Analgesia is a common topic appearing in the program of most recent small animal conferences, reflecting the importance and evolving nature of the topic. This is likely to continue for years to come as we further define nociceptor pathways and central interpretation of received information and as new agents are developed.
Firstly, to understand how analgesia works and why some non-traditional agents appear to have an analgesic effect it is necessary to have an understanding of the nociceptive or pain pathways.
Current Understanding of Nociceptive Processing
Processing of nociceptive information is not a hard wired system in which a nociceptor (pain receptor) is stimulated, information travels to the spinal cord, synapses with spinal neurons and the nociceptive information is transmitted to the cerebrum so that 'pain' is felt.
Pain perception is modified by many factors including other incoming information, descending pathways and multiple chemical substrates and neurotransmitters. Surgery or trauma not only directly stimulate pain receptors (nociceptors), but the cell damage causes the release of inflammatory mediators (e.g., prostaglandins) that lower the threshold for nociceptor firing, causing an increase in spontaneous activity, increased and prolonged firing. This is termed 'peripheral sensitization' and as a result, low intensity stimuli that don't normally produce a painful response become perceived as pain ('allodynia') . Central sensitization is an increase in spinal neuron receptivity due to prolonged exposure to nociceptive afferent input from the peripheral neurons. Peripheral and central sensitization combine to produce 'spinal wind-up' that is responsible for a decrease in the pain threshold at the site of injury and in the surrounding uninjured tissue.
Sustained input from peripheral neurons can lead to the death of inhibitory neurons, replacement with excitatory neurons and the establishment of abnormal synaptic connections. This is termed chronic pain and is not simply due to an extension of acute pain but due to functional and anatomical abnormalities in the nociception pathways.
It has been theorised that sensitization could be prevented by administering drugs to inhibit continued input of nociceptive information. It has been demonstrated that this is the case in many laboratory studies but data from human clinical trials provides little conclusive evidence that pre-emptive analgesia reduces post-surgical pain or the need for analgesia. However, it seems like it ought to work! Some of the drugs that have been used in these trials include opioids, NSAIDs, alpha-2 agonists, and NMDA antagonists (ketamine, dextromethorphan).
Techniques for Providing Analgesia
There are multiple sites in the pain pathway where anaesthetic/analgesic agents can modify nociceptive transmission. Local anaesthetic agents act peripherally to prevent transmission of neuronal activity, opioids alter synaptic neuroreceptor release in the dorsal horn and may also modulate pain transmission within the afferent nerves and NSAIDs reduce the formation of inflammatory mediators that lower the nociceptor threshold. Multimodal analgesia also allows for reduction in dosage of single agents which reduces the possibility of side effects.
Opioids reduce neurotransmitter release from afferent nociceptor neurons in the spinal cord. Tolerance to these drugs may develop rapidly so they are usually only provided in the short-term (48-72 h) which is often sufficient to get the patient through acute post-traumatic or post-surgical pain.
The provision of non-steroidal anti-inflammatory drugs (NSAIDs) in the peri-operative period in cats and dogs and the timing of administration remains a contentious area. Recommendations to give these agents pre-operatively (either orally about 8 h before surgery or IV shortly before surgery) are based on theoretical advantages as covered above. There has been no clear evidence that the pre-emptive use of these agents reduces pain perception or analgesia requirements and my personal opinion is that it is risky to do so because of the potential for side effects. If it is considered necessary to provide pre-operative analgesia for a particular case then close monitoring of the patient during the anaesthesia to assess blood pressure and tissue perfusion, and adequate fluid provision to maintain renal perfusion is important. Side effects of NSAID use include reduced renal function, gastro-intestinal ulceration or erosion and compromised liver function (noted in some Labradors), some of which are idiosyncratic and others which can be predicted based on knowledge of mechanism of action of these agents.
NSAIDs inhibit cyclo-oxygenase isoenzymes and it is through this mechanism that both analgesia and side effects are induced. It is well known that COX-1 and COX-2 isoenzymes are found in the body and it had been thought that the COX-1 enzyme was responsible for homeostatic functions such as maintaining and protecting the gastrointestinal tract, while COX-2 isoenzymes were involved in the inflammatory process. So, the development of COX-2 selective inhibitors seemed to be the answer as analgesics that would inhibit inflammation without inducing the side effects associated with NSAID use. However, it is now recognised that both COX-1 and COX-2 isoenzymes are involved in inflammation and in homeostatic tasks and that selectively blocking one isoenzyme has not produced side-effect free drugs. In addition NSAIDs appear to have an analgesic effect that is independent of cyclo-oxygenase.
