The role of inhaled methoxyflurane in acute pain management

Figures & data

Figure 1 Timeline of methoxyflurane use.

Abbreviation: FDA, US Food and Drug Administration.

Figure 2 The Penthrox^® inhaler.

Abbreviation: AC, activated charcoal.

Table 1 Inclusion and exclusion criteria used in the review of available literature

Inclusion criteria	Exclusion criteria
Publications were included that	Publications were excluded that
• Discussed the clinical application of inhaled methoxyflurane at analgesic doses in pain or medical procedures • Related solely to the treatment of trauma pain in specific patient groups including pediatrics, elderly • Related to the treatment patterns and pain management of moderate to severe trauma pain • Explored the safety or inhaled analgesic methoxyflurane with respect to health and safety of healthcare workers and patients	• Discussed the use of inhaled methoxyflurane at anesthetic dosing • Were not conducted in patients or were not focused on human data • Did not report on pain or treatment for pain (emergency or procedural) • Focused on long-term or chronic pain • Focused on the treatment of pain in major trauma • Related solely to patients whose treatment would be outside the legal licensed indication for inhaled analgesic methoxyflurane including pregnant patients or patients with reduced consciousness

Table 2 Overview of studies of methoxyflurane in patients with trauma pain

Reference	Evidence level	Design	Number of patients (received analgesic methoxyflurane)	Age restriction (years)^a	Efficacy results
Registration trial
Coffey et al (20l4)^25,^b	1	Randomized, double-blind, placebo-controlled, multicenter study	300 (149)	≥12	• Significant reduction in 100 mm VAS pain scores compared with placebo at 5, 10, 15, and 20 minutes (P<0.000l) • Greatest estimated treatment effect of -18.5 mm seen at 15 minutes • Pain relief within 10 inhalations for 84.6% receiving methoxyflurane and 51% receiving placebo • 2 patients (1.3%) needed rescue medication vs 25 (16.8% in the placebo group; P=0.0002) • Global medication performance rated significantly better for methoxyflurane than placebo (P<0.000l)
Emergency department use
Gillis et al (2008)^Citation28,^Table Footnoteb,Table Footnotec	5	Observational case series	(59)	>3	• VNRS pain scores significantly reduced by 2.3 at 15 minutes and 3.3 at 30 minutes (P<0.025)
Konkayev (2013)^Citation29	2	Prospective single center cohort study vs IM tramadol	40 (20)	>18	• After 5 minutes: • Pain scores had reduced from 4.1 to 0.6 with methoxyflurane and from 5.5 to 4.2 with tramadol o • Anxiety scores had reduced from 3.9 to 0.4 with methoxyflurane and from 4.6 to 3.4 with tramadol • After 30 minutes, pain and anxiety scores were 0.2 in both groups
Prehospital use
Buntine et al (2007)^Citation26	5	Observational case series	(83)	>18	• Mean (±SE) reduction in VNRS-II scores • 5 minutes: 2.47 (±0.24) • Arrival at hospital: 3.21 (±0.24) by arrival at hospital (both P<0.000l vs baseline) • 72% of patients and 82% of paramedics were satisfied with the level of analgesia
Oxer and wilkes (2007)^Citation30,^Table Footnoteb,Table Footnotec	3	Retrospective study vs IN fentanyl	13,963 (10,706)	NR	• For both agents, >90% of patients reported good or partial pain relief
Middleton et al (2010)^Citation27	3	Retrospective study vs IV morphine and IN fentanyl	42,844 (19,235)	16-100	• Mean (95% CI) reduction in VNRS-II: 3.2 (3.1, 3.2) for methoxyflurane; 4.5 (4.5, 4.6) for morphine; 4.5 (4.4, 4.6) for fentanyl • Effective analgesia (≥30% reduction in pain severity) achieved by 59.1% of patients receiving methoxyflurane, 81.8% receiving morphine, 80.0% receiving fentanyl
Lim et al (20l6)^Citation31,Table Footnotec	1	Prospective, cluster- randomized, crossover study vs IM tramadol	311 (135)	>16	• Median (IQR) reduction in pain scores: • At 5 minutes: 3.0 (-1.3, 4.8) with methoxyflurane vs 1.0 (0.0, 2.0) with tramadol • At 10 minutes: 2.0 (-1.0, 3.0) with methoxyflurane vs 1.0 (0.0, 2.0) with tramadol • Median (IQR) time to effective analgesia: 3.0 (-1.0, 5.0) minutes with methoxyflurane vs 5.0 (-3.0, 5.0) minutes with tramadol • Median (IQR) time to administer first dose: 9.0 (-6.0, 14.0) minutes with methoxyflurane vs 11 (-8.0, 15.0) minutes with tramadol

