(Penthrox) for Emergency Relief of Moderate to Severe Pain

Horizon Scanning Research February 2016 & Intelligence Centre

Methoxyflurane (Penthrox) for emergency relief of moderate to severe pain

LAY SUMMARY

Acute pain is a type of pain that typically does not last longer than 6 months and stops when its underlying cause has been treated or has This briefing is based on healed. It is commonly associated with broken bones, burns, pain after information surgery or medical conditions such as heart attacks. available at the time of research and a Methoxyflurane is a new drug for the emergency treatment of acute limited literature pain. It is inhaled (breathed in) by the patient using a special inhaler. search. It is not Some studies have suggested that methoxyflurane may be helpful for intended to be a conscious patients with moderate to severe acute pain following definitive statement accidents, burns, operation or other trauma. on the safety, efficacy or Methoxyflurane (as Penthrox) is already licensed for use in the UK; it effectiveness of the could be an alternative treatment option for patients requiring health technology emergency pain relief. covered and should not be used for commercial NIHR HSRIC ID: 11830 purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Acute pain: moderate to severe; in conscious patients with trauma and associated pain – emergency analgesia.

TECHNOLOGY

DESCRIPTION

Methoxyflurane (Penthrox) is a fast onset, inhaled, non-opioid analgesic intended for the emergency treatment of pain. It induces muscle relaxation and reduces pain sensitivity by modulating tissue excitability. It does this by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. Methoxyflurane (as Penthrox) is self-administered at 3mL (99.9% methoxyflurane) vaporised in a Penthrox inhaler, with a maximum dose of 6mL in a single administration1.

Methoxyflurane (as Penthrox) is already licensed in the United Kingdom for this indication in adult patients. Common (≥1% to <10%) reported adverse events include amnesia, anxiety, depression, dizziness, dysarthria, dysgeusia, euphoria, headache, sensory neuropathy, somnolence, hypotension, coughing, dry mouth, nausea, and sweating1.

INNOVATION and/or ADVANTAGES

Methoxyflurane offers an additional fast-acting and self-administered treatment option for the emergency relief of pain in conscious patients with trauma or associated pain.

DEVELOPER

Galen Limited.

AVAILABILITY, LAUNCH OR MARKETING

The company received Marketing Authorisation from the MHRA for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain in October 2015. Methoxyflurane (as Penthrox) was launched in the UK in January 2016.

PATIENT GROUP

BACKGROUND

Pain is defined by the International Association for the Study of Pain (IASP 2015) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”2. Acute pain is commonly associated with surgery, trauma, non-surgical interventions and some medical conditions, for example myocardial infarction, acute pancreatitis and ureteric colic10. It is an individual, multifactorial experience influenced, among other things, by culture, previous experience, belief, mood and ability to cope3.

Effective treatment of acute pain is a fundamental component of quality patient care, due to the adverse physiological and psychological effects which may result from unrelieved severe

2 Horizon Scanning Research & Intelligence Centre

acute pain12. Acute pain is of limited duration and usually ceases when the wound heals or the medical condition improves10. However, it is important to anticipate and treat acute pain effectively to prevent the development of chronic pain syndromes3.

NHS or GOVERNMENT PRIORITY AREA

• NHS England. 2013/14 NHS Standard Contract for Specialised Pain. D08/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Inadequately managed acute pain can have psychological, physiological and socioeconomic consequences that can worsen patient suffering, clinical outcome, and increase the financial costs of healthcare10. In 2013, it was estimated that approximately two-thirds of inpatients experience acute pain during their stay in hospital4. This pain is often poorly relieved, with up to 20% of all inpatients suffering moderate to severe pain at any given time9.

Within primary care, approximately £305 million was spent in 2014 on opioid analgesics (£495 million on all analgesics), with almost 23 million prescriptions dispensed in England5. However, it is likely that an unknown but large proportion of these items were for chronic rather than acute pain conditions.

In 2014-15, there were 19.6million Accident and Emergency attendances recorded in England. Approximately 25% of these patients received treatment due to sports injury, road traffic accident, assault, deliberate self-harm, firework injury or other accident6. In the same year, approximately 6.5million patients received treatment from ambulance personnel, of which 63% required transportation to an Accident and Emergency department7. In 2014-15, there were 660,338 hospital admissions in England due to external injuries and burns (ICD- 10 S00-99, T00-14 and T20-32), equating to 3,737,171 bed days and 801,240 finished consultant episodes8.

The company states that the primary use of methoxyflurane (as Penthrox) will be in secondary care, specifically hospital emergency departments and pre-hospital applications such as ambulances.

