Analgesic anaesthetic compositions

An analgesic anaesthetic composition comprising up to 50% v.backslash.v nitrous oxide, the balance being oxygen and another respirable gas; characterized by the addition of an analgesically effective amount of an ether-based analgesic anaesthetic disposed in a single container above its pseudo-critical temperature at a pressure of up to 2000 psi, thereby to form and maintain a homogenous analgesic composition.

This application is a 371 of PCT/GB94/00839 filed Apr. 21, 1994. 
The present invention relates to analgesic anaesthetic compositions, and 
particularly to such a composition comprising about 50% v/v nitrous oxide 
and oxygen, sold under the Registered Trade Mark `Entonox`. 
The storage of gas mixtures in a homogenous state in a pressurized 
container is well established. It was shown in 1961 that a permanent gas, 
such as oxygen, was able to sustain nitrous oxide (a gas with analgesic 
and anaesthetic properties) in a homogenous gaseous admixture at 
temperatures and pressures at which previously part of the nitrous oxide 
was expected to separate out into liquid form (The Lancet 28 Oct. 1961, p 
964) and in GB-A-967,930. 
Following further studies, premixed nitrous oxide and oxygen at 
approximately 50/50 v/v mixture was made available. This was utilised for 
the relief of labour pains in child-birth from 1965 under the Trade Name 
`Entonox`. Entonox is inhaled for self-administered inhalation analgesia 
via a demand regulator under medical, nursing or paramedical supervision 
for many applications in addition to child-birth. The fundamental 
advantages of premixing the gases in a single pressurized container are 
safety (the oxygen supply cannot fail), and simplicity (no mixing device 
is required). 
Nitrous oxide at 50% is itself a potent analgesic agent, which after more 
than a minute or so of deep and rapid inhalations causes a number of 
patients to become amnesic, inaccessible to instructions and 
uncontrollable in response to strong stimuli. Its uptake and excretion are 
both rapid. It is because the pain of each uterine contraction of 
child-birth is both of such relatively short duration and is separated by 
a few minutes from the next pain that 50% nitrous oxide has been practical 
for use as an analgesic. Each episode of inhalations during child-birth is 
normally too short to allow amnesic levels of nitrous oxide to be reached 
in the brain. Nitrous oxide at a concentration of 50% is generally the 
lowest concentration used for women in labour and will make a number of 
people unresponsive if breathed for long enough. Nitrous oxide at a 
concentration of 30% has been used in dentistry for more prolonged times. 
This is probably the lowest concentration that is used. 
The rapid uptake and excretion of nitrous oxide requires special 
understanding by those supervising the use of Entonox. For constant pain, 
say during ambulance transport following injury, the patient needs to be 
instructed in the correct intermittent use of Entonox to make the most of 
its advantages. When Entonox is administered for short painful procedures 
not requiring a general anaesthetic, such as the withdrawal of drainage 
tubes and certain other therapeutic procedures, it is always a problem to 
attain the correct timing and duration of inhalation to cover the peak of 
pain. 
These problems suggest that an inhalation admixture with a lower 
concentration of nitrous oxide, but with the addition of a volatile 
ether-based analgesic agent such as isoflurane, would allow a longer 
duration of inhalation, better maintenance of co-operation and more 
prolonged pain relief. Such mixtures, with their slower onset and decline 
of analgesia, have already been shown to be beneficial. 
Gas mixtures containing nitrous oxide and oxygen were covered in 
GB-A-967930 (1961). Included in that disclosure was the use of the 
volatile anaesthetic agent Halothane at up to 1% as an adjuvant to the 
admixture. Halothane is a volatile non-analgesic anaesthetic agent which 
however has been shown to be unstable in the presence of light, oxygen and 
metal (see British Journal of Anaesthesia, 1984, Volume 56, Supplement 3s 
to 7s; R. C. Terrell). 
