Dr John Wright is Consultant in Emergency Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP (john.wright@nuth.nhs.uk)

Dr Will Passmore is Specialist Registrar in Emergency Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne

A guide toInhaled patient-controlled analgesia

What is inhaled patient-controlled analgesia? Inhaled patient-controlled analgesia allows fully conscious patients to self-administer analgesia by inhaling a gas through a facemask or mouthpiece. The patient determines the concentration of drug delivered.

Although various inhalational anaesthetics have been used for inhaled patient-controlled analgesia (examples include isoflurane and sevoflurane) there are currently only two drugs licensed for this purpose in the UK: nitrous oxide 50% combined with oxygen 50% (N2O/O2) and methoxyflurane. Inhaled patient-controlled analgesia has the advantage over oral and parenteral drugs in that it is non-narcotic, with minimal side effects. It allows the patient to regulate the dose he/she receives while requiring relatively little training for the clinician. Table 1 outlines some indications for inhaled analgesia.

On the other hand, inhaled patient-controlled analgesia has to be used with the same caution as other forms of analgesia in some cases, such as patients with head injury, while it is uniquely contraindicated (in the case of N2O/O2) in the presence of pathological air-containing spaces such as pneumothorax.

At last, PENTHROX® is here...Fast, effective pain management designed for fast, efficient patient management.

PENTHROX is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain

Advancing Acute Pain Management

NEW

Penthrox Educational materials and training on its administration are available from Galen on request. Date of preparation: January 2016. PMR-JAN-2016-0042.

Penthrox is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain. Please consult the Summary of Product Characteristics before prescribing. Information about this product, including adverse reactions, precautions, contra-indications and method of use can be found at www.medicines.org.uk/emc. Legal category: POM. Further information is available on request from Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, United Kingdom.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Galen Limited on 028 3833 4974 and select the customer services option, or e-mail customer.services@galen-pharma.com. Medical information enquiries should also be directed to Galen Limited.

PEN-15-075 A5 Abbreviated ED Ad.indd 1 01/02/2016 16:41Untitled-3 1 01/02/2016 17:06

There are many analgesic options in the management of acute pain episodes (Figure 1). Oral analgesia is often limited by the latency of onset of therapeutic effect. Acute pain episodes require rapid and effective pain relief. In these situations clinicians will use more than one route of analgesic drug administration to achieve rapid analgesia.

Prescribing inhaled patient-controlled analgesiaNitrous oxide 50% and oxygen 50% (N2O/O2)Until recently, doctors and allied health professionals only had this gas as the sole readily available choice

of inhaled patient-controlled analgesia. The 50:50 mix of nitrous oxide and oxygen is commonly known as Entonox and also Nitronox or Equanox, and is colloquially known as ‘gas and air’. N2O/O2 is inhaled and exhaled from a portable cylinder through a mouthpiece or facemask, via a regulator.

IndicationsN2O/O2 is a popular option because of its rapid onset and recovery characteristics combined with predictable and reliable analgesic properties (O’Sullivan and Benger, 2003). The analgesic effect is reported to be equivalent to a dose of

Figure 1. Analgesic options in acute pain.

Table 1. Indications for inhaled analgesia

Medical* Surgical* Trauma

Breakthrough pain, palliative patients

Postoperative pain Fracture reductionSplint or plaster application

Acute on chronic pain in patients where intravenous access is not possible

Renal colic Burns dressings application and changes

Obstetric labour pain from contractions

Procedural sedationFlexible sigmoidoscopy

Injured patient without intravenous access in acute pain

Venepuncture Dental proceduresTooth extraction

Procedural sedation, e.g. joint reduction

Minor surgical procedures: suturing, incision and drainage

Distressed and in pain, injured paediatric patient not tolerating intramuscular or intravenous drug administration

*Inhaled methoxyflurane is only licensed in the UK for use in trauma pain, not medical or surgical pain

Methoxyflurane (Penthrox)

Options

Intranasal opioids, e.g. fentanyl, sulfentanyl

Intranasal benzodiazepines, e.g. midazolam, lorazepam,

diazepam

Intranasal diamorphine

Nitrous oxide/oxygen (Entonox)

Intranasal ketamine

Intravenous analgesia

15 mg subcutaneous morphine (Chapman et al, 1943). It has proved to be a very safe agent with minimal side effects and is particularly useful for managing transient acute pain caused by short-term procedures such as wound dressings. Its poor solubility in blood allows rapid achievement of analgesia, with an effect usually apparent within 60 seconds. When the patient inhales, gas first enters the lungs then the pulmonary and systemic circulations. It takes 1–2 minutes to build up reasonable concentrations of nitrous oxide in the brain. It is also fast to washout of the system (the effects begin to wane after about 30 seconds; Latto et al, 1973), which is excellent for its safety profile, but also means patients need to have a constant supply at hand available for adequate analgesia.

