Penthrox®▼ (methoxyflurane) in the Emergency Department (ED)

- is it worth the hype?Dr Lakshmi GangadharanSpeciality and Associate Specialist DoctorBedford Hospital NHS Trust

MAT-PEN-UK-000180Date of Preparation: March 2019

Penthrox educational materials and training on its use are available from Galen on request

Prescribing information and information on adverse event reporting can be found at the end of this presentation

Sponsored by Galen Limited

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

Trauma pain management in Bedford ED (another bad day at the office)

88 year old lady, ASA Grade III, 5 day old Colles’ fracture

82 year old male, frail, given IV morphine after fall, with suspected fracture neck of femur

22 year old male with a moderate pneumothorax after trauma, requiring intercostal drain insertion

30 year old male with recurrent dislocation of shoulder

How could we improve patient throughput?

Penthrox®

(methoxyflurane) in the ED

• 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 of a person trained in its administration

• Halogenated ether• Provides high-quality, well-tolerated analgesia

which may negate the need for procedural sedation

• 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

• H hypersensitivity to methoxyflurane or any fluorinated anaesthetics

• E elevated temperature from an anesthetic (malignant hyperthermia)

• C consciousness reduced (including alcohol)

• K kidney impairment

• A age below 18 years

• L lung/respiratory impairment

• L liver impairment

• L last administration of methoxyflurane

• Drugs- CYP 450 inducersalcohol, isoniazid, phenobarbital,rifampicin

• Nephrotoxic antibioticstetracycline, gentamicin, colistin,polymyxin B, amphotericin B

Penthrox®

audit

Methods

• Use of proforma to collect retrospective and prospective data

• 30 patients’ data collected between December 2017 to April 2018

• Compared with RCEM procedural sedation audit data (2015-16)

• Penthrox was used as a first-line drug for trauma analgesia and as primary analgesia for reduction of fractures and dislocations

• Our focus was:• 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 propofol/fentanyl)

• 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

Adverse effects

A small number of adverse events were recorded in some cases

By contrast, in the RCEM procedural sedation audit (2015-16) an adverse event rate of 4.7% was recorded for procedural sedation

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

None of the patients withdrew from the audit

There were no observed effects on cardiovascular or respiratory parameters

Costs

• Procedural sedation for reduction of fractures/dislocations requires:o a second doctor and suitably qualified nurseo continuous monitoringo IV accesso IV drugs/fluidso oxygeno suctiono resuscitation roomo capnographyo etc

• Penthrox requires:o two trained personnelo a trolley in the EDo one inhaler costing £17.89

Limitations

Limitations of audit• Small single-center study • Lack of comparative data• Uniformity of assessment, operator

confidence/experience

Limitations of Penthrox- 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

Conclusions – A CLEAR

BENEFIT!

• 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

• Can be used as an alternative to Entonox, as it is portable and can be used in trauma where there is encapsulated air in the body

• Fewer potential adverse effects • Rapid recovery• Decreased time to discharge• Excellent cost effectiveness

Trauma pain management (a better day at the office)

88 year old lady, ASA Grade III, 5 day old Colles’ fracture

82 year old male, frail, given IV morphine after fall, with suspected fracture neck of femur

22 year old male with a moderate pneumothorax after trauma, requiring intercostal drain insertion

30 year old male with recurrent dislocation of shoulder

Ongoing work

Incorporated into Trust guidelines standard operating procedure as primary analgesia for trauma, in conscious patients

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

Further data being analysed for publication

My Take-Home Message:

Use Penthrox®

in your ED

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

Easy administration, high compliance, well-tolerated and effective

Early return to normal activities, early discharge and lower burden on the available resources

