Moving on from NSAIDs and opioids: what is the evidence base?

OPIOIDS AND NSAIDS CURRENTLY FORM THE FOUNDATION of peri-operative analgesic regimens in cats and dogs and with good reason.

There is a large evidence base of clinical studies in both species that support dose requirement and efficacy and there are licensed products available for use. However, in challenging cases, analgesia with NSAIDs and opioids alone may be insufficient, leading to the requirement for additional analgesia using adjunctive agents.

There is also an increasing tendency for analgesia and anaesthesia regimens to become more complex in practice, with the use of some adjunctive agents such as ketamine becoming commonplace for even routine surgeries such as ovariohysterectomy in dogs. The aim of this article is to examine the evidence base for using adjunctive agents in cats and dogs and discuss the clinical application of adjunctives in veterinary practice.

Ketamine

Ketamine is an anaesthetic agent that has analgesic properties even at sub-anaesthetic doses. The major mechanism by which ketamine is considered to provide analgesia is via its action as an antagonist at the NMDA receptor in the central nervous system.

Under normal circumstances the NMDA receptor does not contribute to nociceptive transmission, but the receptor becomes involved in sensory processing as a consequence of sustained noxious input into the spinal cord as seen with tissue injury such as that caused by surgery.

Activation of the NMDA receptor is considered pivotal to the development of central sensitisation, which results in hyperalgesia, allodynia and spontaneous pain and makes post-operative pain management significantly more challenging in clinical patients. Therefore, administration of a drug that blocks the NMDA receptor is an attractive construct for the management of peri-operative pain in both humans and animals.

There is good evidence that ketamine is analgesic and antihyperalgesic when administered intrathecally to laboratory animals and it is this literature which has formed the basis for the IV administration of low doses of ketamine throughout surgery and in the post-operative period in humans and dogs.

In the human field, low dose ketamine (2.5-5μg/kg/hour) administered by continuous rate infusion (CRI) appears to reduce morphine consumption in patients rated to have moderate to severe pain (Carstensen and Moller, 2010; McGuiness et al, 2011; Yang et al, 2014) although these meta-analyses state that further randomised, controlled studies with more homogeneous patient populations are needed to further support the evidence base for ketamine for this purpose.

There have been a few studies that have investigated a ketamine CRI as an analgesic in dogs in the peri-operative period. The first published study of a ketamine CRI in dogs (Wagner et al, 2002) investigated the efficacy of low-dose ketamine in dogs undergoing forelimb amputation.

Although ketamine (intra-operative 10μg/kg/min, post-operative 2μg/kg/min) statistically significantly reduced pain scores compared to a control group that did not receive ketamine, the reduction in pain score was small and it can be argued that this reduction was not biologically relevant.

Subsequent studies (e.g. Sarrau et al, 2007) of ketamine administered alone have shown similar results. There have been no robust clinical studies of the effect of a ketamine CRI on peri-operative pain in cats.

The difference between the strong positive evidence for ketamine in the laboratory animal literature and the weak clinical evidence might be attributed to the route of administration or a dose effect. Ketamine probably has a place in the management of peri-operative pain in dogs and cats but it appears that administration alone, at current dose rates, has little direct effect on peri operative pain scores. Administration with opioids (e.g. an opioid CRI) is recommended and frequent assessment of pain is manadatory.

Lidocaine

Recently, the administration of a low dose of lidocaine, intravenously, by continuous rate infusion, has become popular for the provision of peri-operative pain relief. The mechanism by which lidocaine provides analgesia when administered systemically has not been fully elucidated but it is considered that lidocaine acts as a sodium channel blocker both peripherally and in the central nervous system.

The literature as to the analgesic effects of lidocaine administered by CRI in dogs is controversial. The most common dose studied is 50μg/kg/min, preceded by a loading dose of 1-2mg/kg. At this dose rate a reduction in the required concentration of inhalant agent is expected (MAC sparing effect) but studies show both an effect on intra-operative nociceptive parameters (Ortega and Cruz, 2011) and no effect (Columbano et al, 2012), with no clear methodological differences between studies to explain the differing results.

