22 Feb 2016
Rebecca Robinson
Job Title
Figure 1. A basic overview of the pain pathway from transduction of a noxious stimulation through to transmission via afferent pathways to the CNS. The stimulus may undergo modulation before projection to the brain, where it is perceived. Various descending pathways can occur, which could modulate the signal further as it traverses through efferent pathways to effector muscles.
The official definition for pain is “an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage” (International Association for the Study of Pain; Merskey and Bogduk, 1994).
As animals are unable to verbally communicate pain, a specific definition of animal pain is “an aversive sensory and emotional experience representing awareness by the animal of damage or threat to the integrity of its tissues; it changes the animal’s physiology and behaviour to reduce or avoid damage, to reduce the likelihood or recurrence and promote recovery” (Molony and Kent, 1997).
Acute pain occurs after an injury, but is usually self-limiting. It can occur as a result of surgical stimulus, injury, inflammation or damage to the nerves.
Acute pain can be useful to an animal and involved in a learning process to avoid tissue injury. Assessment of pain is critical and often considered the “fifth vital sign”, following temperature, heart and respiratory rate, and blood pressure.
Treatment of pain is required, not only as part of our moral duty, but also to ensure a rapid return to normal function. Generally, acute pain is relatively easy to treat with standard analgesic agents. However, treatment can be challenging due to a lack of objective criteria to measure pain intensity. This is particularly important in veterinary medicine, although discussions regarding pain assessment are beyond the scope of this article.
A basic understanding of the pain pathway is required as it allows areas to be targeted for analgesia provision. Figure 1 illustrates a simplistic pain pathway with transmission from the peripheral nervous system towards the CNS.
Two main types of nerve fibres are responsible for transmitting nociception to the dorsal horn of the spinal cord and one main fibre type transmitting non-noxious stimuli (Table 1).
Two concepts to be remembered when treating postoperative and acute pain are the use of:
Tissue injury and nociceptive stimulation results in local inflammation. This process causes the release of many substances, including:
Such substances are often called an “inflammatory soup” and can further sensitise nociceptors. Once activated, these not only transmit efferent signals to the dorsal horn, but also release neurotransmitters – such as substance P and calcitonin gene-related peptide – thus initiating the process of neurogenic inflammation.
This whole process is known as peripheral sensitisation and can be partly responsible for an increased sensitivity or response to a normal painful stimulus (hyperalgesia) or sensitivity to a normally innocuous stimulus (allodynia).
Chronic, high intensity nociceptive stimulation can result in central sensitisation. This occurs due to CNS and neuronal plasticity, and involves recruitment of previously silent nociceptors and Aβ afferent fibres that can contribute to hyperalgesia and allodynia.
Central sensitisation also increases sensitivity of spinal cord neurones, which results in activation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This is important for the treatment of chronic pain where NMDA receptor antagonists, such as ketamine, can play a role.
Knowledge of peripheral and central sensitisation is relevant to the use of pre-emptive analgesia. Analgesia administered prior to noxious stimuli reduces the subsequent pain experience and makes it easier to manage. Pre-emptive analgesia will reduce the initiation and maintenance of peripheral and central sensitisation.
However, it is important to appreciate, for continued efficacy, analgesia needs to be maintained throughout the period of expected postoperative pain and inflammation, otherwise sensitisation may still occur.
In some instances, it is impossible to provide true pre-emptive analgesia as the tissue injury may have already occurred; for example, road traffic accident trauma. In such instances it is advised to start analgesia provision as soon as possible to minimise the extent to which sensitisation may occur.
Multiple areas exist where nociception transmission or pain perception can be modified (Figure 2). It is generally accepted using a combination of analgesia methods, thus affecting multiple sites along the pain pathway, will lead to more effective analgesia quality.
Additionally, using complementary or synergistically acting drugs allows the absolute dose of any drug to be reduced. This can minimise potential adverse effects of singular drugs.
Many classes of analgesic agents are available for use and can be beneficial. The prescriber should be aware of local licensing regulations and, when in the UK, ensure they follow the VMD’s prescribing cascade with regards to drug use. Drug doses and route of administration are generally only mentioned where no licensed product is available and the datasheet should be referred to for further information.
NSAIDs are typically used for their anti-inflammatory, analgesic and antipyretic properties. They work through inhibition of the cyclooxygenase (COX) enzyme, responsible for converting arachidonic acid into prostaglandins, prostacyclins and thromboxanes as part of the inflammatory response (Figure 3).