Clinical managementIn most UK clinical settings, N2O/O2 is supplied as an Entonox cylinder, which is white with blue and white shoulders (Figure 2). The additional equipment required consists of a demand valve, inhalation tubing, an individual patient filter and either a mask or individual patient mouthpiece (Figure 3). The demand valve ensures that the gas does not flow unless a negative pressure is achieved, i.e. the patient inhales through the closed circuit.

There are a number of restrictions to its use. Nitrous oxide inhalation is contraindicated in the presence of pathological air-containing spaces. These spaces may expand as the nitrous oxide diffuses into them faster than nitrogen diffuses out. The manufacturers explicitly warn against use in conditions such as gross abdominal distension, bowel obstruction, pneumothorax, middle ear and sinus disease (BOC Healthcare, 2015). N2O/O2 should be used with caution in patients with significant head injury or decreased levels of consciousness. Since nitrous oxide affects white blood cell production and function if it is used for several hours, it has been recommended that N2O/O2 should not be administered to immunosuppressed patients or to patients requiring multiple general anaesthetics (Lazyer, 1978; Brodsky and Cohen, 1986).

The contraindications to using N2O/O2 can be limiting in the pre-hospital environment and for many patients who attend the emergency department requiring pain relief. An unusual feature of this analgesia is that at temperatures below -7°C the two constituent gases separate, resulting in the potential outcome of hypoxia because an oxygen-rich mixture is inhaled initially (Litwin, 2010). Another disadvantage of having to have a constant supply of N2O/O2 available is that when a patient is required to move from one department to another, e.g. emergency department to radiology, he/she has to be escorted by a porter who also has to transport a large cylinder of gas. Similarly, storage and replacement

Figure 3. Mouthpiece used to deliver Entonox.

Figure 2. Entonox cylinder.

of these large cylinders can be a logistical problem for many emergency departments.

MethoxyfluraneThe alternative inhaled patient-controlled analgesia is methoxyflurane. Methoxyflurane is an almost colourless liquid belonging to the fluorinated hydrocarbon group of volatile anaesthetic agents. It has the characteristic pungent but not unpleasant odour of the halogenated anaesthetics (Coffey et al, 2014). Initially used as an anaesthetic agent, it fell out of favour with the introduction of newer, non-gaseous anaesthetic techniques and because of concerns about renal toxicity (Crandell et al, 1966). However, methoxyflurane has analgesic properties not shared by other halogenated anaesthetics. At sub-anaesthetic levels it is a safe and very effective analgesic (Tomi et al, 1993).

IndicationsMethoxyflurane has been used effectively and safely in Australia, since the 1970s, as an inhalational analgesic in many areas including trauma, for postoperative analgesia and as analgesia during burns dressing changes (Grindlay and Babl, 2009). In the UK it is indicated for emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain. It has the unique ability of causing rapid and profound analgesia at low concentrations. The pain relief produced is equivalent to 10 mg intramuscular morphine (Yakaitis et al, 1972). It is therefore excellent in situations requiring easy and safe administration to achieve rapid relief of pain with minimal side effects.

Clinical management The ‘green whistle’ delivery system (Figure 4)(Penthrox™ inhaler – Medical Developments International) has been in use for almost 40 years. This device delivers a small dose (3 ml) of methoxyfluorane which provides strong and long-lasting analgesia in a variety of settings. It is used by ambulance services, the military, first aid officers, in ski-fields and mines, and in the emergency departments of several major hospitals.

A single dose of 3 ml of methoxyflurane provides approximately 25–30 minutes of effective analgesia if used continuously and up to 1 hour if used intermittently. An additional dose of 3 ml (total of 6 ml) can be administered subsequently, providing up to 2 hours of effective analgesia (Galen Ltd, 2016). It is self-administered under observation (with assistance if necessary) using the hand-held Penthrox inhaler. At the recommended dose, anaesthesia cannot occur.