The population likely to be eligible to receive methoxyflurane could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE guidelines. Neuropathic pain in adults: pharmacological management in non- specialist settings (CG173). November 2013. • NICE guidelines. Palliative care for adults: strong opioids for pain relief (CG140). May 2012. • NICE guidelines. Chest pain of recent onset: assessment and diagnosis. March 2010. • NICE guidelines. Low back pain in adults: early management (CG88). May 2009. • NICE interventional procedure guidance. Percutaneous electrical nerve stimulation for refractory neuropathic pain (IPG450). March 2013.

3 Horizon Scanning Research & Intelligence Centre

• NICE interventional procedure guidance. Extracorporeal shockwave therapy for refractory greater trochanteric pain syndrome (IPG376). January 2011. • NICE interventional procedure guidance. Distal iliotibial band lengthening for refractory greater trochanteric pain syndrome (IPG375). January 2011. • NICE interventional procedure guidance. Non-rigid stabilisation techniques for the treatment of low back pain (IPG366). November 2010.

Other Guidance

• Faculty of Pain Medicine: The Royal College of Anaesthetists. Core Standards for Pain Management Services in the UK. 20159. • The Royal College of Anaesthetists. Guidelines for the Provision of Anaesthetic Services for Acute Pain Management. 201410. • The College of Emergency Medicine. Best Practice Guideline: Management of Pain in Adults. 201411. • Australian and New Zealand College of Anaesthetists. Guidelines on Acute Pain Management. 201312. • American Pain Society. Recommendations for Improving the Quality of Acute and Cancer Pain Management. 200513.

CURRENT TREATMENT OPTIONS

The assessment and measurement of pain are fundamental to the process of diagnosing the cause of the pain, selecting an appropriate analgesic therapy and evaluating and modifying that therapy according to the response3. Pain is recognised as the fifth vital sign9 and standardised assessment tools are used to measure the intensity of pain that an individual is suffering3. Regular and repeated measurements of pain are made to assess ongoing adequacy of analgesic therapy3. Treatment of acute pain is tailored to the assessment and requirements of an individual patient3.

The ‘analgesic ladder’ introduced for treatment of cancer pain by the World Health Organization (WHO) has been adapted for the treatment of acute pain. It is made up of the following three steps3,14:

Step one • Non-opioid +/- adjunct; e.g. paracetamol, aspirin or non-steroidal anti-inflammatory drugs +/- nitrous oxide, gabapentinoids, ketamine, lignocaine and clonidine. Step two • Weak opioid +/- non-opioid +/- adjunct; e.g. codeine or tramadol +/- paracetamol, aspirin or non-steroidal anti-inflammatory drugs +/- nitrous oxide, gabapentinoids, ketamine, lignocaine or clonidine. Step three • Strong opioid +/- non-opioid +/- adjunct; e.g. oxycodone, diamorphine, fentanyl, or alfentanil +/- paracetamol, aspirin or non-steroidal anti-inflammatory drugs +/- nitrous oxide, gabapentinoids, ketamine, lignocaine or clonidine.

Drugs should be initiated at the step in the analgesic ladder appropriate to the level of pain, as dictated by the pain scale14.

The provision of effective acute pain management can be optimised by collaboration with other healthcare professionals such as physiotherapists, pharmacists and clinical psychologists10.

4 Horizon Scanning Research & Intelligence Centre

Expert opinion states that the main second line treatment of acute pain is paracetamol, used orally or intravenously (IV), in combination with morphine. Paracetamol is considered a very effective base-line medication but morphine has variable effect and patients may suffer from nausea with this medicationa. Furthermore, expert opinion states that modalities already exist for effective control of acute pain, such as IV ketamine titrated for analgesia, but they are under-used most likely due to training requirements and lack of familiarity by cliniciansa.