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 nitrous oxide? 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, liquid: Please refer to theSummary of Product Characteristics (SmPC) before prescribing.Abbreviated Prescribing Information. Presentation: Each bottle ofPENTHROX contains 3 ml of methoxyflurane 99.9%, a clear, almost colourless,volatile liquid, with a characteristic fruity odour. Each PENTHROX combinationpack consists of one bottle of 3 ml PENTHROX, one PENTHROX Inhaler andone Activated Carbon (AC) chamber. Indications: Emergency relief ofmoderate to severe pain in conscious adult patients with trauma and associatedpain. Dosage and administration: PENTHROX should be self-administeredunder supervision of a person trained in its administration, using the hand heldPENTHROX Inhaler. It is inhaled through the custom-built PENTHROX inhaler.Adults: One bottle of 3 ml PENTHROX as a single dose, administered usingthe device provided. A second bottle should only be used where needed. Thefrequency at which PENTHROX can be safely used is not established. Thefollowing administration schedule is recommended: no more than 6 ml in asingle day, administration on consecutive days is not recommended and thetotal dose to a patient in a week should not exceed 15 ml. Onset of pain relief israpid and occurs after 6-10 inhalations. Patients are able to titrate the amount ofPENTHROX inhaled and should be instructed to inhale intermittently to achieveadequate analgesia. Continuous inhalation of a bottle containing 3 ml providesanalgesic relief for up to 25-30 minutes; intermittent inhalation may providelonger analgesic relief. Patients should be advised to use the lowest possibledose to achieve pain relief. Renal impairment: Methoxyflurane may cause renalfailure if the recommended dose is exceeded. Caution should be exercised forpatients diagnosed with clinical conditions that would pre-dispose to renal injury.Hepatic impairment: Cautious clinical judgement should be exercised whenPENTHROX is to be used more frequently than on one occasion every 3months. Paediatric population: PENTHROX should not be used in childrenand adolescents under 18 years. For detailed information on the method ofadministration refer to the SmPC. Contraindications: Use as an anaestheticagent. Hypersensitivity to methoxyflurane, any fluorinated anaesthetic or to anyof the excipients. Patients who are known to be genetically susceptible tomalignant hyperthermia. Patients or patients with a known family history ofsevere adverse reactions after being administered with inhaled anaesthetics.Patients who have a history of showing signs of liver damage after previousmethoxyflurane use or halogenated hydrocarbon anaesthesia. Clinicallysignificant renal impairment. Altered level of consciousness due to any causeincluding head injury, drugs or alcohol. Clinically evident cardiovascularinstability. Clinically evident respiratory depression. Warnings andPrecautions: To ensure the safe use of PENTHROX as an analgesic thelowest effective dose to control pain should be used and it should be used withcaution in the elderly or other patients with known risk factors for renal disease,and in patients diagnosed with clinical conditions which may pre-dispose torenal injury. Methoxyflurane causes significant nephrotoxicity at high doses.Nephrotoxicity is thought to be associated with inorganic fluoride ions, ametabolic breakdown product. When administered as instructed for the

analgesic indication, a single dose of 3 ml methoxyflurane produces serumlevels of inorganic fluoride ions below 10 micromol/l. In the past when used asan anaesthetic agent, methoxyflurane at high doses caused significantnephrotoxicity, which was determined to occur at serum levels of inorganicfluoride ions greater than 40 micromol/l. Nephrotoxicity is also related to the rateof metabolism. Factors that increase the rate of metabolism such as drugs thatinduce hepatic enzymes can increase the risk of toxicity with methoxyflurane aswell as sub-groups of people with genetic variations that may result in fastmetaboliser status. Methoxyflurane is metabolised in the liver, thereforeincreased exposures in patients with hepatic impairment can cause toxicity.PENTHROX should be used with care in patients with underlying hepaticconditions or with risks for hepatic dysfunction. Previous exposure tohalogenated hydrocarbon anaesthetics (including methoxyflurane when used asan anaesthetic agent), especially if the interval is less than 3 months, mayincrease the potential for hepatic injury. Potential effects on blood pressure andheart rate are known class-effects of high-dose methoxyflurane used inanaesthesia and other anaesthetics. Caution is required with use in the elderlydue to possible reduction in blood pressure. Potential CNS effects such assedation, euphoria, amnesia, ability to concentrate, altered sensorimotor co-ordination and change in mood are known class-effects. The possibility of CNSeffects may be seen as a risk factor for potential abuse, however reports arevery rare in post-marketing use. PENTHROX is not appropriate for providingrelief of break-through pain/exacerbations in chronic pain conditions or for therelief of trauma related pain in closely repeated episodes for the same patient.PENTHROX contains the excipient, butylated hydroxytoluene (E321) which maycause local skin reactions (e.g. contact dermatitis), or irritation to the eyes andmucous membranes. To reduce occupational exposure to methoxyflurane, thePENTHROX Inhaler should always be used with the AC Chamber whichadsorbs exhaled methoxyflurane. Multiple use of PENTHROX Inhaler withoutthe AC Chamber creates additional risk. Elevation of liver enzymes, blood ureanitrogen and serum uric acid have been reported in exposed maternity wardstaff when methoxyflurane was used in the past at the time of labour anddelivery. Interactions: There are no reported drug interactions when used atthe analgesic dosage (3 – 6 ml). Methoxyflurane is metabolised by the CYP 450enzymes, particularly CYP 2E1 and to some extent CYP 2A6. It is possible thatenzyme inducers (such as alcohol or isoniazid for CYP 2E1 and phenobarbitalor rifampicin for CYP 2A6) which increase the rate of methoxyfluranemetabolism might increase its potential toxicity and they should be avoidedconcomitantly with methoxyflurane. Concomitant use of methoxyflurane withmedicines (e.g. contrast agents and some antibiotics) which are known to havea nephrotoxic effect should be avoided as there may be an additive effect onnephrotoxicity; tetracycline, gentamicin, colistin, polymyxin B and amphotericinB have known nephrotoxic potential. Sevoflurane anaesthesia should beavoided following methoxyflurane analgesia, as sevoflurane increases serumfluoride levels and methoxyflurane nephrotoxicity is associated with raisedserum fluoride. Concomitant use of PENTHROX with CNS depressants, such

