METHOD OF TREATING PAIN IN PATIENTS Field of the Invention The present invention relates to methods of treating pain in patients. It has particular, application to methods involving the use of methoxyflurane to treat pain in patients.

Background to the Invention

Methoxyflurane (2,2-dichloro- 1 ,1-difluoroethyl methyl ether) (also referred to as 'MEOF' in this specification), first introduced around 1960', was widely used for anaesthesia during the 1960s and early 1970s. It belongs to the fluorinated hydrocarbon group of volatile anaesthetics. Its chemical structure is depicted below:

The molecular formula for MEOF is CsH ₄ CbF ₂ O.

The main advantages of Methoxyflurane in clinical practice are (1) its analgesic properties (including at relatively low doses) and (2) its physiological stability, with minimal changes in the cardiovascular system ' even in high doses (up to 3%). ^π

During the initial use of MEOF as an anaesthetic, it was often regarded as a complete anaesthetic, and used to provide analgesia, hypnosis and relaxation, which it was able to do with little or no physiological disturbance. The physiological stability associated with methoxyflurane led to large doses being administered with consequent over-dosage in many series." ¹ Due to the high fat solubility of MEOF, large amounts were retained, especially in obese patients. The retained MEOF was subsequently released slowly into the bloodstream and

then broken down. Metabolism of large doses of methoxyflurane was associated with a high output renal failure; a syndrome termed 'Methoxyflurane Nephrotoxicity ¹ . While the cause of the nephrotoxicity remains the topic of debate, what is clear is that the nephrotoxicity is associated with inorganic fluoride levels, and is dose related. As a result of the nephrotoxicity, from the early 1970s, the use of methoxyflurane in anaesthesia diminished.

During use of MEOF as an anaesthetic, it was noted that the analgesia extended into the postoperative period, ^ιv reducing the need for administering analgesia via opioids. Analgesia at sub-anaesthetic doses is a feature of MEOF not shared by other halogenated inhalational anaesthetics/ Therefore, as the anaesthetic use of MEOF declined, it continued to be used in low doses for conscious analgesia.

In 1968, Abbott Laboratories Inc. (Abbott) introduced the Analgizer ^® device for low dose self-administration of MEOF by inhalation for pain relief. The Analgizer ^® was a very simple device consisting of a cylindrical polyethylene tube, 15 cm long and 2.5 cm in diameter. (The sign Analgizer™ is registered as a trade mark in the United States of America pursuant to United States Trade Mark Registration No 0868724, which at the date of this specification, is owned by Hospira Inc, a Delaware Corporation, of 275 N. Field Drive, Lake Forest, IL 60045, United States of America) The device contained a tightly wound, absorbent wick of polypropylene. At one end of the device there was an air inlet aperture and the other end was formed into a mouthpiece, next to which there was a dilution aperture to vary the concentration of methoxyflurane being inhaled. The recommended charging dose of methoxyflurane was 15 mL. This technique of administration was used routinely in obstetrics, ^vι ' ^v "' ^vι " post-operative analgesia, ^ιx ' ^x for analgesia during burns dressing changes, ^{xι x} " in the pre-hospital setting ^xι " and for minor painful injuries ^xιv or surgical procedures.™

In Australia, Medical Developments International Limited (Australian Company Number 106 340 667) of 7/56 Smith Road, Springvale 3171 Australia, markets a product which consists of a combination of MEOF (sold under of by reference to the trade mark Penthrox™, which at the date of this specification is

the subject of Australian trade mark application No 1054046, proceeding in the name of Medical Developments International Limited), with a drug delivery device, the Penthrox™ Inhaler. The Penthrox™ Inhaler is essentially similar to the Analgizer ^® , although with some improvements. The Penthrox™ Inhaler has an 'S' shaped wick, is less tightly wound and the intake port at the base is larger to reduce inspiratory resistance and allow a smaller dose to be used (3-6 ml_ vs. 15 mL). In addition, the base has been modified to include an inlet nipple, to which an oxygen line can be attached and a one-way valve has been included on the inside of the base to allow inhalation through the wick but prevent exhalations blowing back through the wick into the atmosphere.

MEOF is self-administered under observation by patients using the handheld Penthrox™ Inhaler (and the patients are assisted, if necessary). It is indicated for self-administration to patients for the relief of pre-hospital pain, under supervision by personnel trained in its use, and for the relief of pain in short surgical procedures such as the change of dressings, dislocations and greenstick fractures. It is presently used by Australian Ambulance Services, Australian Defence, First-aid Officers, ski-fields and mines and in the Emergency Department of several major Australian hospitals.

