Analgesia for Small Animals Pharmacology & Clinical Practice. Jill Maddison The Royal Veterinary College Hawkshead Lane, North Mymms, AL9 7TA, UK

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1 Analgesia for Small Animals Pharmacology & Clinical Practice Jill Maddison The Royal Veterinary College Hawkshead Lane, North Mymms, AL9 7TA, UK Colin Dunlop Advanced Anaesthesia Specialists Unit 13, Buffalo Road, Gladesville NSW 2111 Pain is a subjective modality resulting from the conscious perception of a noxious stimulus. Pain perception depends on conduction via neural pathways from peripheral nociceptors to the spinal cord neurones and then to an intact cerebral cortex (via the brain stem and thalamus). In humans, somatic pain conducted by A-delta (fast) and C (slow) nerve fibres can be discretely localized. Visceral pain, conducted by C fibres, is not well localized. Although animals cannot verbally describe or quantify the perceived response following noxious stimulation (ie the type or quality of pain), methodology for pain management must assume its perception for a given species of animal. Painful stimulation causes physical discomfort and stress which alter behaviour, homeostasis including sleep patterns, feed intake, water intake and recovery from tissue injury. Analgesia can be achieved via exogenous and or endogenous pharmacological agents acting on peripheral nociceptors, peripheral sensory nerves, spinal cord neurones, spinal cord pathways and brain sensory neurones. Understanding the clinical pharmacology of commonly used analgesic drugs is important to enable successful management of clinical patients. CLINICAL PHARMACOLOGY OF COMMONLY USED ANALGESIC DRUGS NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Non-narcotic analgesics, specifically non-steroidal anti-inflammatories (NSAIDs), are used in the management of pain associated with acute trauma or surgery, painful medical conditions such as abscesses and otitis externa or chronic pain associated with degenerative conditions such as osteoarthritis or neoplasia. Mechanism of action Nonsteroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, analgesic and antipyretic activity and effects on platelet aggregation. Their mechanism of action includes inhibition of the production of several mediators of inflammation, including prostaglandins and thromboxane via inhibition of the enzyme cyclo-oxygenase. COX-1, COX-2 and COX-3 There are now believed to be three forms of cyclo-oxygenase, COX-1, COX-2 and COX-3. The traditional view is that COX-1 is responsible for the production of prostaglandins (e.g. prostacyclin) important in the physiological modulation of function whereas induction of COX- 2 is associated with production of inflammatory prostaglandins and hence disease processes. As we will discuss however, the picture is not quite as simple as initially thought. COX-3 has recently been discovered it is proposed it is involved with central pain relief.

2 Physiological role for COX-2 While the simplistic assessment of COX-1 and COX-2 runs along the lines of COX-1 good, COX-2 bad the reality is far from being this clear cut. COX-2 appears to have important physiological functions in some circumstances which have yet to be fully identified. For example, COX-2 is expressed constitutively in the kidney, particularly by the macular densa and has a role in the control of renin release. This role is greater in dogs than in humans, further evidence that one should never extrapolate data on NSAID therapeutic or toxicological effects from one species to another. Considerations for clinical use of NSAIDs Patients receiving NSAIDS should be well hydrated and have no condition that may affect gut or renal blood flow. NSAIDs should be avoided is possible in patients with hepatic disease due to slower metabolism, potential to aggravate sodium and fluid retention and possibly the increased risk of exacerbating GI ulceration. If the use of NSAIDs in hepatic patients is believed essential then the dose interval should be reduced. In patients where renal blood flow is reduced or may be reduced or when pathological sodium retention is present such as patient with nephrotic syndrome, cardiac failure and cirrhotic hepatic disease NSAIDs (selective as well as non-selective) should be avoided. During anaesthesia, particularly in older or dehydrated patients, renal blood flow is reduced so administration of IV fluids should be considered NSAIDs might be better administered following recovery from anaesthesia. OPIOID ANALGESICS The opioid analgesics are among the most potent systemic analgesic drugs in veterinary medicine. The standard opiate drug is morphine, named after the Greek god of dreams, Morpheus. Opioids are most effective for treatment of moderate to severe pain particularly acute pain following trauma or surgical procedures. Some side effects that may be of concern in critically ill patients include CNS depression, respiratory depression, bradycardia and oesophageal reflux or regurgitation. Opioid drugs are scheduled as S8 so have storage and record keeping obligations. Although these drugs can have significant side effects, for most animals in serious pain, these are usually not of sufficient concern to prevent use of these drugs to relieve pain. Efficacy of analgesia Morphine, methadone and fentanyl are pure opioid (mu) agonists and provide the most effective systemic opiate analgesia for severe pain such as from orthopaedic or thoracic surgery. Pethidine, buprenorphine and butorphanol are partial agonists and provide a lesser degree of analgesia. The long duration of buprenorphine makes it particularly useful for mild to moderate pain such as from soft tissue trauma. Pethidine's provides only moderate analgesia and its usefulness is limited by its short duration of action (1-2 hours) although it s use may result in less sedation. Opioid analgesia does vary between species Mixing opioid agonists and partial agonists can result in interactions at opioid receptors resulting in unpredictable (or no) analgesia.