It has recently been shown that the inhalation of Entonox, with the 
separate addition of 0.25% isoflurane vapour, provides more relief for the 
pains of childbirth than Entonox alone (International Journal of Obstetric 
Anaesthesia 1992, Vol 1 p199-202). Isoflurane is a volatile ether-based 
analgesic anaesthetic agent. In this disclosure, isoflurane was added to 
Entonox via a vaporiser in line with the breathing hose from the demand 
regulator. For general surgical anaesthesia, isoflurane is normally 
utilised at concentrations of 0.5 to 1.5% rising to 1.5 to 3%, usually in 
combination with various other medications. It is always administered via 
its own separate vaporiser. 
Isoflurane, for example, is 1-chloro-2,2,2-trifluoroethyl difluoromethyl 
ether and hence has a molecular configuration and molecular weight (185) 
which indicates that an evenly distributed gaseous admixture with Entonox 
cannot be achieved at the necessary concentrations at normal filling 
pressures for medical gas cylinders. 
Moreover at 2000 psi the theoretical maximum of isoflurane which would 
admix is below about 0.2%; a level which is too low for significant 
analgesia. Further, this limit is significantly reduced if the ambient 
temperature of the stored admixture falls from 20.degree. C. to say 
5.degree. C. during heavy use of the cylinder, the temperature may also 
fall below the pseudo-critical temperature of the admixture. The 
pseudocritical temperature is the temperature above which any component of 
the gaseous mixture can not be compressed to a liquid. 
The inventors have now discovered that ether-based analgesic anaesthetics 
in fact successfully admix evenly above their theoretical maxima, and 
further that the pseudo-critical temperature of admixtures of nitrous 
oxide and oxygen rise significantly in the presence of small amounts of 
the said ethers. 
Thus at below 0.4% v/v isoflurane vapour the admixture is in fact evenly 
distributed and also at that level the isoflurane has a significant 
analgesic, as opposed to anaesthetic effect, allowing if desired a 
reduction of the percentage of nitrous oxide. Other ether-based analgesic 
agents suitable for use in the invention are Enflurane, Sevoflurane and 
Desflurane. 
According therefore to a first aspect of the present invention there is 
provided an analgesic anaesthetic composition comprising up to 50% v/v 
nitrous oxide, the balance being oxygen or other respirable gas mixture, 
characterised by the addition of an analgesically effective amount of an 
ether-based analgesic anaesthetic, said composition being disposable in a 
single container above its pseudo critical temperature at a pressure of 
2000 psi, thereby to form a homogenous analgesic anaesthetic composition. 
Where the ether-based analgesic is isoflurane vapour the amount is 
preferably up to 0.4% v/v and most preferably between 0.25% and 0.325% 
v/v. With the higher percentages of isoflurane or of other ether-bases 
analgesic anaesthetics, the amounts of nitrous oxide may be commensurately 
reduced thus prolonging the period before serious amnesic or anaesthetic 
complications arise. When used in this context, "commensurate" refers to 
anaesthetic potency. Thus, for example, 50% nitrous oxide has the same 
potency as 0.6% isoflurane. Thus, if one added 0.3% isoflurane to a 
gaseous mixture, the nitrous oxide content could be reduced by half and 
the oxygen content would rise accordingly. 
A further relatively minor problem with the utilisation of these 
ether-based analgesics such as isoflurane is caused by sputter which in 
theory could cause discomfort. Sputter occurs especially when the pressure 
drop from the storage container to a first stage reduction chamber in the 
demand regulator exceeds 62 bar or thereabouts. Sputter is manifested by 
rapid fluctuations of isoflurane concentration recorded by a gas analyzer 
measuring the delivered mixture. It is due to condensation and 
revaporisation of the isoflurane within the regulator or flow control 
valve, Although usually the sputter range is within clinically accentable 
limits and the average concentration per breath corresponds to the 
concentration within the pressurised supply container, there is a problem 
on cessation of inhalation that a small residue of condensate in the first 
stage reduction chamber vaporises to give a peak concentration in the next 
breath after the rest period. This may be alleviated by maintaining the 
pressure drop between the container and the first stage reduction chamber 
at a value of less than 62 bar; arranging that a 1 liter/minute gas bleed 
occurs from the first stage reduction chamber into the breathing circuit, 
by mechanically discarding or diluting the first breath after a rest 
period from the reduction chamber, or by using an absorbative system in 
the breathing circuit to take up liquidised ether-based analgesic such as 
isoflurane and then releasing it slowly. In practice however sputter has 
not yet demonstrated itself to be a clinical problem requiring solution. 
