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Proglumide Reversing Opiate Tolerance – A Comprehensive Review of Opiate Potentiation

Posted by Anonymous on July 07, 2015  /   Posted in Khemcorp Originals, Reverse Tolerance

Article is work in progress. Link to the first article here :  Proglumide Summary 

A second comprehensive review of patent and medical literature for Opiate Potentiation

Why are you revisiting Proglumide?

Research is never complete, we have had a lot of people asking us difficult questions with answers we wish we knew. So its important we box up and learn as much about what we are dealing with as possible.

We would like to revisit Proglumide today after much more detailed research with how Proglumide helps opiate tolerance and the various patents that have been registered for it’s use as a adjunct to opiate usage or for tolerance reversal.

In our research of medical literature we found some very interesting findings. Some this information will be a rehash of the stuff we posted before, but most of it will be new. Especially of to note, is the proglumide to opiate ratio suggested in one of the patents.

It is obviously interesting to note that opiates according to this literature that do not deal with neuropathic pain, which is another type of pain prominent net to noriceptive pain (the traditional form), this neuropathic pain cannot be addressed by continue to increased dosages. It is notable prominent in cancer breakthrough pain.

What happens in treatment is that from time to time opiates become insufficient or ineffective to treat pain, which is why non-opiates are looked into an option to increase effectiveness of opiates. Tolerance developes rapidly with continued dose escalation required within days, when opiates like morphine is used chronically. The increase of side effects and decrease of effectiveness of opiates causes a serious degradation on the quality of life of patients at the receiving end of pain.

Proglumide Summary Part 2 – Understanding tolerance, the power of a true tolerance reversal agent.

Proglumide has been referenced various times in literature to potentiate opiates, boosting analgesia.

It is a prime candidate for various reasons it is often chosen as the non-opiate chemicals for the treatment of pain (Patent CA2542837A1 – The use of non-opiates for the potentiation of opiates).

Referencing Merck Index No. 7680 – Proglumide was found unexpectedly potentiate analgesic activity of morphine and all related opiates.

From experiments conducted, even at 5mg/kg proglumide can at least double the analgesic effect of morphine and methadone, of course these are using intravenous preparations, and may not apply to other opiates, and also “analgesic effect” may just mean one aspect of opiates. (Experiment No. 2 US4576951).

The higher the proglumide dosage the more significant the effects in intensity and duration (20mg/kg) (Experiment No. 3 US4576951).

A secondary effect on top of potentiation, it also restores pharmaceutical effects of opiates that have fallen off, the way this is written in the patent makes it unclear whether proglumide would work better being administrated towards the end of an opiate dose or not, it would be interesting to experiment if this is the case.

Finally tertiary effect of Proglumide is that it also acts as it’s own pain killer by the potentiation of enkephalins (opioids produced by the body.

What Potentiates Opiates?

6 chemicals notably potentiate opiates such as morphine, dihydrocodeine, and heroine.

A comprehensive list of all the suitable candidates:

  • CCK (CCKg) Antagonists like Proglumide
  • NMDA Antagonists – like Magnesium / Memantine
  • NR2B Antagonists
  • Cox Inhibitiors
  • Andrenergic Stimulators such as those which stimulate alpha 2 andrenoceptors and potentiates opiates
  • Some types of serotonin inhibitors

Method of Administration

We found that oral administration in the quoted patents were not the suggested forms of administration, despite the current research using research in oral administration. It is suggested that a non-opiate is administrated sublingual or by injection. This is to bypass the first pass metabolism, and for the drug to achieve relief and potentiation in the quickest possible way. It is suggested the first pass metabolism by liver reduces the impact of Proglumide on CCKg receptors responsible for development of tolerance to opiate analgesia. (Patent CA2542837A1 – The use of non-opiates for the potentiation of opiates).

So if oral administration has no effect, its worth trying to put it under the tongue, this is likely to create a very different effect from proglumide, since it may not have 3rd order kinetics.

There is also mention that proglumide can be administrated in three different ways.

  1. Simultaneous (This is the main proposal of the research and patents, to combine Proglumide and Opiate tablets, obviously this did not happen – perhaps tolerance was developed to Proglumide, or big pharma would not want to reduce sales of it’s own medicine)
  2. Separate
  3. Sequential (This means after the initial opiate administration I would imagine)

The administration method from the experiment was as follows for opiate tolerance prevention and reversal (opposing): Proglumide was given 1 hour before the opiates. (Experiment No. 5)

More on Proglumide Dosage:

According to the patent US4576951 (Proglumide, pharmaceutical compositions for opiates). 4000 grams was mixed with 50grams of methadone. This means the suggested dosage for 5mg equivalent of methadone or methadone itself should be paired with 400mg of Proglumide. (this needs checking, as this may be based on intravenous administration, as it does not obey the established ratio before)

The ratio established is about 200:1 (proglumide:opiate) on molecular weight, as pills and stuff contain binders and stuff. This discovery has big implications for our knowledge about Proglumide – that more proglumide does need to be taken with higher opiate dosages, which explains some of the feedback we have been getting.

Dosage range for Proglumide in the patent is anywhere from 10mg to 1500mg, with 200 to 400mg suggested for oral dosages.

So researchers should figure out how much equivalent methadone they are taking on their current dosage, and work out their proglumide dosage that way.

Typically proglumide is administered to the patient a rate of 0.5 to 30mg/kg of body weight.

In the a confusing statement it says it is possible to make proglumide tablets form 10mg to 100mg, does this mean that the effective dosage for Proglumide can be much lower, for mild use of opiates?

Will update this section when we find out more.

About Proglumide

More bullet point information extracted from research and patent documents:

  • CCK Antagonists such as Proglumide have been demonstrated to reverse tolerance.
  • Proglumide has been demonstrated to boost opiate analgesia, meaning less opiate dosage needed
  • Proglumide is a mixed CCKa and CCKg antagonist. CCKa is responsible for its anti ulceration effects. CCKg is the effect that holds the potential and is relatively unexplored.
  • The CCKg receptor has been known to be involved in the development of opiate tolerance.
  • Lowering doses of opiate using non-opiates to potentiate, can have the advantage of lower side effects commonly attributed to opiates.
  • Proglumide’s full chemical name is : D, L -4-benzamido-N, N-dipropylglutaramic acid…

Among our research we found a secret never been used new opiate tolerance reversal chemical that we are going to investigate, see if you can find it in the papers : )

– Khemcorp

Research Links (Research papers are referenced in patents for all points above)

ABSTRACT
A non-opioid analgesic is used for the treatment of intermittent or episodic pain experienced by a patient undergoing chronic pain treatment with an opioid analgesic.
ABSTRACT
A product comprises proglumide and tramadol as a combined preparation for simultaneous, separate or sequential use in the treatment of a pain condition.