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What are the options for managing pain in a different way?

Non-conventional analgesics may be useful when traditional drugs are insufficient or need to be avoided

01 May 2020, at 8:30am

To manage pain, it is helpful to understand how it is recognised and altered by the body. This is called the pain pathway and consists of four different stages. Different analgesic drugs work at various levels of the pain pathway, so you can interrupt the signal getting to the brain at different levels (Table 1). This use of multimodal analgesia (using several analgesics targeting different parts of the pain path-way) has been associated with improved pain control com-pared to monotherapy and a lower incidence of side effects, as the quantity of individual drugs needed is lower.

table showing the different pain pathways and which drugs are active at each level
TABLE (1) An explanation of the four stages of the pain pathway and the drugs active at those levels

Traditional acute pain management usually involves opioids, COX-inhibiting NSAIDs and local anaesthetics, meaning all stages of the pain pathway are covered. However, at times these drugs may still be insufficient or we may want to avoid one or more of them. It is therefore useful to be familiar with the effects of other “non-conventional” analgesics.

Alpha-2 adrenergic agonists

Medetomidine and dexmedetomidine (medetomidine’s active isomer) are licensed α2-adrenergic agonists in small animal practice. They can be administered intravenously, intramuscularly, subcutaneously and transmucosally. When bound to the α2-adrenoceptors in an animal’s central nervous system, they produce profound sedation and analgesia.

α2-agonists are usually given as part of the animal’s pre-anaesthetic medication, to sedate the animal and to provide a stable background to the general anaesthesia. The drugs afford a reduction in maintenance requirements. However, analgesia is of limited duration so to provide sustained analgesia a constant rate infusion (CRI) can be used (intra-operatively and in conscious animals). A dexmedetomidine CRI has been shown to provide similar analgesia to a CRI of morphine (Valtolina et al., 2009). Analgesia will not occur without some sedation, which may be undesirable in some hospitalised animals. In animals with visceral pain, or those needing some sedation alongside analgesia, these drugs can be very helpful. It is important to remember that α2-agonists work in synergy with opioids. This means the combination gives especially effective analgesia.

Before choosing to use these drugs, the animals’ cardiovascular stability should be considered as they cause vasoconstriction and hypertension, followed by a decrease in cardiac output via a reflex bradycardia. Atrioventricular blocks may be observed on an ECG. Some animals may also become nauseous or vomit. These side effects are rarely observed when a CRI is started without or with only a small bolus dose. Attention should be paid to bladder management as urinary output will rise.

The drugs are metabolised in the liver and excreted in the urine. When atipamezole, a specific antagonist, is used to antagonise sedation it also stops analgesia. As sedation out-lasts analgesia an animal can look sleepy but may be painful.

NMDA-antagonists: ketamine, amantadine and memantine

Ketamine is a Schedule II drug in the UK and should be kept in a locked cupboard. Records must be kept regarding purchase and administration.

Although ketamine is a mostly used as an induction agent, at sub-anaesthetic doses it is a very effective analgesic as NMDA (N-methyl D-aspartate) receptors are involved in modulation of the pain signal and the development of central sensitisation. Antagonists will interfere with this process.

It can be used intravenously, intramuscularly or subcutaneously, is suitable for CRIs (in intravenous fluids, Figure 1, or separately) and can be used intra- and post-operatively. In humans, even a single perioperative dose can reduce the need for post-operative opioids (Riddell et al., 2019).

FIGURE (1) A constant rate infusion of ketamine can be added to intravenous fluid therapy
FIGURE (1) A constant rate infusion of ketamine can be added to intravenous fluid therapy

Ketamine works well in animals with chronic pain, which may not be alleviated by “normal” analgesic drugs, and in neuro-pathic pain, such as animals with a spinal cord injury. There is some suggestion it may also have neuroprotective effects. Ketamine is useful for treatment of somatic pain (superficial tissues, skin) and may be a useful additive to sedation pro-tocols for wound management.

Ketamine undergoes hepatic metabolism and renal excretion in dogs, whereas in the cat it is excreted unchanged in the urine. As the dose needed to provide analgesia is so small, the side effects of this drug are also limited. Dysphoria is seen at times in awake animals. When ketamine is given as a bolus under anaesthesia the animal will frequently go into several minutes of apnoea. This is seldom harmful, just be prepared to ventilate the animal. In awake animals, this respiratory depression is not seen. Animals on a ketamine CRI should regularly have their eyes lubricated as otherwise they could develop corneal ulcerations.

