Fentanyl, ketamine or combination?

Next time you choose to use a continuous rate infusion, are you thinking ketamine or fentanyl? Or maybe you are thinking, is there a benefit to the combination of ketamine and fentanyl?

Well, if that's the case, this paper will help you to understand that. Published in BMC Veterinary Research and titled "Plasma concentration, cardiorespiratory and analgesic effects of ketamine-fentanyl infusion in dogs submitted to mastectomy", this work by Sousa de Moura et al. will help to answer that question. They studied the analgesic and cardiorespiratory effects of either a ketamine, or fentanyl, or a ketamine-fentanyl continuous rate infusion in dogs undergoing mastectomy.

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There were 17 female dogs included in this study:- six in the ketamine group- five in the fentanyl group and six in the combination group. The ketamine group received a bolus of 0.5 mg/kg ketamine intravenously followed by a continuous rate infusion of 20 μg/kg/min during surgery and in the post-op period. The fentanyl group received a bolus of 20 μg/kg of fentanyl, followed by a CRI of 5 μg/kg/hr during the surgery and then postoperatively that was reduced to 2 μg/kg/hr. In the ketamine-fentanyl combination group, they received the combination of the aforementioned doses. The infusion continued post-operatively for 8 hours. Cardiorespiratory parameters, blood gases, plasma drug concentrations, sedation score and pain scores were evaluated over the course of the study.

Looking at vital parameters, the heart rate decreased in the fentanyl group and the ketamine-fentanyl group. Mean arterial pressure was lower in the ketamine-fentanyl group than in the ketamine alone group at the 35-minute time point. Maximum plasma concentrations were observed 5 minutes after the bolus in the ketamine group and 5 minutes after the bolus in the ketamine-fentanyl group.

Morphine 0.5 mg/kg was used as premedication. 15 minutes later anaesthesia was induced. Anaesthesia was maintained with isoflurane delivered in oxygen. Dogs were maintained under anaesthesia with controlled mandatory ventilation. Blood pressure was monitored using direct arterial blood pressure measurement via an arterial line. Mastectomy was performed by an experienced surgeon and at the end of the infusions, each dog received meloxicam 0.1 mg/kg intravenously. And then after discharge, they were prescribed meloxicam orally and metamizole.

The loading dose was given five minutes before skin incision, and then the intraop CRI started immediately after bolus administration. At extubation, the CRI rate was decreased to the post-operative CRI rate and continued for eight hours. Post-op pain was scored according to the Short Form of the Glasgow Composite Pain Scale and mechanical nociceptive threshold testing was also included. This started at the end of the surgical procedure, once extubation was complete, every 15 minutes in the first hour. And then after that, every two hours for up to 12 hours, and then at day seven and day 14. If the post-op pain scores were more than 5/20, according to the Glasgow pain scale, 0.1 mg/kg of morphine was administered IV as a rescue. This study was conducted in Brazil, hence the use of morphine as opposed to methadone.

In the statistical analysis section of this paper, they refer to it as a sample size calculation. They say that it was performed, however, they don't actually say how many dogs in each group were required. They say in the results section a total of 58 dogs were screened for enrolment but only 18 met the inclusion criteria. So I think we can allude from that that there were a really small number of dogs in the study and therefore probably can't apply statistics and talk about statistical significance in this case.

As far as the analgesia results go, they say between these three groups, there was no difference in the number of analgesia rescues among the groups studied. Looking to the number of animals rescued, in the ketamine group, one animal was rescued at 15 minutes, then another at two hours. In the ketamine-fentanyl group, two animals received rescue at two hours. In the fentanyl group, one animal received rescue at six hours and then another one at eight hours. So, very similar requirement of rescue analgesia between groups. But like I say, we can't draw conclusions about that from a statistical point of view.

Looking at the mechanical nociceptive threshold tests, there was a significant reduction in MNT scores up to 12 hours after surgery. And at 24 hours, it remained significantly lower than baseline. So this is evidence that, not surprisingly, after surgery, there is greater wound sensitivity as a result of the action of inflammatory mediators causing that nociceptive pain.

In the discussion, they state the main findings of the study were as follows: the infusions did not trigger significant cardiovascular changes in any of the groups throughout the study phase. I think that's a fair conclusion.

All groups experienced satisfactory analgesia during the intraoperative period and there were no significant differences between groups regarding post-op analgesia during that first 24 hours.

Looking at plasma levels, fentanyl and ketamine doses used did not promote a steady state, but did guarantee minimal plasma levels with the potential for analgesia during the eight hours of administration. Heart rate did reduce in the groups treated with fentanyl, which we expect. I think a really interesting point they make, they say the ketamine-fentanyl association did not culminate in the sympathetic stimulation expected by the use of ketamine. Now, as much as I like to think ketamine has a sympathetic effect and that's going to balance a cardiac caused by the fentanyl, I think in my hands certainly clinical practice, I don't think that is necessarily the case.They do state, however, that looking at the ketamine infusion when infused alone, the drug contributed to the maintenance of heart rate at a level close to baseline levels during the infusion period. Now, do we know that's necessarily related to a sympathomimetic effect? I don't think we 100% do know that. It could be related to differences in analgesia provided between these two different drugs. They clarify that by saying this: Instances of ketamine, such as increased heart rate, have been demonstrated by infusions delivering doses of more than 40 μg/kg/hr in awake dogs, which is pretty high. Yes, they definitely mean micrograms per minute when talking about ketamine doses. That is not the only error in this paper - in the abstract the doses are confusingly written. You do have to be careful with some of these papers. Some of these journals turn these papers around so quickly that the accuracy is really bad and that is not a good thing. If we're reading this paper and thinking, right, okay, well, I'm going to use those doses and we use an incorrectly published dose, that could have catastrophic consequences.

So what are they saying in conclusion? The infusion of ketamine alone or in combination with fentanyl could promote satisfactory analgesia in the intraoperative and post-op period and the doses used did not cause cardiorespiratory changes requiring cessation of its use in the post-op period for up to 8 hours. I think that's a fair conclusion. I guess what is quite an interesting conclusion to draw is that we don't have enough dogs in each group to say that there is a statistically significant difference between these. I think what we can say is when used in this situation, an infusion of either ketamine or an infusion of fentanyl or the combination of ketamine and fentanyl, at these doses is used, appear to provide satisfactory analgesia and I think we have to put a big full stop behind that and leave it there.

This post was written by Matt Gurney.

Matt & Carl established Zero Pain Philosophy to provide educational resources & telemedicine to veterinary professionals globally, enabling optimal management of pain.

Matt sees referrals in the pain clinic at Eastcott Referrals. You can also receive telemedicine advice from us here if you have a pain case where you need a helping hand.

Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is Past President of the European College of Veterinary Anaesthesia & Analgesia and works at Eastcott Referrals in the UK.

Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is Past President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists in the UK.

The intended audience for this pain update is veterinary professionals. This pain update is based on clinical experience and independent opinion.