There have been many published papers on the safety and efficacy of MEOF at analgesic doses in both adults and children. However, very few of the identified papers study the administration of MEOF using the Penthrox™ Inhaler. In addition, the most desirable study design is always the randomised, double- blind controlled trial, and only one such study has been identified . ^xvι ' ^ ¹ ' ¹ ^ ¹ '' This study was conducted using Penthrox™ self-administered via the Penthrox™ Inhaler in children only and does not address its efficacy and safety in the adult population. For this reason, the applicant decided to investigate the safety and efficacy of MEOF and the Penthrox™ Inhaler at analgesic doses in adults, specifically, adult cancer patients who are likely to experience incident pain associated with a predetermined medical procedure. For this purpose, the applicant retained the Peter MacCallum Cancer Centre in Melbourne, Victoria to conduct those investigations on its behalf.

Incident pain in patients with cancer remains a clinical challenge. To manage incident pain effectively requires a rapidly acting analgesic of short duration with minimal toxicity and potent analgesia. Many cancer patients are taking routine "maintenance" analgesia for a constant background of pain. In addition, patients may use intermittent doses of analgesia ("breakthrough") for exacerbations of pain, be they spontaneous or associated with movement or other precipitants (so called "incident" pain).

Such exacerbations occur frequently in the cancer inpatient population in relation to investigational procedures such as bone marrow biopsies, positioning on an examination table for a CT (computer automated tomography) or MRI

(medical resonance imaging) scan or therapeutic procedures such as radiotherapy, which may require (1) positioning the patient on a hard treatment surface or (2) movement of limbs affected by bone metastases or fractures. Other frequent examples of incident pain are pain caused by dressing changes, and also by simple hygiene cares such as bathing and toileting in patients with painful vertebral metastases.

The current management of incident pain is to administer breakthrough analgesia pre-emptively, using the usual oral breakthrough opioid analgesia for that patient. The problems with this approach include (1) staff time to administer the opioid, with at least two staff members required to cross check the dose, delay in onset of action up to 30 minutes for morphine and oxycodone, two of the commonly used opioid analgesics, (2) the 4 hour half life of these agents, which far exceeds the duration of the painful incident and (3) the side effects experienced, in particular sedation in most and nausea in some patients. Therefore, the post procedure recovery time can be prolonged and necessitates additional time in hospital for outpatient procedures before the patient can safely be discharged home. The investigations which have led to the elucidation of the present invention have therefore arisen against the background of the prior art problems discussed above. In particular, the present invention aims to provide a method of treating pain in patients which overcomes one or more of the prior art problems discussed previously.

General disclosure of the Invention The invention generally provides a method of treating pain in a patient, the method comprising the step of administering to the patient, an effective dose of Methoxyflurane via an inhaler means.

Preferably, the patient is a mammal. The patient may be a human or non human mammal. In an especially preferred embodiment, the patient is a human subject. Alternatively, the patient could be a non-human mammal.

Whether the patient is a human or a non-human mammal, the invention may be used in order to treat either or both: • adult; and

• non-adult patients.

Preferably, the patient is an adult patient.

In an especially preferred embodiment of the invention, the patient is a human adult subject.

The forms of pain experienced by the patient, and which are amenable to treatment by the use of the invention, may arise from any number of causes, including on (or combinations of two or more) of:

• As a result of a disease or pathological process in the patient;

• As a result of an injury sustained by the patient; or

• As a result of, or following an invasive medical procedure performed on the patient.

In addition, pain or anxiety may arise where the patient is to undergo a radiological procedure, and in such circumstances, the administration of Methoxyflurane to the patient in accordance with the invention may assist in relieving the patient's pain, and to alleviate the patient's anxiety.

Pain may be generated in a patient by any number of diseases or pathological conditions. One of the principal disease or pathological conditions which causes pain in patients is cancer. Cancer of cause takes many forms, but in terms of the invention, all forms of cancer induced pain (or forms of pain that are augmented or exacerbated by one or more neoplastic conditions) in a patient are amenable to treatment in accordance with the invention. Particular forms of pain experienced by cancer patients that are amenable to treatment in accordance with the invention include:

• Pain which results from a body tissue or structure in the patient coming into contact with a surface (and particularly, a hard surface); and

• Pain which results from the movement of body parts, such as limbs or joints.

The invention may also be used to treat pain in patients who sustain an injury or damage. Typical examples here would include the pain suffered by patients who break a bone, or who dislocate a bone or joint.

The invention may also be used to treat pain in patients who have undergone an invasive medical procedure. Such procedures include: • Surgical procedures;

• Dental procedures; and

• Investigative procedures.

Irrespective of the cause, the physiological nature of the pain experienced by the patient may take one or more of several forms. They include:

• Nociceptive pain; and

• Neuropathic pain.

As used in this specification, these terms have the following meanings.

