A new approach in pain management for trauma and minor surgical procedures Narges Daliri MD,FAAP
Consultant Pediatric Emergency Medicine
MDI & Global Vision Medical Trading Services Consultant
Clinical Need
We need to offer patients analgesia for existing or potential pain
Current options:• Local anaesthetics, oral analgesics, narcotics
and …
Clinical Need
Current analgesic options may be less than ideal due to:
• Limited efficacy• Inconvenient administration• Length of onset or duration of action• Adverse reactions (e.g., respiratory depression)
Methoxyflurane
• Originally a general anaesthetic agent (no longer)
• Unique in producing powerful analgesic properties at very low sub-anaesthetic concentrations
• Currently indicated for trauma and minor surgical procedures
• Needs NO pre-medication
or fasting
Chemical DescriptionChemical Description
• 2.2 dichloro – 1,1 difluoro-ethyl methyl ether
• C3H4Cl2F2O
• Fluorinated hydrocarbon
• Mildly pungent odour
PharmacologyPharmacology• Analgesia at very low concentrations
• Cmax achieved at 0.59 MAC hours
– No toxic effects recorded under 2.5 MAC hours• Metabolized within liver (CYP 2AE)
– free fluoride– Dichloro-acetic acid– Oxalic acid– Difluromethoxyacetic acid
• Highly Lipophilic
May prolong action Excretion via kidneys
Nephrotoxicity?
• Cases of nephrotoxicity reported in 1970s after large/prolonged anesthetic doses
• Nephrotoxicity is Dose related (anesthesia versus analgesia)– Anaesthetic dose
• Approx. 40 – 60 mL (over 2.5 MAC hours)
– Analgesic dose• 3 – 6 mL (0.3 MAC hours)
• Nephrotoxicity has not been reported when administered in analgesic doses
Study – Nephrotoxicity (Cousins et al):
• 26 male patients divided into four groups
• Age range = 46 years to 57 years
• Methoxyflurane administered at varying anaesthetic levels: 0.5, 1.0 and 1.5 MAC hours
• Administration duration = 3.8 hours (± 0.5 hours)
• Serum inorganic fluoride concentrations measured pre and post operatively
Study (Cousins): Results• Nephrotoxicity is dose related
• Maximum dose of Penthrox® (methoxyflurane) = 6mLs, which equates to approx. 22 µmols/L of fluoride ions
SERUM INORGANIC FLUORIDE IONS
CLINICAL FEATURES
NO TOXICITY2.0 MAC HOURS
40 µmol/L Nil
SUB-CLINICAL TOXICITY
2.5 – 3.0 MAC HOURS
50 - 80 µmol/LDelayed return to max pre-op urine
osmolality. Unresponsive to vasopressin. Elevated serum uric acid.
MILD CLINICAL TOXICITY
5.0 MAC HOURS
90 - 120 µmol/L
ABOVE PLUS:Serum hyperosmolality,
hypernatraemia, polyuria. Low urine osmolality
CLINICAL TOXICITY
7.0 MAC HOURS
80 - 175 µmol/LABOVE PLUS:
Pronounced thirst, polyuria
Clinical Studies
The analgesic safety and efficacy of methoxyflurane has been evaluated in a variety of areas:
• Pre-hospital• Emergency• Burns• Dental• Obstetrics• Aesthetic surgery
Clinical StudiesDragon & Goldstein
Packer Lewis Babl
Patient population
Dental BurnsAesthetic surgery
Pre-hospital
Number of patients
26288 (totalling 406
procedures)4 per week (over 15
years)105
Design Case series Case series Case series Case series
FindingsEffective analgesic with no significant
side effects
No undue sedation, cardiovascular or
respiratory depression, nausea
or vomiting
Changes a possibly unpleasant situation into a relaxing and
pleasant experience
43% reduction in pain scores
within 10 minutes
Clinical Poster (Wilkes and Oxer): Results
• No significant side effects reported• Methoxyflurane particularly useful in children• Analgesic efficacy of methoxyflurane found to be
equivalent to intra-nasal fentanyl
Good / excellent relief
Partial relief No relief
Methoxyflurane 54.3% 38.4% 7.3%
Intra-nasal fentanyl
52.9% 39.8% 7.4%
Study (Jones): Results
• Nausea and vomiting was significantly less with MF
• MF induced a placid state of detachment from pain
Assessment of analgesia
Measure MF NO
Anaesthetist All factors satisfactory 73.8% 70.9%
Midwife Complete or considerable pain relief
83% 65%
Patient Complete pain relief 29% 18%
Patient (+ 48 hrs) Complete or considerable pain relief
92% 83%
Clinical experience in Australia
Western Australia State Ambulance ServiceData over 4 years January 2004-December 2007:
18,478 patients received methoxyflurane (1,493 (8.1%) were aged 2-17 years)
• 9,981 (54.0%) = excellent/good relief• 7,138 (38.6%) = partial relief• 1,359 ( 7.4%) = poor/nil relief
Trauma, musculoskeletal, and abdominal pain were the most numerous individual categories of patients with pain.
Clinical Development Program
Studies are underway in:
• Bone marrow biopsy • Longitudinal epidemiological study (over 37,000
patients)
Investigator-lead studies• Primary/Ancillary analgesia (Emergency department)• Wound management (Burns department)• Interventional radiology (CT Enteroclysis)
Stated contra-indications
• Patients with personal or family history of malignant hyperthermia
• Severe renal or hepatic impairment / failure
• Hypersensitivity to inhaled anaesthetics such as methoxyflurane
• Acute head injury and/or loss of consciousness
Other Considerations
• Characteristic smell (sweet, strong)
• Do not ingest orally or nebulise
• No driving after administration (24 hours) - precaution– Can resume normal days activities– Escort is not required– Use public transport, taxi, etc.
Examples of Use – Ambulance and Rescue
• Physical trauma
• Domestic trauma
• Motor vehicle accidents
• Pain / injury
• Mass casualty
• Emergency rescue
Hospital
• Accident and emergency
• Minor surgical procedures
• Burns / wound management
• Radiology
• Oncology
• Acute pain services
First Response
• Worksite injuries
• Sporting injuries
• Injuries at mass public
gatherings
• Physical trauma
• Fractures / dislocations
• Burns
Defence Forces• Battlefield injuries
• Wounds
• Physical trauma
• Minor surgical procedures
• Military vehicles
• First aid kits / soldiers packs
• Casualty stations / field hospitals
National Emergency
• Emergency rescue
• Physical trauma
• Mass casualty
• Remote areas
• Minimal infrastructure and
resources
Methoxyflurane Use – Severe Burns
• Patient with severe burns and excruciating pain – immersed in water to cool
• Immediate relief from suffering • watch patient’s face
• Clinical team can immediately treat patient
Potential PopulationPatients who may benefit include those:
• In pain• Anxious• Pain intolerant• Dislike of needles or injections• Uncooperative• Preparing for a painful
procedure
Summary
Methoxyflurane has been clinically
demonstrated over many years to be
a safe and effective agent offering
patients comfort and relief from pain