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Inhaled methoxyflurane vs intranasal fentanyl in acute tactical

analgesia within the NZDF


Capt M OʼReilly MBChB, RNZAMC

Introduction

Traditionally the NZDF has managed acute severe pain in a tactical environ-
ment, specifically in echelon I / II care, with either Intravenous (IV) or Intramuscular
(IM) morphine.

IV morphine is the gold standard against which alternatives have been typi-
cally measured. It is rapid, effective, titratable and well tolerated by most patients
with minimal significant side effects. However, it is contingent on the availability of
IV access. This can be difficult to accomplish in an austere battlefield environment
and in the context of battlefield casualties.

IM morphine has typically been utilised in the tactical phases of care by both
non medical and medically trained personnel. Historically, in the form of an IM
autoinjector. The widespread use of IM morphine autoinjectors, sometimes issued
down to the level of the individual soldier, has fallen out of favour internationally,
primarily due to a lack of proven efficacy and both potential and realised risks as-
sociated with their use.

The primary benefit of IM Morphine in a tactical environment was the ability


to provide relatively effective analgesia in a simple delivery vehicle without the
need for IV access. Meaning that analgesia could, in theory, be delivered quickly
and effectively to patients in a high stress, austere environment. IM Morphine is
however a relatively poor tactical analgesic. Time to maximum plasma concentra-
tion, and hence effect, is highly variable between individuals; a factor of both de-
livery technique and variable local blood flow at the site of injection. Maximum
plasma concentration can occur between 5 and 30 minutes post IM injection mak-
ing effective titration of dose difficult in anything other then the most controlled of
clinical environments. It also shares the cardiovascular depression, familiar to the
opiate family, making it’s use in hypovolaemic trauma patients potentially risky.

The NZDF has recently added Inhaled Methoxyflurane (MTX) to it’s treatment
protocols for acute relief of severe pain, including combat related injuries. It has, in
theory, many of the benefits of IM morphine without the drawbacks. It provides
rapid effective analgesia in a simple delivery system with predictable pharmacoki-
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

netics. It has a long pedigree, having been extensively utilised by Australian Pre-
hospital Providers, including the military.

Given that it has some proven utility in the civilian prehospital environment,
it’s tactical use however remains untested and controversial.

There are significant limitations inherent in the pharmacology of MTX, within


the military setting, particularly in the context of the tactical environment that
should preclude it’s use.

Fentanyl is used by US military medics, in the form of 400µg Trans Buccal


Lozenges, as an analgesic in battlefield care. It has a rapid onset, short duration of
action and has a safer side effect profile than other opiates. As a result, it appears
an effective alternative to IM / IV morphine. However, it’s use in the NZDF would
be limited by cost and availability. A more readily available alternative to the buc-
cal route is Intranasal fentanyl (INF). Intranasal dosing of medications is an attrac-
tive prehospital delivery mechanism. It is needleless and relatively painless. The na-
sal mucosa has a large and well perfused absorptive surface facilitating rapid drug
absorbance. As in IV delivery, it allows direct absorption to the blood stream avoid-
ing first pass metabolism and ensuring good bioavailability resulting in plasma con-
centrations similar to that achieved by comparable doses of IV medications. Intra-
nasal Fentanyl is used extensively in australasian inpatient settings in the manage-
ment of acute paediatric pain, however it retains it’s utility in the treatment of adult
pain. It shares the favourable pharmacokinetics of the IV route, whilst obviating the
need to achieve the same.

Intranasal fentanyl may be a more appropriate option in the management of


acute pain secondary to trauma in a battlefield setting.
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

Methoxyflurane

MTX is a volatile, flourinated, hydrocarbon anaesthesic used in both adult and


paediatric populations since the 1960’s. It has been associated with irreversible,
occasionally fatal nephrotoxicity in anaesthetic doses and it is for this reason that it
is unavailable for use in any dose or format in the US, by edict of the Food and
Drug Administration.

MTX, however, is the most commonly used analgesic in Australian Pre Hospi-
tal Services. It is utilised in doses, less than that recorded to cause significant com-
plications. There have been upward of 3 million patient uses of MTX without re-
corded complication in Australia. Although there remains a relative dearth of re-
search material with regard to it’s use in this setting.

MTX has been adopted by the NZDF as an alternate or adjunct to intravenous


(IV) morphine. It has the advantages of being patient controlled, rapid and effective.
It also obviates the need for IV access.