"Nociceptive pain" is pain arising from damage to tissues, transmitted to the central nervous system by Aδ and C pain fibres. The term may be further explained as follows.

"Normally, pain is felt when impulses reach a conscious brain along thinly myelinated (Aδ) and unmyelinated (C) nociceptive afferents. Eg a pinprick or stubbed toe. ...The resulting sensation (pain) matches the stimulus (noxious) "

(Reference:

Textbook of Pain (4 ^th Edition) Wall, Patrick and Melzack, Ronald (Editors) p 129.

"Neuropathic pain" is pain arising from damage injury and diseases that affect the nervous system directly. The term may be further explained as follows:

"Neuropathic pain is thought to result when sensory neurons in the peripheral nervous system generate impulses at abnormal locations, for example at sites of nerve injury."

(Reference:

Textbook of Pain (4 ^th Edition) Wall, Patrick and Melzack, Ronald (Editors) p 130.

Neuropathic pain often has distinguishing clinical characteristics, which include an unusual quality of the pain (pins and needles, burning, stabbing quality), pain experienced with non-painful stimulation (eg light touch) of an area of skin ("allodynia"), and pain experienced in an area of skin that is numb to touch. Neuropathic pain is generally regarded as being more difficult to relieve successfully.

Both these forms of pain are amenable to treatment in accordance with the invention.

At ambient or room temperature (about 23 - 25 degrees Celsius), Methoxyflurane is substantially a liquid which may be volatilised, and which has a vapour above the liquid surface. Accordingly, in the method of the invention, the dose of Methoxyflurane is initially in the form of a substantially liquid substance (which is

essentially free of other liquids or solvents) in a container which is sealed until use is desired. Typically, as marketed by Medical Developments International Limited, Methoxyflurane is presented in medical delivery members, such as sealed bottles, vials or jars that contain an amount (normally 3 ml_) of Methoxyflurane in liquid form. However, the dose could be presented in any suitable form, the nature of which would be apparent to persons of skill in the art.

Preferably, the dose administered to the patient is up to 6 mL per day and no more than 15 mL per week. In a preferred form of the invention, the dose is up to 3mL of Methoxyflurane, administered over 24 hours. In another embodiment of the invention, the dose is administered in two stages, namely:

(a) via an initial (or "loading" dose); and

(b) via continued administration after the initial dose.

The loading dose may be administered over a period of up to 10 minutes. A preferred time for administering the loading dose is a shorter period, such as between one and eight minutes.

The continued administration of Methoxyflurane may take place over a longer period, ranging up to 40 minutes or longer. The patient's pain management needs will determine the length of this stage of the administration regime.

In the method of the invention, the Methoxyflurane is administered via an inhaler means. A preferred inhaler means is one which comprises:

(1) a body member with a cylindrical wall defining a generally hollow chamber; and

(2) a patient delivery member in fluid communication with the chamber, through which a dose of Methoxyflurane may be delivered to the patient, including:

(a) a mouthpiece through which the patient can inspire the Methoxyflurane from the chamber and expire gases,

(b) .an inspiratory valve coupled between the mouthpiece and the chamber, the inspiratory valve being configured for opening on inspiration by the patient, and closing upon expiration by the patient,

(c) An expiratory valve coupled between the mouthpiece and an exhaust external of the chamber, and disposed coaxialiy with the inspiratory valve, the expiratory valve configured for opening upon expiration by the patient, and closing upon inspiration by the patient, and

(3) a medication inlet in fluid communication with the chamber, through which medication can be introduced to the chamber, the medication inlet including a dispenser retainer for retaining a medication delivery member on the medication inlet.

An embodiment of a suitable apparatus is described in Canadian patent No 2, 199, 957, the entire disclosure of which is expressly incorporated into this specification by reference.

The use of the method of the invention results in effective pain relief for the patient over a period of time. The use of the method may optionally also be combined with the use of one or more other analgesic agents, including opioid analgesics, paracetamol and other agents, the nature of which would be apparent to those of skill in the art.

The use of the method of the invention, whether via the use of Methoxyflurane alone or in combination with one or more other pain relief agents results in effective pain relief, while avoiding the disadvantages, unwanted effects and/or side effects of the use of traditional opioid analgesia alone. The effective use of the method also optimises the possibility of managing "incident" or "breakthrough" pain associated with inherently painful conditions, such as many neoplastic ailments.

Detailed description of a preferred embodiment of the Invention

A preferred embodiment of the Invention will now be described by way of example only, with reference to the following example.