Separation of the nitrous oxide and oxygen of Entonox can occur within the 
pressurized container if the container has been exposed to cold. In which 
case it is necessary to roll the container for 5-10 minutes after 
rewarming. The described composition may require more prolonged rolling. 
According therefore to a further feature of the invention there is provided 
a method of filling a pressure cylinder with a medical gas composition 
which method comprises: 
evacuating the cylinder to a significant negative pressure, partially 
filling the said pressure cylinder with said gas composition, cooling said 
partially said cylinder to a temperature below the liquification 
temperature of at least one of the components of said composition, and 
completely completing the filling process and allowing the cylinder to 
re-warm to room temperature, followed either by horizontal storage above 
10.degree. C. for about 48 hours, or followed by prolonged rolling. 
In a preferred form of this aspect of the invention a higher molecular 
weight analgesic or anaesthetic adjunct for example an ether-based 
analgesic may be added after vacuum formation within the cylinder and 
prior to addition of the other components of gaseous admixture. 
The invention will now be described, by way of illustration only, with 
reference to the following Examples.

EXAMPLE 1 
Use of a Gas Composition According to the Invention 
An analgesic anaesthetic gaseous composition comprising 50% v/v nitrous 
oxide, 0.25% v/v isoflurane and the balance of oxygen or other respirable 
gas (referred to hereinafter as Gas Mix A) was charged into a pressurized 
container as described in Example 3. This composition was administered 
during childbirth via a demand regulator in the usual way to a subject 
using the normal instructions given during the self-administration of 
Entonox. 
It was found that the levels of analgesia were greater than would have been 
expected with Entonox. 
EXAMPLE 2 
Use of a Gas Composition According to the Invention 
An analgesic anaesthetic composition of 30% v/v nitrous oxide, and 0.3% 
isoflurane the balance being of oxygen, was charged into a pressurised 
container as described in Example 3. This composition was 
self-administered during removal of chest drains in patients after 
surgery. In a small controlled study it was found that patients indicated 
a distinct preference for the composition in accordance with this example, 
rather than the control composition of Entonox without further additives. 
EXAMPLE 3 
Preparation of a Gas Composition According to the Invention 
The production of the composition in accordance to the present invention 
may be effected as follows: 
A gas storage cylinder having a safe working capacity of about 2000 psi was 
evacuated with a vacuum pump to a significant negative pressure of up to 
30 inches/Hg. A measured quantity of isoflurane was injected by syringe 
into the cylinder whilst still under negative pressure. Nitrous oxide and 
oxygen was then added as percentages by weight until the cylinder was 
fully charged at 2000 psi. The gaseous composition was then used through 
the usual demand valve system as is done with Entonox administration. The 
cylinder so charged was used in Examples 1 and 2. 
EXAMPLE 4 
Use of Gas Mix A and Entonox in the Removal of Chest Drains 
An analgesic anaesthetic gaseous composition comprising up to 50% v/v 
nitrous oxide, 0.25% v/v isoflurane and the balance of oxygen or other 
respirable gas (referred to hereinafter as gas mix A) was charged into a 
pressurised container as follows. 12 molybdenum steel cylinders were 
evacuated and liquid isoflurane injected into them sufficient to give a 
final concentration of 0.25% isoflurane. The cylinder was then filled to a 
pressure of 137 bar by decanting Entonox from high pressure cylinders in a 
two stage process. An initial fill brought cylinder pressure up to between 
50 and 100 bar. The cylinder was then chilled to -40.degree. C. allowing 
the nitrous oxide to liquefy and cylinder pressure to drop. Further 
Entonox was then added such that, when the cylinder returned to room 
temperature, a cylinder pressure of 137 bar was attained. Cylinders of gas 
mix A so prepared were then rolled to ensure complete mixing of the 
contents. The final gas mixture was analysed for oxygen (Taylor Servomex 
paramagnetic oxygen analyser) and for isoflurane (Datex Normal infra-red 
analyser) to ensure that target concentrations were achieved. 