The Penthrox inhaler is a small, lightweight, cylindrical polyethylene device, approximately 15 cm long. It has a distinctive green colour and effectively looks like a large green whistle. At one end is a mouthpiece, near which is sited an activated carbon chamber which has a dilutor hole on top which, when covered with the patient’s index finger, allows a higher concentration of methoxyflurane to be inhaled. Internally, the device contains a polypropylene S-shaped wick which absorbs the liquid methoxyflurane. An internal one-way valve near the base allows air and methoxyflurane vapour to be inhaled through the wick. The valve closes on expiration to prevent exhalations passing into the atmosphere. A tape is attached to the inhaler

Figure 4. Penthrox delivery system for methoxyflurane.

to provide support around the patient’s wrist. The inhaler is a single-patient use device which prevents cross contamination between patients and is easily disposed of after use.

The major concern with methoxyflurane is nephrotoxicity, which has only been reported following anaesthetic use (large doses for several hours) and has been attributed to the breakdown product, inorganic fluoride ions (Kharasch et al, 1995). There is no evidence of nephrotoxicity associated with subanaesthetic doses. There have been reported cases of hepatitis, thought to be an idiosyncratic response resulting from a hypersensitivity reaction.

Comparing N2O/O2 and methoxyfluraneEffective use of N2O/O2 requires a tight fit between the patient’s face and the mask or a constant seal with the mouthpiece to ensure that any demand valve system functions correctly. The weight and bulk of the equipment presents a storage, transport and usage problem, and excludes its use in many circumstances. Clinicians need to ensure that the gases do not separate in cold conditions and care is always required during cleaning and decontamination to eliminate the possible transmission of microorganisms between patients. When N2O/O2 is used continuously over 1 hour, up to 250 litres of nitrous oxide can be excreted into the atmosphere, a potential hazard to operators chronically exposed to nitrous oxide (Koulaouzos, 2004). On the other hand, methoxyflurane is single-patient use, easily administered with a rapid onset but gradual offset. The operator does not have to worry about the potential expansion of gas-filled cavities and the potential pollution factor is 200 times less than N2O/O2. The main concern clinicians need to keep in mind is to avoid administering methoxyflurane to patients with renal disease.

There have been few studies directly comparing the efficacy of the two main options for inhaled patient-controlled analgesia, and there is a compelling argument that a randomized controlled trial comparing the two drugs should be done.

What evidence there is suggests that methoxyflurane compares well to N2O/O2 (Tomlin et al, 1973; Abdullah et al, 2011). Furthermore, a review article assessing the efficacy of methoxyflurane in the pre-hospital and emergency department setting concluded that it was an efficacious analgesic with no significant adverse effects (Grindlay and Babl, 2009). A UK-based multicentre double-blind, randomized, controlled clinical study was conducted to investigate the safety and efficacy of methoxyflurane at analgesic doses vs placebo in patients aged ≥12 years presenting to the emergency department with pain associated with minor to moderate trauma. The authors concluded that ‘methoxyflurane administered via the Penthrox inhaler is an efficacious, safe, and rapidly acting analgesic’ (Coffey et al, 2014). In 2015 Penthrox received regulatory approval in Europe, including the UK.

Managing inhaled patient-controlled analgesia N2O/O2 Staff instructionsAlthough rules vary within the UK NHS, in general, staff who have undergone in-service training in the use of N2O/O2 and have achieved competencies in the locally agreed clinical procedure can administer N2O/O2 without a prescription. Examples of professionals who can administer N2O/O2 include doctors, paramedics and ambulance technicians, nurses, midwives, physiotherapists, radiographers and operating department practitioners. Students may administer N2O/O2 under the supervision of a qualified member of staff.

The patient’s suitability should be assessed to ensure that he/she understands the use of N2O/O2 and has the manual dexterity to hold the hand piece or facemask unaided. An Entonox cylinder is white in colour with blue and white shoulders. ‘Entonox’ should be clearly written on the side of the cylinder. Additional equipment includes a demand valve, inhalation tubing, individual patient filter and either a mask or individual patient mouthpiece. The cylinder should be stored at room temperature for at least 24 hours before use and should be stored

with the valve in the ‘off’ position. The tap on the Entonox cylinder should be turned in an anti-clockwise direction to open the demand valve. The gauge should be examined to determine how much gas is in the cylinder and ensure there is enough to complete the procedure. The effectiveness of N2O/O2 should be assessed by questioning the patient throughout and following the procedure to ensure that adequate levels of analgesia are being achieved.

Patient instructionsThe patient should be shown the equipment and asked to select for use the mouthpiece or facemask. If the patient chooses to use the mask, explain that he/she should hold it over his/her mouth and nose, maintaining an airtight seal, and that he/she should breathe normally. If the patient chooses to use the mouthpiece, explain that he/she should hold the mouthpiece between the teeth and should breathe through the mouth only. Explain how N2O/O2 is used while the clinical procedure is being carried out, and describe possible side effects.