Example

A study was conducted in adult human cancer patients requiring analgesia associated with the conduct of a pre-determined medical procedure. All patients with pre-existing pain undergoing a procedure which might exacerbate the pain, or patients undergoing a painful procedure, were assessed for eligibility to participate in the study. Patients were recruited from the inpatient or outpatient settings. Patients with abnormal renal function (creatinine >0.13mmol/l), cognitive impairment, dyspnoea at rest, inability to speak English, taking tetracyclines or who were unable to use the assessment tool for pain were excluded. The MEOF was administered via the Penthrox™ Inhaler. A dose of 3ml was loaded just before the procedure commenced and patients were instructed to take 8-10 inhalations as a 'loading dose'. Patients then took additional breaths as required, for pain relief during the entire procedure.

Patient demographics were record for the patient group, and these included age, gender, diagnosis, presence of metastases, pain diagnosis, comorbidities, ECOG status, standard analgesia, creatinine, as well as the nature and length of the procedure. The number of breaths taken to load and throughout the procedure was recorded as was concurrent use of oxygen.

Pain scores were measured on an 11 -point Numerical Rating Scale (0-10) at preloading dose, after loading dose, during and at the end of and 60 minutes after the procedure. Side effects, in particular sedation, confusion, nausea and dissociation were recorded.

A nurse attending the patient rated the perceived effectiveness and preference over standard analgesia. A research assistant also rated the performance of the medication using the following parameters: pain control (poor to excellent), side effects, smell and ^" the perceived acceptability to the patient.

Usual breakthrough analgesia and actual breakthrough given immediately prior to the procedure were recorded.

The Penthrox™ Inhaler was stored in a sealed plastic bag at the end of the procedure and returned to pharmacy for disposal. Patients could elect to cease using MEOF at any time during the procedure or ask for an alternative form of pain management. All patients gave informed consent for the study. The study received ethics approval. The study was approved by the Expedited Review Committee at Peter MacCallum Cancer Centre in January 2005.

The results of the study are reported from line 24 of this page onwards.

[Lines 11 to 23 of this page have intentionally been left blank].

Results 28 patients were recruited from January 2005 until the end of May 2005.

The patient demographics are shown in Table 1 Twenty patients had nociceptive pain, one had neuropathic pain, and seven had mixed pain. Patient functional status was generally satisfactory, with fifteen (54%) patients being fully active and able to carry out work activities (ECOG=O). Overall, every patient had a normal mean creatinine level of 0.07 mmol/L (range = 0.04 - 0.13 mmol/L).

Table 1. Baseline Characteristics of the Patients. Values are numbers (percentages) unless otherwise indicated.

Characteristic

Median age in years 58.5

Range 25 - 79

Sex

Female 16 (57)

Male 12 (43)

Classification of Malignancy

Breast 6 (21)

Gastro-intestinal 2 (7)

Gynaecological 1 (4)

Haematological 12 (43)

Melanoma 4 (14)

Thoracic 0 (0)

Unknown Primary Site 1 (4)

Urological 2 (7)

Metastatic Disease

Yes 9 (32)

No 19 (68)

Pain Diagnosis

Neuropathic 1 (4)

Nociceptive 20 (71)

Mixed 7 (25)

Comorbidities

None 16 (57)

Respiratory 2 (7)

Renal 3 (11)

Gastro-intestinal 0 (0)

Other 6 (21)

Mixed 1 (4)

ECOG ^X

0 = Fully active 15 (54)

1 = Restricted in strenuous activity only 5 (18)

2 = Unable to work; up and about more than 50% of waking hours 4 (14)

3 = Confined to bed or chair more than 50% of waking hours 2 (7)

4 = Completely disabled; totally confined to bed or chair 2 (7)

Mean (SD) ² Serum Creatinine (mmol/L) ³ 0.07 (0.02) ⁴

Median 0.08

Range 0.04 - 0.13

The procedures for which MEOF was given for analgesia are listed in Table 2. The most common procedure was bone marrow biopsy (32%). In some instances, the procedure itself was painful, as for bone marrow biopsy. In others, the patient's pre-existing pain was exacerbated by the movement associated with the procedure.

Table 2. Procedural Type. Values are numbers (percentages) unless otherwise indicated.

Indication for Analgesia

Bathing / toileting 1 (3.5)

Bone marrow biopsy 9 (32)

Change of dressing 5 (18)

Diagnostic procedure-change of stent 1 (3.5)

Transfer to and or positioning for diagnostic 3 (11) imaging

Transfer to and or positioning for radiotherapy 6 (21)

Sentinel lymphoscintigraphy node biopsy 3 (11)

Fifteen (54%) patients were taking maintenance pain medication (Table 3). In all fifteen, opioids alone or in conjunction with non-opioids and or adjuvants were used for maintenance pain relief.

Table 3. Maintenance Analgesia. Values are numbers (percentages) unless otherwise indicated.

