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Three Part Question

In [pre-hospital care with adults suffering with mild/sever pain] does [Morphine or Entonox] provide [the most effective pain relief]?

Clinical Scenario

You receive an emergency call to a 47 year old male with a fractured right ankle from playing football. On arrival you can identify a possible closed fracture of the distal tibia and proximal fibular. Your patient is in a great deal of pain causing him to move his leg and irritate his injuries. On closer inspection you find a strong pedal pulse with good perfusion distal to the injury. There are no other injuries. You turn your attention to pain relief. On taking a history you find your patient has not been SCUBA diving or ever had any pulmonary problems, you patient has also never been exposed to opiate based drugs. You wonder whether you should give Morphine or Entonox? Which one is more effective and safer?

Search Strategy

Medline using the PubMed interface:
Nitrous Oxide OR Entonox AND Morphine AND Pain NOT Nitric – searching all years with no filters
CINAHL with full text using the EBSCO host:
Nitrous oxide OR Entonox AND Morphine AND Pain - Limited to Randomised Control Trials
BestBETS Database:
BET Keywords: Nitrous, Entonox, Morphine
The Cochrane Library:
Nitrous oxide OR Entonox AND Morphine AND Pain
Google:
Entonox, Morphine, Pain

Search Outcome

Medline – 170 matches found of which only 4 were relevant
CINAHL – 8 matches with no relevant papers found
BestBETS – No matches found
Cochrane Reviews – 70 matches with no relevant papers
Google – 67,400 matches. All results not search. A brief search produced 1 new article
Total of 5 relevant papers

