Abstract
Recently approved in Australia for the management of major depression and obsessive-complusive disorder, fluvoxamine has a different profile of drug interactions to those involving other selective serotonin re-uptake inhibitors (SSRIs) [1, 1,2]. Methadone is widely prescribed in Australia as a pharmacological strategy for the management of opioid dependence, although regional prescribing patterns are variable [3]. In addition, methadone is also prescribed as an analgesic for the treatment of chronic pain. Factors associated with deaths resulting from methadone overdose have recently been systematically examined in a large cohort, with psychotropic drug combinations identified in 86% of cases [4]. This case report describes a patient who developed symptomatic methadone toxicity after the addition of fluvoxamine to an otherwise stable drug therapy regimen.
Clinical picture
A 28-year-old moderately obese woman was admitted to hospital for the management of an acute exacerbation of asthma with intractable cough. Her past medical history included polycystic ovaries, deep venous thrombosis with multiple pulmonary emboli, previous knee surgery, opiate dependency and depression. Her medication prior to admission had been stable, and included nebulised salbutamol and ipratropium, ranitidine 150 mg twice daily, spironolactone 100 mg twice daily, diazepam 2 mg twice daily and methadone 70 mg daily. Three weeks prior to admission she had commenced treatment with fluvoxamine at a dose of 100 mg daily.
At admission, she was afebrile and normotensive on examination. There were no clinical signs or symptoms of heart failure. Respiratory examination revealed generally decreased air entry and soft expiratory wheeze. A ventilation/perfusion scan and spiral computerised tomography (CT) scan revealed no evidence of pulmonary embolus. Her spirometry was only mildly impaired and her asthma was not considered to be in a significant exacerbation.
Arterial blood gas measurements (ABGs) obtained 5 days after admission revealed that the pCO2 was 48 mmHg (reference range = 33–46) and the pO2 was 56.9 mmHg (range = 82–105) while breathing room air. In view of severe hypoxaemia and hypercapnia indicating hypoventilation, the possibility of respiratory depression secondary to methadone and/or diazepam was considered. On day 8, the pCO2 was 50 mmHg and the pO2 was 56.2 mmHg on air. At this time, methadone was decreased to 50 mg daily and diazepam was tapered to zero during the next 48 h.
Analysis of a venous blood sample obtained at admission revealed a serum methadone concentration of 262 ng mL−1. At the time of discharge (day 12), the serum methadone concentration had declined to 202 ng mL−1, oxygenation had improved but hypoventilation persisted (pCO2 50.3 mmHg, pO2 68.5 mmHg on air). Further improvement was noted at review on day 22, when the pCO2 was 45.3 mmHg and the pO2 79.2 mmHg.
Discussion
Fluvoxamine is a weaker inhibitor of the hepatic isoenzyme cytochrome p450 IID6 (CYP2D6) than other SSRIs, but does inhibit other isoenzymes such as CYP3A4 and CYP1A2 [1, 1,2]. Serious interactions are therefore possible between fluvoxamine and drugs which are substrates for these isoenzymes (see Table 1). This case report is the first to describe an interaction between methadone and fluvoxamine detected after the presentation of a patient with clinical signs and symptoms of methadone toxicity. It is also possible that the severity of the interaction in this case was compounded by concurrent treatment with diazepam.
Methadone is metabolised by the cytochrome p450 3A4 isoenzyme [5]. Bertschy et al. systematically examined the effect of fluvoxamine treatment upon serum methadone concentrations in a series of five patients [6]. Fluvoxamine treatment (50–250 mg daily) resulted in an increase of serum methadone concentrations by up to 40–100% in this study [6]. A subsequent study found that concurrent treatment with fluoxetine has a less-marked effect upon serum methadone concentrations than that observed with fluvoxamine [7]. In a review of the clinical pharmacokinetics of the SSRIs, Bauman also suggests that the interaction between methadone and fluvoxamine may also be partially attributable to the inhibition of CYP1A2 by fluvoxamine, as this isoenzyme is involved in the N-demethylation of some tertiary amine compounds [8].
Drug interactions involving inhibition of CYP3A4 or CYP1A2
The significance of the serum methadone concentrations are difficult to assess in this case. Previous reports [09, 9,10] have revealed that steady-state serum methadone concentrations are subject to considerable interpatient variability. A further complexity is that neurotolerance may result in diminished response to methadone after extended treatment. Notwithstanding these issues, the reduction in serum concentration and clinical improvement observed after the reduction in methadone dosage in this case suggest that this option may be an appropriate management strategy if combination treatment with fluvoxamine and methadone is considered necessary.
There is also potential for a similar interaction between methadone and nefazodone, another recently marketed antidepressant which also inhibits CYP3A4 [2]. In a recent discussion of the clinical pharmacokinetics of nefazodone, Greene and Barbhaiya review reports of clinically significant interactions between nefazodone and drugs metabolised by CYP3A4, and highlight the possibility for other important interactions [11]. Possible drug interactions involving nefazodone are listed in Table 1.
Depression is common among opioid-dependent patients [12]. In addition to its use for the management of substance abuse, methadone is also being increasingly prescribed as an analgesic for patients who are not necessarily opioid dependent. Combination treatment with fluvoxamine and methadone is intrinsically attractive for patients with pain disorders or opioid dependence and comorbid depression. Although single case-reports such as this one cannot provide information about the possible frequency and clinical significance of drug interactions, they can serve to highlight awareness among prescribers. Methadone toxicity secondary to a pharmacokinetic interaction with fluvoxamine is one possible explanation for the findings reported in this case. Clinicians should be aware of the potential for a significant drug interaction between fluvoxamine and methadone.