In addition to playing a role in inflammation, prostaglandins and thromboxanes are important molecules for homeostatic mechanisms. Prostaglandins are responsible for regulating blood flow in peripheral tissues, such as the gastric mucosa, kidney and intestinal tract, while thromboxanes are important for platelet aggregation.
Two isoforms of the COX enzyme exist: COX-1 and COX-2. COX-1 is responsible for production of substances involved in normal homeostasis, while COX-2 is produced in response to inflammatory mediators after tissue injury. COX-1 is known as the constitutive form of the enzyme, while COX-2 is the inducible form.
Originally, NSAIDs affected both COX isoforms equally. However, as COX-2 was considered to be primarily responsible for the negative inflammatory effects, there has been a drive to create COX-1 sparing drugs, thus reducing the likelihood of adverse effects. However, it has been shown COX-2 is involved in some normal homeostatic mechanisms, including maintenance of renal blood flow and involvement in the repair of gastrointestinal erosions. Therefore, although COX-2 selective and specific drugs tend to have fewer side effects, there are still the risks of adverse events.
Many NSAIDs are licensed for veterinary use, although specific species and condition indications may vary between drugs, so it is best to clarify with product datasheets. This is particularly relevant as some preparations may not be licensed for use in the perioperative period where anaesthesia-related reductions in systemic blood pressure, combined with constitutive COX inhibition, may increase the risk of adverse events – particularly those associated with the kidneys and gastrointestinal tract.
Various formulations are now marketed with additional features, such as blocking COX and lysyl oxidase enzymes (Figure 3), or a duration of action for up to 28 days, which may be relevant for treatment of chronic conditions such as osteoarthritis.
Compared to regular NSAIDs, paracetamol offers analgesic properties with some antipyretic properties, but with weaker anti-inflammatory effects. Its mode of action is still controversial, but is thought to have multiple actions (Sharma and Mehta, 2014), including:
Paracetamol should never be used in cats as there is no safe dose and doses as low as 10mg/kg have proved toxic (Richardson, 2000). Toxicity is possible in dogs, but the risk is lower, with adverse events occurring at doses of around 100mg/kg. A licensed preparation of paracetamol in combination with codeine is available for use in dogs.
As paracetamol has less inhibitive action on peripheral COX enzymes, typical adverse events associated with NSAIDs are reduced and can be useful in dogs when administration of NSAIDs is contraindicated; for example, in patients suffering from bleeding tendencies, those at risk of gastrointestinal disease or where corticosteroids have been administered.
Opioids are a mainstay for managing moderate to severe pain. All opioid drugs act on opioid receptors (Table 2) and can either be agonistic or antagonistic. Partial agonists will never reach the same efficacy as full agonists.
Opioids are primarily used for their analgesic and occasional sedative effects. Additional effects are often unwanted. Opioids have an analgesic action through decreasing pain perception within the CNS, resulting in a decreased reaction and increased tolerance. They specifically reduce nociception, leaving touch, pressure and proprioception unaffected.
Opioids tend to be more effective for continuous dull pain rather than sharp intermittent pain. There is often variation in terms of required dose as some cases require lower doses than those stipulated on the datasheet. Therefore, it is vital to continually assess the patient and adjust the dose or dosing interval, if required.
A number of opioids are now licensed for veterinary use, although the species and indications they are licensed for vary (Table 3). There are numerous reports of opioids being effective when administered by alternative, off-licence routes, such as extradurally, intrathecally or intra-articularly.
Some opioids, particularly full mu agonists, fall under the Misuse of Drugs regulations in the UK. This results in strict methods of storage and recording of use. Guidelines are available on the VMD website (VMD, 2015).
Local anaesthetics are unique in producing blockades of peripheral nociceptive input and prevent nociception transmission to the CNS. If given prior to the nociceptive stimulus, they are the most effective way to prevent sensitisation and development of pathological pain.
This has applications with regards to perioperative regional anaesthesia, depending on the local anaesthetic used and its duration of action (bupivacaine> ropivacaine>> lidocaine> procaine). Regional techniques performed perioperatively may provide immediate analgesia (Table 4).
