To our knowledge, this is the first study presenting fatalities associated with LAI BUP despite previous studies of the characteristics of buprenorphine deaths [13]. LAI BUP includes several benefits for OAT patients, OAT units, and society [3, 4, 6]. In 2020, in Finland, over half of the deceased BUP OAT patients received LAI BUP.

OAT in Finland is regulated by the Decree of the Ministry of Social Affairs and Health on the detoxification and substitution treatment of opioid addicts with certain medicinal products [14]. According to the legislation, OAT must be based on a treatment plan that specifies, besides pharmacotherapy, the objective of the patient’s treatment, other medical and psychosocial treatment of the patient, rehabilitation, and treatment follow-up [14]. According to Finnish treatment recommendations, OAT should always include individually planned psychosocial treatment [15]. A study that involved interviewing LAI BUP patients reported that it is essential to offer regular contact and additional forms of non-medical support to allow patients the best opportunity to succeed [16]. Despite the inevitable need for psychosocial treatment and rehabilitation, the results of our study demonstrate that LAI BUP treatment mainly consisted of delivering medication, while psychosocial treatment was lacking. Even patients who had recently started OAT received only minimal psychosocial support.

LAI BUP was initially recommended for compliant patients wishing to avoid daily visits to OAT units [3, 4]. Most Finnish OAT patients have concomitant use of ethanol, illegal drugs, or prescribable medications [9, 17]. In our study, nine out of ten patients had regular concomitant substance use, four had been in OAT less than six months before death, and three patients were classified as non-compliant with OAT. When OAT medication is delivered daily at the OAT unit, personnel meet the patients regularly and assess their need for extra support or withdrawal of concomitant substances. The three non-compliant patients in our data had shown signs of non-compliance with OAT, such as missed OAT visits and clinical signs of intoxication, but received no extra support. In OAT with LAI BUP, it might be even more essential to monitor patients carefully to recognize the need for additional support because patients visit OAT units less frequently than in BUP-NAL or methadone treatment. It seems that more actions could have been taken to support the LAI BUP patients’ treatment adherence before they died.

Concomitant substance use is a persistent concern among Finnish OAT patients [18]. In the United Kingdom, six months after initiation of LAI BUP, three out of 12 patients had used morphine or heroin, based on either self-reporting or urine drug screens, two had used cocaine, and none had used benzodiazepine or amphetamine [19]. According to the patient records in our study, one patient had known concomitant tramadol use, but none had known concomitant buprenorphine use. The PM toxicology results, however, suggested concomitant buprenorphine use by two additional individuals in this study. Previously reported average plasma BUP concentrations in intravenous BUP use, sublingual BUP OAT, and LAI BUP aligned with each other [20]. They were lower than the average PM whole-blood concentration in our study. For example, with a 128 mg LAI BUP dose, the maximum BUP concentration was reported to be 6.59 µg/l and the trough concentration 0.93 µg/l [20], whereas our patient #9 had PM BUP concentration of 21 µg/l 22 days after the injection. Non-prescribed benzodiazepines were detected in the patients. The potentially dangerous combination of benzodiazepines and buprenorphine is well documented [21]. Benzodiazepine prescriptions have been associated with an increased risk of fatal and non-fatal opioid overdose and all-cause mortality [22]. Co-prescription of benzodiazepines, z-drugs (zopiclone and zolpidem), and gabapentinoids has been associated with increased mortality among opioid-dependent individuals [23].

More deaths occurred among patients receiving LAI BUP than sublingual BUP-NAL, although BUP-NAL was the most common OAT medication at the time of this study. However, as the number of cases was relatively small, it is difficult to draw further conclusions from this disproportion. Only 8% of buprenorphine deaths in Finland occurred among OAT patients [9], but it remains unknown whether LAI BUP possesses a greater risk of OAT death. Future research is essential in order to reveal risk factors in LAI BUP treatment and fatalities.

The PM BUP and NBUP concentrations among patients in LAI BUP treatment, with the medians of 8.5 µg/l and 6.6 µg/l, respectively, were higher than previously reported in parenteral buprenorphine abuse. The PM median BUP concentrations in Finnish buprenorphine-related deaths were 1.2–1.4 µg/l [24] and 4 µg/l [9], in France 5.8 µg/l [25] and 2.2 µg/l [26], in Singapore 1.3 µg/l [27], in Sweden 0.4–2.7 ng/g [28], and in Australia 3.0 µg/l [13]. In our study, the blood BUP/NBUP ratio was greater than 1 in eight cases, and only three of them were determined to be buprenorphine poisonings. Previous studies have reported median BUP/NBUP ratios greater than 1 in buprenorphine poisonings, and < 1 in cases other than poisonings [24, 28]. In general, buprenorphine toxicity is difficult to assess by PM blood concentrations only, and consequently, urinary metabolite ratios have often been used to support diagnosis [29]. OAT medications and treatment practices are developing, which poses a challenge for forensic toxicology and the interpretation of toxicology results in the context of cause-of-death investigations.

The strength of our study was the population-based setting, which meant that our data most likely included all LAI BUP deaths in Finland. All unexpected deaths and possible poisoning deaths underwent a medico-legal cause-of-death investigation with toxicological analysis, and over 95% of the OAT units replied to our inquiry about OAT status and sent us patient records. Having all the patient records of the deceased OAT patients allowed us to thoroughly assess their OAT performance.

The small number of deaths in LAI BUP treatment was a limitation. No statistical comparisons between LAI BUP and other OAT medications or generalizations of mortality in LAI BUP treatment were possible.