Updated: Dec 11, 2020
The most common NMDA antagonist we use in every day practice is ketamine which we use as an infusion or bolus. Ketamine is a modulator of pain processing. The NMDA receptor is located in the dorsal horn of the spinal cord and becomes activated in cases of extreme or persistent pain. The NMDA receptor is key to the establishment of altered central processing in maladaptive pain.
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Ketamine interacts with the NMDA receptor in a non-competitive manner and has a specific binding site – the phencyclidine site. This site is internal to the ion channel and one school of thought says that the receptor must be activated in order for ketamine to work – this is known as use-dependent blockade - hence the logic that ketamine works best when there is pre-existing pain. Further works suggests a second binding site on the NMDA receptor which decreases the frequency of channel opening.
So do we need pre-existing pain to see the full benefit of ketamine? Another angle on this is that ketamine has several modes of action and our experience of it being useful in the acute pain setting is due to one or several of these actions. These other actions include action at nicotinic and muscarinic receptors, mu, kappa and delta opioid receptors and sodium channels both centrally and peripherally. Work in people gives early insights into an anti-inflammatory role (reduction of IL-6) for ketamine, although dose determination is required Dale et al (2012). In veterinary practice, ketamine infusions appear to offer a benefit when used in a pre-emptive sense as well as for patients with existing pain.
In humans ketamine reduces post-incisional hyperalgesia (Duque et al 2004). Similar evidence was demonstrated in dogs undergoing ovariohysterectomy using a single injection technique, rather than a CRI. This study by Slingsby & Waterman Pearson (2000) investigated the use of 2.5mg/kg ketamine IM either pre-surgery, post-surgery or no ketamine using pain scoring and mechanical threshold testing as outcome measures. The dogs in the pre-surgery group showed less hyperalgesia compared to the dogs in the no analgesia group. Pain in the post-surgery ketamine group was lower 20 minutes after extubation – suggesting a time related effect. At 18 hours both ketamine groups were more comfortable than the control group. I find this IM injection a really useful option for cases where nociception (pain in the anaesthetised patient) is a problem. For example, the bitch spay where each time the ovarian ligament is tractioned the heart rate and respiratory rate climb. At that point 1-2mg/kg ketamine IM (or 0.5mg/kg IV – slowly though as this can cause short term apnoea) will settle your patient back down. Or take the orthopaedic op where despite further analgesia the patient is unsettled – use the IM option here.
Studies in dogs with ketamine CRIs have shown improvements in activity and pain scores following limb amputation (Wagner et al 2002) and improved food intake after mastectomy (Sarrau et al 2007).
The rate I would suggest is 0.6mg/kg/hr (10mcg/kg/min) for surgery and 0.3mg/kg/hr (5mcg/kg/min) for recovery and post operatively. The doses in brackets are in mcg/kg/min which is how you may also see these doses written in other references.
If you add 1ml (100mg) ketamine to a 100ml bag of saline then it makes 1mg/ml and your calculations are easy.
For example a 10kg dog = 6mg/hr which is 6ml/hr of a 1mg/ml solution.
The other easy option is 0.75ml (75mg) in a 500ml bag of fluids (Hartmann’s or saline – either is ok). You run this at 2ml/kg/hr. The rate works out at 0.3mg/kg/hr. You can use this in hospitalised patients that are painful.
Are there any concerns? At these doses we are using much lower rates than for induction of anaesthesia – so-called analgesic doses. Any concerns over cardiac disease or seizures are unfounded. Some cats (and the occasional dog) will look a little ‘ketaminey’. Advice for these cases is to either stop the infusion for an hour and then restart, or reduce the rate by half and reassess.
A recently published meta-analysis (Riddell et al 2019) examined the analgesic benefit of low dose ketamine after orthopaedic surgery in people. Low dose was defined as a bolus of 0.1-0.5mg/kg which in some cases was followed by an infusion of 1-10mcg/kg/min. Primary outcomes were total opioid requirement, time to first opioid, pain scores at 12, 24 and 48 hours, presence of hallucinations, incidence of post-op nausea and vomiting (PONV) and finally, the development of chronic pain. From the 20 studies in the final analysis there was a significant decrease in opioid use as well as time to first opioid request with pain scores were lower at 24 and 48 hours. The incidence of PONV and hallucinations was not significantly greater than the control group. Due to low numbers regarding the development of chronic pain, conclusions could not be drawn on this. It would now be really interesting to examine the effects of a bolus of ketamine on post-op pain in dogs and cats - to date most, if not all studies have used infusions.
Ketamine is suitable for any painful patient, both pre, during and post surgery so make it part of your analgesic armoury for a zero pain approach.