Study objective: We assess the efficacy of intravenous ketamine compared with intravenous morphine in reducing pain in adults with significant out-of-hospital traumatic pain.
Methods: This study was an out-of-hospital, prospective, randomized, controlled, open-label study. Patients with trauma and a verbal pain score of greater than 5 after 5 mg intravenous morphine were eligible for enrollment. Patients allocated to the ketamine group received a bolus of 10 or 20 mg, followed by 10 mg every 3 minutes thereafter. Patients allocated to the morphine alone group received 5 mg intravenously every 5 minutes until pain free. Pain scores were measured at baseline and at hospital arrival.
Results: A total of 135 patients were enrolled between December 2007 and July 2010. There were no differences between the groups at baseline. After the initial 5-mg dose of intravenous morphine, patients allocated to ketamine received a mean of 40.6 mg (SD 25 mg) of ketamine. Patients allocated to morphine alone received a mean of 14.4 mg (SD 9.4 mg) of morphine. The mean pain score change was −5.6 (95% confidence interval [CI] −6.2 to −5.0) in the ketamine group compared with −3.2 (95% CI −3.7 to −2.7) in the morphine group. The difference in mean pain score change was −2.4 (95% CI −3.2 to −1.6) points. The intravenous morphine group had 9 of 65 (14%; 95% CI 6% to 25%) adverse effects reported (most commonly nausea [6/65; 9%]) compared with 27 of 70 (39%; 95% CI 27% to 51%) in the ketamine group (most commonly disorientation [8/70; 11%]).
Conclusion: Intravenous morphine plus ketamine for out-of-hospital adult trauma patients provides analgesia superior to that of intravenous morphine alone but was associated with an increase in the rate of minor adverse effects.
Well the authors of the article have gone about trying to answer a question similar to the question I have outlined above. Roughly summarised; if morphine isn’t working is it best to keep going with more morphine or switch to something else? The something else in particular in this article is, unsurprisingly, ketamine. They have specifically looked at cases of trauma where initially pain management has not been controlled by IV morphine. If the patients were still in pain after 5mg of IV morphine they were randomised to either continuing with more IV morphine or switching to IV ketamine, both driven by specific administration protocols.
Well the results as they’ve presented them are pretty interesting. They quite clearly show that when you switch to ketamine after a poor initial response to morphine you get better and faster control of pain than if you simply carried on with the opiates. Indeed the difference between the two groups, based on the verbal 0-10 scoring of pain severity, was an impressive -2.4 in favour of ketamine. I think that both the box plot and the graphs they use in the paper do an even better job of conveying the difference between the 2 groups (figures 2, 3 and 4), with clear visual representation of the difference across the patient group.
Obviously there must be some downside to this approach and it comes when the authors highlight the adverse effects experienced by each group. 39% of the ketamine group had some form of adverse effect noted, compared with just 14% of the morphine only group. When you analyse the nature of these adverse events though there aren’t many significant ones for either group. The most notable for the ketamine group is the relatively high number who experienced the well known ‘emergence phenomenon’ and an even higher number who experienced some disorientation. Conversely though, the ketamine group were better off for some adverse effects, with fewer of them experiencing nausea that those who had morphine repeatedly administered.
Well I hope from my little preamble you can get an idea of the relevance that I think this sort of study can play for clinical practice in certain situations. Obviously the specific circumstances of the trial (prehospital management of trauma pain) mean that the results can’t be immediately extrapolated to every single acute pain patient I see but I think it does a good job, (along with a few of the other papers that I have glanced at) at trying to build upon the old idea that IV opiates are the be all and end all of acute pain relief. It has also given me a bit more confidence that the adverse effects profile of ketamine at the doses used for analgesia are not actually that scary. Indeed, as was alluded to by the authors at the start, it actually has some pretty positive side effects when you compare it to the effects that excess morphine can have on blood pressure, respiratory drive etc.
Well as with any piece of new information a bit of critical analysis of the work needs doing before we can draw any solid conclusions. So let us cover the good points first. Overall I think that the study had a good set up to answer its question. Randomisation of patients was undertaken in a clearly explained straightforward manner and the inclusion/exclusion criteria were also clearly explained and sensible. Their approach to measuring outcome (numerical pain score change) also seemed to be sensible and rooted in actual clinical practice (at least the way I approach acute pain). Finally, the analysis of their results was straightforward to follow and left me with a clear understanding of how each group fared; exactly what I want from a statistical analysis. As part of this they included a thorough description of the adverse effects that each group experienced, presenting them for the reader to make up their own mind about the relevance of these.
What could have been better then? Well I suppose the sample size could do with being a little bigger. As they have highlighted in their initial description, they were actually hoping to recruit greater numbers of patients and were left surprised by how long this took. However, based on the power calculations they have redone they have still managed to recruit enough to demonstrate a significant difference so I don’t feel it makes a big impact on the conclusions we are able to draw from their data. I think the main area of the study that I find a little bit precarious comes from the actual implementation of the treatment protocols. Obviously, pain is a somewhat subjective and fluid concept, and thus something that can’t be managed by a fixed ‘one size fits all’ protocolised approach. This is acknowledged by the degree of flexibility that is given to the paramedics for administration of further analgesia after the initial dose, allowing quite a variety of doses based on their clinical judgement. This is of course completely sensible for clinical practice and yet just makes it feel a bit less scientifically rigorous when it comes to critically appraising it. Similarly, they have made the decision to not blind the paramedics to the drug that was being administered. Again this was for clinically practical purposes which is understandable given the limit for how perfectly scientific conditions can be upheld whilst managing a trauma patient in the back of an ambulance. That being said, it once again detracts slightly from the weight that the results can hold at the end. There are a few other areas that the authors have covered in their own analysis but these are the main ones that came to my mind.
So another fairly rambling review from me there but lets put it into a quick summary:
- There is a pretty good suggestion that switching to ketamine instead of persevering with morphine provides quicker, better analgesia in patients with trauma pain.
- Ketamine use is associated with an increased incidence of adverse effects compared with morphine on its own but nothing incredibly dramatic.
Yes the study has a few weaknesses and limitations to it but it still has a bit of weight behind these conclusions. Alongside the other trials out there looking at ketamine I think there is increasing evidence for its use. Some of its side effects are actually positively favourable in haemodynamically unstable patients when you compare it to the side effects profile of morphine (which can lower BP further for example). So altogether then a pretty interesting article which has expanded the way I think about acute pain management, even if it isn’t going to change my clinical practice straight away. I hope you found it interesting and please let me know your thoughts.