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Proglumide and Opioid Tolerance Reversal – A Summary

Posted by Khemcorp on January 15, 2014  /   Posted in Khemcorp Originals, Reverse Tolerance

Disclaimer: All thoughts and advice expressed are the personal opinions and gatherings of the author and do not constitute medical advice. If you are seeking medical advice please consult a doctor.

What is Proglumide?

Chemical Structure of the Opoid Tolerance Reduction Chemical Proglumide

Chemical Structure of the Opoid Tolerance Reduction Chemical Proglumide

Proglumide was developed in Germany during the 50s, although this drug was prescribed as ulcer medication it is no longer used since advances in ulcer medications rendered it obsolete.

Unbeknownst to many people while Proglumide was being tested in clinical trials, a separate effect came to light. Test subjects taking certain pain medicines felt enhanced pain reduction effects from their usual medicine at their usual dosage. It was ruled out as a drug interaction.

As time went on Proglumide became completely obsolete and was pretty much no longer prescribed for anything, however a scientist discovered the original research and was interested in the side effects, he conducted clinical trials and even got grants for his work.

He discovered that Proglumide when used as intermittently  actually reduce and seemed to prevent tolerance to opiods. A kind of cure for tolerance if you want to call it that.

Unfortunately because the lack of interest in a drug that would essentially reduce opiate usage the research never gained any new traction as it would cost the industry many dollars in revenue, due to reducing the need for repeat prescription for expensive drugs (as with many other things like laser photo therapy or transcranial stimulation).

What is the mechanism behind Proglumide?

When a person takes opiods/opiates regularly even on a weekly or monthly basis, levels of a neuropeptide known as CCK increases in the nervous system and the brain.

CCK acts as an antagonist on the opoids, which is why a person needs more and more opiods to produce the same degree of pain reduction, after some time the one small effective dosages become less and less effective over time. This isn’t an imaginary effect, it is a real effect, its called drug tolerance and the big problem is regularly administration of opiates reduce their effectiveness until even stunningly large dosages become ineffective.

This is how addiction starts as the prescription has to be raised every few months, eventually the patient becomes dependent on a high dosage which is no longer effective, worst when the patient stops taking the pain medication. The reverse happens, patients get withdrawal symptoms and become sick and in pain. Most people don’t become addicted though, rather they just realize that the medication is no longer effective.

Clinical research shows Proglumide reduce CCK levels and thus restores the effectiveness of opoids almost instantly, it is best used when trying to reduce withdrawal symptoms and restore the effectiveness of previous effective opiate dosage, thus achieving opiod tolerance reversal.

Tolerance can develop to Proglumide for that reason it should not be used for potentiation; there is a difference between potentiation and tolerance reduction.

Whats the difference between tolerance reduction and potentiation?

These two terms often get confused, as they both mean increasing the effect of pain reduction opiate medication or any other medication for that matter, but they mean very different things.

Potentiation is enhancing the effect of an opiate or opoid by inhibiting certain processes, such as enzmyes that metabolise the opiates to deliver a larger amount of the drug into circulation in same amount of time, this increases the effect. An example is grape juice, which competes directly in the metabolic pathway.

This can be done to basically increase the effect when the effect is no longer sufficient without potentiation, but this is not tolerance reduction, as it hasn’t changed how tolerant the brain and body of the user.

Tolerance reduction is when something is happening so the patient or user is experiencing a larger effect from the same dosage without any inhibition of processes that enhances the drug. In a sense potentiation is pretty much increasing the dosage of the drug to reduce tolerance, whilst tolerance reduction is actually reducing the tolerance to the drug and thus increasing the drugs effectiveness.

Tolerance reduction is much harder to achieve than potentiation, as the results actually means the body will be able to become less tolerance of dosages that has since become ineffective. Proglumide is one of the few drugs that has shown this capability in clinical trials, which is why its so important to not let this drug go into obscurity.