During surgery for coronary artery bypass grafting (CABG) two drains are 
placed to drain blood from the mediastinum and pericardial sac in the 
post-operative period and so to prevent cardiac tamponade and help detect 
undue bleeding. The drains exit below the costal margin on each side of 
the mid-line. The mediastinal drain passes up behind the sternum and is 
taken out to the right of the mid-line. The pericardial drain curves 
dorsally under the caudal surface of the heart within the pericardium and 
exits to the left of the mid-line. Both drains are about 300 mm in length 
and have the same diameter. These drains are generally removed on the 
second post-operative day after the patient's return to the thoracic high 
dependency ward from the intensive care unit. The removal of the drains is 
painful and within the Cardiothoracic Surgery Unit at Aberdeen Royal 
Infirmary for example, it has become standard practice for the nurse who 
is removing the drains to supplement analgesia by administering Entonox. 
The analgesic efficacy of gas mix A was compared to Entonox in this study. 
The gas mixtures were self-administered by a demand valve system (Ohmeda), 
currently used for the administration of Entonox. 
Gas Mixture Administration and Assessment of Analgesia 
Prior to drain removal, the patient was allowed to breath gas, through a 
demand valve and facemask or mouth piece. The gas was breathed until the 
patient was observed to become drowsy and, in the opinion of the attendant 
staff, was adequately narcotised without being unconscious. This generally 
took about two minutes. The drain was then removed. The same procedure was 
repeated with the other gas after 10-15 minutes and the second drain 
removed. There was no attempt to fix which drain was removed first. The 
procedure was medically supervised for all patients in this trial although 
removal of such drains is usually a nursing procedure. 
The patient's state of consciousness and degree of comfort were assessed 
before and during the procedure. Heart-rate, blood pressure and oxygen 
saturation (pulse oximetry were also noted before and after the removal of 
each drain. Scores for discomfort, sedation, co-operation and reaction to 
removal of the drain were also noted. 
The patient was asked to complete a Patient Assessment Form after removal 
of each drain. The patient was asked to note the degree of pain caused by 
removal of the drain on a 100 mm linear analogue scale, to note whether 
the gas had a pleasant or unpleasant odour and whether any nausea was 
experienced. At the end of the procedure the patient indicated which gas 
was preferred and which drain removal was least painful. 
Statistical analysis was performed using the computer program Minitab. 
Scores obtained while breathing the second gas mix were subtracted from 
those obtained for breathing the first gas mix. The resulting difference 
was analysed using a sign test (Minitab). Analogue pain scores were 
analysed differently. Paired scores obtained from patients breathing the 
first and second gas were compared using a Wilcoxon signed rank test. 
Comparisons between the group of patients breathing Entonox as first gas 
and the group breathing gas mix A as the first gas were made by 
Mann-Whitney tests. Comparisons were made both between gas mix A and 
Entonox and between data obtained during the first gas breathed and the 
second gas breathed. 
35 patients were admitted to the trial; 15 receiving gas mix A as the first 
gas and 20 receiving Entonox as the first gas. Not all patients were able 
to provide complete sets of data and so `n` is quoted for the statistics 
calculated. The results are shown in Table 1 below 
TABLE 1 
______________________________________ 
Pain scores (paired data only) 
Interquartile range 
Group n Median 25% 75% 
______________________________________ 
Entonox for first drain 
13 10 5 23 
Gas mix A for second drain 
13 18 10.5 26.5 
Gas mix A for first drain 
12 15.5 4.75 23.75 
Entonox for second drain 
12 33.5 15 65 
First drain 25 13 5 23.5 
Second drain 25 25 12.5 38.5 
______________________________________ 
Both Entonox and gas mix A were well tolerated by patients and there were 
no technical problems experienced during the trial. Both Entonox and gas 
mix A were detected as having an odour by some patients although in 
general neither were thought to have a smell and there was no overall 
difference between the two mixtures (n=35). There was no difference 
between the two mixtures or the order of gas administration with regard to 
the level of sedation (n=35), patient co-operation (n=35), reaction to 
removal of the drain (35), memory of drain removal (n=34), nausea (n=34) 
or dizziness (n=35). 6 patients had no memory of drain removal under gas 
mix A while 7 had no memory of events under Entonox. 
