The Pharmacology of Analgesic Drugs in Small Animals
World Small Animal Veterinary Association World Congress Proceedings, 2004
Andrea Nolan, MVB, MRCVS, DVA, PhD, DECVA, DECVPT
Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow
Glasgow, Scotland

Significant advances have been made in the last two decades in understanding the pathophysiology of pain in humans and animals, and increased emphasis on recognising patterns of pain and managing pain in animals has resulted. Pain may be classified as physiological/nociceptive pain and clinical/pathological pain. Physiological pain serves as a warning and a protective system for the animal. It initiates withdrawal reflexes and moderates the animal's behaviour to minimise further damage (Cousins and Power 1999). It is associated with direct activation of high threshold sensory receptors (nociceptors); it is generally sudden in onset and transient in nature and often there is little or no tissue damage. In contrast, clinical or pathological pain arises from tissue damage, as a consequence of trauma, elective surgery, inflammatory processes, infection or neoplasia. Significant tissue damage leads to peripheral and central alterations in neuronal activity, which together generates spontaneous pain and pain hypersensitivity (hyperalgesia, increased responsiveness to painful stimuli, and allodynia, reduction in pain threshold). Thus pain management is a two-step process aimed at reducing the nociceptive barrage, which induces pain, and managing the development of a hypersensitive state. Clinical pain has been classified as either inflammatory pain, that arising from acute or chronic inflammatory processes, or neuropathic pain, a severe and often intractable pain resulting from damage to peripheral nerves or to the central nervous system. Cancer pain in humans may comprise sufficiently different profiles to warrant a unique category, in which many features of both inflammatory and neuropathic pain co-exist. Pain is also described in terms of its pattern and duration, as acute, chronic and 'acute on chronic' which reflects acute exacerbations of an underlying chronic condition (Cousins and Power 1999; Lamont et al. 2000; Muir, III and Woolf 2001).

Most of the analgesic drugs in use today have been available for many years, although new products within various classes have been introduced for veterinary species. Analgesic drugs used in small animals include the opioid drugs, the local anaesthetic drugs, the non-steroidal anti-inflammatory drugs (NSAID), the alpha2 adrenoceptor agonists and other agents such as ketamine. Newer agents introduced in human and in some cases veterinary medicine include the cyclooxygenase (COX)-2 inhibitors such as rofecoxib, a category of NSAID, gabapentin, a drug licensed for the treatment of neuropathic pain in humans, and tramadol, a drug with mixed effects. The use of the anti-depressant drugs, amitriptyline and imipramine, although not licensed have been advocated for chronic pain in dogs.

Opioid drugs, also referred to as narcotic analgesics, are the drugs of choice for the treatment of moderate to severe pain in small animals. All the drugs currently used in small animals act on the m opioid receptor, including morphine, pethidine, fentanyl, alfentanil, buprenorphine and butorphanol (which also has significant activity at k receptors), and include agonists and partial agonists The degree of analgesia produced and its duration of effect, and consequently the drugs effectiveness in managing mild, moderate, or severe pain, will depend on whether the drug is an agonist or a partial agonist, on the dose administered and on the pharmacokinetics of the drug.

Side effects of opioid drugs include a reduction in gastrointestinal tract motility, vomiting (morphine) and respiratory depression. In general, breathing rate is slowed but tidal volume is unaffected although dogs in particular may pant following high doses. The potent opioids fentanyl and alfentanil used in animals intraoperatively to provide profound analgesia, may cause severe respiratory depression. Opioids induce bradycardia and may cause hypotension, but in general have little effect on cardiac contractility, an advantage when used in the perioperative period. Other effects include anti-tussive properties and mood alterations (euphoria and occasionally dysphoria). Opioids induce tolerance and dependence in humans during prolonged administration, however, it is unusual for opioids to be used therapeutically for longer than 6-7 days in small animals, and consequently these effects are rarely seen. In general the opioids are well absorbed from intramuscular and subcutaneous sites and from the gut, but due to a high first-pass metabolism effect, are only poorly bioavailable when given orally. They are generally highly metabolised by the liver (glucuronidation, demethylation etc.). Methods of supplying opioids for longer-term management of pain, have led to the development of fentanyl transdermal patches, which have been used in dogs and cats to provide analgesia or between 2 and 4 days (Kyles, 1998). Absorption is slow, however once peak plasma concentrations are achieved, the plasma concentrations remain until the patch is removed, with decay of plasma levels occurring over 12h. Problems with the patches include alteration in drug delivery/absorption rates with alterations in skin temperature and skin blood flow, and lack of efficacy.

