Post Authorisation Safety Study (PASS) to Evaluate the Risks of Hepatotoxicity and Nephrotoxicity from Administration of Methoxyflurane (Penthrox) for Pain Relief in Hospital Accident & Emergency Departments in the United Kingdom

Date of ISAC Approval: 
Lay Summary: 
Methoxyflurane (Penthrox) is an emergency pain relief drug that is given in inhaler form in ambulances and Accident & Emergency (A&E) departments. It was approved for use in the UK in 2016. methoxyflurane has been used in Australia since 1975. During that time, there have only been a handful of negative effects that involved the liver and no link to methoxyflurane was proven. However, the UK Medicines and Healthcare products Regulatory Agency (MHRA) suspect that methoxyflurane could possibly be harmful to the liver or kidneys. The MHRA have requested this study to confirm that methoxyflurane does not cause harm to patients. Patients administered methoxyflurane will be compared to patients administered other routinely used pain relief medicines in A&E departments to see if there is a difference in the harmful effects between the groups. The Clinical Practice Research Datalink (CPRD) will be used to boost the number of patients who have used other pain relief so that there can be more confidence in the findings.
Technical Summary: 
Background: Methoxyflurane is an oral inhalation analgesic for emergency relief of moderate-severe pain in conscious adult patients with trauma and associated pain in pre-hospital and A&E departments. Launched in the UK in 25 January 2016, a PASS was imposed to confirm the absence of significant risks of hepatotoxicity and nephrotoxicity. Objectives: The objective of the study is to assess whether there is an increased risk of hepatic or renal events due to methoxyflurane during routine clinical practice pre-hospital and in A&E departments in the UK. Methods: This study is part of a hybrid study design that combines a primary data collection prospective comparative cohort study with methoxyflurane and a concurrent control group, with a retrospective non-concurrent cohort from routinely collected data. Data on exposure to methoxyflurane in patients aged >18 years and 12-week follow-up have been collected from 12 A&E departments. Data on exposure to other analgesics have been collected in the same way for the concurrent control arm. For the non-concurrent control cohort, patients aged >18 admitted with a fracture to A&E (index date) in the 24-month period from 2 November 2013 to 1 November 2015 (prior to the launch of methoxyflurane) will be obtained from the CPRD Gold-HES A&E linkage dataset. Hepatic and renal outcomes in the 12 weeks following index date will be identified in the CPRD Gold and Hospital Episode Statistics (HES) inpatient data. This study will describe each cohort and estimate the incidence rates of hepatic/renal events (cases/patient-month). Comparisons between rates in the prospective-exposure and the historical cohorts will use Poisson regression. Multivariable logistic regression will study factors associated with hepatic/renal events. Event free survival will use Kaplan-Meier analysis. Importance: This study will provide information on the safety of the use of methoxyflurane for emergency pain relief in routine clinical care in A&E.
Health Outcomes to be Measured: 
Hepatic and renal events in primary or secondary care.

Dr Michelle Bradney - Chief Investigator - Medical Developments International
Mr Andrea Falco - Collaborator - OXON Epidemiology - Spain
Mr Ignacio Mendez - Collaborator - OXON Epidemiology - Spain
Miss Kirsty Andresen - Collaborator - OXON Epidemiology - Spain
Miss Lorena Baquero - Collaborator - OXON Epidemiology - Spain
Lucy Tran - Collaborator - OXON Epidemiology - UK
Dr Mai Duong - Collaborator - OXON Epidemiology - Spain
Dr Nawab Qizilbash - Corresponding Applicant - OXON Epidemiology - Spain
Miss Olga de Agustin Bua - Collaborator - OXON Epidemiology - Spain
Mr Raul Rehecho - Collaborator - OXON Epidemiology - Spain

HES A&E;HES Admitted