Patients on Some Form of Maintenance Analgesia 15 (54)

Single Opioid Analgesics 8 (53)

Combined Opioid Analgesics 7 (47)

Simple Analgesics with Opioid: Paracetamol 8 (53)

Adjuvants: Gabapentin 4 (27)

Ketamine 3 (20)

Ten patients received their usual breakthrough analgesia in addition to MEOF. Nine of these were inpatients. The tenth patient was an outpatient who had severe pain from bone metastases and was admitted to hospital soon after the trial. The inpatients who received breakthrough in addition to MEOF had a range of procedures performed. Two had dressing changes, five received MEOF for transfers to radiotherapy for treatment and two for transfer to diagnostic imaging

for investigations. Six had nociceptive pain, one neuropathic pain and two mixed pain.

Table 4 Administration of MEOF. Values are numbers (percentages) unless otherwise indicated.

Screening and Assessing MEOF .

Patients Received Standard Breakthrough Analgesia Pre 10 (36)

Procedure 2 (20)

Simple Analgesics: Paracetamol 8 (80)

Single Opioid Analgesics

Loading Up Time of MEOF

Mean (SD) 1'56" (2'05")

Median 58"

Range 34" - 7'41 "

Total Time of Using MEOF

Mean (SD) 10'47" (8'30")

Median 9'29"

Range 23" - 39'47"

Of the 18 patients who did not receive any form of standard analgesia prior to the procedure, 9 received local anaesthetic only (lignocaine 1%) infused locally, in the bone marrow biopsy site at the start of their bone marrow procedure.

All patients were loaded with MEOF for 10 breaths; none were oxygen dependant and none used MEOF together with oxygen. There was only one patient who loaded with 10-20 breaths. Most patients used 10-20 breaths only throughout the procedure with treatment periods ranging from 23 seconds to 39 minutes and 47 seconds. The median total time using MEOF was 9 minutes and 29 seconds (Table 4).

Patients who received standard analgesia (MEOF+) tended to be inpatients who were attending diagnostic imaging or radiotherapy departments for

treatment. They tended to have a higher level of baseline pain pre procedure and a higher level of worst pain during the procedure (Table 5). However, 80% found the MEOF helpful during their worst pain as did 89% of the MEOF alone group.

Seventy per cent of the MEOF+ rated MEOF as highly effective and 20% as moderately effective. Of the MEOF alone group, 50% found it moderately and 36% highly effective, with an overall effectiveness rating of 89% at least moderately effective (Table 5). [Line 8 to the end of this page has intentionally been left blank].

Table 5. Effectiveness of MEOF. Values are numbers (percentages) unless otherwise indicated

Measure Mean Score

Pain Scores (NRS) All MEOF MEOF

Patients Alone Together

(N=28) (N=18) with

Standard

Analgesia

(N=10)

Mean (SD) Pain Score in the Past 24 Hours 2 (2.6) 1 (1.3) 5 (2.6)

Mean (SD) Pre-painful Episode (before taking MEOF) 1 (2.3) 1 (1.2) 3 (2.8)

Mean (SD) Pain During Painful Episode

Mean (SD) Pain Score at the Start of Procedure 1 (2.2) 1 (1.4) 3 (2.5)

Mean (SD) Pain Score at the End of Procedure 2 (2.4) 1 (1.6) 4(3.1)

Mean (SD) Worst Pain Score (VAS) 5 (3.0) 4 (2.6) 7 (2.9)

Range of worst pain score (VAS) 0-10 0-7 3-10

Mean (SD) Post Painful Episode (VAS) 1 (2.5) 1 (1.2) 3(3.4)

Pain Adequately Controlled

Yes 24 (86) 16(89) 8(80)

No 4(14) 2(11) 2(20)

Helpfulness During Worst Pain

Yes 24 (86) 16(89) 8(80)

No 4(14) 2(11) 2(20)

Effectiveness of MEOF

Not effective 2 (7) 1 (6) 1 (10)

Slightly 1 (4) 1 (6) 0 (0)

Moderately 11 (39) 9(50) 2(20)

Highly 14(50) 7(38) 7(70)

Comparison of Procedures and Patient Groups

Eight of the nine bone marrow biopsy patients had no pain at baseline and none were on maintenance analgesia. The non-parametric Mann-Whitney test was used to compare pain scores between treatment groups, MEOF (methoxyflurane) or MEOF+ (methoxyflurane + standard analgesia) and between procedures, BMB (bone marrow biopsy) or Other (all other procedures). There is an indication that pre-procedure pain (P=O.003) and worst pain during the procedure (P=O.035) is significantly higher for MEOF+ patients than for MEOF patients. (Table 6)

Table 6. Comparison of Pain Scores in MEOF+ and MEOF Groups and Bone Marrow Biopsy and Other Procedure Groups

