1. 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

2. Clinical Need We need to offer patients analgesia for existing or potential pain Current options: Local anaesthetics, oral analgesics, narcotics and …

3. 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)

4. 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

5. Chemical Description 2.2 dichloro – 1,1 difluoro-ethyl methyl ether C 3 H 4 Cl 2 F 2 O Fluorinated hydrocarbon Mildly pungent odour

6. Pharmacology Analgesia at very low concentrations C max 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

7. 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

8. 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

9. 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 TOXICITY 2.0 MAC HOURS 40 µ mol/LNil SUB-CLINICAL TOXICITY 2.5 – 3.0 MAC HOURS 50 - 80 µ mol/L Delayed return to max pre-op urine osmolality. Unresponsive to vasopressin. Elevated serum uric acid. MILD CLINICAL TOXICITY 5.0 MAC HOURS 90 - 120 µ mol/L ABOVE PLUS: Serum hyperosmolality, hypernatraemia, polyuria. Low urine osmolality CLINICAL TOXICITY 7.0 MAC HOURS 80 - 175 µ mol/L ABOVE PLUS: Pronounced thirst, polyuria

10. 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

11. Clinical Studies Dragon & Goldstein PackerLewisBabl Patient population DentalBurns Aesthetic surgery Pre-hospital Number of patients 262 88 (totalling 406 procedures) 4 per week (over 15 years) 105 Design Case series Findings Effective 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

12. 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 reliefNo relief Methoxyflurane 54.3%38.4%7.3% Intra-nasal fentanyl 52.9%39.8%7.4%

13. Study (Jones): Results Nausea and vomiting was significantly less with MF MF induced a placid state of detachment from pain Assessment of analgesia MeasureMFNO AnaesthetistAll factors satisfactory73.8%70.9% MidwifeComplete or considerable pain relief 83%65% PatientComplete pain relief29%18% Patient (+ 48 hrs)Complete or considerable pain relief 92%83%

14. Clinical experience in Australia Western Australia State Ambulance Service Data 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.

15. 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)

16. 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

17. 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.

18. Examples of Use – Ambulance and Rescue Physical trauma Domestic trauma Motor vehicle accidents Pain / injury Mass casualty Emergency rescue

19. Hospital Accident and emergency Minor surgical procedures Burns / wound management Radiology Oncology Acute pain services

20. First Response Worksite injuries Sporting injuries Injuries at mass public gatherings Physical trauma Fractures / dislocations Burns

21. Defence Forces Battlefield injuries Wounds Physical trauma Minor surgical procedures Military vehicles First aid kits / soldiers packs Casualty stations / field hospitals

22. National Emergency Emergency rescue Physical trauma Mass casualty Remote areas Minimal infrastructure and resources

23. 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

24. Potential Population Patients who may benefit include those: In pain Anxious Pain intolerant Dislike of needles or injections Uncooperative Preparing for a painful procedure

25. Summary Methoxyflurane has been clinically demonstrated over many years to be a safe and effective agent offering patients comfort and relief from pain