Related posts:

Proglumide Dosage, Tolerance and Strategy – A Simple Guide to Mediating or Reducing Opiate Tolerance

Scientific references:

CCK inhibitors enhancing opioid analgesia and/or preventing tolerance
Dourish, C.T. et al. (1988) Eur. J. Pharmacol. 147: 469-472. “Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718.” [C.T. Dourish, D. Hawley & S.D. Iversen]Dourish, C.T. et al. (1990) Eur. J. Pharmacol. 176: 35-44. “The selective CCK-B antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat.” [C.T. Dourish, M.F. O’Neill, J. Coughlan, S.J. Kitchener, D. Hawley & S.D. Iversen] Hoffmann, O. & Z. Wiesenfeld-Hallin (1994) Neuro. Report 5: 2565-2568. “The CCK-B receptor antagonist CI 988 reverses tolerance to morphine in rats.” Hughes, J. et al. (1990) Proceedings of the National Academy of Science (USA) 87: 6728-6732. “Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity.” [J. Hughes, P. Boden, B. Costall, A. Domeney, E. Kelly, D.C. Horwell, J.C. Hunter, R.D. Pinnock & G.N. Woodruff] O’Neill, M.F. et al. (1989) Neuropharmacology 28: 243-249. “Morphine-induced analgesia in the rat paw is blocked by CCK and enhanced by the CCK antagonist MK-329.” [M.F. O’Neill, C.T. Dourish & S.D. Iversen] Watkins, L.R. et al. (1985) Brain Research 327: 181-190. “Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates.” [L.R. Watkins, I.B. Kinscheck, E.F.S. Kaufman, J. Miller, H. Frenk & D.J. Mayer] Wiesenfeld, Z. et al. (1990) Proceedings of the National Academy of Science (USA) 87: 7105-7109. “PD134308, a selective antagonist of cholecystokinin type-B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes.” [Z. Wiesenfeld, X.-J. Xu, J. Hughes, D.C. Horwell & T. Hökfelt] Xu, X,-J. et al. (1992) British Journal of Pharmacology 105: 591-596. “CI988, a selective antagonist of cholecystokinin type-B receptor, prevents morphine tolerance in the rat.” [X.-J. Xu, Z. Wiesenfeld-Hallin, J. Hughes, D.C. Horwell & T. Hökfelt]

Proglumide
Chiodo, L.A. & B.S. Bunney (1983) Science 219: 1449-1450. “Proglumide, selective antagonism of excitatory effect of cholecystokinin in central nervous system.”Katsuura, G. & S. Itoh (1985) Eur. J. Pharmacol. 107: 363-366. “Potentiation of ß-endorphin effects by proglumide in the rat.” Lavigne, G. et al. (1987) Pain, Suppl. 4: S229. “Potentiation of morphine analgesia by proglumide for acute clinical pain.” [G. Lavigne, K.M. Hargreaves, G.P. Miller, E.S. Schmidt & R.A. Dionne] McCleane, G.J. (1998) Anesth. Anal. 87: 1117-1120. “The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain.” McCleane, G.J. (1998) The Pain Clinic 11: 103-107. “The cholecystokinin antagonist proglumide enhances the analgesic effect of morphine in chronic benign nociceptive and neuropathic pain.” Rovati, L.C. et al. (1985) Annals of the New York Academy of Science 448: 630-632. “Effects of proglumide on morphine analgesia and tolerance.” [L.C. Rovati, P. Sacerdote & A.E. Panerai] Tang, J. et al. (1984) Neuropharmacology 23 (6): 715-718. “Proglumide prevents and curtails acute tolerance to morphine in rats.” [J. Tang, J. Chou, M. Iadarola, H.-Y.T. Yang & E. Costa] Watkins, L.R. et al. (1985) Brain Research 327: 169-180. “Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide.” [L.R. Watkins, I.B. Kinscheck & D.J. Mayer]

 

 

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