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Parbrook GD, Rees GAD. and Robertson GS. August 1964 United Kingdom	The exact patient group size is not clear, best estimate of 20. Each had undergone upper abdominal surgery 24 hours previously. Each participant first received 10 minutes of 25% nitrous oxide therapy, 15 minutes later morphine (0.16 mg./kg.) was administered intramuscularly.	Open labelled cross over pilot trial – Evidence level 3	Respiration Restoration Factor (RRF) for vital capacity	Entonox produced a 19.17% mean RRF whereas morphine’s mean RRF was 10.84%. The difference of 8.33% is statistically significant at P < 0.01.	Randomisation method is unclear. Patient follow up is unclear. No table of patient characteristics. Group sizes are unclear. There is no RRF percentage for the combination treatment, however it is stated as statistically significant. The results from the peak flow measure are not included. There is no presentation of the data collected from the peak flow readings. No comment has been made about ethical consideration or approval. Consideration for attrition and detection bias unclear
			Duration of Nitrous oxide analgesia	The results show the greatest RRF improvement on inspiration, with the effects ceasing after 15 minutes.
			Combined therapy	15 participants were given nitrous oxide again 1 hour after the administration of morphine. The RRF was recalculated showing combination therapy to be more effective than isolated therapy (P < 0.05).
			Peak Flow	The results for peak flow follow the same trend as that for vital capacity RRF.
			Side effects	Nearly all patients presented as drowsy after the nitrous oxide. One patient had to stop inhaling as the mouthpiece initiated retching.
Paris A. February 2008 France	33 participants who had painful bed sores or ulcers were enrolled in the trial and were split evenly into three groups. Each group received a different sequence of analgesic therapies over a 6 day period (performed on days 0, 2 and 4). The treatments were morphine chlorhydrate (M) subcutaneously (1mg / 10 kg or 10% daily rate), nitrous oxide/oxygen mixture (E) (5 minutes before and during treatment) or both therapies combined (ME).	Randomised crossover multicentre prospective open labelled pilot study – Evidence level 2	Level of pain using the: Evaluation of Pain in noncommunicting Adults (ECPA)	The mean difference in ECPA from baseline were: M = 5.2, E = - 0.3 and ME = -0.6. Indicating a statistically significant difference between M and E, and M and ME (P <0.01). No difference was found between E and ME (P= 0.971)	The VAS scale was implemented poorly. Arterial pressure change is noted in the morphine group, and changes in the oxygen saturation of the other two groups. No consideration of the significance of the changes or whether the change is +ve or -ve. Adverse effects are subjectively recorded. Consideration for detection bias is unclear.
			Level of pain using the Visual Analog Scale (VAS)	VAS scores were only recorded for 4 participants, so this system of measurement was not included in analysis
			Level of pain using the Global Hetero-Evaluation Scale (GHES) and DOLOPLUS-2 scale	These results mirrored those found by the ECPA system. Statistical significance was found between M and E, and M and ME (P<0.01). No difference was found between E and ME (P= 0.17)
			Duration of wound care	Average wound care in the E (16.7 minutes) and ME (17 minutes) groups was shorter than in the M (20 minutes) P <0.001
			Changes in pulse, arterial pressure and oxygen saturation	The heart rate remained the same in all groups. There was significant augmentation in the arterial pressure in the M group (P=0.048) but not in E (P=0.27) or ME (P=0.80). There was a significant difference in before and after oxygen saturation in groups E and ME (both P=0.05) but not in M (P=0.80)
			Adverse effects	8 participants had an adverse reaction to Morphine. 2 - inebriation, 3 - drowsiness, 2 -mental confusion and 1 vomiting. 8 participants also had an reaction effect to nitrous oxide/oxygen. 1 - drowsiness, 3 – inebriation, 1- euphoria, 1- tears, 1 – restlessness and 1 – nausea.
Bruce E. Franck L. and Howard RE. 2006 United Kingdom	16 children undergoing chest drain removal were recruited for this trial (14 completed it). The children were randomised into two groups with similar characteristics. Group A received intravenous morphine (0.1 mg/kg max of 10mg) and continuous air flow. Group B received intravenous saline (0.1 ml/ kg max of 10 ml) and continuous flow Entonox. Clinicians and patients were both blinded to their treatments	Blinded parallel group randomised control pilot trial – Evidence Level 2	Level of pain using the Childrens Hospital of Eastern Ontario Pain Scale (CHEOPS)	There was no statistical difference in pain score before (P= 0.751) during (P= 0.946) or after (P= 0.529) chest drain removal in either group	The trial group size was relatively small and therefore easily affected by individual anomalies. There was no presentation of patient characteristics which makes it hard for the evidence to be reinterpreted. Although the author reported results showing a decrease in anxiety levels with the use of Entonox, they then go on to discuss that no difference was found. A significant decrease in oxygen levels in the morphine group, however the author does not go on to discuss the importance or relevance of these findings.
			Level of anxiety	Anxiety levels in both groups were similar before (P= 0.467) and after (P=0.267). However during the procedure there was an increase in anxiety in the morphine group compared Entonox group (P= 0.027)
			Level of sedation	There was mild to moderate sedation in both groups. In the morphine group 2 patients were still moderately sedated 1 hour post procedure
			Routine Observations	Heart rate and mean blood pressure were both equal in each group. However, 1 hour post procedure there was a significant difference in oxygen saturation in the morphine group (P=0.023). One participant in the morphine group suffered from a clinically significant drop in oxygen saturation and was administered oxygen
			Adverse events	There were no recorded side effects or adverse reactions
Akrofi M. et al. 2005 United Kingdom	66 adults who were undergoing coronary artery bypass graft or valve surgery, who also needed chest drains were recruited into this study. Patients were randomised to receive one treatment before chest drain removal. The treatments were: Intravenous morphine (0.1 mg/kg), subcutaneous bupivacaine (0.5%) or 50% nitrous oxide/oxygen. All group characteristics were similar	Parallel group randomised control trial – Evidence Level 2	Pain level on the Visual Analog Scale (VAS)	A statistically significant increase in pain score was found between the nitrous oxide/oxygen group and bupivacaine group (P= 0.005), and between the morphine and bupivacaine group (P= 0.047). The mean pain score differences on removal in comparison to the baselines are: Bupivacaine = -0.5 mm, Entonox = +10mm and Morphine = -3.00mm. These results indicate higher pain scores in the Entonox group (P= 0.062). Participants reported an increase in pain from the baseline in the: Bupivacaine group = 36%, Entonox group = 77% and Morphine group = 41%. Participants in the Entonox group reported significantly greater increase in pain scores in comparison to the other groups (P= 0.012).	All 3 groups had an equal mean opiate preload before the trial. The data from the sedation scores are not reported. The trail size of 66 participants has produced large interquartile ranges in all groups but most noticeable in the Entonox group. This reduces the accuracy of means to represent the group data. Consideration for detection bias is unclear.
			Pain level on the Verbal Rating Scale (VRS)	Immediately post-procedure the mean pain scores were 1 in all groups with no differences between groups (P= 0.139). One day post-procedure the mean pain score was 0 with no differences between the groups (P= 0.892). 4 patients had no recollection of the event, of which 3 had Entonox.
			Sedation level on the Bloomsbury sedation score	There was no difference in sedation scores between the two groups.
			Arterial blood pressure, heart rate and blood gas analysis	There was no difference in the arterial blood pressure or heart rate in the groups. The blood gas analysis showed a carbon dioxide level difference from baseline of: bupivacaine = -0.10 KPa, Entonox = -0.06 KPa and morphine = + 0.19 KPa. This indicates higher carbon dioxide levels with morphine use (P= 0.052).
			Chest drain size based on VAS score	Two drain sizes were compared, 19F and 28F. The mean pain difference from baseline in the 19F group = -5.5mm whereas the 28F group = +10.1. This shows a significant increase of pain in the 28F group (P= 0.0164).
Homayounfar S. and Broomandi S. 2006 Iran	120 adults with well-established acute myocardial infarctions. Split into two groups. Group One received Entonox for 5 minutes. Group Two received 3mg of morphine or 25mg of meperidine intravenously	Open labelled randomised control trial – Evidence level 3	Pain level using the Visual Analogue Scale (VAS)	There was no statistical difference between the groups. Mean difference in VAS score for Entonox was 4.55. In the morphine/meperidine group it was 4.4 (P= 0.82).	Method of randomisation is not stated. No mention of patient characteristics apart from age. No consideration of other medical treatments. Base line observations are not included. No mentions of side effects. Consideration for performance and detection bias is unclear. No comment on patient consent or ethical approval. The significance of the two different opiate drugs is not explored.

