Characteristics of methadone-related fatalities in Norway

Highlights

• 82% of decedents had used diverted methadone before death.

• Methadone was most often detected in addition to multiple drugs below lethal levels.

• Decedents with no relation to OMT were younger than decedents prescribed methadone.

• Methadone concentrations were not influenced by additional toxicological findings.

Abstract

There are currently over 7000 patients enrolled in opioid maintenance treatment (OMT) programs in Norway. A rise in methadone-related deaths proportional to increasing methadone sales over the period 2000–2006 has been observed, but the causative factors for these fatalities have been elusive. In the present study, individual characteristics, methadone concentrations and additional toxicological findings were analyzed. Methadone intoxication deaths (n = 264) were divided into 3 groups according to toxicological findings in whole blood: group 1 – methadone detected alone, or together with one additional drug at low or therapeutic levels, or a low concentration of ethanol (<1 g/L) (n = 21); group 2 – multiple additional drugs/substances detected below lethal levels (n = 175); group 3 – one or more additional drugs/substances detected at lethal levels, or ethanol >3 g/L (n = 55). Methadone blood concentrations in decedents who had been enrolled in OMT were higher than for decedents not in treatment, in all groups. Blood methadone concentrations around 1 mg/L were present in fatal multi-drug intoxications in OMT patients. Results suggest that some patients may be at risk of dying when combining therapeutic concentrations of methadone with other psychoactive substances. Somatic disease was a common finding among deceased OMT patients. Concentrations in methadone users not enrolled in OMT were predominantly between 0.3 and 0.4 mg/L and were not related to the presence of other drugs. However, methadone concentrations below 0.1 mg/L may be associated with intoxication following methadone use, both alone and in combination with other drugs. Younger male users (mean age 34 years) seemed to have a higher susceptibility to methadone intoxication.

Introduction

Opioid maintenance treatment (OMT) is a key factor in the treatment of heroin addiction and in reducing the morbidity and mortality related to heroin use. By reducing intravenous drug use, OMT additionally helps reduce the spread of HIV and hepatitis C, as well as the medical morbidity associated with these diseases.1, 2, 3 The World Health Organization (WHO) recommends either methadone or buprenorphine for opioid agonist maintenance treatment, and refers to studies showing more effective retention in treatment and reduction in heroin use by methadone when compared to buprenorphine in standard doses.⁴ A recently published study on the evidence-based treatment of opioid addiction⁵ highlighted the importance of using a daily methadone dose exceeding 80 mg and achieving an average plasma concentration of about 0.4 mg/L (corresponding to a concentration in whole blood of approximately 0.3 mg/L, based on a plasma-blood ratio of 1.3:16, 7), to reduce illicit drug use and achieve better treatment outcomes. However, as this concentration⁵ and several other reported therapeutic levels7, 8, 9 overlap with concentrations reported in the literature for methadone-related deaths (Table 1), this could give rise to concern regarding the safety of such recommendations. As summarized below, previous studies of methadone fatalities have not always defined whether decedents were enrolled in OMT or not, whether additional potentially toxic blood drug concentrations were present in addition to methadone or whether decedents had a history of somatic illness. These are all factors that may be relevant in determining causality in methadone-related deaths.

Findings in methadone fatalities in Norway over the period 2000–2006 are previously published.¹⁰ The deaths were in most cases characterized by the presence of multiple additional psychoactive substances. Less than a quarter of the deceased died while in OMT. Methadone concentrations in post-mortem blood from decedents who had died of methadone intoxication did not differ significantly from concentrations in decedents who had died due to other, non-drug related causes of death. This raised the question as to what extent methadone was a critical factor in the deaths attributed to intoxication and, accordingly, whether a specific methadone concentration level could be regarded as potentially life threatening.

Additional information about the causal role of methadone might be garnered through a detailed study of the drug concentrations measured in the previous study.¹⁰ We hypothesized that a causal role for methadone in fatal intoxications would be revealed by lower concentrations in cases where other substances were present at potentially lethal blood concentrations. Methadone concentrations in the absence of lethal levels of other drugs would therefore represent potentially risky concentrations for methadone users. In decedents who had been enrolled in OMT, the effect of a history of somatic disease and/or somatic findings at post-mortem on blood methadone concentrations was studied.

Ultimately, the aim of the present study was to identify potentially life threatening blood methadone concentrations for different groups of methadone users in the studied deceased population.