Amantadine and memantine are used in chronic pain management. Amantadine has been shown to increase activity in dogs with osteoarthritis when combined with meloxicam (Lascelles et al., 2008). Memantine works similarly but may additionally have some local anaesthetic activity and is friendlier on the gastrointestinal tract. Neither are licensed for use in small animals.

Systemic lidocaine

Lidocaine can provide analgesia when given intravenously as a bolus or an infusion (Figure 2). Other local anaes-thetics should not be used systemically due to the risk of cardiotoxicity. As with local blocks, care must be taken not to overdose, as both central nervous system and cardiac complications may ensue. The use of intravenous lidocaine is not recommended in cats as the safety margin is lower.

FIGURE (2) Constant rate infusion can also be administered via syringe driver, here lidocaine
FIGURE (2) Constant rate infusion can also be administered via syringe driver, here lidocaine

The mechanism of action is through a sodium channel blockade. It is used for intraoperative (offering MAC reduction) or post-operative analgesia, mainly in patients with visceral or neuropathic pain. It also has anti-arrhythmic effects and is prokinetic, anti-inflammatory and anti-endotoxaemic. Awake animals may become sedated, nauseous and anorexic but only rarely to such a degree that treatment needs to be stopped completely.

Paracetamol

Paracetamol inhibits prostaglandin synthesis centrally and peripherally, and interferes with the endogenous opioid, serotoninergic and cannabinoid systems. It provides analgesia and is anti-pyretic, but has limited anti-inflammatory effects.

It can be used safely in animals where COX inhibition is a concern (eg renal or gastrointestinal disease). Pardale V (400mg paracetamol/9mg codeine) is licensed for use in dogs for five days. An intravenous formulation exists but is not licensed. The use in dogs with liver failure is contraindicated, as is the use of any formulation in the cat.

Gabapentinoids

Gabapentin and pregabalin are available as capsules, tablets and syrup for oral administration. All are categorized as Schedule III drugs. They can be used in dogs and cats.

They bind to calcium and sodium channels in the nervous system, stabilise membranes and prevent release of excitatory neurotransmitters. Although they’re mostly used in chronic pain management oral uptake is quick.

It can take up to two weeks for the full effect to appear though. They are useful for treatment of neuropathic pain.

Side effects include sedation and ataxia, but these are mostly transient. In dogs they are partly metabolised in the liver and excreted unchanged by the kidneys. Gabapentin is well tolerated long term, although some sources suggest a gradual tapering of dose to prevent status epilepticus and rebound pain. Pregabalin may be more effective in some dogs.

Gastrointestinal drugs

Although not strictly speaking analgesics, drugs such as antiemetics, antacids, prokinetics and antispasmodics may all have a place in making a patient more comfortable.

The antiemetic maropitant blocks the NK1-receptor, where substance P (a neurotransmitter) binds in the pain pathways so may contribute to (visceral) analgesia (Marquez et al., 2015). It has been shown to decrease the MAC of volatile anaesthetics in dogs and cats.

Conclusion

Other drugs than opioids, COX-inhibiting NSAIDs and local anaesthetics can be useful to manage pain. An important message in these troubled times: you can always find help in unexpected corners!

References
Author Year Title
Duke-Novakovski, T., de Vries, M. and Seymour, C. 2016 BSAVA Manual of Canine and Feline Anaesthesia and Analgesia, 3rd ed. John Wiley & Sons
Lascelles, B., Gaynor, J., Smith, E., Roe, S., Marcellin-Little, D., Davidson, G., Boland, E. and Carr, J. 2008 Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. Journal of Veterinary Internal Medicine, 22, 53-59
Marquez, M., Boscan, P., Weir, H., Vogel, P. and Twedt, D. 2015 Comparison of NK-1 receptor antagonist (maropitant) to morphine as a pre-anaesthetic agent for canine ovariohysterectomy. PLOS ONE, 10, p.e0140734
Riddell, J., Trummel, J. and Onakpoya, I. 2019 Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis. British Journal of Anaesthesia, 123, 325-334
Self, I. 2019 BSAVA Guide to Pain Management in Small Animal Practice
Valtolina, C., Robben, J., Uilenreef, J., Murrell, J., Aspegrén, J., McKusick, B. and Hellebrekers, L. 2009 Clinical evaluation of the efficacy and safety of a constant rate infusion of dexmedetomidine for postoperative pain management in dogs. Veterinary Anaesthesia and Analgesia, 36, 369-383

Sanne Melis, MVM, DipECVAA, MRCVS, is a Diplomate of the European College of Veterinary Anaesthesia and Analgesia and an RCVS Recognised Specialist in Veter-inary Anaesthesia. She works as a senior anaesthetist at Pride Veterinary Centre and has a special interest in pain management.

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