as opioids, sedatives or hypnotics, general anaesthetics, phenothiazines,tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcoholmay produce additive depressant effects. If opioids are given concomitantly withPENTHROX, the patient should be observed closely. When methoxyflurane wasused for anaesthesia at the higher doses of 40–60 ml, there were reports ofdrug interaction with hepatic enzyme inducers (e.g. barbiturates) increasingmetabolism of methoxyflurane and resulting in a few reported cases ofnephrotoxicity; reduction of renal blood flow and hence anticipated enhancedrenal effect when used in combination with drugs (e.g. barbiturates) reducingcardiac output; and class effect on cardiac depression, which may be enhancedby other cardiac depressant drugs, e.g. intravenous practolol during cardiacsurgery. Fertility, pregnancy and lactation: No clinical data on effects ofmethoxyflurane on fertility are available. As with all medicines care should beexercised when administered during pregnancy especially the first trimester.There is insufficient information on the excretion of methoxyflurane in humanmilk. Caution should be exercised when methoxyflurane is administered to anursing mother. Effects on ability to drive and use machines:Methoxyflurane may have a minor influence on the ability to drive and usemachines. Patients should be advised not to drive or operate machinery if theyare feeling drowsy or dizzy. Undesirable effects: The common non-seriousreactions are CNS type reactions such as dizziness and somnolence and aregenerally easily reversible. Serious dose-related nephrotoxicity has only beenassociated with methoxyflurane when used in large doses over prolongedperiods during general anaesthesia. The following adverse drug reactions haveeither been observed in PENTHROX clinical trials in analgesia, with analgesicuse of methoxyflurane following post-marketing experience or are linked tomethoxyflurane use in analgesia found in post-marketing experience and inscientific literature (refer to the SmPC for further details): Very common(≥1/10): dizziness; common (≥1/100 to <1/10): Euphoric mood, amnesia,dysarthria, dysgeusia, headache, somnolence, hypotension, cough, dry mouth,nausea, feeling drunk; uncommon (≥1/1,000 to <1/100): increased appetite,anxiety, depression, inappropriate affect, paraesthesia, peripheral sensoryneuropathy, diplopia, flushing, oral discomfort, hyperhidrosis, fatigue, feelingabnormal, chills, feeling of relaxation; not known: affect lability, agitation,confusional state, dissociation, restlessness, altered state of consciousness,nystagmus, vision blurred, blood pressure fluctuation, choking, hypoxia,vomiting, hepatic failure, hepatitis, jaundice, liver injury, renal failure, hepaticenzyme increased, blood urea increased, blood uric acid increased, bloodcreatinine increased. Overdose: Refer to SmPC. Legal Category: POM. NHSPrice: £17.89. Marketing Authorisation Holder: Medical Developments UKLimited c/o Price Bailey LLP, Causeway House, 1 Dane Street, Bishop’sStortford, Herts, CM23 3BT, United Kingdom. MA Number: PL 42467/0001.Full prescribing information available from: Galen Limited, Seagoe IndustrialEstate, Craigavon, BT63 5UA, United Kingdom. Date of Preparation: February2019.