Does clonidine or hydroxyzine interact with buprenorphine?/nA male in-patient with heroin addiction

Fråga: Does clonidine or hydroxyzine interact with buprenorphine? A male in-patient with heroin addiction is undergoing detoxification with a moderate dose of buprenorphine (Subutex) 8 mg q.d. with clonidine (Catapresan) 75 micrograms orally on demand (up to 375 micrograms/day) and hydroxyzine (Atarax) 25 mg 2 in the evening and 2 at bed-time for anxiety. Buprenorphine was instituted 5 days ago. He is not served grape fruit juice. He wakes up with withdrawal symptoms at 5 or 6 in the morning and is very drowsy in the first hours after buprenorphine. Therapeutic drug monitoring has been done. Results are pending.

Sammanfattning: There should not be any significant pharmacokinetic interaction between buprenorphine, clonidine, or hydroxyzine. However, all of the three drugs can cause drowsiness and thus potentiate each other´s sedative effects.

The time-pattern in this case seems to indicate an opioid overdosing in the morning and an underdosing during the night. This might reflect the biphasic distribution-elimination of buprenorphine and this particular patient might benefit from a divided dosing regime, which, however, may be difficult in an out-patient setting. It is also possible that this patient was not as tolerant to opioids as was suspected and that he therefore gets drowsy at peak concentrations and then gets withdrawal symptoms after redistribution of buprenorphine. This should get better as tolerance develops and steady-state levels of buprenorphine are achieved.

Svar: No case reports or studies of drug-drug interactions between buprenorphine and clonidine or hydroxyzine have been found in the literature.

Buprenorphine is a partial agonist at opioid mu receptors and an antagonist at opioid kappa receptors. It is metabolised by cytochrome P450 3A4 (CYP3A4) to norbuprenorphine that is considered inactive in vivo. Buprenorphine has a bi- or triphasic elimination, comprising a distribution phase with a plasma half-life of 2-5 hours, and a terminal elimination phase with a plasma half-life of 20-73 hours (1). Due to the long and variable terminal half-life of buprenorphine, it might take up to 15 days to reach steady state concentrations.

Since buprenorphine is a CYP3A4 substrate, simultaneous intake of grapefruit juice could inhibit first-pass metabolism in the gut, thus resulting in higher peak concentrations but unchanged terminal elimination half-life.

Clonidine is an antagonist of imidazoline and adrenergic alpha-2 receptors and is used for treatment of both hypertension and the heroin withdrawal syndrome. Its effects on withdrawal symptoms are thought to be mainly mediated by alpha-2 blockade in locus caeruleus. Sixty percent of a given dose is excreted unchanged in the urine (2). It may cause drowsiness as a common side effect. The plasma half-life is 10-20 hours (3).

Hydroxyzine is a sedative histamine-1 receptor antagonist used for pruritus and psychoneurotic stress reactions (3). It is thought to be metabolised by CYP2D6 (4). The half-life is 15-20 hours in single-dose trials (3).