Does a patient taking mirtazapine require higher doses of buprenorphine due to pharmacokinetic inte

Fråga: Does a patient taking mirtazapine require higher doses of buprenorphine due to pharmacokinetic interactions?

A 37-year-old male heroin addict has successfully been treated with Remeron (mirtazapine) 30 mg every evening for depression for more than six months. Two months ago, buprenorphine was added after he ceased taking heroin. He receives 16 mg/d of buprenorphine Monday-Friday, 32 mg every Saturday and nil on Sundays. The effect of buprenorphine is satisfactory throughout the week, with good control of opioid withdrawal symptoms and only minor adverse effects (perspiration and obstipation). However, 2-3 weeks after initiating the buprenorphine treatment, sleep disturbances with frequent awakenings and nocturnal restlessness appeared. These symptoms seem to disappear Saturday nights (ie after the doubled buprenorphine dose) and are somewhat attenuated Sunday nights. He is otherwise healthy and on no other medication.

Sammanfattning: Since mirtazapine is an antagonist at the adrenergic alpha-2-receptor, it could theoretically worsen the heroin withdrawal symptoms, although this has not been demonstrated experimentally. Both mirtazapine and buprenorphine are metabolised by cytochrome P450 CYP3A4 and could therefore interact pharmacokinetically. However, such an interaction would cause elevated plasma concentrations of one or both of the substances, and result in lower dose requirements. It is possible that the present patient suffers from insomnia due to heroin withdrawal or some other reason, and benefits from the sedating effects of the high buprenorphine dose Saturdays.

Svar: No information on interactions between buprenorphine and mirtazapine was found in Medline, Drugline or standard pharmacological literature.

None of the substances is known to cause insomnia, but sedation is a common adverse effect of both buprenorphine and mirtazapine (1, 2).

Buprenorphine is a partial agonist at the opioid mu-receptors and an antagonist at the kappa-receptors (3). Mirtazapine is an antagonist at the adrenergic alpha-2-receptors, thereby enhancing the synaptic release of noradrenaline and serotonin (4). It is also an antagonist at the 5-HT2 and 5-HT3 receptors (4). Alpha-2-receptors in locus coeruleus are thought to be involved in the heroin withdrawal syndrome, and the alpha-2-receptor agonist clonidine is known to reduce some of the symptoms of opioid abstinence (5, 6). Since mirtazapine is an antagonist on this receptor, one might hypothesize that it might aggravate the heroin withdrawal symptoms, thereby antagonising the effect of buprenorphine.

Mirtazapine is mainly metabolised by cytochrome P450 isoenzyme CYP3A4, and is a weak inhibitor of this enzyme (7, 8). It has an elimination half-time of 20-40 hours (2) and possible day-to-day differences in clearance due to interactions with buprenorphine should therefore not affect the plasma concentration levels to any great extent. Buprenorphine too is metabolised by CYP3A4, and inhibits this enzyme in vitro (9). Consequently, both substances theoretically have the ability to raise the plasma concentrations of each other. Thus, a pharmacokinetic interaction between mirtazapine and buprenorphine would theoretically augment rather than decrease the effects of buprenorphine. 1 Drugdex, Drug evaluations: Buprenorphine. Micromedex, Inc. Vol 104, 2000

2 Drugdex, Drug evaluations: Mirtazapine. Micromedex, Inc. Vol 104, 2000
3 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p. B102-106
4 Parfitt K, editor. Martindale, The complete drug reference. 32nd ed. London: Pharmaceutical Press; 1999
5 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p. C294-300
6 FASS 2000 (The Swedish catalogue of approved medical products). p. 289-290
7 Drugline no 16456 (year 2000)
8 Drugline no 14379 (year 1997)

9 Produktresume Subutex, Läkemedelsverket (www.mpa.se/documentum/SPC/09001be580043dbd.html)