Assessment Group N Median Range Mean SD ¹

Pre Pain MEOF 18 0 0 - 4 0.5 1.2 0.003

MEOF+ 10 3.5 0 - 7 3.3 2.8

BMB 9 0 0 - 4 0.4 1.3 0.085

Other 19 1 0 - 7 2.0 2.5

Worst Pain MEOF 18 4.5 0 - 8 4.3 2.6 0.035

MEOF+ 10 6.5 3 - 10 7.0 2.9

BMB 9 5 0 - 7 4.3 2.2 0.308

Other 19 5 0 -10 5.7 3.2

Change in pain MEOF 18 4 0 - 8 3.8 2.6 0.796

(worst - pre)

MEOF+ 10 3.5 0 - 10 3.7 2.8

BMB 9 4 0 - 7 3.9 2.5 0.809

Other 19 3 0 - 10 3.7 2.8

1 standard deviation Mann-Whitney test

Patient Preference and Acceptability Base-line

(N=28)

Patients who have had procedure before in the past 21 (75)

Preferred MEOF alone 18 (86)

Preferred MEOF together with standard analgesia 2 (9)

Preferred standard analgesia 1 (5)

Acceptable Taste

Yes 23 (82)

No 2 (7)

Not sure 3 (11)

Acceptable Smell

Yes 26 (93)

No 1 (3.5)

Not sure 1 (3.5)

Table 7 Patient Preference. Values are numbers (percentages) unless otherwise indicated. (Discussed overleaf)

[Line 26 to the end of this page has intentionally been left blank].

Discussion of the results presented in table 7

Patients who preferred MEOF over previous analgesia for the same procedure (18) cited one or more reasons for their preference as follows: the instant pain relief obtained (86%); better personal self control (27%); feeling more at ease, calm and comforted attributed to holding the Penthrox™ Inhaler (7%); minimal side effects (13%) and rapid onset and short acting (13%) (Table 7). Two of the seven patients who had not had the same procedure before preferred Penthrox Inhaler because of a sense of control and lack of discomfort. 5 patients had no preference because they were unable to compare. All patients found the mode of administration acceptable and valued the control it gave them. In addition, both the taste and smell of the vapour was well accepted by patients with only 3 patients finding the taste (2) or smell (1) unpleasant.

Most of the treating staff preferred MEOF over other forms of breakthrough analgesia. The Medical Day Unit staff felt that MEOF had many benefits over the anxiolytic, diazepam, given to patients prior to the bone marrow procedures. In particular, the more rapid and brief action saved time both before the procedure as diazepam takes 20-30 minutes to work as well as after, with the lack of prolonged sedation. Patients also valued the control it gave them over their pain and the distraction of holding the inhaler was also of benefit in minimising the impact of the pain.

[Lines 26 to 29 of this page have intentionally been left blank].

Table 8. Side Effects Documented by Patients. (Overleaf) Values are numbers (percentages) unless otherwise indicated.

Side Effects Score

All MEOF Alone MEOF patients (N=18) Together with

(N=28) Standard

Analgesia

(N=10)

Side Effects

Yes 10 (36) 4 (22) 6 (10)

Confusion 1 (10) 0 (0) 1 (17)

Dissociation 4 (40) 1 (25) 3 (50)

Nausea 2 (20) 1 (25) 1 (17)

Sedation 8 (80) 4 (100) 4 (67)

Shortness of 1 (10) 0 (0) 1 (17)

Breath

Table 8 indicates that 36% (95% Cl 19-56%) of patients experienced at least one side effect, with 8 patients (80%) experiencing sedation. One patient discontinued MEOF because of nausea, despite excellent pain relief.

Discussion of the results of the study

The results of this study demonstrate the efficacy and safety of MEOF administered via Penthrox™ Inhaler for cancer patients with incident pain associated with procedures.

In this study, 15 patients were on maintenance analgesia with opioids. Of these 87% responded to MEOF, rating it moderately or highly effective. This indicates that the analgesia provided by MEOF is sufficient to contribute additional benefit to patients on regular opioid therapy.

The range of procedures varied, with 32% having a bone marrow biopsy.

None of the bone marrow biopsy group was on maintenance analgesia. There was no significant difference in pre-procedure, worst or change in pain score between the bone marrow biopsy group and those having other procedures.

Inpatients tended to have higher baseline pain associated with metastatic disease. Of these, 9 received standard analgesia as well as MEOF (MEOF+), according to standard of care in the hospital. Despite this, the mean worst pain score for the MEOF+ group was significantly higher than the MEOF alone group (P=O.035), as was the pre-procedure pain score (p=0.003) in keeping with a more severe pain syndrome in this group. Nevertheless, 70% of these patients rated the MEOF as highly effective and 20% rated it as moderately effective. This compares with 38% and 50% respectively in the MEOF alone group.