One of the advantages of MTX over alternate battlefield analgesics is a rapid


onset of action. It has however a short duration of effect. Intermittent inhalation of a
single dose of 3 mL MTX, with oxygen, can extend duration of action to approxi-
mately 60 minutes, however duration of action is typically 15-30 minutes. Only a
small proportion is removed directly from the patients lungs, the remainder is me-
tabolised to flouride, oxalate, difluouromethoxyacetate and dichloracetate. Free
flouride, oxalate and dichloracetate are associated with dose related irreversible
nephrotoxicity. Repeat doses of MTX are limited by this risk of nephrotoxicity, with
a maximum of 6 mL in a single 24 hour period. The short duration of action and a
limit of two doses in a 24 hour period does not usually pose a problem in civilian
pre hospital environments, however with the longer evacuation times typical of bat-
tlefield evacuation systems it’s utility is questionable.

Common side effects of MTX include nausea, vomiting, drowsiness, headache


& dizziness. There are reports of these symptoms being experienced by civilian
providers. Typically civilian providers carry single patients over short distances.
Military ambulances are designed to carry multiple patients sometimes for ex-
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

tended periods. The risk of inadvertent inhalation of MTX is increased as result.


MTX could, in theory, impair the function of medics or drivers operating in the vi-
cinity of the volatilized gas resulting in an increased risk to patients and providers
in the evacuation phase of battlefield care. MTX is associated with hepato-toxicity
even in analgesic doses, though incidence is rare. The repeated exposure to low
doses of incidentally inhaled MTX could theoretically be associated with an in-
creased risk of both hepatic and renal complications.

MTX is significantly less efficacious than both IV Morphine and INF in the
prehospital setting.

MTX is used in civilian practise for the management of pain associated with
isolated orthopaedic injury or with visceral pain associated with blunt trauma or
other causes. It’s use in complex penetrating trauma, typical of battlefield injury, is
untested and potentially risky.

MTX is, by design, a patient controlled analgesic. It is dependent on an effec-


tive inhalation of the gas, initiated and maintained by the patient. Patients with an
altered level of consciousness, impaired ventilation or with facial injuries would be
unable to utilise the device as designed. It has been associated with a transient hy-
potension and bradycardia in anaesthesia. It retains the potential for this in analge-
sic doses and this may limit it’s utility in the management of combat trauma.

MTX has a flash point of 32.8°c in a closed circuit oxygen system and 62.8°c
in air. It is recommended by the manufacturer that care should be used in it’s use in
temperatures greater than 40°c. Recent deployments in both the pacific and central
asia have been to climates in which environmental temperatures have regularly ex-
ceeded this recommended limit and temperatures within typical evacuation plat-
forms have been even higher. While the risk of explosion is minimal, even in the
presence of supplemental oxygen, it cannot be excluded given these conditions.

Given that MTX appears to be a relatively safe and effective analgesic in the
context of civilian pre hospital care, the peculiar and very specific conditions asso-
ciated with the battlefield environment pose significant limitations to it’s use in this
context.
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

Intranasal Fentanyl

Fentanyl is a synthetic opioid with desirable characteristics for the pre hospital
setting. It has a rapid onset, relatively short duration of action and favourable side
effect profile relative to IV morphine. It is used in IV, Intranasal (IN), transbuccal
and transdermal formats. IV Fentanyl has been shown to be as effective as IV Mor-
phine in the prehospital setting. However, it retains the necessity for IV access
which potentially limits it’s utility in a military context as discussed above.

Fentanyl demonstrates rapid and near complete absorption via both the trans-
buccal and IN routes. The US military has favoured the transbuccal route in the
form of 400µg “lollipops” Observational evidence suggests these to be effective first
line analgesics in the care of combat casualties prior to their arrival at surgical care.
However they have some significant limitations. They are vulnerable to abuse in
that they are portable, concealable and easy to access. Though they have a rela-
tively rapid onset for most patients, there is considerable variation in time to peak
concentration (Tpeak ). The median Tpeak of a single 400µg oral lozenge is approxi-
mately 25 minutes though it ranges between 20 − 240 minutes.

