Abstract
Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug–drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.
Highlights
In the past years, the prevalence of cannabis consumption has steadily increased with differential Δ9-tetrahydrocannabinol (THC) content in different preparations [1]
A positive test for any cannabinoid measured by immunological test was considered a positive test for Patients reported once-daily cannabis use at night had their serum cannabinoid levels measured, as outlined above
A decreased metabolite-to-parent drug ratio indicates reduced N-dealkylation, suggesting that cannabis preparations consumed by our patients inhibited CYP3A4 activity in favor of other metabolic pathways
Summary
The prevalence of cannabis consumption has steadily increased with differential Δ9-tetrahydrocannabinol (THC) content in different preparations [1]. Patients undergoing opioid maintenance therapy (OMT) represent a. European Archives of Psychiatry and Clinical Neuroscience (2021) 271:847–856 symptoms and successful OMT [9]. Relapse prevention depends on sufficiently high drug concentrations [11,12,13]. To optimize efficacy and tolerability and to control buprenorphine’s susceptibility to critical drug–drug or food–drug interactions [9, 10, 14], therapeutic drug monitoring (TDM) should be applied [8]. Analysis of buprenorphine and norbuprenorphine in blood may support the clinician regarding the need for changes in drug dosage or administration patterns and enables detection of non-compliance. The drug concentration-to-dose ratio in conjunction with the metabolite-to-parent drug ratio presents a valid parameter for assessing compliance [15, 16]
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