Ketamine provides analgesia by antagonising NMDA receptors in the CNS. It can be given as small boluses (0.1-1.0 mg/kg IV or IM or as a constant rate infusion (CRI) (10 μg/kg/min or 0.6 mg/kg/hr) in sub-anaesthetic doses. After a CRI the dose must be tapered to prevent hypersensitivity that may occur if the infusion is suddenly stopped. Ketamine is most useful when it is given in combination with other agents such as the opioids. A combination that is particularly popular is MLK (morphine-lidocaine-ketamine) or FLK (fentanyl-lidocaine-ketamine). Dextromethorphan (cough suppressant) and amantadine are NMDA antagonists and are given orally.
Medetomidine at 1-2 μg/kg can provide analgesia but some cardiovascular side effects can be anticipated. Analgesia is most useful when alpha-2 agents are given in conjunction with opioids. These agents may also be given as a CRI and should be considered in anxious patients as the infusion provides combined analgesia and reduces stress and anxiety. Side effects of even low doses (1.5 μg/kg/hr) in healthy dogs include a fall in cardiac index and tissue oxygen delivery and bradycardia, so patients must be closely monitored and it is not a technique for patients with cardiovascular disease or other systemic compromise.
Lignocaine is commonly administered as a CRI for management of arrhythmias but similar doses (50-80 μg/kg/min) can also provide dose dependent systemic analgesia. It can be given during surgery either alone or in conjunction with ketamine and or morphine/fentanyl to reduce the concentration of inhaled anaesthetic agent required to maintain anaesthesia. Lignocaine also has the advantage of scavenging oxygen derived free radicals and increasing GI motility.
The administration of local, regional or spinal anaesthesia is an inexpensive, effective method for providing analgesia though it requires some technical proficiency. Various agents have been administered by this route. Local anaesthesia provided by CRI of lignocaine or bupivacaine has been shown to be an effective method for reducing nociceptive input.
Monitoring the Patient Receiving Analgesics
There is considerable inter-patient variability in analgesic requirements so it is important not to use a standard analgesic protocol and assume that the patient is going to be pain free. Initial assessment should ensure that the dosage administered adequately provides analgesia and continued monitoring thereafter will determine when the effects are beginning to wane and a subsequent dose is required. For those patients receiving a CRI, the aim of monitoring is to ensure that the patient does not become excessively sedated as both ketamine and morphine/fentanyl are CNS depressant agents and marked sedation can be anticipated in some animals at a dosage that in others causes no such effect.
Green Lipped Mussels
New Zealand green lipped mussels (GLM) contain anti-inflammatory agents and glycosaminoglycans but the precise mechanism by which the mussels and their extracts provide relief from arthritic pain is unknown. In double-blinded controlled studies, dogs have shown mild to marked improvement in joint swelling and lameness after eight weeks of treatment. It has been concluded that GLM supplementation may reduce the requirements for conventional arthritis medication (e.g., NSAIDs) and so decrease the potential for side effects.
A Word on Cats
Cats are often neglected when it comes to recognising and treating pain. In part, this is because their behavioural response to nociceptive input is different to that which we associate with pain and secondly, the high prevalence of side effects associated with analgesic agents in cats reduces their use. Lack of recognition of pain is more likely in chronic conditions such as post-surgical and post-traumatic pain, arthritis, neoplasia, interstitial cystitis and chronic non-healing wounds. The analgesic agents that are commonly administered to dogs can also be given to cats but it is necessary to recognise that the half life of some agents is longer and this must be taken into consideration when determining an analgesic protocol. Pain management is further complicated by the fact that there is considerable inter-cat variability in response to therapy.
Analgesia should be considered in all surgical and post-traumatic patients and in those with chronic conditions that are associated with nociceptor input. There are many variations on the 'analgesia' theme and it should be possible to provide a protocol that is effective for a particular patient.