In total, 86% patients found the MEOF helpful during their worst pain.

Patient who were able to compare MEOF with alternative analgesia for the same procedure preferred MEOF alone or in combination with standard analgesia in

95% of cases. The instant pain relief obtained and personal control over their analgesia were cited by 74% of patients.

MEOF was simple to use. Toxicity was experienced in 36% of patients but was only significant for one patient who elected to discontinue using MEOF because of nausea. No patient discontinued it because of its smell or taste. Staff attending the patients preferred it to usual breakthrough because of the simplicity of use and efficacy. There was excellent agreement between patient and Research Assistant's assessment of efficacy (Cohens Kappa 0.57, p=0.0001) (Reference: Jacob Cohen (1960). A coefficient of agreement for nominal scales. Educational and Psychological Measurement 20, 37-46).

This study is the first to evaluate the efficacy and safety of Penthrox™ Inhaler administration of MEOF for pain control in cancer patients experiencing incident pain. The results have supported a role for this application in this patient group, in addition to the other settings previously identified.

The advantages of MEOF in this clinical setting include its potent analgesic properties, short onset and duration of activity and minimal toxicity. Furthermore, the patient is able to control their own analgesia by using the handheld device

whenever they need to during the procedure. This and the resultant minimisation of staff time are important advantages. The uniform dose is also advantageous in comparison to opioid breakthroughs, which require titration for the individual, particularly if they are taking an opioid regularly for pain management. ^xviii

Interpretation of this specification

It will therefore be understood that the invention could take many forms and be put to many different uses. All such forms and uses are embodied within the spirit and scope of the invention, which is to be understood as not being limited to the particular constructional details of the embodiments discussed above, but which extends to each novel feature and combination of features disclosed in or evident from this specification and the accompanying claims and drawings. All of these different combinations constitute various alternative aspects of the invention.

It will also be understood that the term "comprises" (or its grammatical variants), as used in this specification, is equivalent in meaning to the term "includes" and should not be taken as excluding the presence of other elements or features. Further, wherever used in this specification, the term "includes" is not a term of limitation, and is not be taken as excluding the presence of other elements or features.

It is also to be understood that any discussion in this specification of background or prior art documents, devices, acts, information, knowledge or use ('Background Information') is included solely to explain the context of the invention. Any discussions of such Background Information is not be taken as an admission that any such Background Information constitutes part of the prior art base or the common general knowledge in the field of the invention on or before the priority date of the appended claims or any amended claims later introduced into this specification.

Finally, the List of References that appears on the attached document forms part of this specification.

List of References

i Tomlin PJ. Methoxyflurane. Br. J Anaesth. 1965;37(9):706-9. ii Komesaroff D. Pre-Hospital Pain relief: Penthrane or Entonox? Aust J Emerg Care 1995;2(2):28-9. iii Komesaroff D. A critical appraisal of methoxyflurane and its place in modern anaesthesia. Paper presented at the 4 ^th Asian and Australasian Congress of Anaesthesiologists, Singapore, September 1974. iv Stephen CR. Clinical applications of methoxyflurane. Acta Anaesthesiol Scand Suppl 1966;24:215-22. v Tomi K, Mashimo T, Tashiro C et al. Alterations in pain threshold and psychomotor response associated with sub-anaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth 1993;70:684-6. vi Bergsjø P, Lindbask E. Comparison between nitrous oxide and methoxyflurane for obstetrical analgesia. Acta Obstet Gynecol Scand. 1971;50(3):285-90. vii Fielding ME, Hurry DJ. Analgesia in instrumental vaginal delivery by the intermittent self-administration of methoxyflurane using a disposable vaporizer. Br J Anaesth 1972;44(4):386-90. viii Marx GF, Chen LK, Tabora JA. Experiences with a disposable inhaler for methoxyflurane analgesia during labour: clinical and biochemical results. Can

Anaesth Soc J 1969;16(1):66-71. ix Yakaitis RW, Cooke JE, Redding JS. Self-administered methoxyflurane for postoperative pain: effectiveness and patient acceptance. Anesth Analg 1972:51(2):208-12. x Yakaitis RW, Redding JS. Self-administered methoxyflurane for improved postoperative ventilation. Anesth Analg 1970;49(3):345-50. xi Packer KJ, Titel JH. Methoxyflurane analgesia for burns dressings: experience with the Analgizer ^® . Br J Anaesth 1969;41(12):1080-5. xii Packer KJ. Methoxyflurane analgesia for burns dressings. Postgrad Med J 1972;48(557): 128-32. xiii Komesaroff D. Serum fluoride ion levels following the administration of methoxyflurane for analgesia. Paper presented at the Australian Society of Anaesthetists Annual General Meeting, Adelaide, South Australia, October 1979. xiv Romagnoli A. Busque L, Power DJ. The "Analgizer ^® " in a general hospital: a preliminary report. Can Anaesth Soc J 1970;17(3):275-8. xv Lewis LA. Methoxyflurane analgesia for office surgery. Surgical gem. J Dermatol Surg Oncol 1984;10(2):85-6. xvi McCaskill M, Chin R, Gosby H, Lam L, Browne G. (manuscript in preparation).