There was no significant alteration in oxygen saturation, pulse rate or 
blood pressure due to removal of the drains and there was no change caused 
by changing the analgesic gas mixture. 
Across both groups the removal of the second drain caused more discomfort 
(n=35, p 0.027) and the first gas administered was thought to be most 
helpful (n=30, p 0.013). Pain scores were also highest for the second 
drain (n=25, p 027) (Table 1). 
When Entonox was administered for the first drain there was no difference 
in pain scores between the two gas mixtures (n=13 for both groups) (Table 
1). When gas mix A was given for the first drain, pain score for the 
second drain was significantly higher (n=12 for both groups, p 0.028) 
(Table 1). Comparison between scores obtained while Entonox was being 
given showed that pain scores obtained while Entonox was given for the 
second drain were higher (n=15 and 14, p 0.005) (Table 2). Comparison 
between scores obtained while gas mix A was being given showed no 
difference. This is shown in Table 2 below 
TABLE 2 
______________________________________ 
Pain scores (all data) 
Interquartile range 
Group n Median 25% 75% 
______________________________________ 
Entonox for first drain 
15 10 5 25 
Gas mix A for second drain 
15 17 6 25 
Gas mix A for first drain 
12 15.5 4.75 23.75 
Entonox for second drain 
14 38.5 21 65.25 
______________________________________ 
The experimental design was chosen in the expectation that the painful 
stimulus elicited by the removal of each drain would be similar. This is 
not so with the data clearly showing that the second drain was more 
painful and that more help was obtained from the gas mixture during the 
first drain. The study does not offer an explanation of this phenomenon 
although several are possible. It may have been that there was a tendency 
for one or other of the two drains to be removed first and that the site 
of the drain influenced the pain suffered. Alternatively the experience of 
the first might have raised the expectation of pain for the second. Since 
the administration of the gas mixtures was controlled by the response of 
the patient it is unlikely that differences in gas uptake or distribution 
were of importance. 
Comparison of Entonox and gas mix A indicate that while gas mix A 
controlled the pain of the removal of the second drain to a level similar 
to that of the removal of the first drain, this was not so for Entonox. 
When Entonox was given for the removal of the second drain, pain scores 
were higher than for any of the other three conditions during which pain 
scores were not dissimilar. 
EXAMPLE 5 
Use of a Gas Mix A and Entonox in Childbirth 
An analgesic anaesthetic gaseous composition comprising up to 50% v/v 
nitrous oxide, 0.25% isoflurane and the balance of oxygen or other 
respirable gas (referred to hereinafter as gas mix A) was prepared as in 
Example 4. 
The study describes the use of gas mix A in 56 women in labour. Ten of 
these participated in a trial comparing the efficacy of gas mix A as 
compared to Entonox and so there was no element of midwife or patient 
choice in the inhalational analgesic used apart from the mother consenting 
to participate in the study. In 46 women, however, choice of agent was 
left to the mother and midwife. Gas mix A and Entonox were 
self-administered by a demand valve system (Ohmeda), currently used for 
the self-administration of Entonox. 
The use of gaseous analgesia was tested in the patients shown in Table 3 
below. 
TABLE 3 
______________________________________ 
Summary of Patients 
AGE Gestation 
(years) (weeks) 
mean ITY 2nd 3rd 4th mean 
(range) Primip child child 
child 
Twins (range) 
______________________________________ 
Free 27.83 27 9 9 1 2 39.5 
Study (16-39) (32-42) 
Pilot 27.30 8 2 39.8 
Study (18-32) (37-42) 
All 27.7 35 11 9 1 2 39.6 
Mothers 
(16-39) (s.d. 1.87) 
______________________________________ 
56 mothers in total received gas mix A (table 3). 10 mothers received gas 
mix A as part of a pilot, prospective and controlled clinical trial 
studying the efficacy of gas mix A in comparison with Entonox. These were 
assessed as uncomplicated cases. 46 mothers received gas mix A as it was 
thought indicated by their attending midwife for the management of pain in 
labour and if gas mix A was available. 