Comment(s)

With only five reports looking at the effectiveness of Morphine and Entonox, it appears this is an area of patient care with a poor evidence base. Of these four reports two, Parbrook (1964) and Paris (2008), conclude that Entonox is slightly more effective than Morphine. Akrofi (2005) however, advocates Morphine as the preferred analgesic. Bruce (2006) and Homayounfar (2006) claim the difference is undeterminable. This appears to show that what evidence there is, weighs slightly in favour of Entonox being just as effective or a more effective than Morphine. Morphine produced more side effects than Entonox. Bruce (2006) and Paris (2008) report a drop in oxygen saturation with the use of Morphine. Akrofi (2005) also noted a rise in carbon dioxide levels. These changes may have clinical significance, but remain unexplored. Paris (2008) and Parbrook (2005) have also shown combination therapy to be more efficient than either drug in isolation. These small studies are subject to great heterogeneity on evaluation. This may explain the variance in the outcomes. The effect the type of pain has on the effectiveness of the pain relief needs to be considered. Research, using participants in the prehospital setting, needs to be conducted in order to fully explore the benefits of Entonox in comparison to Morphine.

Clinical Bottom Line

Where all contra-indications are absent– Entonox is effective for pain management and carries fewer side effects than Morphine. Combination therapy may provide a greater analgesic effect than either in isolation.

References

1. Parbrook GD, Reed GA, and Robertson GS. Relief of Post-operative Pain: Comparison of a 25% Nitrous-oxide and Oxygen Mixture with Morphine British Medical Journal 1964;2:480 – 482
2. Paris A, et al. Nitrous Oxide-Oxygen Mixture During Care of Bedsores and Painful Ulcers in the Elderly: A Randomized, Crossover, Open-Label Pilot Study Journal of Pain and Symptom Management 2008;35(2):171 – 176
3. Bruce E, Franck L, and Howard R. The efficacy of morphine and Entonox analgesia during chest drain removal in children Paediatric Anaesthesia 2006;16:302 – 308
4. Akrofi M, et al. A Randomized Comparison of Three Methods of Analgesia for Chest Drain Removal in Postcardiac Surgical Patients Anaesthesia and Analgesia 2005;100:205 – 209
5. Homayounfar S, and Broomandi S. Evaluation of Entonox as an Analgesic for Relief of Pain in Patients with Acute Myocardial Infarction Iranian Heart Journal 2006; 7(3);16-19