CODEINE

• Cytochrome P450 enzyme substrate: CYP3A4, and CYP2D6
• Action to be taken: Caution with close monitoring for side effects
• Rationale: Patients taking cytochrome P-450 enzyme inducers or inhibitors may demonstrate an altered response to codeine, therefore analgesic activity should be monitored. Codeine sulfate is metabolized by the cytochrome P-450 3A4 and 2D6 isoenzymes.The concurrent use of drugs that preferentially induce codeine N-demethylation (cytochrome P-450 3A4) may increase the plasma concentrations of codeine’s inactive metabolite norcodeine. Drugs that are strong inhibitors of codeine O-demethylation (cytochrome P-450 2D6) may decrease the plasma concentrations of codeine’s active metabolites, morphine and morphine-6-glucuronide. In vitro studies have found that cannabis is a weak inhibitor of CYP450 enzymes, thus it may impact metabolism of codeine. Furthermore, concurrent use of other CNS depressants concomitantly with codeine sulfate tablets may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma. Use codeine sulfate with caution and in reduced dosages in patients taking these agents.

HYDROCODONE + ACETAMINOPHEN

• Cytochrome P450 enzyme substrate: CYP3A4, CYP1A2,CYP2E1 and CYP2D6
• Action to be taken: Caution with close monitoring for side effects
• Rationale: In vitro studies have found that cannabis is a weak inhibitor of CYP450 enzymes including CYP3A4, CYP2D6 and CYP1A2. The concomitant use of NORCO with all Cytochrome P450 3A4 inhibitors may result in an increase in NORCO plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used Cytochrome P450 3A4 inducer may result in an increase in NORCO plasma concentrations. Monitor patients receiving NORCO and any Cytochrome P450 3A4 inhibitor or inducer for signs of respiratory depression or sedation.

METHADONE

• Cytochrome P450 enzyme substrate: CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6
• Action to be taken: Caution with close monitoring for side effects
• Rationale: Methadone metabolism may be decreased by CYP3A4 or CYP2D6 inhibitors, such as SSRI’s. In patients are treated with SSRI’s or other inhibitors, the plasma concentration of methadone increased. The R-enantiomer (the active species) was increased in these patients. Patients may experience increases in CNS depressive effects or respiratory depression.

MORPHINE

• Cytochrome P450 enzyme substrate: CYP3A4
• P-gp substrate
• Action to be taken: Caution with close monitoring
• Rationale: Morphine is a P-glycoprotein substrate. Increased concentrations of morphine may occur; co-administration with a P-gp efflux transporter inhibitor warrants exercising caution.
  

OXYCODONE

• Cytochrome P450 enzyme substrate: CYP3A4 and CYP2D6
• Action to be taken: Caution with close monitoring. Potential dose adjustments
• Rationale: Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If co-administration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
  

TRAMADOL

• Cytochrome P450 enzyme substrate: CYP3A4, CYP2B6, and CYP2D6
• Action to be taken: Caution with close monitoring for side effects. Monitor for signs of serotonin syndrome (hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g. delirium or coma), and in rare cases, death.
  
• Rationale: Ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4; concurrent therapy may decrease tramadol metabolism. In vitro studies show that cannabis is a weak CYP2D6 and CYP3A4 inhibitor. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.

References

1. Codeine (package insert) Roxane Laboratories, Inc.Columbus, OH 2009
   
2. Sativex (tetrahydrocannabinol and cannabidiol) [Canadian product monograph]. Histon, Cambridge, United Kingdom: GW Pharma Ltd; March 2015
3. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
4. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
5. Norco (hydrocodone/ acetaminophen) package insert. Allergan USA, Inc. Irvine, CA 2016
   
6. Kharasch ED, Hoffer C, Whittington D, et al. Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther 2003;74:543—54.
7. OxyContin (oxycodone HCl extended-release) package insert. Stamford, CT: Purdue Pharma L.P.; 2015.
8. Prozac (fluoxetine hydrochloride) package insert. Indianapolis, IN: Eli Lilly and Company; 2014.
   
9. Dolophine® (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; 2006
10. Ranexa (ranolazine extended-release tablets) package insert. Foster City, CA: Gilead Sciences, Inc. 2016.
11. Geerts WH, Pineo GH, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004;126:338S—400S.
12. Ultram® (tramadol) package insert. Raritan, NJ; Ortho-McNeil Pharmaceutical, Inc.; 2007
13. Rybix ODT (tramadol) package insert. San Diego, CA: Victory Pharma, Inc.; 2009