3 Co-administration of mild sedatives (e.g acepromazine mg/kg SC) may improve the clinical response to opioid analgesics. Considerations for clinical use Morphine produces profound analgesia and sedation in the dog for up to 6 hours although its duration may be considerably less in patients with severe pain. High doses of some opioids in cats (e.g morphine 1 mg/kg IV) may result in excitement. However, administration of more typical clinical doses (e.g morphine 0.3 mg/kg SC) avoids this problem and effective analgesia is achieved. In dogs, vomiting may follow the administration of the initial dose of morphine but this does not seem to occur with subsequent doses. Methadone is more lipid soluble than morphine so may have a more rapid onset than morphine, but may also have a shorter duration of action. Its duration of action in dogs may be 3-5 hours and it is less likely to result in vomiting following administration of the initial dose, compared to morphine. Methadone may result in a better clinical response in cats compared to morphine. Fentanyl is a potent synthetic opioid which can cause dose-dependent sedation and respiratory depression. Auditory sensitisation and altered thermoregulation (resulting in panting) may occur. It can be used with a sedative (e.g. acepromazine mg/kg) to produce neuroleptanalgesia. Because of its pharmacologic properties it is available for use in transdermal patches which provide a slow onset (dog 12 hrs, cat 6 hrs) but a long duration ( hrs) of analgesia. They are useful for management of longer duration post surgical pain or neoplastic pain but there can be variability of efficacy. Interestingly at usual doses (3 to 5 ug/kg/hr) there is little sedative effect when fentanyl is administered via a patch. Excessive periods of administration (via repeat use of patches) can produce euphoria in some patients. Buprenorphine has a long duration of action (8-12 hours) due to its slow dissociation from mu receptors. In cats, the quality of analgesia may be as effective as that achieved by use of morphine or methadone and in addition it is absorbed from oral mucosa so can be squirted into the mouth in un-cooperative animals. Butorphanol (Torbugesic) causes less potent analgesia of a shorter duration compared to morphine. KETAMINE Ketamine is a non-competitive NMDA (N-methyl-d-aspartate) antagonist. The NMDA receptor is thought to be a crucial part of the mechanism of CNS hypersensitisation and wind up (neuropathic pain). Use of ketamine can be limited by its unpleasant, excitatory side effects, and it is often infused with other sedative or analgesic drugs to reduce the incidence of side effects. Ketamine does not act on primary pain, but on CNS hypersensitisation, therefore it is not recommended for use as a sole analgesic regime, but is probably most useful when used in conjunction with opioid and other analgesic agents at low doses. MEDETOMIDINE

