Low-dose methoxyflurane showed superior and faster onset of pain relief compared with standard of care analgesics, therefore should be considered for the management of acute trauma-related pain in emergency settings.

Prompt and effective analgesia is often recommended in patients with acute trauma pain in both pre-hospital and hospital settings. Despite these recommendations, many patients remain under treated leading to dissatisfaction, unnecessary patient suffering and prolonged hospital stay. Several analgesics available in a variety of formulations and routes of administration are widely used in the pre-hospital and emergency care departments. Therefore, it is challenging for health care providers to assess the most suitable and effective treatment. Also, the use of analgesics is correlated with some factors which lead to oligoanalgesia among patients with moderate-to-severe trauma pain. These factors include difficulties with intravenous administration, adverse events, limited efficacy of weak analgesics, logistical constraints and the high administrative burden associated with controlled drugs.

Low-dose methoxyflurane is a non-opioid analgesic that is provided to patients under medical supervision. It is usually self-administered using a handheld inhaler, which is compact, easy to use and also helps to control the level of analgesia. It exhibits several features which makes it an attractive and reliable option for analgesia in emergency and hospital settings. It provides rapid pain relief and if used continuously, this pain-relieving effect can last for 25–30 minutes and can be longer with intermittent use. The adverse events associated with methoxyflurane are also transient and mild which resolves quickly after stopping inhalation. It does not affect cardiovascular function and did not cause respiratory depression.

It is widely prescribed for treating acute pain in adults and children in Australia. However, in Europe, it is approved for the treatment of moderate-to-severe trauma pain in adults. This approval was granted based on the randomized, double-blind, placebo-controlled trial (STOP trial), which indicated statistically and clinically significant reductions in pain intensity with low-dose methoxyflurane. Also, it was found to be more effective than standard of care analgesics for the management of moderate and severe acute trauma pain.

Rationale behind research

There is a need to conduct high-quality analysis for evaluating the efficacy and safety of analgesics in acute trauma-related pain to help healthcare providers in treatment-related decision making. Therefore, this study was conducted. 

Objective

The purpose of this study was to compare the safety and efficacy of low-dose methoxyflurane and standard of care analgesics in patients with emergency trauma-related pain.

Literature search

Clinical databases such as MEDLINE and Embase were searched for relevant articles using search terms methoxyflurane AND emergency AND randomi*. The PICO (population, interventions, comparisons, and outcome) framework was used to define eligibility criteria.

Inclusion criteria

The studies were eligible for inclusion if:

• they were prospective randomized clinical trials published in English
• they comprise adults who had received emergency care for acute musculoskeletal and trauma-related pain
• they involve the use of low-dose methoxyflurane and the standard of care analgesics (NSAIDs, paracetamol, weak or strong opioids, or no treatment) ± placebo as the comparator. If the placebo inhaler was used then all the standard of care analgesics were utilised before treatment initiation and if a placebo was not used, the standard of care analgesics was administered at the initiation of treatment or in the first minute after treatment initiation

Study selection and Data extraction

Independent screening of all the titles and abstracts which were identified in the search was done. The full text of eligible abstracts was further screened and reviewed. The articles which met the eligibility criteria after full-text screening were enrolled.  Data related to demographics, pain intensity scores, exposure, time to pain relief, treatment satisfaction, and AEs was extracted from included studies by two reviewers independently. A third reviewer was referred for resolving any disagreement.

Statistical Analysis

Individual patient data was used to carry out analysis with the one-step approach. A repeated-measures analysis of variance (ANOVA) model was used to compare differences in pain intensity. This model includes the study, nominal time point, treatment, and the interaction between treatment and nominal time point. Evaluation of heterogeneity between the studies and consolidation of results was done using a two-step approach. Repeated measures ANOVA was used to interpret each data set separately.  The weighted average of treatment effects with a random-effects model was used to combine the treatment effects across studies.

Quality assessment

• The efficacy analysis was done on population (MAP1) which comprised of all the patients aged ≥18 years and randomized to receive low-dose methoxyflurane or standard of care analgesics ± placebo
• Safety analysis was carried in all the patients who were administered with at least one dose of study medication and a subpopulation of elderly patients aged ≥65 years
• Sensitivity analysis was carried in studies considering the use of standard care analgesics which were administered before initiation of treatment or in the first 20 minutes after treatment initiation

Risk of Bias

The pain intensity was recorded on a 100 mm VAS [where 0=no pain and 100=worst pain imaginable] in most of the studies. The association between NRS at randomization and the closest value in the VAS was evaluated to assess potential bias regarding the use of NRS.

Study outcomes

• The primary outcome was differences in pain intensity between baseline and various time intervals (5, 10, 15, 20, and 30 minutes) after starting treatment
• The secondary outcomes included differences in relative pain intensity, response criteria (level of pain ≤30 mm), time to pain relief after the first inhalation, treatment satisfaction and safety

Outcomes

Study characteristics:

• Among 56 articles identified, only 4 articles with a total of 1,260 patients were included

Study quality:

• All the 5 studies included were randomized controlled trials

Effect of intervention on the outcome:

• Treatment with low-dose methoxyflurane showed statistically significant differences in pain intensity compared to standard of care analgesics. These differences were maintained across all time points
• Low dose methoxyflurane showed superiority over standard care analgesics for achieving response criteria of pain intensity, relative reductions in pain intensity and time to pain relief
• Treatment satisfaction was greater in the proportion of patients administered with low-dose methoxyflurane (63.5%) compared to those treated with standard care analgesics (49.2%)
• The incidence of adverse events was comparable between methoxyflurane and standard of care analgesics

The present meta-analysis confirmed the superior efficacy of low dose methoxyflurane over a range of standard of care analgesics for the treatment of acute trauma pain in emergency care settings. It has also demonstrated the faster onset of pain relief among patient administered with low dose methoxyflurane. The superior analgesic effect of low-dose methoxyflurane was consistent for a range of other endpoints, including response criteria and time to pain relief.

Patients administered with low dose methoxyflurane also reported greater treatment satisfaction compared to standard of care analgesics. The adverse event profile of all the analgesics was also comparable. The incidence of mild transient dizziness and somnolence was higher with low-dose methoxyflurane. Also, the efficacy of low dose methoxyflurane was comparable in patients aged ≥65 years and the overall population, but the data in the elderly subgroup should be interpreted with caution due to low patient numbers.

Along with faster pain relief, methoxyflurane exhibits additional benefits over other short-acting analgesics such as a non-opioid mechanism of action, ease of use, and the ability to self-titrate for pain control. This study also established the use of low-dose methoxyflurane as a highly effective short-term treatment option, thereby providing reassurance to healthcare providers in emergency settings.

For self-administration, it is essential to coach patients for inhaler use. Methoxyflurane should be added to the inhaler through a one-way valve and absorbed by a polypropylene wick. After absorption, the methoxyflurane vaporizes and therefore can be easily inhaled through the mouthpiece. At first, patients are advised to take gentle breaths and inhale intermittently for adequate analgesia. Any exhaled methoxyflurane will be captured in an activated chamber, thereby reducing the exposure risk.