Only the patient should apply and hold the apparatus in position. Encourage the patient to practice the technique of N2O/O2 inhalation, by self-demand, before the procedure starts. Allow the patient to practice using the apparatus for at least 30 seconds, ideally 1–2 minutes, before commencing any painful procedure. Encourage the patient to breathe normally throughout the procedure and to inform staff if he/she experiences pain. If the patient hyperventilates he/she should be encouraged to exhale slowly. If the patient experiences any N2O/O2-related side effects reassure the patient and cease inhalation until the side effects have worn off and the sensation of pain starts to return. Inform the patient not to walk around unaided until dizziness or disorientation has subsided.

Inappropriate inhalation of N2O/O2 will cause light-headedness, euphoria and intoxication, ultimately leading to unconsciousness. Be aware that if N2O/O2 has been stored at temperatures below -7°C separation of gases may occur. This will initially result in lack of analgesia as the patient inhales pure oxygen. However, once the oxygen is consumed, the

patient will then be inhaling pure nitrous oxide, which will result in loss of consciousness. Therefore check for any signs of frost on the lower half of the cylinder or a ‘sloshing’ sound when moving the cylinder, which indicates that separation of gases has occurred. The cylinder may need to be inverted three times to ensure adequate mixing of the gases.

If excessive sedation or loss of consciousness occurs, remove the facemask or mouthpiece from the patient and clear the airway. Support respiration if necessary. Administer oxygen and contact the medical team. If treatment exceeds 4 days, twice-weekly blood cell counts should be performed looking for evidence of bone marrow suppression (megaloblastic changes in red cells or hypersegmentation of neutrophils).

After careObserve the patient until the effects of the gas have worn off. Turn off the N2O/O2 supply by turning the tap in a clockwise direction. Depress the diaphragm under the valve. Decontaminate the hand piece, demand valve and facemask in hot soapy water. If the patient has tested positive for meticillin-resistant Staphylococcus aureus, discuss this with the infection control team. Document the use of Entonox in the patient’s notes.

Methoxyflurane Staff instructionsPenthrox is a prescription-only drug, but non-medical prescribing is permitted. It should therefore be possible for the same groups of health professionals permitted to administer N2O/O2 to administer methoxyflurane via the Penthrox inhaler. The patient’s suitability should be assessed to ensure that he/she understands the use of methoxyflurane and has the manual dexterity to hold the inhaler. Ensure that the patient does not have renal disease or any of the other contraindications before using. The Penthrox inhaler is a cylindrical green polyethylene device (Figure 3), approximately 15 cm long. An activated carbon chamber is inserted into the dilution hole on the top of the inhaler. Then, while holding the inhaler upright, the base can be

used to begin unscrewing the cap with a half turn. The bottle is then separated from the inhaler and the cap completely unscrewed. The inhaler is then turned upside down at a 45° angle and the contents of one 3 ml bottle are poured in while rotating and shaking the inhaler lightly. The wrist loop is placed over the patient’s wrist and the patient inhales and exhales through the mouthpiece.

If stronger analgesia is required, the patient can cover the diluter hole on the activated carbon chamber with the index finger, allowing a higher concentration of methoxyflurane to be inhaled. A second dose of 3 ml can be administered, if necessary. Up to 6 ml can be used per day. The total weekly dose should not exceed 15 ml and administration on consecutive days is not recommended.

Patient instructionsThe patient should be shown the inhaler. It should be explained that he/she breathes normally but inhales and exhales through the mouthpiece. The patient should be instructed to start breathing in and out of the mouthpiece, gently initially and then normally. Explain that the patient can occlude the dilution hole for stronger analgesia if required. The patient should be instructed to inhale and exhale through the mouthpiece intermittently to achieve adequate analgesia. Continuous administration will reduce the time of analgesia. Patients should self-administer the minimum dose required.

After careObserve the patient until the effects of methoxyflurane have worn off. The cap should be replaced on the 3 ml bottle and both the inhaler and bottle should be placed in the plastic bag provided. The bag is sealed and the bag and contents should be disposed of in the clinical waste. Document the use of the Penthrox inhaler in the patient’s notes.

The publication of this guide has been supported by an unrestricted educational grant from Galen Ltd. Galen Ltd has not had any editorial input into this publication.

