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Written by

Dr Frank Coffey Dr Frank Coffey is associate professor and consultant in emergency medicine and is director of DREEAM (Department of Research and Education in Emergency medicine Acute medicine and Major trauma), Queen’s Medical Centre Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK

Treating acute trauma pain – the STOP! study

Published 7 October 2016

Dr Frank Coffey summarises the outcomes of the STOP! study investigating the use of methoxyflurane for analgesia in trauma patients

Key learning points

  • Methoxyflurane inhaler (Penthrox®) is an analgesic with rapid onset with many qualities that make it a useful addition to the emergency formulary.
  • In the STOP! study, methoxyflurane reduced pain severity by ~44% and 79.4% of patients achieved pain relief in <10 breaths.

Background

Methoxyflurane is an inhalational analgesic that has been used extensively for over 30 years in emergency settings in Australia and New Zealand. It is self-administered via a handheld, single-use inhaler (Penthrox®), known colloquially as the ‘green whistle’ (see Figure 1).

Figure 1. Penthrox® inhaler

Penthrox

A member of the fluorinated hydrocarbon group of anaesthetics, methoxyflurane anaesthesia was popular worldwide until the 1970s, when it was overtaken by newer anaesthetics and tainted by reports of dose-related nephrotoxicity.1 Clinical experience and laboratory data support the use of methoxyflurane at the much lower doses required for analgesia.2,3 Despite accounts of its effectiveness,4,5 methoxyflurane was not licensed in Europe until recently, and there had been little in the way of high-quality trials evaluating its use. The ‘STOP!’ study was designed to address this gap in the literature.3 Methoxyflurane is licensed for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain.

Study design

STOP! was a randomised, double-blind, placebo-controlled trial conducted at six emergency department (EDs) in the UK. Although desirable, an active comparator was not included due to the practical difficulties in blinding any of the obvious agents for comparison. Some 300 patients presenting with a pain score ≥2 to ≤7 following trauma were randomised 1:1 to receive either methoxyflurane or placebo via a Penthrox® inhaler. The primary endpoint was the change in pain intensity using the visual analogue scale (VAS) from baseline at 5, 10, 15 and 20 minutes. Rescue medication (paracetamol/opioids) was immediately available on request and patients were closely monitored in the ED for adverse events. Blood samples were drawn at the start of the study and at a 14-day follow up visit.3

Results

The results presented here relate to the 204 adult patients recruited into the trial. The demographics and baseline characteristics were comparable between the two groups. Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at all points tested (see Table 1), with the maximum treatment effect of –21mm seen at 15 minutes.3 Overall, methoxyflurane reduced pain severity by ~44%.3 The median time to first pain relief was 5 minutes and 79.4% patients achieved pain relief in <10 breaths.3


Table 1. Analysis of VAS pain intensity score (intention-to-treat population)

Time point
Adjusted* change from baseline
  Estimated treatment effect (95% confidence interval)
 p value

Methoxyflurane (N=102)
Placebo (N=101)

 
Overall
-29.0
 -11.6 -17.4 (-22.3, -12.5)
 <0.0001
5 mins
-20.7
 -8.0 -12.6 (-17.0, -8.3)
 
10 mins
-27.4
 -11.1 -16.3 (-21.4, -11.1)
 
15 mins -33.3  -12.3 -21.0 (-26.8, -15.3)
 
20 mins -34.8  -15.2 -19.7 (-26.0, -13.3)
 
Time by treatment interaction        0.0004

VAS = visual analogue scale.

Pain scores recorded following the start of the planned emergency department procedure were excluded from the analysis. Pain scores taken after initiation of rescue medication were included in the analysis.

*Least squares mean adjusted for baseline VAS pain score and time by treatment interaction. 


There was a higher occurrence of adverse events in the methoxyflurane-treated patients, but overall it was well tolerated, with the majority of reactions reported as mild and transient.3 Blood tests showed no evidence of nephrotoxicity or hepatotoxicity.3

Approximately three-quarters of patients, physicians and research nurses rated methoxyflurane treatment as excellent, very good or good (p<0.0001) on global medication performance.3

Conclusions and implications for clinical practice

The STOP! study supports previous evidence that methoxyflurane is an efficacious analgesic with rapid onset of action.3 It has many qualities that make it a useful addition to the emergency formulary. Methoxyflurane does not require IV access and is not a controlled drug, making it straightforward to prescribe and requiring less patient monitoring. Its portability provides advantages over other inhaled analgesics and it is not contraindicated in suspected pneumothorax or intestinal perforation.

Methoxyflurane may be suitable as a bridging analgesic until access is obtained when more powerful IV analgesia is required. Its use might avoid the need for opioid analgesia in many fractures and dislocations by facilitating splinting or reduction. As well as its role in acute trauma, methoxyflurane has been shown to be effective for non-traumatic pain and as a procedural anaesthetic; however methoxyflurane is not currently licensed for these indications.6,7

  • Dr Frank Coffey is associate professor and consultant in emergency medicine and is director of DREEAM (Department of Research and Education in Emergency medicine Acute medicine and Major trauma), Queen’s Medical Centre Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK

References

  1. Mazze RI, Shue GL, et al. Journal of the American Medical Association 1971;216(2):278–288.
  2. Dayan AD. Human and Experimental Toxicology 2016;35(1):91–100.
  3. Coffey F, Dissman P, et al. Methoxyflurane analgesia in adult patients in the emergency department: a subgroup analysis of a randomized, double-blind, placebo-controlled study (STOP!). Advances in Therapy 2016 Aug 27 [Epub ahead of print].
  4. Grindlay J, Babl FE. Emergency Medicine Australasia 2009;21(1):4–11.
  5. Buntine P, Thom O, et al. Emergency Medicine Australasia 2007;19(6):509–514.
  6. Gaskell AL, Jephcott CG, et al. Anaesthesia 2016;71(4):417–423.
  7. Nguyen NQ, Toscano L, et al. Gastrointestinal Endoscopy 2013;78(6):892–901.

Date of preparation: October 2016; MINT/PAEU-16037