Notes: Evidence level: Level 1=evidence from meta-analysis or randomized clinical trials, Level 2=evidence from individual studies, Level 3=evidence from quasi-experimental studies, Level 4=evidence from descriptive studies, Level 5=evidence from case reports, Level 6=specialist opinion. ^aAs stipulated in inclusion criteria.

b Mixed population of adults and children.

c Only available as an abstract.

Abbreviations: IQR, interquartile range; IV, intravenous; IN, intranasal; NR, not reported; VAS, visual analog scale; VNRS, verbal numeric rating scale; IM, intramuscula..

Table 3 Overview of studies in pediatric patients

Reference	Evidence level	Design	Number of patients (received Penthrox)	Age restriction (years)^a	Efficacy results
Prehospital
Babl et al (2006)^Citation33	4	Prospective observational case series	(105)	None	• Mean (95% CI) VNRS pain scores (rated by paramedics): • At administration: 7.9 (7.5, 8.3) • At 10 minutes: 3.2 (2.8, 3.7) • 88.5% of paramedics and 91.3% of parents were satisfied to very satisfied with the level of analgesia
Bendall et al (2011)^Citation34	2	Retrospective, comparative study vs IV morphine and IV fentanyl	3,312 (2,093)	5–15	• Effective analgesia (VNRS-II reduced by ≥30%) for 78.3% of patients receiving methoxyflurane, 87.5% receiving morphine and 89.5% receiving fentanyl
Emergency de partment
Chin et al (2002)^35,^b	1	Randomized, double­blind, placebo-controlled study	(41)	>5	• Mean reduction in pain score (faces scale) between 0 and 10 minutes: 4.0 for methoxyflurane and 1.3 for placebo (P<0.05)
Babl et al (2007)^32,^c	3	Prospective observational case series	(14)	5–18	• Four patients with trauma receiving methoxyflurane for bridging analgesia experienced large reductions in pain score • Six patients undergoing medical procedures had satisfactory analgesia

Notes: Evidence level: Level 1=evidence from meta-analysis or randomized clinical trials, Level 2=evidence from individual studies, Level 3=evidence from quasi-experimental studies, Level 4=evidence from descriptive studies, Level 5=evidence from case reports, Level 6=specialist opinion. ^aAs specified in the inclusion criteria.

b Abstract only.

c Mixed population of trauma and procedural pain (all other studies were in trauma pain only).

Abbreviations: IN, intranasal; IV, intravenous; VNRS, verbal numerical rating scale.