Abdullah WA, Sheta SA, Nooh NS (2011) Inhaled methoxyflurane (Penthrox) sedation for third molar extraction: a comparison to nitrous oxide sedation.

Aust Dent J 56: 296–301BOC Healthcare (2015) ENTONOX® – The Essential

Guide. www.bochealthcare.co.uk/internet.lh.lh.gbr/en/images/entonox_essential_guide_hlc401955_Sep10409_64836.pdf (accessed 27 January 2016)

Brodsky JB, Cohen EN (1986) Adverse effects of nitrous oxide. Med Toxicol 5: 362–74

Chapman WP, Arrowhead JG, Beecher HK (1943) The analgesic effects of low concentrations of nitrous oxide compared in man with morphine sulphate. J Clin Invest 22: 871–5

Coffey F, Wright J, Hartshorn S, et al (2014) STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J 31: 613–18

Crandell WB, Pappas SG, Macdonald A (1966) Nephrotoxicity associated with methoxyflurane anaesthesia. Anesthesiology 27: 591–607

Galen Ltd (2016) PENTHROX 3mL inhalation vapour, liquid summary of product characteristics. www.medicines.org.uk/emc/medicine/31391 (accessed 27 January 2016)

Grindlay J, Babl FE (2009) Review article: efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas 21: 4–11

Kharasch ED, Hankins DC, Thummel KE (1995) Human kidney methoxyflurane and sevoflurane metabolism. Anesthesiology 82: 689–99

Koulaouzos A (2004) Application for inclusion of methoxyflurane in the WHO model list of essential medicines. http://archives.who.int/eml/expcom/expcom14/methoxyflurane/methoxyflurane_meddevelopmentsint-ltd_application.pdf (accessed 27 January 2016)

Latto IP, Molloy MJ, Rosen M (1973) Arterial concentration of nitrous oxide during intermittent patient controlled inhalation of 50% nitrous oxide in oxygen (ENTONOX) during the first stage of labour. Br J Anaesth 45: 1029–34

Lazyer RB (1978) Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet ii: 1227–30

Litwin PD (2010) The effects of temperature on nitrous oxide and oxygen mixture homogeneity and stability. BMC Anesthesiology 10: 19

O’Sullivan I, Benger J (2003) Nitrous oxide in emergency medicine. Emerg Med J 20: 214–17

Tomi K, Mashimo T, Tashiro C et al (1993) Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth 70: 684–6

Tomlin PJ, Jones BC, Edwards R et al (1973) Subjective and objective sensory responses to inhalation of nitrous oxide and methoxyflurane. Br J Anaesth 45: 719–25

Yakaitis RW, Cooke JE, Redding JS (1972) Self-administered methoxyflurane for postoperative pain: effectiveness and patient acceptance. Anesth Analg 51: 208–12

At last, PENTHROX® is here...Fast, effective pain management designed for fast, efficient patient management.

PENTHROX is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain

Advancing Acute Pain Management

NEW

Penthrox Educational materials and training on its administration are available from Galen on request. Date of preparation: January 2016. PMR-JAN-2016-0042.

Penthrox is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain. Please consult the Summary of Product Characteristics before prescribing. Information about this product, including adverse reactions, precautions, contra-indications and method of use can be found at www.medicines.org.uk/emc. Legal category: POM. Further information is available on request from Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, United Kingdom.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Galen Limited on 028 3833 4974 and select the customer services option, or e-mail customer.services@galen-pharma.com. Medical information enquiries should also be directed to Galen Limited.

PEN-15-075 A5 Abbreviated ED Ad.indd 1 01/02/2016 16:41Untitled-3 1 01/02/2016 17:06

At last, PENTHROX® is here...Fast, effective pain management designed for fast, efficient patient management.

PENTHROX is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain

Advancing Acute Pain Management

NEW

Penthrox Educational materials and training on its administration are available from Galen on request. Date of preparation: January 2016. PMR-JAN-2016-0042.

Penthrox is indicated for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain. Please consult the Summary of Product Characteristics before prescribing. Information about this product, including adverse reactions, precautions, contra-indications and method of use can be found at www.medicines.org.uk/emc. Legal category: POM. Further information is available on request from Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, United Kingdom.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Galen Limited on 028 3833 4974 and select the customer services option, or e-mail customer.services@galen-pharma.com. Medical information enquiries should also be directed to Galen Limited.

PEN-15-075 A5 Abbreviated ED Ad.indd 1 01/02/2016 16:41Untitled-3 1 01/02/2016 17:06