Understanding the mechanisms behind acute pain in dogs and cats

Transduction

At sites of tissue damage or injury, nociceptive stimuli (which may be mechanical, chemical or thermal) activate specialised free nerve endings, known as nociceptors (Farquhar-Smith, 2008). These nociceptors are different from other receptors present in tissues (e.g. those responsible for touch), in that they only respond to high threshold inputs, i.e. they are only activated by stimuli of potentially noxious intensity. Transduction is the process by which the chemical signal informing the nociceptor that a potentially damaging stimulus is being applied is converted to an electrical signal (Wood, 2008).

Transmission

Activation of nociceptors leads to the generation of action potentials in afferent nerve fibres — Aδ fibres which transmit ‘fast’ pain, and C fibres which transmit ‘slow’ pain (Farquhar-Smith, 2008). The Aδ fibres signal actual or potential tissue damage, and cause the patient to withdraw from the noxious stimulus (if possible), before any/further tissue damage occurs. The feeling experienced when Aδ fibres are stimulated is not aversively painful — their fast transmission pattern is simply to indicate to the patient that potential tissue damage may occur if the stimulus continues. C fibres, on the other hand, have much slower transmission to the spinal cord, and they are responsible for the dull, throbbing (aversive) aspects of pain. The classical example is that of placing one's hand into a flame — there is immediate withdrawal (due to Aδ fibres), and then the hand begins to throb after it has been withdrawn (C fibres). Once the impulses from Aδ and C fibres enter the spinal cord, they are transmitted to specific nociceptive cells in the dorsal horn of the grey matter. From here, nociceptive impulses are relayed to higher centres in the brain by various ascending pathways, and it is only once the signal reaches these higher centres that it is consciously perceived as being painful (Farquhar-Smith, 2008).

Modulation

Modulation of the nociceptive signal may occur at both peripheral and central sites. Under normal conditions, mechanical, chemical or thermal stimulation will trigger nociceptors to generate an action potential. If, however, there has been sufficient tissue damage, the nociceptors will be exposed to a range of agents released by the damaged cells. These inflammatory mediators (the so-called ‘inflammatory soup’) comprise a large number of different compounds, which may have varying effects: in particular, some, such as hydrogen ions, may directly stimulate nociceptive firing, while others, such as prostaglandins, may sensitise the nerve endings to other inflammatory mediators or to subsequent noxious stimuli, thus reducing their threshold for firing. In addition to the effects of these inflammatory mediators on the already active nociceptors, they are also responsible for recruiting silent or ‘sleeping’ nociceptors around the periphery of the damaged tissue, increasing the area over which noxious input is perceived (Farquhar-Smith, 2008). The net result of all of these changes is a phenomenon known as peripheral sensitisation.

Changes may also take place in both the brain and spinal cord during ongoing nociceptive transmission (Farquhar-Smith, 2008). With repeated activation of nociceptive afferent nerves, synaptic transmission at the level of the dorsal horn cells is enhanced, a phenomenon known as ‘wind-up’ (Herrero et al. 2000). This plasticity in the central nervous system in response to ongoing nociceptive transmission, ultimately results in an increased perception of the noxious stimulus, referred to as central sensitisation (Woolf, 2011). Although many people use the terms ‘wind-up’ and ‘central sensitisation’ interchangeably, they are not the same thing, with wind-up being a specific initiator of central sensitisation that shares some common mechanisms with other initiators (Farquhar-Smith, 2008). One of the major receptor types involved in central sensitisation is the N-methyl-D-aspartate (NMDA) receptor, and much research has been directed towards the relationship between this receptor and nociceptive transmission (Woolf, 2011). Experimentally, wind-up is blocked, and may be reversed, by NMDA receptor antagonists (Eide, 2000), and this has important implications for clinical analgesia.

Peripheral and central sensitisation result in two important phenomena in relation to pain:

Perception

The mechanism by which a noxious stimulus is ultimately perceived by an individual as being painful is extremely complex, and much of the overall process is still unclear. Perception of pain is the end result of nociceptive transmission, and occurs once the action potentials from the spinal cord reach the brain stem and thalamus (Figure 1), from where they are then transmitted to higher centres such as the reticular activating system and cortex (Wood, 2008). The term ‘nociception’ is used to specifically describe the neural response to noxious stimuli; thus, nociception and pain are related, but are not interchangeable. For example, during surgery under general anaesthesia, nociception will occur, but pain will not be experienced at that point, since pain is a conscious phenomenon and the anaesthetic agents will be inducing unconsciousness. However, failure to provide adequate analgesia during surgery will result in increased bombardment of the central nervous system by noxious stimuli, and is likely to induce significant enhancement of central sensitisation (Abram and Yaksh, 1993). The major consequence is that pain will then be more intense and more difficult to control once the patient recovers consciousness (Figure 2). In addition, the sympathetic response to noxious stimulation will also be greater during surgery under general anaesthesia where analgesia has not been provided, resulting in potential detrimental side effects such as tachycardia and cardiac arrhythmias (Kehlet and Dahl, 2003).