INF shares most of the pharmacokinetic properties of IV Fentanyl. Though it’s


Tpeak is longer than IVF (13min to 6min), it remains favourable compared to the
transbuccal route. It’s absorption and time to effect are relatively consistent be-
tween subjects. Time to effect is delayed relative to IVF (5 minutes to seconds),
though time to offset of effect is delayed also. Duration of effect is directly related
to dose, between 120 minutes (75µg INF) and 240 minutes (200µg INF). Given, it’s
predictable kinetics it allows for safe titration to effect.

Fentanyl causes less histamine activation than comparable opiates. As a result


it results in less cardiovascular depression and hence better maintenance of blood
pressure in hypovolaemic patients.

It retains the respiratory and CNS depressive characteristics of morphine.


Though this remains a significant and real risk, the effects are reversible by Na-
loxone as per other opiates. Training should emphasise the same cautions, as cur-
rently highlighted, in the teaching of opiate use to military medics.
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

INF has comparative analgesic benefit to IVM. Rickard et al demonstrated no


significant difference between the two. Though the study has some structural diffi-
culties, it strongly suggests a benefit in the use of INF in patients with difficult IV
access, relative to IVM. This is precisely the benefit we are looking for in a battle-
field analgesic.

There are several commercial vehicles for delivery of intranasal fentanyl. The
simplest and most readily available is the Mucosal Atomiser Device, available as a
consumable leur lock tip with or without 3mm syringe. It is cost effective relative to
the MTX inhaler, simple to use and compact.

MAD Device (Wolfe - Tory)


Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

Summary

Inhaled Methoxyflurane is used in the NZDF for management of severe pain,


including combat related injuries. It has proven utility in the management of acute
orthopaedic and visceral pain in a civilian setting, having been used by Australasian
pre hospital providers over several years. However, it has significant limitations in
it’s use in a tactical setting, including:

• Dose related toxicity

• Inability to titrate to effect

• Short duration of action

• Potential for provider toxicity

• Unsuitability for combat related injuries

Intranasal Fentanyl is a preferable alternative to Methoxyflurane in the tactical set-


ting, where IV access is impractical or unachievable. It’s time to effect is compara-
ble to methoxyflurane but it’s effects are more prolonged. It has predictable phar-
macokinetics and is hence titratable. It’s efficacy is comparable to both IV Mor-
phine and Fentanyl and greatly exceeds that of methoxyflurane. Although it has
side effects similar to other opiates, these effects are reversible and in the instance
of cardiovascular depression, better than comparable opiates.
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

Recommendations

1. Inhaled methoxyflurane
• Append note to DMTP
• Not for use in tactical trauma
• Not to be used if suspicion of pneumothorax
• Caution in prolonged exposure without adequate ventilation
2. Intranasal Fentanyl
• For use in
• Tactical trauma
• Prolonged evacuation time
• Where IV access is impractical or unobtainable
• Dose
• Initial dose
• 180µg (90µg / nostril)
• Subsequent doses
• 60µg q15min
• If RR >10
• Maintain BP > 100 (Palpable radial pulse)
• Titrate to effect
• Prepackaged 90µg doses with 3mm syringe
• Packaging should be locked with an access indicator
• Access to packaging should be accountable to carrying medic
Inhaled methoxyflurane vs intranasal fentanyl in acute tactical
analgesia within the NZDF
Capt M OʼReilly MBChB, RNZAMC

References

1. Johnston S, Wilkes GJ, Thomson JA et al: Inhaled methoxyflurane and intranasal


fentanyl for prehospital management of visceral pain in an Australian ambulance
service. Emerg Med J. Published online May 13, 2010 doi:
10.1136/emj.2009.078717
2. Mclennan JV: Is methoxyflurane a suitable battlefield analgesic? JR Army Med
Corps 2007 153(2):111-113
3. Black IH, McManus J: Pain management in current combat operations. Prehosp
Emer Care 2009:223-227
4. Rickard C, OʼMeara P, McGrail M et al: A randomised controlled trial of intranasal
fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J
Emerg Med 2007 25, 911-17
5. Medsafe NZ, Penthrox Datasheet:
http://www.medsafe.govt.nz/profs/datasheet/p/penthroxinh.pdf
6. Wolfe, TR, Bernstone T: Intranasal drug delivery: An alternative to intravenous
administration in selected emergency cases. J of Emer Nursing 2004 141-47
7. Foster D, Upton R, Christrup L et al: Pharmacokinetics and pharmacodynamics of
intranasal versus intravenous fentanyl in patients with pain after oral surgery. The
Annals of Pharmacotherapy 2008; 42(10): 1380-87