Received: 4 August 2018 Revised: 2 May 2019 Accepted: 19 July 2019 DOI: 10.1111/bcp.14082 ORIGINAL ARTICLE Risk assessment of using off‐label morphine sulfate in a population‐based retrospective cohort of opioid‐dependent patients Célian Bertin1,2 | Jessica Delorme1,2 | Marie Riquelme1,2 Georges Brousse4 | Alain Eschalier1,2,5 | Denis Ardid1,2,5 | | Hélène Peyrière3 Chouki Chenaf1,2 | | Nicolas Authier1,2,5 1 CHU Clermont‐Ferrand, Inserm 1107, Neuro‐ Dol, Service de Pharmacologie médicale, Centres Addictovigilance et Pharmacovigilance, Centre Evaluation et Traitement de la Douleur, Université Clermont Auvergne, Clermont‐Ferrand, France 2 Observatoire Français des Médicaments Antalgiques (OFMA), CHU Clermont‐Ferrand and Université Clermont Auvergne, Clermont– Ferrand, France 3 CHU Montpellier, Laboratoire de Pharmacie Clinique, Département de Pharmacologie Médicale et Toxicologie, Centre Addictovigilance, Université de Montpellier, Montpellier, France 4 CIRCEA, Service de Psychiatrie‐addictologie, Université Clermont Auvergne, Clermont‐ Ferrand, France 5 Faculté de Médecine, Institut Analgesia, Clermont‐Ferrand, France Correspondence Célian Bertin, Service de Pharmacologie médicale, 58 rue Montalembert, BP69, FR ‐ 63003 Clermont‐Ferrand. Email: cbertin@chu‐clermontferrand.fr Funding information Agence Nationale de Sécurité du Médicament et des Produits de Santé, Grant/Award Number: 20145013 Aims: Several addictovigilance studies have described the off‐label use of morphine sulfate (MS) for nonchronic pain in opioid use disorder (OUD) patients as an alternative to conventional opioid substitution treatments (OSTs). This study primarily sought to compare the incidence of unintentional opioid‐related overdose in the year following the prescription initiation in off‐label MS users, compared to OST‐ maintained patients. Methods: Sequential cohorts of OUD patients who were regularly dispensed MS, buprenorphine, or methadone, between 1 April 2012 and 31 December 2014, were retrospectively identified using the French nationwide healthcare data system. The incidence of overdoses, deaths, doctor shopping, and complications of a viral, bacterial or thrombotic nature, was compared using the Cox regression method. Results: Overall, 1075, 20 834 and 9778 OUD patients without chronic‐pain were included in the MS, buprenorphine, and methadone cohorts, respectively. Overdose incidence was 3.8 (P < .01 [95% confidence interval (CI): 2.1–6.8]) and 2.0 (P = .02 [95%CI: 1.1–3.6]) higher in the MS cohort vs buprenorphine and methadone, respectively. Death incidence was 9.1 (P < .01 [95%CI: 3.2–25.9]) and 3.9 (P < .01 [95%CI: 1.4–10.7]) higher in the MS cohort vs buprenorphine and methadone, respectively. The incidences of other associated risks were significantly higher in the MS group vs OSTs, except for hepatitis C viral infection and thrombotic complications. Conclusion: This first French comprehensive nationwide study reveals increasing overdose, death, bacterial infection, abuse and diversion risks when off‐label MS is initiated as alternative to OST. These results question the relevance of prescribing MS as a safe opioid maintenance treatment, considering its health risk profile. K E YW OR D S abuse, addiction, misuse, opioid, overdose The authors confirm that the PI for this paper is Prof. Authier Nicolas, and that he had direct clinical responsibility for patients and databases. 2338 © 2019 The British Pharmacological Society wileyonlinelibrary.com/journal/bcp Br J Clin Pharmacol. 2020;86:2338–2348. BERTIN ET AL. 1 I N T RO D U CT I O N | 2339 What is already known about this subject Over the past decade, we have noticed a rise in pharmacovigilance sig- • In France, slow‐release oral morphine sulfate is at times nals associated with increased opioid‐related overdose and death in prescribed off‐label to patients with opioid use disorder developed countries. These alerts, initially focused on North America, after failure or undesirable effects with conventional have gradually spread to most industrialized countries, thus becoming treatments (methadone or buprenorphine). a global public health concern.1-5 These signals reveal a worrying • Previous field studies have shown that prescribed oral increase in unintentional intoxications linked to prescribed opioid anal6,7 gesic overuse, causing many deaths. morphine sulfate is commonly diverted by intravenous This has led the US Public injection at high doses, without knowledge of this 8 Health Agency to declare this situation a national health emergency. practice's associated risks. While oxycodone is likely to be the most often implicated drug in the USA, other opioid analgesics, such as fentanyl or morphine sulfate What this study adds (MS), are involved in the worldwide spread.2,5,9 • Comprehensive data confirm the field findings and clarify In France, MS is