Data suggest that a lidocaine infusion alone is inadequate for post-operative pain relief (Gutierrez-Blanco et al, 2015). The use of lidocaine by CRI in cats is not recommended due to profound haemodynamic effects (Pypendop and Ilkiw, 2005). Therefore, evidence in dogs suggests that, similar to ketamine, lidocaine should be used in combination with other analgesics in order to ensure adequate peri-operative analgesia.

Alpha2agonists

Medetomidine and dexmedetomidine are widely used in veterinary anaesthesia for sedation and premedication. However, more recently these drugs, administered at a low dose by CRI, have been used specifically to provide peri-operative analgesia in dogs and cats.

Valtolina et al (2009) compared analgesia provided by dexmedetomidine (1μg/kg/hour) and morphine (0.1mg/kg/hour) in dogs after surgery and found that although rescue analgesia was required in both groups of dogs, analgesia was superior in the group treated with dexmedetomidine. Sedation is an inevitable side-effect when using alpha2agonists for peri-operative analgesia (van Oostrom et al, 2011), although in some types of patient, e.g. patients that are particularly anxious in a hospitalised environment, this can be advantageous.

Cardiovascular side-effects are a major consideration when choosing whether or not to use an alpha2agonist in an individual animal as they are likely to occur even at very low dose rates (e.g. < 1μg/kg/hour).

Tramadol

There has been an explosion in the use of tramadol for the management of both peri-operative and chronic pain in animals, although the evidence base to support the efficacy of oral tramadol for pain management is weak in both cats and dogs.

In contrast, there is fairly good evidence of efficacy of parenteral tramadol for peri-operative pain management, but injectable preparations are not readily available in the UK.

Tramadol has a multimodal mechanism of action. The parent compound inhibits neuronal re-uptake of norepinephrine and serotonin and may even facilitate serotonin release, whereas the M1 metabolite of tramadol is a weak μ receptor agonist.

There appear to be significant differences between cats and dogs in the metabolism of tramadol, with cats generating significantly higher concentrations of the M1 metabolite than dogs and therefore likely to benefit from more μ mediated analgesia than dogs.

Two studies in dogs have investigated oral tramadol (4-5mg/kg) for peri-operative pain relief and found tramadol to be inadequate, with a large proportion of dogs in the tramadol treated groups requiring rescue analgesia (Davila et al, 2013; Delgardo et al, 2014).

Davila et al (2013) compared pain scores in dogs after TPLO treated with either rocoxib, tramadol or rocoxib and tramadol and found that there was no difference in pain scores between the rocoxib alone and the rocoxib and tramadol groups, suggesting that combining tramadol with a NSAID is not beneficial post-operatively.

There are no studies investigating the efficacy of oral tramadol in cats for peri-operative pain relief, although the bitter taste of tramadol can make oral dosing in cats problematic.

Conclusions

The evidence base for the use of adjunctive agents to provide analgesia in cats and dogs is poor. Current studies suggest that adjunctives should be used in addition to pain relief with opioids and reserved for cases that are refractory to opioid and NSAID treatment alone.

References

1. Carstensen and Moller (2010) British Journal of Anaesthesia 104: 401-406. Columbano et al (2012) The Veterinary Journal 193: 448-455.
2. Davila et al (2013). Journal of the American Veterinary Medical Association 243: 225-231.
3. Delgardo et al (2014) Journal of the American Veterinary Medical Association 245: 1,375-1,381.
4. Gutierrez-Blanco et al (2015) Veterinary Anaesthesia and Analgesia 42: 309-318.
5. McGuiness et al (2011) Pain Medicine 12: 1,551-1,558.
6. Ortega and Cruz (2011) The Canadian Veterinary Journal 52: 856-860. Pypendop and Ilkiw (2005) The American Journal of Veterinary Research 66: 661-668.
7. Sarrau et al (2007) Journal of Small Animal Practice 48: 670-676. van Oostrom et al (2011) The Veterinary Journal 190: 338-344.
8. Valtolina et al (2009) Veterinary Anaesthesia and Analgesia 36: 369-383.
9. Wagner et al (2002) Journal of the American Veterinary Medical Association 221: 72-75. Yang et al (2014). Acta Cirurgica Brasileira 29, 820-825.