XVU Chin R, McCaskill M, Browne G ₅ Lam L. A randomised control trial of inhaled methoxyflurane pain relief, in children with upper limb fracture. J Paediatr Child Health 2002;38(5):A13-A14.

XVlIl Holaday DA, Rudofsky S, Treuhaft PS. The metabolic degradation of methoxyflurane in man. Anesthesiology 1970;33(6):579-93.

XlX Christie JM, Simmonds M, Patt R, coluzzi P, Busch MA, Nordbrock E ₅ Portenoy RK. Dose titration, multicenter study of oral transmucosal fentanyl citrte for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16(10):3233-3245

Oken, M. M., Creech, R. H., Tormey, D. C, Horton, J., Davis, T. E., McFadden, E. T. et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 5: 649, 1982

^iU Tomlin PJ. Methoxyflurane. Br. J Anaesth. 1965;37(9):706-9.

¹ Komesaroff D. Pre-Hospital Pain relief: Penthrane or Entonox? Aust J Emerg Care 1995;2(2):28-9.

'Komesaroff D. A critical appraisal of methoxyflurane and its place in modern anaesthesia. Paper presented at the 4 ^th Asian and Australasian Congress of Anaesthesiologists, Singapore, September 1974.

^lv Stephen CR. Clinical applications of methoxyflurane. Acta Anaesthesiol Scand Suppl 1966;24:215-22. ^v Tomi K, Mashimo T, Tashiro C et al. Alterations in pain threshold and psychomotor response associated with sub-anaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth 1993;70:684-6.

^V1 Bergsjø P, Lindbask E. Comparison between nitrous oxide and methoxyflurane for obstetrical analgesia. Acta Obstet Gynecol Scand. 1971;50(3):285-90. ^vu Fielding ME, Hurry DJ. Analgesia in instrumental vaginal delivery by the intermittent self-administration of methoxyflurane using a disposable vaporizer. Br J Anaesth 1972;44(4):386-90. ^vm Marx GF, Chen LK, Tabora JA. Experiences with a disposable inhaler for methoxyflurane analgesia during labour: clinical and biochemical results. Can Anaesth Soc J 1969;16(l):66-71.

^IX Yakaitis RW, Cooke JE, Redding JS. Self-administered methoxyflurane for postoperative pain: effectiveness and patient acceptance. Anesth Analg 1972:51(2):208-12. ^x Yakaitis RW, Redding JS. Self-administered methoxyflurane for improved postoperative ventilation. Anesth Analg 1970;49(3):345-50.

^X1 Packer KJ, Titel JH. Methoxyflurane analgesia for burns dressings: experience with the Analgizer ^® . Br J Anaesth 1969;41(12):1080-5. ^xn Packer KJ. Methoxyflurane analgesia for burns dressings. Postgrad Med J 1972;48(557):128-32. ^xiπ Komesaroff D. Serum fluoride ion levels following the administration of methoxyflurane for analgesia. Paper presented at the Australian Society of Anaesthetists Annual General Meeting, Adelaide, South Australia, October 1979.

^X1V Romagnoli A. Busque L, Power DJ. The "Analgizer ^® " in a general hospital: a preliminary report. Can Anaesth Soc J 1970;17(3):275-8.

Lewis LA. Methoxyflurane analgesia for office surgery. Surgical gem. J Dermatol Surg Oncol 1984;10(2):85-6.

McCaskill M, Chin R, Gosby H, Lam L, Browne G. (manuscript in preparation).

^xyπ Chin R, McCaskill M, Browne G, Lam L. A randomised control trial of inhaled methoxyflurane pain relief, in children with upper limb fracture. J Paediatr Child Health 2002;38(5):A13-A14. ^xviii Holaday DA ₅ Rudofsky S, Treuhaft PS. The metabolic degradation of methoxyflurane in man. Anesthesiology 1970;33(6):579-93. ^xix Christie JM, Simmonds M, Patt R, coluzzi P, Busch MA, Nordbrock E, Portenoy RK. Dose titration, multicenter study of oral transmucosal fentanyl citrte for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16(10):3233-3245