Many local anaesthetic techniques are possible, with varying degrees of skill needed. The only local anaesthetics licensed for use in small animals are lidocaine and procaine. Prolonged postoperative analgesia can be achieved through the use of wound soaker catheters, inserted during surgery, for continued intermittent administration of local anaesthetic postoperatively.
IV infusion offers an alternative way to administer local anaesthetics, particularly for those patients with visceral or neuropathic pain. Lidocaine is the only suitable drug for this purpose. Use of lidocaine in this way is off-licence: no product is licensed for IV use.
Preservative and adrenaline-free preparations should be used. Doses for continuous infusions in dogs can vary from 25µgkg-1min-1 to 50µgkg-1min-1 and can be administered undiluted or diluted in IV fluids. The use of a syringe driver or fluid pump is recommended to ensure accurate dosing.
Over time, tachyphylaxis may occur, so continued pain assessment is necessary. Nausea and vomiting are a potential adverse effect when using higher doses. Caution is advised when used in cats due to their apparent increased sensitivity to local anaesthetic toxicity. If used, doses at the lower end of the range are advised, combined with careful monitoring for neurological signs indicating toxicity.
Alpha-2 agonists used in small animal medicine include medetomidine, dexmedetomidine and xylazine, although
the latter is used less frequently due to its reduced alpha-2 agonist specificity. Alpha-2 agonist drugs are primarily used for their sedative effects, but some degree of analgesia is offered through spinal and supraspinal mechanisms in a similar fashion and synergistic to that given by opioids.
This drug class is also said to have local anaesthetic-type actions, with xylazine being the most potent in this regard. Analgesia from alpha-2 agonists is usually shorter-lived then sedative effects and is antagonised with the use of atipamezole. Off-license use of alpha-2 agonists for analgesia has been reported and includes the use of IV infusions of dexmedetomidine or medetomidine (doses starting at 1µgkg-1min-1 and titrating to effect), intra-articular and
extradural use.
Cardiovascular effects, such as vasoconstriction and bradycardia, do occur with the use of alpha-2 agonists, although these may be minimised when using doses <5µgkg-1 of medetomidine. However, the use of this drug class is possibly limited to patients with healthy cardiovascular systems, with few exceptions. Caution is also advised with patients where vomiting could have serious deleterious effects, such as patients with increased intraocular or intracranial pressure, or an upper gastrointestinal obstruction.
As mentioned previously, NMDA receptor stimulation is associated with central sensitisation (De Kock and Lavand’homme, 2007). The use of NMDA antagonists, therefore, provides analgesia through altering central modulation of the nociceptive stimulus. This can have applications for treatment of acute and chronic pain states.
Ketamine is the most common NMDA antagonist used in veterinary medicine. In addition to NMDA antagonism, there may be other modes of analgesic action, including agonism of opioid receptors and activation of the monoaminergic descending inhibitory system.
When used as an analgesic, rather than anaesthetic agent, microdoses of ketamine appear to be effective, although this uses the drug in an off-licence manner. Reported doses include an IV loading dose of 0.5mgkg-1, followed by an infusion of 5µgkg-1min-1 to 20µgkg-1min-1. As with lidocaine, this can be administered either with a syringe driver or diluted in IV fluids. A fluid pump is recommended to ensure accurate doses are administered (Figure 4).
It is generally accepted ketamine can have a valuable place in postoperative analgesia, forming part of a multimodal approach, but as a sole analgesic agent its effect may be quite weak. It should be noted ketamine has been reclassified from a Schedule 4 drug to a Schedule 2 drug.
Amantadine is an orally administered NMDA antagonist that has found use as a treatment for neuropathic or chronic pain. Evidence of its use in veterinary medicine is limited, but one report has shown its potential benefit in dogs when administered at a dose of 3mgkg-1 to 5mgkg-1 once daily as part of a multimodal analgesic regime for refractory osteoarthritis (Lascelles et al, 2008).
Simple, non-pharmacological methods in the immediate perioperative period can significantly improve a patient’s comfort (Figure 5):
It is imperative appropriate analgesia is provided in the postoperative period to ensure rapid return to normal function. To achieve this, regular pain assessment is crucial to assess both the animal’s baseline pain and its response to therapy.
In most cases, a staged reduction in analgesia is appropriate, migrating from parentally administered drugs while the animal is hospitalised to oral drugs administered at home. A holistic approach to pain management must be taken, recruiting all members of the veterinary team and the owner to ensure the patient’s welfare needs are met.