4 Medetomidine acts on alpha-2 pre-synaptic receptors found within the brain (thalamus, cerebral cortex) and spinal cord to inhibit release of noradrenaline which reduces the conscious perception of pain. It causes dose-dependent sedation and analgesia. Concerns for the use of medetomidine, either by bolus dose or CRI, is that firstly it can result in increased vaso-motor tone and therefore reduced peripheral perfusion. Secondly if the animal becomes profoundly sedated, it may be unable to display signs of pain even if it is experiencing pain. Therefore it may be more appropriate to use medetomidine at lower doses in combination with other drugs (e.g. medetomidine 3-5 ug/kg with acepromazine 0.02 mg/kg & morphine or methadone 0.3 mg/kg all SC). LOCAL ANAESTHESIA Lignocaine and bupivacaine are commonly used in small animals depending on the desired duration of action and potential for undesirable responses. Lignocaine s duration is up to 2 hours compared to bupivacaine s (up to 6 hours). Both are usually dosed at 1 to 2 mg/kg but Bupivicaine is more cardio-toxic when inadvertently administered IV (doses > 4 mg/kg). Infuse local anaesthetic via small gauge needles e.g. 25 ga., or dental needles or use spinal needles if it is likely that a blood vessel could be hit inadvertently; aspirate prior to injection. If you hit a blood vessel, remove the needle and start again Contraindications include Blood flowing from a needle placed at the injection site Skin or mucosal infection at the site of needle insertion Coagulopathies or sepsis (especially for epidural injections) Trauma involving the injection site Mandibular nerve blocks for dentistry include: - Mental foramen n. block anterior mandible back to the level of the premolar teeth - Mandibular (intra-oral) foramen block body of the mandible and the caudal molar teeth Maxillary nerve blocks for dentistry include: - Anterior Infraorbital foramen block nose, anterior maxilla to the level of the premolars - Caudal (intra-oral) Maxillary n. block maxilla, palate and caudal molar teeth Epidural Anaesthesia using local anaesthetic is blockade of all nerve fibres exiting the spinal cord and can be used alone to permit surgical procedures lasting up to 6 hours. Epidural opioids modulate spinal cord neurones and typically provides good analgesia for up to 24 hours in postsurgical recovery but cannot be used alone to permit surgery. CLINICAL PRACTICE OF ANALGESIA Previous retrospective studies in dogs and cats (Hansen and Hardie JAVMA 1989) showed that: - fewer analgesics were administered to smaller and younger animals - cats were treated less frequently than dogs, possibly because they vocalise less - analgesics were administered less frequently if it was on a as needed basis rather than administered on an interval based on either pharmacokinetics or duration of efficacy - medical records reported animals as painful, but no treatment was administered Pre-emptive analgesia

5 - prevents/reduces sensitization of pain pathways & neurones (block painful sensory input to the spinal cord) to reduce the requirement for anaesthetic and analgesic drugs - premedicate surgical patients with analgesic and/or anti-inflammatory drugs - consider a combination of therapies including o systemic analgesic drugs; duration is associated with method of administration o regional nerve blocks with local anaesthetics such as for dentistry o intra-articular analgesia with local anaesthetics and longer acting opioids o epidural local anaesthesia and or analgesia Acute intra-operative or post-surgical pain increases circulating catecholamines, causing vasoconstriction which alters distribution of blood flow and drugs, therefore altering responses to anaesthetic and analgesic drugs. Painful patients that wake up during anaesthesia or painful post-surgical patients require larger doses of anaesthetic and analgesic drugs administered more frequently to achieve an effective response and may require multi-modal therapy. Intra operative analgesia - use additional doses of parenteral analgesics (e.g. morphine 0.1 mg/kg IV prn every 20 to 30 min. or prior to painful manipulation OR by continuous infusion) as well as increased anaesthetic dose, implementing a degree of balanced anaesthesia - careful positioning & padding during anaesthesia to prevent nerve/muscle injury - consider administration of analgesic drugs (e.g. lignocaine, medetomidine & ketamine) - use long acting local anaesthetics (e.g. bupivacaine) intra-operatively for tissue infiltration, nerve blocks, intra-articular or topical analgesia Postoperative analgesia - routine use of systemic analgesia and sedation (vasodilation) immediately postanaesthesia (e.g. morphine mg/kg usually with acepromazine 0.02 mg/kg SC) - consider intra-pleural local anaesthetic administration for animals with chest drains - use longer term therapies such as NSAID s, analgesic infusions and fentanyl patches - there is increasing availability of orally administered, effective analgesic agents that can provide longer term therapy - with chronic pain where neural hypersensitization has developed, standard analgesic drug choices, dosages and dosage intervals may not be adequate (use higher doses more frequently and combinations of drugs that target a variety of receptors) - what is the place for acupuncture and physiotherapy for management of chronic pain Practical Considerations for acute pain management if it is working stick with it! If it is not working, do something different. a combination of systemic therapies can result in more effective analgesia at lower drug doses than relying on a single drug. local and regional nerve blocks are the most effective method of blocking pain perception avoid simultaneously mixing opiate drugs (agonists vs. antagonists) in the same patient