Proglumide Explained

Proglumide (Milid) is a drug that inhibits gastrointestinal motility and reduces gastric secretions. It acts as a cholecystokinin antagonist,^[1] which blocks both the CCK_A and CCK_B subtypes.^[2] It was used mainly in the treatment of stomach ulcers,^{[3] [4]} although it has now been largely replaced by newer drugs for this application.

An interesting side effect of proglumide is that it enhances the analgesia produced by opioid drugs,^[5] and can prevent or even reverse the development of tolerance to opioid drugs.^{[6] [7]} This can make it a useful adjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.^{[8] [9]}

Proglumide has also been shown to act as a δ-opioid receptor (DOR) agonist, which may contribute to its analgesic effects.^[10] However, other studies show that proglumide has low affinity to the μ-opioid receptor (MOR) and the κ-opioid receptor (KOR) (13% of MOR and 17% of KOR occupancy at 100 μM), but no affinity to DOR.^[11] It is questionable whether this is clinically significant, since the concentration they used was very high, and the occupancies were low even at that point.

Proglumide also works as a placebo effect amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretly, it does not have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness.^[12] The supposed mechanism is an enhancement of the neural pathways of expectation as a result of dopamine and endogenous opioids being suddenly released throughout numerous structures of the brain and spinal cord.

The ventral tegmental area is the structure believed to mediate proglumide's analgesic and euphoric effects, however dozens of areas with a wide range of physical and psychological functions are implicated in the mediation of the placebo effect (this accounts for proglumide's ability to produce physically measurable effects on vital signs such as heart rate, blood pressure, respiration rate, and tidal volume which cannot be accounted for by its clinically insignificant δ-opioid affinity.

See also

• Proglumetacin

Notes and References

1. Bunney BS, Chiodo LA, Freeman AS . Further studies on the specificity of proglumide as a selective cholecystokinin antagonist in the central nervous system . Annals of the New York Academy of Sciences . 448 . 1 . 345–351 . 1985 . 2862828 . 10.1111/j.1749-6632.1985.tb29929.x . 1985NYASA.448..345B . 28298172 .
2. González-Puga C, García-Navarro A, Escames G, León J, López-Cantarero M, Ros E, Acuña-Castroviejo D . Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin . Journal of Pineal Research . 39 . 3 . 243–250 . October 2005 . 16150104 . 10.1111/j.1600-079X.2005.00239.x . 20187767 .
3. Bergemann W, Consentius K, Braun HE, Hirschmann H, Marowski B, Munck A, Rehs HU, Stopik D, Wilke G . 6 . [Duodenal ulcer - multicenter double-blind study with proglumide] . Medizinische Klinik . 76 . 8 . 226–229 . April 1981 . 7231338 .
4. Tariq M, Parmar NS, Ageel AM . Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats . The Journal of Pharmacology and Experimental Therapeutics . 241 . 2 . 602–607 . May 1987 . 3572816 .
5. McCleane GJ . The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine . The Clinical Journal of Pain . 19 . 3 . 200–201 . 2003 . 12792559 . 10.1097/00002508-200305000-00008 . 29229782 .
6. Watkins LR, Kinscheck IB, Mayer DJ . Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide . Science . 224 . 4647 . 395–396 . April 1984 . 6546809 . 10.1126/science.6546809 . 1984Sci...224..395W .
7. Tang J, Chou J, Iadarola M, Yang HY, Costa E . Proglumide prevents and curtails acute tolerance to morphine in rats . Neuropharmacology . 23 . 6 . 715–718 . June 1984 . 6462377 . 10.1016/0028-3908(84)90171-0 . 33168040 .
8. Bernstein ZP, Yucht S, Battista E, Lema M, Spaulding MB . Proglumide as a morphine adjunct in cancer pain management . Journal of Pain and Symptom Management . 15 . 5 . 314–320 . May 1998 . 9654837 . 10.1016/s0885-3924(98)00003-7 . free .
9. McCleane GJ . The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain . Anesthesia and Analgesia . 87 . 5 . 1117–1120 . November 1998 . 9806692 . 10.1213/00000539-199811000-00025 . 10735834 .
10. Rezvani A, Stokes KB, Rhoads DL, Way EL . Proglumide exhibits delta opioid agonist properties . Alcohol and Drug Research . 7 . 3 . 135–146 . 1987 . 3030338 .
11. Gaudreau P, Lavigne GJ, Quirion R . Cholecystokinin antagonists proglumide, lorglumide and benzotript, but not L-364,718, interact with brain opioid binding sites . Neuropeptides . 16 . 1 . 51–55 . May 1990 . 2174522 . 10.1016/0143-4179(90)90029-X . 25646937 .
12. Benedetti F, Amanzio M, Maggi G . Potentiation of placebo analgesia by proglumide . Lancet . 346 . 8984 . 1231 . November 1995 . 7475687 . 10.1016/S0140-6736(95)92938-X . free .