Table 4 Overview of studies in medical procedures

Reference	Evidence level	Design	Number of patients (received analgesic methoxyflurane)	Age restriction (years)^a	Efficacy results
Colonoscopy
Nguyen et al (2013)^Citation49	1	Prospective, multicenter, randomized study vs IV midazolam plus fentanyl	251 (125)	18-75	• Pain and anxiety scores similar between the two groups before, during, and after the procedure • Methoxyflurane associated with a shorter recovery time: patients discharged on average 15 minutes earlier than those receiving IV sedation • Overall satisfaction score for methoxyflurane: 94/100
Nguyen et al (2015)^Citation50	1	Prospective, single- center, comparative study vs AADS. Patients were required to have morbid obesity or obstructive sleep apnea	140 (85)	18-75	• Methoxyflurane associated with shorter total procedural time than AADS (24±1 vs 52±1 minutes; P<0.001) • Discharge from hospital occurred earlier with methoxyflurane than with AADS (27.2±2 vs 97±5 minutes; P<0.0001) • 28/34 patients (82%) who received methoxyflurane, and had received AADS previously, said they would prefer to receive methoxyflurane in the future
Prostate biopsy
Grummet et al (2012)^Citation45	2	Prospective, single- center, single-arm study	(42)	NR	• Median VRS pain score immediately after the procedure was 3 (IQR 2-5) • All patients stated they would be happy to undergo the procedure again
Lee and Woo (2015)^Citation47	2	Prospective, single- center, single-arm study	(64)	NR	• Median pain scores (10 cm VAS) were 2.0, 2.4, and 3.0 during digital rectal examination, probe insertion, and needle biopsy, respectively • 30 patients (46.8%) said they would undergo the procedure using the inhaler again; 9 (14%) said they would prefer local anesthetic
Huang et al (2016)^Citation46	2	Prospective, single center, comparative study vs methoxyflurane plus PILA	72 (42 methoxyflurane alone; 30 methoxyflurane+ PILA)	NR	• Median postbiopsy VRS pain intensity was 3 (IQR 2-5) in the methoxyflurane group vs 2 (IQR 1-3) in the methoxyflurane+PILA group (P=0.014)
Bone marrow biopsy
Spruyt et al (2014)^Citation43	2	Single center, randomized, double­blind, placebo­controlled study. Patients in both groups also received local anesthesia	97 (49)	≥18	• Mean NRS (±SD) scores for “worst pain”: • Overall: 4.90 (±2.07) for methoxyflurane vs 6.0 (±2.24) for placebo (P=0.011) • During aspiration: 3.3 (±2.0) for methoxyflurane vs 5.0 (±2.4) for placebo (P<0.001) • 49% of patients receiving methoxyflurane rated the medication as “very good” or “excellent” vs 16.5% of patients receiving placebo (P=0.005)
Burn and wound care
Wasiak et al (2014)^Citation51	3	Prospective single-center case series	(15)	NR	• Median (IQR) NRS pain scores were significantly higher postdressing than predressing: predressing 2 (1-3) vs postdressing 3 (1.5-4); P=0.01 • Median (IQR) NRS anxiety scores reduced significantly following wound dressing: predressing 5 (4-7) vs postdressing 2 (1-2); P<0.001
Gaskell et al (2016)^Citation44	3	Joint publications including crossover comparator and case series Single center, randomized, crossover study vs ketamine-midazolam PCA	(8)	>16	• Five patients expressed a preference for methoxyflurane over ketamine-midazolam
		Joint publications including crossover comparator and case series Case series	(123)	>16	• Methoxyflurane successfully facilitated analgesia in all 91 dressing changes carried out in 41 patients • 82 patients underwent minor surgical and radiological procedures: PCAmethoxyflurane provided adequate analgesia in 77 (94%) of these
Nasoduodenal intubation
Moss et al (2011)^Citation48	1	Randomized, double­blind, placebo­controlled study	60 (30)	NR	• Patient comfort during nasoduodenal intubation was better with methoxyflurane (5.0, 95% CI 4.0, 6.0) than with placebo (2.7, 95% CI 1.8, 3.7; P=0.002) • No significant differences for comfort levels overall (4.8 vs 4.0, P=ns)
Bridging analgesia in labor
Anwari et al (2015)^Citation52	5	Prospective observational study	(64)	NR	• Mean baseline NRS pain score reduced from 8.2±1.5 to 6.2±2 after first inhalation (P<0.0001), 4.8±2.0 after the second inhalation (P<0.0001), and 3.4±1.5 after the third inhalation (P<0.0001) • Richmond Agitation Sedation Scale improved after each inhalation cycle (P<0.0001)

Notes: Evidence level: Level 1=evidence from meta-analysis or randomized clinical trials, Level 2=evidence from individual studies, Level 3=evidence from quasi-experimental studies, Level 4=evidence from descriptive studies, Level 5=evidence from case reports, Level 6=specialist opinion. ^aAs stipulated in inclusion criteria.

Abbreviations: AADS, anesthesia-assisted deep sedation; IQR, interquartile range; NR, not reported; NRS, numeric rating scale; PCA, patient-controlled analgesia; PILA, peri-prostatic infiltration of local analgesia; VAS, visual analog scale; VRS, verbal rating scale.

Table 5 Overview of nephrotoxicity and serum fluoride levels

	MAC hours	Serum fluoride levels (μmol/L)	Blood methoxyflurane (mg/mL)
Analgesic dosing of methoxyflurane
Penthrox 3 mL	0.3	4.7^b	0.006-0.026^a
Anesthetic dosing of methoxyflurane
Calculated average	1.0	20	10-13
Safe upper limit	2.0	40	20-26
Subclinical toxicity	2.5-3.0	>50	25-33
Clinical toxicity	>5	>90	>45

Notes: Data from Dayan.^{54 a}Based on data of 0.6–2.6 mg/100 mL blood.

b Derived from analysis of mean serum fluoride levels in patients undergoing bone marrow biopsy.

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