EFFICACY and SAFETY

Trial NCT01420159, MEOF-001; methoxyflurane vs placebo; phase III. Sponsor Medical Developments International Limited. Status Complete and published. Source of Publication15, trial registry16. information Location United Kingdom. Design Randomised, placebo-controlled. Participants n=300 ; aged 12 years and older; minor trauma; pain score ≥4 to ≤7 as measured using Numerical Rating Scale at the time of admission; no life-threatening condition requiring immediate admission to operating room or intensive care unit; no known pregnancy or lactation; no presence of any other clinical conditions that may impact on the patient’s ability to participate in the study; no acute intoxication with drugs or alcohol; no current use of analgesics for chronic pain; no known personal or familial hypersensitivity to fluorinated anaesthetics; no known personal or familial history of malignant hyperthermia; no clinically significant respiratory depression; no use of methoxyflurane in the previous 4 weeks; no clinically significant cardiovascular instability. Schedule Randomised to methoxyflurane as two 3mL inhalers self-administered; or placebo as two 5mL inhalers self-administered. Follow-up Follow-up 16 days. Primary Visual analogue scale (VAS) pain score. outcome Secondary Use of rescue medication; time to pain relief; number of responders; safety analysis. outcome/s Key results For methoxyflurane vs placebo groups, respectively: mean change in VAS pain score from baseline to 5 minutes, -23.1 vs -11.3mm; from baseline to 10 minutes, -28.9 vs - 14.8mm; from baseline to 15 minutes, -34.0 vs -15.5mm; from baseline to 20 minutes, - 35.0 vs -19.0mm; median time to first pain relief, 4 vs 10 minutes; use of rescue medication, 2 vs 25 patients. Adverse Treatment-emergent AEs were experienced by 59.1% and 40.9% of methoxyflurane effects (AEs) and placebo groups, respectively; 1.3% of methoxyflurane-treated patients and 2% of placebo-treated patients withdrew due to treatment-emergent AEs.

ESTIMATED COST and IMPACT

COST

Methoxyflurane (as Penthrox) is already marketed in the UK; 3mL dose vaporised in a Penthrox inhaler costs £17.89.

a Expert personal communication.

5 Horizon Scanning Research & Intelligence Centre

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: expert opinion states that the self-  No impact identified administration of pain relief is beneficial as it gives the patient control over their pain, which is an advantage psychologicallyb.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs.  Other reduction in costs.

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion states that the principal area of clinical uncertainty with this medication is the potential for risk of abuse should methoxyflurane cause euphoria. However, this could be avoided by use as a prescription only medication, or use as a controlled substanceb.

REFERENCES

1 electronic Medicines Compendium (eMC). PENTHROX 3mL inhalation vapour, liquid. www.medicines.org.uk/emc/medicine/31391 Accessed 22 February 2016. 2 International Association for the Study of Pain. IASP Taxonomy. www.iasp- pain.org/Taxonomy#Pain Accessed 22 February 2016. 3 Konetic K and Jones M. Management of acute pain. Surgery 2013; 31(2):77-83. 4 Care Quality Commission. National findings from the 2013 inpatients survey. www.cqc.org.uk/sites/default/files/inpatient_survey_national_summary.pdf Accessed 22 February 2016. 5 Health & Social Care Information Centre. Prescription Cost Analysis England, 2014. www.hscic.gov.uk 6 Health & Social Care Information Centre. NHS Accident and Emergency Attendance, 2014-15. www.hscic.gov.uk 7 Health & Social Care Information Centre. Ambulance Services, England, 2014-15. www.hscic.gov.uk 8 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatients statistics, 2014-15. www.hscic.gov.uk

b Expert personal communication.

6 Horizon Scanning Research & Intelligence Centre

9 Faculty of Pain of the Royal College of Anaesthetists. Core Standards for Pain Management Services in the UK: October 2015. www.rcoa.ac.uk/system/files/FPM-CSPMS-UK2015.pdf Accessed 22 February 2016. 10 The Royal College of Anaesthetists. Guidance on the provision of anaesthesia services for acute pain management 2014. www.rcoa.ac.uk/system/files/GPAS-2014-11-ACUTEPAIN_0.pdf Accessed 22 February 2016. 11 The Royal College of Emergency Medicine. College Guidelines. www.rcem.ac.uk/Shop- Floor/Clinical%20Guidelines/College%20Guidelines Accessed 22 February 2016. 12 Australian and New Zealand College of Anaesthetists. Guidelines on acute pain management. www.anzca.edu.au/resources/professional-documents/pdfs/ps41-2013-guidelines-on-acute-pain- management.pdf Accessed 22 February 2016. 13 Gordon D, Dahl J, Miaskowski C et al. American Pain Society: Recommendations for improving the quality of acute and cancer pain management. Archives of Internal Medicine 2005;165(14):1574-1580. 14 Patient. Pain and pain relief. www.patient.info/doctor/pain-and-pain-relief Accessed 22 February 2016. 15 Coffey F, Wright J, Hartshorn S et al. STOP!: a randomised, double-blind, placebo–controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emergency Medicine Journal 2014;31(8):613-618. 16 ClinicalTrials.gov. Efficacy and safety of methoxyflurane (Penthrox) for the treatment of acute pain in minor trauma. www.clinicaltrials.gov/ct2/show/record/NCT01420159 Accessed 22 February 2016.