Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain

Table 2

Drugs commonly used in chronic pain, their main metabolic pathways, efflux transporter implication, and the result of potential interaction with cannabinoids.

Drugs	Efflux transporter substrate	Metabolic pathway	Potential cannabinoid interaction
Morphine	Yes	UGT2B7	Augmented analgesic potency due to efflux transporters downregulation. Dose reduction may be required.
Codeine	No	CYP2D6	Possible augmented analgesia provoked by the active metabolite (morphine) by downregulation of efflux transporter expression. Dose reduction may be required.
Oxycodone	Yes	CYP3A4/5, CYP2D6, UGT2B7, and UGT2B4	Augmented analgesia due to parent drug or active metabolite by efflux transporter downregulation and/or enzyme inhibition. Dose reduction may be required.
Methadone	Yes	CYP3A4, CYP2B6, CYP2C19, CYP2C9, CYP2C8, and CYP2D6	Augmented analgesia due to enzyme inhibition and/or efflux transporter downregulation. Dose reduction may be required.
Tramadol	No	CYP2D6, CYP2B6, and CYP3A	Possible augmented analgesia due to inhibition of metabolism of active metabolite. Dose reduction may be required.
Fentanyl	Yes	CYP3A4	Possible augmented analgesia due to inhibition of metabolism and/or efflux transporter downregulation.
Acetaminophen	Yes	UGT1A1, UGT1A6, UGT1A9, and UGT2B15	Higher levels of acetaminophen due to UGT inhibition and/or efflux transporter downregulation and thus possible hepatotoxicity. Monitor adverse effects.
Duloxetine	No	CYP1A2, CYP2D6	Higher concentration of antidepressant due to metabolizing enzyme inhibition. Dose reduction may be required.; Smoked cannabis may increase clearance of duloxetine. Monitor for loss of efficacy with chronic marijuana use.
Venlafaxine	No	CYP2D6, CYP2C19, CYP2C9, and CYP3A4	Higher concentration of antidepressant due to metabolizing enzyme inhibition. Dose reduction may be required.
Amitriptyline	No	CYP2D6, CYP3A4, CYP2C19, CYP1A2, and CYP2C9	Higher concentration of parent drug and/or active metabolites due to metabolizing enzyme inhibition. Dose reduction may be required.; Smoked cannabis may increase clearance of amitriptyline. Monitor for loss of efficacy with chronic marijuana use.
Valproic acid	No	UGT1A3, A4, A6, A8, A9, A10, UGT2B7, UGT2B15, and β-oxidation in the mitochondria (using carnitine as carrier)	Possible higher levels of valproic acid by inhibition of UGTs or higher levels of cannabinoids due to valproic acid UGT inhibition. In both cases, the interaction could result in hepatic damage. Monitor adverse effects.
Lamotrigine	Yes	UGT1A4, UGT2B7	Higher levels of lamotrigine by UGT inhibition and/or downregulation of efflux transporters. Possible cutaneous reactions. Dose reduction may be required.