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Title: Non-injectable naloxone for the prevention of opioid overdose deaths
Author: McDonald, Rebecca Silvia
ISNI:       0000 0004 7656 4072
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Background and Aims: Naloxone is the standard treatment for reversal of opioid overdoses. Due to risk of needle-stick injury, licensed injectable naloxone products are not well suited for layperson administration or take-home naloxone distribution. The aims of this thesis are threefold: Aim 1) assess the effectiveness and limitations of take-home naloxone provision (any naloxone formulation); Aim 2) compare the pharmacokinetic profiles of non-injectable naloxone formulations; Aim 3) identify non-injectable formulations that provide early naloxone exposure similar to a 0.4mg intramuscular dose. Methods: Primary and secondary data analyses were conducted in two stages. The first stage involved evidence syntheses (including two systematic reviews), with secondary data retrieval from the peer-reviewed literature and international patent applications. The second stage involved pharmacokinetic data analysis of two clinical trials (n=12 and 38 healthy volunteers; open-label randomized cross-over design) of concentrated intranasal naloxone formulations (1mg/0.1mL–16mg/0.4mL range). Results: Re Aim 1: Take-home naloxone meets the Bradford Hill criteria. The intervention is effective at reducing opioid overdose mortality and has a low rate of adverse events. Re Aim 2: Improvised nasal kits using non-concentrated spray (1mg/ml per nostril) have low bioavailability of FIM ≤ 10% (relative to intramuscular administration). Concentrated intranasal spray (≥10mg/ml; administered as ≤0.2mL per nostril) has good bioavailability of FIM = 26-57%. Re Aim 3: Relative to the 0.4mg intramuscular reference, a 2mg/0.1mL nasal spray provided equal naloxone exposure in the first 10-minutes post-dosing and then exceeded blood levels for two hours. Conclusions: Take-home naloxone distribution to opioid users should be introduced as standard of care for the community-based prevention of overdose-related deaths and injury. In the presence of licensed alternatives, continued off-label use of improvised nasal kits is not justified. If approved by relevant regulatory agencies, the 2mg/0.1mL naloxone nasal spray could offer greater acceptability and suitability for take-home naloxone provision.
Supervisor: Strang, John S. ; Taylor, David Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available