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