The Table 4 below shows the analgesic requirements of the patients. 
Usually, Entonox was the initial gaseous agent and gas mix A was offered 
as labour progressed. 
TABLE 4 
______________________________________ 
Summary of Gaseous Analgesic 
Duration Duration 
of Entonox 
of gas mix A Intolerance 
hours, hours, to gas mix A 
mean (range) 
mean (range) (cases) 
______________________________________ 
Free study 
3.58 (0-10) 3.84 3 
(0.2-10.98) 
Pilot Study 
-- 9.1 0 
(3.17-14.12, n 10) 
All Mothers 
3.58 4.77 
(s.d. 2.45, n 45) 
(s.d. 3.52, n 56) 
______________________________________ 
Five mothers who were started on gas mix A after a period of Entonox 
breathing reverted to Entonox. The reason for this was unrecorded in one 
instance and was due to the gas mix A running out in another. In one 
labour, a dose of opiate was given after gas mix A was started and this 
ameliorated pain such that Entonox was adequate thereafter. Of the 
remainder, one mother felt nauseated by gas mix A and the other did not 
like its smell. The level of intolerance to gas mix A was, therefore, in 
the order of 5% if it is assumed that the unrecorded reason for reverting 
to Entonox was gas mix A intolerance. 
TABLE 5 
______________________________________ 
Summary of opiate and regional analgesic requirements 
One Two Three Epidural 
dose doses doses contra- 
opiate opiate opiate Epidurals 
Indicated 
______________________________________ 
Free 27 13 1 9 5 
Study 
Pilot 7 1 0 0 0 
Study 
______________________________________ 
59% of mothers received a single dose of opiate, which was either morphine 
or diamorphine, and 23% received two doses. A third dose of opiate was 
administered on only one occasion to a primigravid mother whose first 
stage lasted 22 hours and who did not want epidural analgesia. 
In ten instances opiate was given before the start of gaseous analgesia and 
seven mothers required no opiate analgesic. In four cases the first dose 
of opiate was given with the start of inhalational analgesia. In the 
remaining mothers the first dose of opiate was given 0.3-8.12 hours (mean 
2.25 s.d. 1.7) after the start of an inhalational analgesic. 
Epidural analgesia was instituted in nine cases (16.1%). This compares with 
an epidural incidence of 16.1% deliveries in Aberdeen Maternity Hospital 
during the study period. In five cases the epidural provided adequate pain 
relief with no other form of analgesia being required. On four occasions, 
however, incomplete analgesia was obtained and inhalational analgesia was 
reintroduced with gas mix A being used twice under these circumstances. 
This study shows that there were no unexpected problems with the 
administration of gas mix A and the level of intolerance was low. Undue 
drowsiness and lack of co-operation was not mentioned as a problem in the 
notes of the patient and in no case was the gas withdrawn because the 
midwife felt it unsafe to continue. 
It was anticipated that gas mix A would only be used in more painful 
labours and after Entonox had been used. In this study, the conclusion was 
reached that gas mix A was used when pain ceased to be controlled 
adequately by Entonox and on occasion, even in place of an epidural 
analgesia. Thus in the free study, gas mix A was used without problem as a 
supplementary gaseous analgesic where a more potent agent was required 
than Entonox for 46 mothers. In a further 10 labours it was used without 
problem as the sole gaseous analgesic. 
EXAMPLE 6 
Stability of Gas Mix A at Low Temperatures in Storage 
Gas mix A was prepared as described in Examples 4 and 5. The phase 
separation characteristics of a gas mix A at 137 bar was studied in 
respect of stability of isoflurane concentration with regard to cylinder 
temperature. Cylinder temperatures of down to -9.3.degree. C. were 
studied. 
The results showed that no separation was detected at a cylinder 
temperature of -3.3.degree. C. Mild separation was seen at -4.degree. C. 
and this was marked at -9.3.degree. C. The lowest cylinder temperature 
likely to be encountered when used at room temperature is -3.degree. C. 
amd thus it is concluded that phase separation will not be seen with a 
properly mixed cylinder in use.