Moving on from Pre-emptive Analgesia

Updated: Aug 25, 2018


Pre-emptive analgesia has been defined as ‘an antinociceptive treatment that prevents establishment of altered central processing of afferent input from injuries’ (Kelly and others 2001), which in practical terms means that applying an analgesic intervention before the incision/stimulus/insult results in better pain control after the operation compared to applying the same intervention after the incision. In daily practice, simply administering an analgesic prior to surgery does not tick the pre-emptive analgesia box without consideration being given to pharmacology of the drug. 


The establishment of an effective level of analgesia is paramount and an inadequate antinociceptive pre-operative intervention should not be regarded as pre-emptive analgesia (Kelly and others 2001). For example, buprenorphine is slow to associate with its receptor and therefore has a slower onset time of 30-45 minutes (Slingsby & Waterman Pearson 1998, Flecknell & Roughan, 2002, Murrell 2007), so clearly a surgical stimulus during this period may fail to achieve the goal of pre-emptive analgesia. Similarly, the time to achieve maximal plasma concentration (and then tissue levels) following subcutaneous administration of commonly used NSAIDs varies from 0.5-2.5 hours (Busch and others 1998, Jung 2009), representing a potentially significant analgesic gap. 


The concept of pre-emptive analgesia is much debated amongst anaesthetists and pain management specialists however there is agreement that neuraxial (epidural or spinal) opioids and systemic or epidural NMDA antagonists (such as ketamine) appear to show the most promising pre-emptive effect (Kelly, Ahmad, & Brull, 2001) whilst for other analgesic interventions the evidence is limited.  


Work in dogs has shown a pre-emptive effect of both pethidine (Lascelles and others 1997) and carprofen (Lascelles and others 1998), which is supported by recent work examining buprenorphine in dogs (Slingsby, Taylor, & Murrell, 2011). None of this debate should deter us from implementing pre-emptive analgesia into our daily practice. 


Effective pre-emptive analgesic techniques require multimodal interception of nociceptive input, increasing the threshold for nociception, and blocking or decreasing nociceptor activation (Kelly et al., 2001). Pain is best controlled using several analgesic agents (multimodal analgesia), each of which acts on a specific site along the pain pathway. The aim is to reduce reliance on one particular agent or mechanism and to achieve synergy between agents , whilst augmenting analgesia. This may avoid side effects associated with high doses of individual agents. 


Synergism has been documented in dogs and cats between alpha-2-agonists and opioids (Grimm and others 2000; Slingsby, Murrell, & Taylor, 2010) and NSAIDs and opioids (Slingsby & Waterman Pearson, 2001; (Shih and others, 2008, Steagall and others, 2009). 


Preventive analgesia?


The concept of pre-emptive analgesia refers to the timing of analgesic administration – either before or after the incision. This classic pre versus post approach assumes that intra-operative factors contribute most to generation of a sensitized state. This concept has been broadened in light of increasing knowledge to consider the influence of multiple factors on the generation of central sensitization, with the aim of attenuating the impact of noxious pre, intra and post-operative stimuli and is termed preventive analgesia. 


Of the three broad peri-operative periods (pre, intra, post) as yet it is unclear the extent to which each period contributes to central sensitization and post-operative pain although there are studies which document beneficial effects of post-operative versus intra-operative nociceptive blockade (Gordon and others 2002). Other studies have demonstrated more effective relief of post-operative pain by targeting pre-operative pain (Klasen and others 2005). With the current state of knowledge we should aim to incorporate excellent pain management at all stages of the peri-operative period based on the ‘Anticipate, Assess, Alleviate’ approach. 


Preventive analgesia is demonstrated when post-operative pain and/or analgesic use are reduced beyond the duration of action of the target drug, defined as 5.5 half-lives of the target drug (Katz, Clarke, & Seltzer, 2011) and the aims of preventive analgesia are to minimize sensitisation induced by noxious perioperative stimuli including those arising pre-operatively, intra-operatively, and postoperatively. With this revised concept the challenge will now be to document preventive analgesia in our veterinary patients. 


An essential aspect in practicing preventive analgesia is that the analgesic intervention should be continued for an long as the sensitizing pain stimulus lasts (Dahl, 2004), highlighting the need to accurately assess pain. 


References


Dahl, J. B. (2004). Pre-emptive analgesia. British Medical Bulletin, 71(1), 13–27. doi:10.1093/bmb/ldh030


Katz, J., Clarke, H., & Seltzer, Z. (2011). Preventive Analgesia. Anesthesia & Analgesia, 113(5), 1242–1253. doi:10.1213/ANE.0b013e31822c9a59


Kelly, D. J., Ahmad, M., & Brull, S. J. (2001). Preemptive analgesia II: recent advances and current trends. Canadian Journal of Anaesthesia = Journal Canadien D'anesthésie, 48(11), 1091–1101. doi:10.1007/BF03020375


Lascelles, B. D. X., Cripps, P. J., Jones, A., & Waterman Pearson, A. E. (1998). Efficacy and kinetics of carprofen, administered preoperatively or postoperatively, for the prevention of pain in dogs undergoing ovariohysterectomy. Veterinary Surgery, 27(6), 568–582.


Shih, A. C., Robertson, S., Isaza, N., Pablo, L., & Davies, W. (2008). Comparison between analgesic effects of buprenorphine, carprofen, and buprenorphine with carprofen for canine ovariohysterectomy. Veterinary Anaesthesia and Analgesia, 35(1), 69–79. doi:10.1111/j.1467-2995.2007.00352.x


Slingsby, L. S., & WATERMAN PEARSON, A. E. (2001). Analgesic effects in dogs of carprofen and pethidine together compared with the effects of either drug alone. The Veterinary Record, 148(14), 441–444.


Slingsby, L. S., Murrell, J. C., & Taylor, P. M. (2010). Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone. Veterinary Anaesthesia and Analgesia, 37(2), 162–170. doi:10.1111/j.1467-2995.2009.00519.x


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