Pre-emptive analgesia

The concept of pre-emptive analgesia is that, if anal-gesics drugs can be administered prior to the onset of noxious stimulation, they will prevent the hypersensitivity that may occur at the site of tissue damage, and also that which occurs within the central nervous system (Dahl and Moiniche, 2004). For this to be suitably achieved, the drugs must be administered at an appropriate dose (i.e. adequate to reach therapeutic concentrations) and also sufficiently in advance of the noxious stimulus being applied so that they have time to reach their peak effect; this will vary from drug to drug but, for an agent such as buprenorphine, this may be up to 1.5 hours (NOAH compendium). In some situations, it may not be possible to be preemptive: for instance, the road traffic accident that is presented having suffered polytrauma. In a case such as this, it is important that analgesic therapy is commenced as soon as possible, and in a sufficient dose so that further wind-up of the central nervous system is minimised (Woolf and Wall, 1986).

Theoretically, pre-emptive analgesia should allow pain to be more easily controlled post operatively, using lower doses of analgesic drugs. Although the concept is fairly widely accepted in veterinary analgesia (Lascelles et al. 1997; Lascelles et al. 1998), it is still controversial in humans, with some studies showing no difference in post-operative pain scores between patients receiving pre-incision versus post-incision analgesia (Holthusen et al. 2002; Gottschalk et al, 2008) while others have reported a beneficial effect of pre-emptive analgesic administration (Tverskoy et al, 1994; Ke et al. 1998). There is also evidence that the efficacy of pre-emptive analgesia may be influenced by the type of surgery being undertaken (Aida et al, 1999).

Preventive analgesia

While the effectiveness of pre-emptive analgesia remains controversial (at least in humans), there has been growing overall acceptance of the concept of preventive analgesia (Pogatzki and Zahn, 2006). Preventive analgesia is defined as ‘an attempt to block pain transmission prior to the injury (incision), during the noxious insult (surgery itself), and after the injury and throughout the recovery period’ (Hurley and Adams, 2011). Essentially, therefore, preventive analgesia aims to avert the continuous barrage of the central nervous system by noxious stimuli throughout the period of tissue damage (including post operatively), thus inhibiting the development of central sensitisation. This emphasises the requirement for adequate intra- and post-operative pain relief, and moves the emphasis away from focussing on preemptive analgesia, which is but one potential component of preventive analgesia. There is strong evidence from human studies of the benefit of preventive anal-gesia (Katz and McCartney, 2002).

Multimodal analgesia

Given the huge complexity of the systems involved in nociception, it makes sense that administering one particular analgesic agent is unlikely to be able to completely block signal transmission, and it would seem logical that by combining drugs from different analgesic classes — with each acting at different areas of the nociceptive pathways — improved analgesia is likely to be achieved. This underlies the concept of multimodal analgesia (Buvanendran and Kroin, 2009). In addition, due to synergistic analgesic effects between different drug groups, there is the potential to reduce side effects since lower doses (of opioid drugs, in particular) are likely to be required (Buvanendran and Kroin, 2009). Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to consistently reduce post-operative opioid consumption in humans (Buvanendran et al, 2003; Feng et al. 2008), while other agents (NMDA receptor antagonists, alpha-2 adrenergic agonists, local anaesthetic agents) provide less consistent results, but this may reflect variations in dose and timing of administration (Buvanendran and Kroin, 2009). While multimodal analgesia has been shown to be effective for chronic osteoarthritic pain in dogs (Lascelles et al, 2008), its use has been less extensively investigated in relation to acute clinical pain in animals, and —where studies have been performed — results have not necessarily provided evidence of beneficial effects of a multimodal analgesic approach (Shih et al. 2008). However, this may merely indicate a relative lack of sensitivity of pain scoring systems in animals when compared to the ‘gold standard’ — self-reporting of pain — used in humans. Consequently, based on both theoretical considerations and extensive evidence from human studies, multimodal analgesia is likely to have a major role in appropriate management of acute pain in animals (Slingsby, 2008).