available in rapid‐ and slow‐release oral formula- the extent of off‐label morphine sulfate use in an opioid‐ tions indicated for severe acute or resistant chronic pain, especially dependent setting. cancer pain. In several European countries like Austria, Luxembourg, Slovenia, Bulgaria and Switzerland, a slow‐release oral morphine • The increased risk of overdose and death found in the (SROM) formulation was approved for managing opioid use disorders year following the initiation of morphine sulfate in (OUD).10 In France, SROM is at times prescribed off‐label, outside its opioid use disorder patients prevents this molecule to analgesic recommendations. MS may then constitute an alternative to be considered a safe alternative to conventional opioid substitution treatment (OST) for a minority of OUD patients treatments. with insufficient efficacy or undesirable events following conventional OST: high‐dose buprenorphine (HDB) or methadone (MTD). These patients are sometimes more relieved by MS. However, as the French initial administration route has become a current public health prob- monitoring centre for drugs and drug addiction has shown, some lem. According to a survey of drug users, the effect of intravenous OUD patients may misuse the prescribed MS without the prescriber's MS injection is likely to be shorter than that of heroin, resulting in knowledge. This misuse corresponds more to a recreational addictive increased injections and the risk of complications, such as overdosing, behaviour than a substitute purpose. Between 2003 and 2006, this viral and bacterial infections, and thrombosis.20 recreational use increased from 3.2 to 9.0% among users of risk Most developed countries worldwide are currently facing a sharp reduction centres, while the proportion of patients using MS as an increase in overdosing and deaths associated with prescribed opioid alternative to OST remained stable during this period.11 While analgesics, which are gradually diverted from their original indications. diverted MS use in OUD patients is not entirely new, this phenome- In France, these MS off‐label prescriptions to OUD patients are per- non remained limited until 2011.12 At that time, for some opioid‐ formed without knowledge of the associated risks, related to both dependent drug users, a shortage in heroin led to a reduction in its the direct effect of the opioid or its route of administration. quality/price ratio and transition to prescribed or black‐market MS, This study primarily sought to compare the incidence of uninten- for which the quality was constant.13 Indeed, by drug users, MS is tional opioid‐related overdose in an OUD cohort, during the year fol- considered as more easily injectable than MTD, procuring a greater lowing the prescription initiation of continuous and regular off‐label high effect than HDB, which some patients are unable to discontinue MS, compared to that of HDB or MTD‐maintained patients. despite maintenance treatment.14 Several studies have investigated SROM formulations as an OST, yielding heterogeneous results. Two meta‐analyses were unable to identify sufficient data in the literature to assess the use of MS as 2 METHODS | OST due to a lack of good‐quality studies.10,15 No data were found In the absence of formal guidelines for pharmaco‐epidemiological on the risks associated with SROM, especially when administered in studies, the TREND and RECORD (extension of the existing STROBE an unconventional manner. Although very few data are so far available pertaining to the MS guidelines) statements were applied to report the study findings.21-23 use in OUD in France, it occurs that, in most cases, oral MS is diverted for intravenous injection.16,17 Initial data from the first French super- 2.1 | Study plan vised drug‐injection facility in Paris reported that 47.6% of intravenous drug users were shown to inject oral formulations of MS This was a population‐based retrospective cohort study of nonchronic (Skenan).18 This finding has meanwhile been confirmed by the results pain OUD patients treated with MS, HDB or MTD, between 2012 and of various field surveys, where 71–93% of MS users in OUD settings 2015, using anonymous data collection from the exhaustive French reported injecting the drug.17,19 This widespread diversion of the health insurance database. 2340 2.2 BERTIN | Data source ET AL. 2015, allowing for a theoretical follow‐up of at least 1 year for each patient (see Supporting information Figure S1). Data were extracted from the French Nationwide Healthcare Data The index date was defined as the first date of a continuous 90‐ System (SNDS). This database, widely employed for public health day sequence, during which the treatment was regularly dispensed, and pharmacoepidemiological purposes, covers 98.8% of the French i.e. with
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