Posted by undopaminergic on May 26, 2008, at 18:53:40
In reply to Re: Suggestions for non-benzo anxiolytics PLEASE.. » undopaminergic, posted by Quintal on May 26, 2008, at 8:38:22
> >Benzos bind to GABA-A receptors, and I think gabapentin (Neurontin) and pregabalin (Lyrica) also work on the GABAergic system, so cross-tolerance may be an issue.
>
> It could be, but since they work at a different site, they could support the GABA system (preventing or attenuating withdrawal symptoms) and allow the benzodiazepine receptors to upregulate, so that when a person starts taking them again tolerence is back to pre-drug levels.
>It may be well worth trying - assuming, of course, that both types of drugs are suffiently effective and well-tolerated in the individual case.
> Dopamine agonists can do a similar job with opiates by supporting the dopamine system during withdrawal while the opiate recetors recover [personal experience].
>Some combination of dopaminergic drugs is quite likely to effectively replace the dopaminergic effects of opioids, but unfortunately not the analgesic effects. Or did you find the dopamine agonists to be effective pain-killers?
> >Perhaps alternating between GABAergic drugs (such as benzos) and opiates would be a better idea, as opiates work on their own set of receptors rather than GABA.
>
> Being realistsic, where would people get these opiates from? They're even more tightly controlled (and addictive) than benzos. The original concern was addiction with benzos.
>The point of alernating between benzos and opioids is to avoid addiction to either of them. Availability can certainly be an issue, but some of the less potent opiates are available without prescription, unlike any benzodiazepine. The ease of getting a prescription for opiate preparations of higher potency is highly variable - as with benzos, some doctors are totally against them, except possibly for terminal cancer, whereas other doctors are more pragmatic and don't have a problem with their usage in moderation.
> >I consider opioids advantageous also because NDMA-antagonists (including at least memantine and dextromethorphan) are highly effective for preventing or reversing tolerance to them, whereas I don't know of anything that prevents or reverses benzodiazepine-tolerance.
>
> I don't think either of those drugs are highly effective at reversing opiate tolerence. I once read an study where lamotrigine was used to delay tolerence to buprenorphine for six months or so, but ultimately it only delayed tolerence, it didn't reverse or prevent it. I've tried lots of these supposed tolerence reversal stratergies and none of them have worked. The only reliable way of reversing tolerence I know of is to slowly withdraw from the drug and stay off it for a few months.
>My personal experience is limited, but my impression from what I've read is that the evidence for the efficacy of NMDA-antagonists in attenuating and preventing the development of tolerance is almost overwhelming, and there are reasonably strong indications that reversal of existing tolerance by NMDA-antagonists is quite feasible under many conditions. I'm not suggesting that it's a workable solution in every case - some people are more prone to devlop tolerance, and some may not tolerate sufficient doses to NDMA-antagonists. Besides, even if tolerance were preventable without exception, there may simply be better solutions than opioids depending on the details of the individual case.
> > Furthermore, opioid-withdrawals are less severe,
>
> I wouldn't say opioid withdrawal is less severe than benzo withdrawal, but it depends on the dose. They're both in the same ballpark, and both are fairly hellish if you're coming abruptly off a high dose.
>Yes, it depends on dose, the degree of dependence, rate of cessation, as well as factors that vary between individuals. However, it's generally accepted that opioid withdrawal is very rarely a serious threat to health physiologically, which is in contrast to benzodiazepines and many other GABAergic drugs.
>
> >and can be further diminished by alpha2-agonists - such as clondidine and guanfacine, whereas I don't know of anything - other than possibly barbiturates and alcohol - that can control benzo-withdrawals.
>
> Clonidine and guanfacine only reduce certain symptoms of opiate withdrawal. They're not a magic cure and carry significant side effects of their own.
>The sympathetic (adrenergic) hyperactivation resulting from the rapid cessation of opiates is the main physiological hazard of the withdrawal syndrome, and these symptoms respond well to the alpha2-agonists. Clonidine is more likely than guanfacine to be troublesome in terms of its side effects; the latter has few adverse effects in my experience, except dryness of the mouth at high doses. A variety of other drugs, including benzos, may be useful for other aspects of the withdrawal syndrome if slow discontinuation or substitution of another opioid is not a suitable alternative.
> Many drugs can attenuate some of the symptoms of benzo withdrawal, including Neurontin and Lyrica, but in both cases the best remedy for withdrawal is to slowly decrese the dose of the original drug.
>A suitably slow rate of discontinuation of any drug that has significant withdrawal effects is generally a sensible way to handle it, but in the case of short-acting drugs, it's often a better idea to switch to a longer acting agent of the same class, such as diazepam in the case of benzos, and methadone or buprenorphine in the case of opiates.
Some references concerning the use of NMDA-antagonists to reduce opiate tolerance -
NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats.
http://www.ncbi.nlm.nih.gov/pubmed/17994223Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice.
http://www.ncbi.nlm.nih.gov/pubmed/12442203Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.
http://www.ncbi.nlm.nih.gov/pubmed/10763858Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test.
http://www.ncbi.nlm.nih.gov/pubmed/10600036Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the development of opiate analgesic tolerance induced by repeated morphine exposures or social defeats in mice.
http://www.ncbi.nlm.nih.gov/pubmed/9750014Morphine with dextromethorphan: conversion from other opioid analgesics.
http://www.ncbi.nlm.nih.gov/pubmed/10687339Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats.
http://www.ncbi.nlm.nih.gov/pubmed/8951930Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study.
http://www.ncbi.nlm.nih.gov/pubmed/14695734NMDA BLOCKERS & Memantine
http://www.drgeorgedavidson.com/ebixa_memantine_experience.htmGetting off Methadone with Memantine
http://www.drgeorgedavidson.com/ebixa_getting_off_methadone.htm
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thread:830647
URL: http://www.dr-bob.org/babble/20080519/msgs/831263.html