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Home , Halogenated ether, Methoxyflurane, Sedation

Penthrox®▼ () in the (ED) - is it worth the hype?

Dr Lakshmi Gangadharan Speciality and Associate Specialist Doctor Bedford Hospital NHS Trust

Penthrox educational materials and Prescribing information and information MAT-PEN-UK-000180 Sponsored by Galen Limited training on its use are available from on adverse event reporting can be Date of Preparation: March 2019 Galen on request found at the end of this presentation Disclosures

• Galen has had no editorial input to this presentation but have reviewed to ensure ABPI code compliance only • I have been asked to give my experience of Penthrox at Bedford General Hospital • I am remunerated by Galen for this talk Bedford Hospital NHS Trust ED • 90,000 footfalls/year • 250 patients/day • Tertiary level DGH 88 year old lady, ASA Grade III, 5 day old Colles’ fracture Trauma pain 82 year old male, frail, given IV after management fall, with suspected fracture neck of femur in Bedford ED (another bad 22 year old male with a moderate day at the pneumothorax after trauma, requiring office) intercostal drain insertion

30 year old male with recurrent dislocation of shoulder How could we improve patient throughput? • Methoxyflurane has been used in Australia for the relief of trauma-associated pain in the ED via a handheld device since the 1970s • Currently indicated in the UK for the emergency relief of moderate-to-severe pain in conscious adult patients with trauma and associated pain ® • Patient-controlled analgesia, under supervision Penthrox of a person trained in its administration (methoxyflurane) • Halogenated in the ED • Provides high-quality, well-tolerated analgesia which may negate the need for procedural • In my experience, Penthrox has shown significant advantages including rapid recovery, early return to normal activities and cost savings Checklist for administration of Penthrox®

• C cardiovascular instability • Drugs- CYP 450 inducers • H hypersensitivity to methoxyflurane or any , isoniazid, , fluorinated anaesthetics rifampicin • E elevated temperature from an () • C consciousness reduced (including alcohol) • Nephrotoxic antibiotics • K kidney impairment , gentamicin, colistin, • A age below 18 years polymyxin B, amphotericin B • L lung/respiratory impairment • L liver impairment • L last administration of methoxyflurane • Use of proforma to collect retrospective and prospective data • 30 patients’ data collected between December 2017 to April 2018 ® Penthrox • Compared with RCEM procedural sedation audit data (2015-16) audit • Penthrox was used as a first-line drug for trauma analgesia and as primary analgesia for reduction of fractures and dislocations • Our focus was: Methods • Efficacy • Adverse effects • Time to discharge • Cost effectiveness Efficacy – pain scores fell five VAS points within first minute

• Pain scores out of 10 - prior to administration, 1 minute post administration and 15 minute post administration were recorded • Patient-controlled analgesia - with supervision by trained personnel • 4 cases required the use of further IV procedural sedation (in the form of /) • Three involved anterior shoulder dislocations and, one a bi-malleolar ankle fracture Average time to discharge: 39 minutes

• For patients not requiring additional sedation (4 patients) or admission (9 patients) • Post IV procedural sedation would require a 60 min observation time as per Trust guidelines • Return to baseline vitals, GCS, pain score, no respiratory compromise would be required as per RCEM Safe Sedation guideline A small number of adverse events were recorded in some cases

A few Penthrox audit patients reported noticing a mild/transient taste/smell of the drug and/or feeling ‘drunk’

Adverse By contrast, in the RCEM procedural sedation audit (2015-16) an effects adverse event rate of 4.7% was recorded for procedural sedation None of the patients withdrew from the audit

There were no observed effects on cardiovascular or respiratory parameters • Procedural sedation for reduction of fractures/dislocations requires: o a second doctor and suitably qualified nurse o continuous o IV access o IV drugs/fluids o Costs o suction o resuscitation room o o etc • Penthrox requires: o two trained personnel o a trolley in the ED o one costing £17.89 Limitations of audit • Small single-center study • Lack of comparative data • Uniformity of assessment, operator confidence/experience

Limitations of Penthrox Limitations - Contraindicated in patients with known renal failure for which active treatment is being given or highly likely to significant renal impairment - Should be followed up with oral analgesia or regional blocks for effective and ethical pain management • Effective analgesia for trauma and first-line approach to where possible, negate the need for procedural sedation, especially in the elderly or high ASA grades Conclusions • Can be used as an alternative to Entonox, as it is portable and can be used in trauma where – A CLEAR there is encapsulated air in the body • Fewer potential adverse effects BENEFIT! • Rapid recovery • Decreased time to discharge • Excellent cost effectiveness 88 year old lady, ASA Grade III, 5 day old Colles’ fracture

82 year old male, frail, given IV morphine after Trauma pain fall, with suspected fracture neck of femur management (a better day 22 year old male with a moderate at the office) pneumothorax after trauma, requiring intercostal drain insertion

30 year old male with recurrent dislocation of shoulder Incorporated into Trust guidelines standard operating procedure as primary analgesia for trauma, in conscious patients

In the process of formulating a Ongoing free fracture NOF pathway using work Penthrox® as bridging analgesia

