

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    #9
    I've heard that kappa antagonists may slow down tolerance. I haven't heard anything about delta antagonists though. Ideally, you do want to antagonize(or leave alone) kappa, as its effects aren't desired.

    From the looks of things, DXM is really the only OTC option one has in regards to lowering tolerance.

    Ordering proglumide off the internet is also a possibility. (I think diacetyldeath did this, I'm not sure)

    Mu mixed agonists/antagonists also cause less tolerance I think.....
    I don't know if it does, but generally they're not as recreational. I'm hoping more people chime in on whether agonists/antagonists do this, and other aspects of this thread.

    Is this buprenorphine's property that causes its ceiling effect?
     

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    #10
    well you can only partially agonize your opioid receptors, which is why i think tramadol and bupe has a ceiling effect. (they are both partial agonist)
     

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    #11
    Bupe's is a therapeutic/effects ceiling. Meaning, exceeding that threshold will not produce stronger effects.

    I'm not too familiar with tramadol, but isn't it's ceiling due to the fact that it may cause seizures when exceeding it? Maybe it's both. I don't know, I never cared to look into tramadol.
     

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    #12
    Bluelighter jasoncrest's Avatar
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    Quote Originally Posted by phrozen
    From the looks of things, DXM is really the only OTC option one has in regards to lowering tolerance.
    Here are some very-easy-to-get options I can think of:

    -NMDA antagonists: DXM as you said, but maybe Cat's Claw too?
    -antagonists: Naloxone or Naltrexone are very easy to get. Doctors will be surprised and happy if you ask for them!

    The Wonder low-tolerance-producing Opioid would be something like Buprenorphine (mu partial agonist, delta & kappa antagonist) BUT with also NDMA antagonist properties, like Methadone!!
     

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    #13
    Bluelighter
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    Uh, DXM will NOT reverse tolerance. I take roughly 400mg/day of DXM, sometimes more. It has absolutely NO effect on tolerance, although I will say that it adds to the opioid high in small amounts (say, 60-75mg).

    If it reduced tolerance, believe me I would have no tolerance at all to opioids.
     

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    #14
    Bluelighter rachamim's Avatar
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    Phrozen: Great thread.

    The thing about NMDA antagonists though is the great danger of neural toxicity. You can mediate or inhibit it with a few different substances but most of them are at least psychoactives, if not outright dangerous in their on right.


    On non-psychoactive NMDA antagonists,there are more than a few substances, the synthetic cannabinoids come to mind.
     

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    #15
    ^
    Good point about the neurotoxicity. Does that apply to all NMDAA antagonists or just specific ones? Some(the methadones) are quite commonly used by many for long periods of time...
     

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    #16
    Bluelighter rachamim's Avatar
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    It is not really known what exactly causes the neural toxicity. Money is on it being the disinhbition of GABAergic inputs to the affected neurons. Since this is a commonality in all the NMDA antagonists, there probably will not be a substance that does not cause it in some what, shape, or form... the few substances used to temper the damage cause damge in other ways (atropines,etc.) so it is a crap shoot anyway.
     

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    #17
    Bluelighter rachamim's Avatar
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    There was one actually, NEU2000 made from aspirin and sulfasalazine but it was experimental and never released (Ajou U,S Korea...Gwag,et al) so the answer is MAYBE, but noy yet.
     

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    #18
    Bluelight Crew Jamshyd's Avatar
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    I honestly don't understand why everyone seems to believe that Ketamine is nurotoxic, when in fact it has been shown to be neuroprotective!

    Ketamine has been used medicinally and recreationally for at least 30 years. If it had any nurotoxicity, we'd have noticed it by now. If everyone is refering to the whole olney's liesons fiasco, that theory has been disproven many years ago.

    As for me, I was dosing Ketamine with my oxycodone during my short-lived oxy habit. It is worthy of mention that my tolerance barely escalated over 2-3 weeks of daily use. Same goes for my amphetamine use.

    Rachamim: which synthetic cannabinoids have NMDA-antagonist effects? I am curious!

