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 (Penthrox-PASS)

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Combined primary data collection and secondary use of data

Non-interventional study

• Non-interventional study design:
  Cross-sectional

Study drug and medical condition

• Medicinal product name:
  PENTHROX
• Study drug International non-proprietary name (INN) or common name:
  METHOXYFLURANE
• Anatomical Therapeutic Chemical (ATC) code:
  (N02BG09) methoxyflurane

  methoxyflurane
• Medical condition to be studied:
  Pain management

  Hepatotoxicity

Population studied

• Age groups:
  • Adults (18 to < 46 years)
  • Adults (46 to < 65 years)
  • Adults (65 to < 75 years)
  • Adults (75 to < 85 years)
  • Adults (85 years and over)

Study design details

• Study design:
  Hybrid observational PASS combining a prospective methoxyflurane exposure cohort, a prospective concurrent analgesic comparator cohort, and a retrospective CPRD-HES historical cohort. Patients were followed for 12 weeks to assess hepatic and renal outcomes.
• Main study objective:
  To evaluate whether administration of methoxyflurane (Penthrox®) for the relief of moderate to severe trauma-related pain in routine clinical practice is associated with an increased risk of hepatotoxicity or nephrotoxicity compared with other commonly used analgesics in UK Accident & Emergency departments. Secondary objectives included assessing risk in specific patient subgroups, evaluating potential off-label use and overdose, and describing use in patients with relevant risk factors.
• Setting:
  The study was conducted in ten Accident & Emergency departments across the United Kingdom and used linked CPRD-HES databases to identify a historical comparator cohort. Eligible adult patients receiving methoxyflurane or standard analgesics for trauma-related pain were enrolled prospectively and followed for 12 weeks. Historical controls were selected from adults attending A&E with fractures during the 24 months before methoxyflurane launch in the UK.
• Comparators:
  Patients receiving other routinely used analgesics for trauma-related pain, including Entonox®, NSAIDs, opiates and ketamine, as well as a historical non-concurrent cohort from CPRD-HES.
• Outcomes:
  Primary outcomes were hepatic and renal events occurring within 12 weeks following methoxyflurane or comparator analgesic administration.
• Data analysis plan:
  Incidence rates of hepatic and renal events were estimated using Poisson regression. Comparisons between cohorts were performed, factors associated with events were assessed using multivariable logistic regression, and event-free survival was evaluated using Kaplan–Meier methods.
• Summary results:
  No excess risk of hepatic events was observed with methoxyflurane compared with other standard analgesics, and renal events were less frequent in methoxyflurane-treated patients. Most events were mild to moderate, and the study found no safety signal for methoxyflurane-related hepatotoxicity or nephrotoxicity.