Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence

Abstract

Vivitrol adverse event reports suggest the need to investigate two months following the last medicine injection as a period of particular concern for overdose. A registry study would best quantify risk. Providers should report suspected post-discontinuation overdoses to government authorities.

Potential Risk Window for Opioid Overdose Related to Treatment with Extended-Release Injectable Naltrexone

“…Out of 263 potential overdose deaths identified, 52 cases had exposure to injectable naltrexone for opioid use disorder. Among those whose last naltrexone administration date was known (n=28), approximately 18% (n=5) were on treatment (i.e., within 28 days of the last injection), 61% (n=17) occurred after 28 days but before two months, and 21% (n=6) occurred later [9]. These hypothesis-generating data suggest that there may be a one -month post-treatment exposure window during which individuals are at high risk for opioid overdose.…”

Comment on “Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence”

“…Here, we raise concerns regarding the methodology used and conclusions reached in a recent publication by Saucier et al [ 1 ] that retrospectively evaluated cases of spontaneously reported opioid overdose in patients treated with extended-release injectable naltrexone (XR-NTX; VIVITROL ® ) using a US FDA dataset. We concentrate on some specific points, but other concerns include failure to cite published data related to longer-term use of XR-NTX [ 2 , 3 ], citations of media articles, and the funding of this study by a non-scientific advocacy organization [ 1 ].…”

“…Post-marketing safety surveillance is a public health imperative, and Alkermes adheres to rigorous FDA standards regarding the collection, follow-up, and submission of spontaneous case reports for all marketed Alkermes products, including VIVITROL. The most recent Alkermes review of cumulative post-marketing safety data submitted to the FDA (April 2017) evaluated > 360,000 patients treated with XR-NTX and included the data evaluated by Saucier et al [ 1 ]. This review did not demonstrate an increased risk of opioid overdose, including fatal overdose, either on treatment with XR-NTX or within 2 months of discontinuation, as implied by Saucier et al [ 1 ].…”

“…Saucier et al [ 1 ] assert the potential presence of a biologic “rebound effect” following XR-NTX discontinuation (i.e., increased susceptibility to overdose as a result of XR-NTX treatment) [ 1 ]. While animal model data have suggested that chronic naltrexone exposure may lead to an upregulation of opioid receptors in the mouse central nervous system [ 4 , 5 ], there is no evidence that the data from animal models translate to an increased risk of overdose as evidenced by human laboratory data [ 6 , 7 ] or clinical trial adverse events [ 2 , 8 – 13 ].…”

“…We have a number of concerns regarding the methodology used in the analysis. The authors assumed that an “overdose” event was an “opioid overdose” even when the case information regarding the drug(s) taken was missing or unclear [ 1 ]. Applying such adjudication assumptions to missing or incomplete data, which are prevalent in spontaneously reported data, can lead to case misclassification and affect the validity of any conclusions.…”