Does omeprazole enhance a methadone high?

“Another product that power methadone is omeprazole…the methadone high I’m feeling is very pleasant.” -Adicted, member of drugs-forum.com

Authored by: Dr. B. Zach Hedges

Background
 Omeprazole

• irreversibly inhibits H+-K+ ATPase to lower gastric acid secretion
• metabolized by 2C19, substrate of 3A4, time to peak 30min – 3hrs
• plasma T1/2 30 min to 1hr, although effects on acid secretion lasts 3-5 days
• ​excreted in urine (77%), T1/2 0.5-1hr​​

​Methadone
            -µ opioid receptor agonist
            -variable oral bioavailability, 36-100%
            -onset 30min-1hr, time to peak ~4hrs
            -85-90% protein bound
            -metabolized by 2B6, 2C19, 2D6 (minor), substrate of 3A4
            -excreted in urine, feces; T1/2 24-36 hours
            -usual formulation is methadone hcl, pka 8.4 (weak base)

Likely mechanism of enhanced effect
 
By increasing gastric pH, the absorption of methadone is increased
 
Angeles-Carlos, et al. (2001):
-Omeprazole 2mg/kg iv 2hr prior to methadone
-rate of absorption faster (k(01) = 0.31 +/- 0.04 min(-1) vs 0.05 +/- 0.007 min(-1)
-peak plasma concentration greater (197.41 +/- 33.70 versus 83.54 +/- 7.97 ng/mL) 
            -time to reach Cmax shorter (11.23 +/- 1.32 versus 39.18 +/- 1.74 min)
            -however, no significant effect on analgesia as assessed by tail twitch testing
 
DeCastro, et al. (1996):
Omeprazole 2mg/kg PO with methadone 5mg/kg PO in rats
            -C­max­ 156 vs 51 ngml-1
            -significant differences in respiratory depression, arterial pCO2
            -replicated with HCO­3 and acidic methadone solution

Other potential mechanisms
Inhibition of P-glycoprotein
-Rodriguez, et al. (2004): Methadone cleared from CNS via P-glycoprotein
            -Administration of valspodar, a P-gp inhibitor, increased analgesic effect of methadone in rats
             three-fold
-Pauili-Magnus, et al. (2001): omeprazole, lansoprazole, pantoprazole inhibit P-glycoprotein
-used digoxin as P-glycoprotein substrate
-no studies directly observing effect on methadone

Inhibition of CYPC19
-Liu, et al. (2005): omeprazole strongly inhibits CYPC19 in vitro
-unlikely to impact methadone metabolism significantly given difference in T1/2

Take home message
-Good theoretical basis for potential interaction between omeprazole and methadone via enhanced absorption with increased gastric pH
-Weaker theoretical basis for interaction via P-glycoprotein and CYP enzyme inhibition
-Never demonstrated in humans in experimental setting
 

​References:
National Center for Biotechnology Information. PubChem Compound Database; CID=4095, https://pubchem.ncbi.nlm.nih.gov/compound/4095 (accessed Nov. 14, 2017).
 
National Center for Biotechnology Information. PubChem Compound Database; CID=4594, https://pubchem.ncbi.nlm.nih.gov/compound/4594 (accessed Nov. 14, 2017).

Carlos MA, DuSouich P, Carolos R, Suarez E, Lukas JC, Calvo R. Effect of omeprazole on oral and intravenous RS-methadone pharmacokinetics and pharmacodynamics in the rat. Journal of Pharmacologic Science 200
DeCastro J, Aguirre C, Rodriguez-sasiain JM, Gomez E, Garrido MJ, Calvo R. The effect of changes in gastric pH induced by omeprazole on the absorption and respiratory depression of methadone. (1996). Biopharmaceutics & Drug Disposition, 1996(17);551-63
Rodriguez M, Ortega I, Soengas I, Suarez E, Lukas JC, Calvo R. Effect of P-glycoprotein inhibition and brain distribution in the rat. (2004) Journal of Pharmacy and Pharmacology. Mar; 56(3):367-74.
Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm M. Interaction of omeprazole, lansoprazole, and pantoprazole with P-glycoprotein. (2001). Naunyn-Schmiedeberg’s Archives of Pharmacology 364(6); 551-57.
Liu KH, Kim MJ, Shon JH, Moon YS, Seol SY, Kang W, Cha IJ, Shin JG. Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro. (2005). Xenobiotica Jan;35(1):27-38.