Further data being analysed for publication Consider Penthrox as a 1st choice as it can negate the need for procedural sedation in the ED (for high-risk patients – especially elderly, obese, poor lung My capacity)

Take-Home Easy administration, high compliance, well-tolerated Message: and effective

Early return to normal activities, early discharge and Use lower burden on the available resources Penthrox® in your ED £ Cost effective Penthrox Additional Learnings/Evidence • Randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain • Coffey F et al. Emerg Med J 2014;31:613-618

• Health effects of patients given methoxyflurane in the pre-hospital setting: A data linkage study • Ian G. Jacobs The Open Emergency Journal 2010, 3, 7-13

• Pre-hospital analgesia in adults using inhaled methoxyflurane • Paul Buntine et al. Emergency Medicine Australasia (2007) 19, 509 - 514 References

• Joint Formulary Committee. British National Formulary. 75th ed. London: BMJ Group and Pharmaceutical Press; 2018. • Royal College of Emergency medicine. Procedural sedation in adults clinical audit 2015-16 national report. • Management of trauma pain in the emergency setting: low-dose methoxyflurane or ? A systematic review and indirect treatment comparison Porter KM, Siddiqui MK, Sharma I, Dickerson S, Eberhardt; A Journal of Pain Research 2018:11 11–21 PENTHROX 99.9%, 3 ml inhalation vapour, : Please refer to the analgesic indication, a single dose of 3 ml methoxyflurane produces serum as , or , general anaesthetics, phenothiazines, Summary of Product Characteristics (SmPC) before prescribing. levels of inorganic fluoride ions below 10 micromol/l. In the past when used as tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol Abbreviated Prescribing Information. Presentation: Each bottle of an anaesthetic agent, methoxyflurane at high doses caused significant may produce additive effects. If opioids are given concomitantly with PENTHROX contains 3 ml of methoxyflurane 99.9%, a clear, almost colourless, , which was determined to occur at serum levels of inorganic PENTHROX, the patient should be observed closely. When methoxyflurane was volatile liquid, with a characteristic fruity odour. Each PENTHROX combination fluoride ions greater than 40 micromol/l. Nephrotoxicity is also related to the rate used for anaesthesia at the higher doses of 40–60 ml, there were reports of pack consists of one bottle of 3 ml PENTHROX, one PENTHROX Inhaler and of metabolism. Factors that increase the rate of metabolism such as drugs that drug interaction with hepatic enzyme inducers (e.g. ) increasing one Activated Carbon (AC) chamber. Indications: Emergency relief of induce hepatic enzymes can increase the risk of toxicity with methoxyflurane as metabolism of methoxyflurane and resulting in a few reported cases of moderate to severe pain in conscious adult patients with trauma and associated well as sub-groups of people with genetic variations that may result in fast nephrotoxicity; reduction of renal blood flow and hence anticipated enhanced pain. Dosage and administration: PENTHROX should be self-administered metaboliser status. Methoxyflurane is metabolised in the liver, therefore renal effect when used in combination with drugs (e.g. barbiturates) reducing under supervision of a person trained in its administration, using the hand held increased exposures in patients with hepatic impairment can cause toxicity. ; and class effect on cardiac depression, which may be enhanced PENTHROX Inhaler. It is inhaled through the custom-built PENTHROX inhaler. PENTHROX should be used with care in patients with underlying hepatic by other cardiac depressant drugs, e.g. intravenous practolol during cardiac Adults: One bottle of 3 ml PENTHROX as a single dose, administered using conditions or with risks for hepatic dysfunction. Previous exposure to surgery. Fertility, and lactation: No clinical data on effects of the device provided. A second bottle should only be used where needed. The halogenated anaesthetics (including methoxyflurane when used as methoxyflurane on fertility are available. As with all medicines care should be frequency at which PENTHROX can be safely used is not established. The an anaesthetic agent), especially if the interval is less than 3 months, may exercised when administered during pregnancy especially the first trimester. following administration schedule is recommended: no more than 6 ml in a increase the potential for hepatic injury. Potential effects on blood pressure and There is insufficient information on the excretion of methoxyflurane in human single day, administration on consecutive days is not recommended and the are known class-effects of high-dose methoxyflurane used in milk. Caution should be exercised when methoxyflurane is administered to a total dose to a patient in a week should not exceed 15 ml. Onset of pain relief is anaesthesia and other anaesthetics. Caution is required with use in the elderly nursing mother. Effects on ability to drive and use machines: rapid and occurs after 6-10 inhalations. Patients are able to titrate the amount of due to possible reduction in blood pressure. Potential CNS effects such as Methoxyflurane may have a minor influence on the ability to drive and use PENTHROX inhaled and should be instructed to inhale intermittently to achieve sedation, euphoria, , ability to concentrate, altered sensorimotor co- machines. Patients should be advised not to drive or operate machinery if they adequate analgesia. Continuous inhalation of a bottle containing 3 ml provides ordination and change in mood are known class-effects. The possibility of CNS are feeling drowsy