Opioids are the mainstay of treatment for moderate to severe pain and are most often used perioperatively (pre-, intra-and postoperatively) and in cases of traumatic injury, less frequently in the management of chronic pain. For severe pain agonists such as morphine and methadone are very effective drugs, while for mild-moderate pain partial agonists such as buprenorphine are often employed. Short-acting agonists such as fentanyl and alfentanil are frequently used by bolus injection or by infusion as part of a balanced anaesthetic technique to provide analgesia and reduce the amount of general anaesthetic required. Morphine is used by epidural injection for the provision of effective perioperative analgesia with a long duration of action, 12-24h (Pascoe, 1992). Opioids are best avoided where an animal is displaying respiratory depression, unless respiratory depression is due to pain e.g., fractured ribs. Many opioids increase intracranial pressure as a consequence of respiratory depression, which raises arterial carbon dioxide tension with the potential to increase cerebral blood flow. Thus opioids are avoided in head injured patients until a diagnosis is obtained and arterial carbon dioxide is controlled by controlled ventilation. In animals with biliary obstruction or pancreatitis, morphine should be avoided as sphincter contraction can exacerbate the conditions.

During the last 10 years there has been a welcome increase in the number of NSAIDs licensed for use as analgesics in small animals. The NSAIDs have long been known for their analgesic, anti-inflammatory and anti-pyretic properties, however, the role of these drugs in pain management had been relatively underestimated, until it was recognised that they also have distinct antihyperalgesic properties through a spinal site of action. They now play an important part in pain management in small animals. The NSAIDs act by inhibiting the enzymes the cyclooxygenases (COX) and thus, they decrease the release of prostaglandins and thromboxane A2, since COX and lipoxygenases catalyse the conversion of arachidonic acid which is released from cell membranes when they are damaged (Vane, 1971). Three isoforms of COX have been identified, COX-1 a constitutive enzyme, COX-2, an inducible enzyme (Xie et al., 1991) and more recently COX-3, a variant of COX-1 (Chandrasekharan, et al., 2002). Until recently, it was considered that the prostaglandins that mediate inflammation, fever and pain were produced by COX-2, while the prostaglandins that are important in gastrointestinal and renal function were produced via COX-1. This led to the belief that the NSAIDs exerted their therapeutically beneficial effects primarily by inhibiting COX-2, while inhibition of COX-1, was considered to be responsible for some of the toxic side effects associated with these drugs, e.g., gastric ulceration and renal papillary necrosis. Recent work has indicated that the distinction between these two roles is not well delineated, and COX-2 has a constitutive role in many tissues. Many commercially available NSAIDs at present licensed for use in animals appear to inhibit both enzymes with varying selectivity and potency which appears to be species dependent.

NSAIDs are generally well absorbed after oral, subcutaneous and intramuscular injection. The NSAIDs are all highly protein bound in plasma, which can limit the passage of drug from plasma into the interstitial fluid. However, protein binding explains the extended therapeutic activity in inflamed tissues, which many of these drugs display when compared with their plasma elimination half-life. Consequently NSAIDs with short half-lives such as flunixin can be administered once daily to good therapeutic effect (for review see Lees, 1998). Metabolism of most NSAIDs occurs in the liver and the metabolites are generally inactive. The cat lacks the hepatic enzyme glucuronyl transferase and aspirin therefore has a long half-life in this species, which will lead to drug cumulation and toxicity if the cat is treated like a small dog and dosed accordingly.

The most commonly encountered toxic side effect of the NSAIDs is gastrointestinal irritation, manifested through diarrhoea and vomiting and possible ulcer formation (a consequence of COX-1 inhibition). Of the commonly used NSAIDs in dogs, a study reported little difference in gastric lesions after 7 days of therapy between meloxicam, carprofen and ketoprofen (Forsyth et al., 1998). The development of COX-2 selective drugs represents a significant advance in producing anti-inflammatory drugs without gastric side effects. Nephrotoxicity is a serious side effect of these drugs when they are used in animals under conditions of reduced renal blood flow as occurs frequently during anaesthesia, or in hypovolemic animals (Elwood et al., 1992) (a consequence of both COX-1 and COX-2 inhibition). Drugs such as carprofen, meloxicam and ketoprofen are used as part of a perioperative balanced analgesia regime with good effect. Use of NSAIDs should be avoided in animals receiving concurrent corticosteroid therapy.