    Jason: Cat's Claw is an NMDA antagonist pharmacologically, and taking large doses of it give off a hint of something like DXM (although I emphasize the word "hint" - I don't recommend anyone try and get high off of this!). I haven't tried it for tolerance issues, though.

    ps. psychoactive doses of NMDA antagonists are not needed for that effect. A mere 10-20mg of Ketamine did the job for me, as did 2X the medicinal dose of DXM...
    Last edited by Jamshyd; 08-10-2007 at 02:54.
     

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    #19
    P450 3A4 inhibitors

    legal, dozens of potential candidates, dont get you 'high' on their own, readily available
     

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    #20
    Bluelight Crew Jamshyd's Avatar
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    ^ These don't do anything for tolerance. They simply potentiate some opioids (not including Heroin, for example). And with that, it can be assumed that they help raise tolerance quicker!
     

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    #21
    Quote Originally Posted by In the Eyes of God
    P450 3A4 inhibitors

    legal, dozens of potential candidates, dont get you 'high' on their own, readily available
    I wish I could find the notes from my pharmacology class where we discussed this, and Jamshyd is correct, they actually raise one's tolerance from what I have learned.
     

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    #22
    I read somewhere a while ago of a mu-agonist delta-antagonist analogue of salvinorin.

    There was also a drug synthed that combined properties of hydromorphinone and a DOR antagonist. I forget what the latter was. It was shown to cause almost no tolerance.

    Ultra-low dose naltrexone has been shown to slow or prevent the development of tolerance. Oxytrex, anyone?
     

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    #23
    Bluelighter rachamim's Avatar
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    Jamshyd: A few like 7-hydroxy-6-tetrahydrocannabinol-1,1-dimethyl... as well as 7 -hydroxy -9...

    As for ketamine. ALL NMDA antagonists have the same problem, including the Disassociatives. Olney is one facet, there a few others. I am wondering though, what are you basing the Olney's having been disproven statement on? I am aware of some people who promote Disassociatives in California claiming that they have disproven it but have never seen or heard of anyone who has seen peer reviewed information on it. I am not taking up a cause one way or another, but for general knowledge would love to see the info.

    To clarify, I am fully aware of the article by Anderson (fully debunked as pure conjecture) and the book by Jansen that purported to rely on "unpublished reports." Jansen's whole argument rests on rodent metabolism. Sorry Jansen but it is the same metabolism used to quantify most other substances in use and when applied to humans the factors are adjusted. They do not use rat metabolism to conclude probability on humans.

    As for ketamine guarding against excito, that is another Jansen claim but either way it would not factor in in discussing other neural damage caused (or purported to have caused) by the substance.
     

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    #24
    There was also a drug synthed that combined properties of hydromorphinone and a DOR antagonist. I forget what the latter was. It was shown to cause almost no tolerance.
    What happened to it?

    Ultra-low dose naltrexone has been shown to slow or prevent the development of tolerance. Oxytrex, anyone?
    Right. Does anyone know if there's a study comparing Suboxone vs. Subutex(regular buprenorphine)? Considering the BA of sublingual naloxone, that could potentially count as ultra low dosing and may actually affect buprenoprhine tolerance.




    Pharaoh, we're not talking about potentiating.
     

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    #25
    It was just being studied in rats, I don't know if it's ever been tested in humans.


    Regarding Olney's Lesions: There's never been anything showing Olney's Lesions in humans, and there's little evidence to indicate they can exist in humans, whether or less be caused by dissociatives.

    I'm assuming the only thing you've ever read about it was the "Your brain on dissociatives" and not the subsequent letter from the author admitting it was probably wrong.

    I had a friend in Canada who used ketamine extensively and developed brain lesions, which was thought to be the first instance of Olney's Lesions in humans. Later, they were shown to be some other kind of lesions.

    There's also really, really good evidence to indicate that Ketamine doesn't even cause brain lesions in rats. They used veterinary ketamine which used a Chloral Hydrate analogue as a preservative that has been shown to cause brain lesions.

    This has been covered on BL (I think pretty recently in the ADD subforum), actually. There's a lot of really good info about it.
     

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