or dizzy. Undesirable effects: The common non-serious analgesic relief for up to 25-30 minutes; intermittent inhalation may provide effects may be seen as a risk factor for potential abuse, however reports are reactions are CNS type reactions such as dizziness and and are longer analgesic relief. Patients should be advised to use the lowest possible very rare in post-marketing use. PENTHROX is not appropriate for providing generally easily reversible. Serious dose-related nephrotoxicity has only been dose to achieve pain relief. Renal impairment: Methoxyflurane may cause renal relief of break-through pain/exacerbations in chronic pain conditions or for the associated with methoxyflurane when used in large doses over prolonged failure if the recommended dose is exceeded. Caution should be exercised for relief of trauma related pain in closely repeated episodes for the same patient. periods during . The following adverse drug reactions have patients diagnosed with clinical conditions that would pre-dispose to renal injury. PENTHROX contains the excipient, butylated hydroxytoluene (E321) which may either been observed in PENTHROX clinical trials in analgesia, with analgesic Hepatic impairment: Cautious clinical judgement should be exercised when cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and use of methoxyflurane following post-marketing experience or are linked to PENTHROX is to be used more frequently than on one occasion every 3 mucous membranes. To reduce occupational exposure to methoxyflurane, the methoxyflurane use in analgesia found in post-marketing experience and in months. Paediatric population: PENTHROX should not be used in children PENTHROX Inhaler should always be used with the AC Chamber which scientific literature (refer to the SmPC for further details): Very common and adolescents under 18 years. For detailed information on the method of adsorbs exhaled methoxyflurane. Multiple use of PENTHROX Inhaler without (≥1/10): dizziness; common (≥1/100 to <1/10): Euphoric mood, amnesia, administration refer to the SmPC. Contraindications: Use as an anaesthetic the AC Chamber creates additional risk. Elevation of liver enzymes, blood urea dysarthria, dysgeusia, headache, somnolence, , , dry mouth, agent. Hypersensitivity to methoxyflurane, any fluorinated anaesthetic or to any and serum uric acid have been reported in exposed maternity ward nausea, feeling drunk; uncommon (≥1/1,000 to <1/100): increased appetite, of the excipients. Patients who are known to be genetically susceptible to staff when methoxyflurane was used in the past at the time of labour and , depression, inappropriate affect, paraesthesia, peripheral sensory malignant hyperthermia. Patients or patients with a known family history of delivery. Interactions: There are no reported drug interactions when used at neuropathy, diplopia, flushing, oral discomfort, hyperhidrosis, fatigue, feeling severe adverse reactions after being administered with inhaled anaesthetics. the analgesic dosage (3 – 6 ml). Methoxyflurane is metabolised by the CYP 450 abnormal, chills, feeling of relaxation; not known: affect lability, agitation, Patients who have a history of showing signs of liver damage after previous enzymes, particularly CYP 2E1 and to some extent CYP 2A6. It is possible that confusional state, dissociation, restlessness, altered state of consciousness, methoxyflurane use or halogenated hydrocarbon anaesthesia. Clinically enzyme inducers (such as alcohol or isoniazid for CYP 2E1 and phenobarbital nystagmus, vision blurred, blood pressure fluctuation, choking, hypoxia, significant renal impairment. Altered level of consciousness due to any cause or rifampicin for CYP 2A6) which increase the rate of methoxyflurane vomiting, hepatic failure, hepatitis, jaundice, liver injury, renal failure, hepatic including head injury, drugs or alcohol. Clinically evident cardiovascular metabolism might increase its potential toxicity and they should be avoided enzyme increased, blood urea increased, blood uric acid increased, blood instability. Clinically evident respiratory depression. Warnings and concomitantly with methoxyflurane. Concomitant use of methoxyflurane with creatinine increased. Overdose: Refer to SmPC. Legal Category: POM. NHS Precautions: To ensure the safe use of PENTHROX as an analgesic the medicines (e.g. contrast agents and some antibiotics) which are known to have Price: £17.89. Marketing Authorisation Holder: Medical Developments UK lowest effective dose to control pain should be used and it should be used with a nephrotoxic effect should be avoided as there may be an additive effect on Limited c/o Price Bailey LLP, Causeway House, 1 Dane Street, Bishop’s caution in the elderly or other patients with known risk factors for renal disease, nephrotoxicity; tetracycline, gentamicin, colistin, polymyxin B and amphotericin Stortford, Herts, CM23 3BT, United Kingdom. MA Number: PL 42467/0001. and in patients diagnosed with clinical conditions which may pre-dispose to B have known nephrotoxic potential. anaesthesia should be Full prescribing information available from: Galen Limited, Seagoe Industrial renal injury. Methoxyflurane causes significant nephrotoxicity at high doses. avoided following methoxyflurane analgesia, as sevoflurane increases serum Estate, Craigavon, BT63 5UA, United Kingdom. Date of Preparation: February Nephrotoxicity is thought to be associated with inorganic fluoride ions, a fluoride levels and methoxyflurane nephrotoxicity is associated with raised 2019. metabolic breakdown product. When administered as instructed for the serum fluoride. Concomitant use of PENTHROX with CNS , such