The local anaesthetic drugs, including lidocaine, mepivacaine, bupivacaine and ropivacaine, have played an important role in pain management over many years. By decreasing or prevent the large transient increase in the permeability of excitable membranes to Na+ that normally occurs when the membrane is slightly depolarised, they stop the transfer of noxious information from the periphery along peripheral nerves. The duration of action of a local anaesthetic is dependent on the time that the drug is in contact with the nerve, which is governed by the lipid solubility of the drug, the blood flow to the tissue and the pH of the tissue. They are optimally used to obtund pain in a local area e.g., use of a brachial plexus block to manage severe forelimb pain, epidural anaesthesia for abdominal and perineal surgery. More recently they have been used intravenously during surgery to reduce the requirement for general anaesthetics, but in higher doses the local anaesthetic drugs induce central nervous system stimulation, restlessness and convulsions, ultimately followed by depression. Local anaesthetics have side effects on the myocardium, decreasing electrical excitability, conduction rate and force of contraction, and they may induce arteriolar dilatation causing hypotension.

The alpha2 adrenoceptor agonists, xylazine and medetomidine are potent analgesic agents that also induce dose-dependent sedation, which restricts their use in pain management protocols. Furthermore their dose related cardiovascular depression can be marked. At the licensed dose rates, these drugs are not commended for use as analgesics, as the cardiovascular depression is considered too great. However, use of low doses may be appropriate during anaesthesia and in fractious animals, where they are often combined with opioids or local anaesthetics drugs.

Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which is intimately involved in the induction and maintenance of altered pain responses following trauma/inflammation. Therefore, modulators of the receptor appear to have analgesic and antihyperalgesic properties. The use of ketamine in conscious patients is restricted due to excitatory actions (except in very low doses) and it is primarily used as an anaesthetic agent in following premedication with an alpha2 adrenoceptor agonist drug, or as an adjunct to anaesthesia e.g., by infusion in isoflurane/halothane anaesthetised dogs and cats. Work in humans has indicated that ketamine may be effective in reversing some chronic pain states e.g., phantom limb pain, and it is used for particularly painful procedures e.g., changing burn dressings. Management of chronic pain in dogs and cats had relied almost exclusively on the use of NSAIDs given intermittently over long periods of time. This mode of therapy is not always optimal and may be associated with side effects or inadequate pain management. Us of drugs such as the anti-depressants used in the management of chronic pain in humans, and more recently gabapentin has been described although they are not licensed and their efficacy has not been validated at this stage.

References

1.  Chandrasekharan, N.V., Dai, H., Turepu Roos, K. L., Evanson, N.K., Tomsik, J., Elton, T.S. & Simmons, D.L. (2002) Proceedings of the National Academy of Sciences, USA, 99, 13926-13931.

2.  Cousins, M. & Power, I. (1999) in: P.D.Wall and R. Melzack (Eds.), Textbook of Pain. Churchil Livingstone, Edinburgh, pp. 447-489.

3.  Elwood, C., Boswood, A., Simpson, K. & Carmichael, S. (1992) Veterinary Record 130, 582-583.

4.  Forsyth, S.F., Guilford, W.G., Haslett, S.J. & Godfrey, J. (1998) Journal of Small Animal Practice 39, 421-424.

5.  Kyles, A.E. (1998) Compendium on Continuing Education for the Practicing Veterinarian 20, 721-726.

6.  Lamont, L.A., Tranquilli, W.J. & Grimm, K.A. (2000) in Veterinary Clinics of North America Small Animal Practice, 30, 703-728.

7.  Lees, P. (1998) in Canine Medicine & Therapeutics. Ed. Neil T. Gorman. Pp 106-118.

8.  Muir,W.W., III & Woolf,C.J. (2001) Journal of the American Veterinary Medical Association, 219, 1346-1356

9.  Pascoe, P.J. (1992) Veterinary Clinics of North America Small Animal Practice 22, 421-423.

10. Stein, C. (1993) Anesthesia & Analgesia 6, 182-191.

11. Vane, J. R. (1971) Nature, 231, 232-235.

12. Wallace, J.L. (1999) Trends in Pharmacological Sciences, 20, 4-6.

13. Xie, W., Chipman, J.G., Robertson, D.L., Erikson, R.L. & Simmons, D.L. (1991) Proceedings of the National Academy of Sciences USA 88, 1692-1696.

Speaker Information
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Andrea Nolan, MVB, MRCVS, DVA, PhD, DECVA, DECVPT
Institute of Comparative Medicine, Faculty of Veterinary Medicine
University of Glasgow
Glasgow, Scotland


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