Proceedings of the European Veterinary Conference Voorjaarsdagen

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1 Close this window to return to IVIS Proceedings of the European Veterinary Conference Voorjaarsdagen Amsterdam, the Netherlands Apr , 2009 Next Meeting: Reprinted in IVIS with the permission of the Conference Organizers

2 Scientific proceedings: companion animals programme WHAT ANALGESIC, WHEN AND WHY? Pain Acute pain is pain that is short duration. The intensity may vary from mild to severe and it may be self limiting and easily resolved or may continue unabated to become a chronic pain syndrome. Even though it may resolve in its own the consequences of not administering analgesics may be far reaching. The painful patient may become dehydrated and catabolic and the physiological stress can decrease immune function and slow wound healing. Untreated pain may also result in an upregulation of the pain processing pathways. Chronic pain is important because it is a welfare issue; if the animal s quality of life is being adversely affected then we have a duty of care to either provide some kind of relief from the pain or consider euthanasia to end its suffering. Additionally as a major physiological stressor it may impair healing of lesions or recovery from illnesses. Pre-emptive analgesia Administration of analgesic before pain actually occurs will help decrease or even prevent the amount of nervous system upregulation that occurs as a consequence of the painful stimulus. This means that it will tend to be easier to provide good analgesia by getting agents on board before the pain is established; good analgesia may be achieved by using lower doses than if they are not given until after the animal is pain. Most analgesic agents are suitable for use as pre-emptive analgesics and they must be administered sufficiently in advance of the painful stimulus so that effective plasma concentrations are achieved before the painful stimulus. This obviously is only a tactic that is of use for elective pain (after surgery)! Multimodal/ balanced analgesia There is no magic bullet analgesic agent that will give total pain relief to every patient, in every type of pain with no side effects. Multimodal analgesia involves using two or more analgesic agents that have different modes of action to provide better analgesia than using either agent alone and with less risk of side effects since lower doses can be used. The drugs may act in an additive or synergistic manner. Some or all of the analgesic may also be given pre-emptively within the multimodal regimen. NSAIDs: These may be used for acute or chronic pain. They act primarily by decreasing prostaglandin synthesis via cyclooxygenase (COX) inhibition. As prostaglandins have a protective function in the kidney, NSAIDs should be used carefully if administered before induction of anaesthesia. Since the safety margin for NSAIDs tends to be small it is important that an accurate dose is administered. Opioids: These are often the first choice for acute analgesia for cases of moderate to severe pain, they may be less effective long term for chronic analgesia except in cancer related pain. The primary analgesic action is via mu opioid receptors.opioids are relatively safe analgesics and have a much wider safety margin than NSAIDs. If opioid overdose occurs it may be reversed with naloxone. There are a wide range of potential side effects but they are rarely problematic enough to prevent the use of opioids for analgesia. The duration of action last from minutes (e.g. fentanyl) to up to 8 hours (buprenorphine) and they may be given via a variety of routes and either as bolus administrations or via constant rate infusions. Alpha-2 agonists: In veterinary practice medetomidine, romifidine, xylazine and dexmedetomidine are licensed for use in small animals. These agents are thought of primarily as sedatives but they are also analgesic. They act via the alpha 2 receptors located in the periphery, spinal cord and brain. The sedative/ analgesic effects are widely exploited in small animal practice but (unlike in humans) these agents are not currently used primarily for analgesia but they may be a useful component in a multimodal regimen. NB if the specific antagonist, atipamazole, is used to reverse sedation analgesia will also be reversed. NMDA antagonists: The NMDA receptor has been associated with CNS sensitisation and blockade has the ability to help block or reverse this effect. Ketamine is indicated as a dissociative anaesthetic and is mostly used in combination with sedatives such as alpha agonists and benzodiazepines; as such ketamine may be a useful component of a multimodal regimen. Subanaesthetic doses of ketamine are analgesic but single boluses tend to be very short acting (about 30 minutes). Ketamine infusions may be used in painful patients especially those who may be opioid resistant, additionally they may be useful to augment analgesia during a surgical procedure. Amantidine is another NMDA antagonist (not licensed for use in animals) which may be useful in chronic pain. CHAPTER 2 PAIN MANAGEMENT 1

3 Local anaesthetics: these reversibly block transmission of nerve ending or fibres. Generally local anaesthetics are used for regional anaesthesia either by topical or local infiltration and may be a useful addition to a multimodal regimen. Nitrous oxide: at a maximum 2/3 of inspired gas, mixed with oxygen, this will significantly decrease volatile anaesthetic agent requirement during surgery and is a useful contributor to multimodal analgesia. It has no long lasting effects and will cease to act when administration finishes. Tramadol: This is a centrally acting analgesic that binds to mu opioid receptors and also inhibits reuptake of norepinephrine and serotonin. In humans it is classed with being equianalgesic with pethidine and has been used for both acute and chronic pain. Gabapentin: This drug was developed as an anticonvulsant and was discovered to be effective against neuropathic pain in humans. The mechanism of action is unclear as yet. It does not alter nociceptive/ pain thresholds and therefore does not specifically act as an analgesic but it assists other drugs in producing analgesia. Tricyclic antidepressants: Amitriptyline, clomipramine and imipramine can provide analgesia for chronic pain conditions in humans. CHRONIC PAIN IN CATS Recognition of chronic pain may be difficult and is often associated with non specific signs such as behavioural changes (e.g. increased aggression or inappropriate toileting behaviour); reluctance to move/ increased sleeping; weight loss or weight gain; poor grooming. Although more specific signs such as lameness, self mutilation or halitosis may be seen. In some cases it is possible to eliminate the cause of the chronic pain e.g. dental disease. However for most conditions this may not be practical or possible and we must use a combination of medical management and lifestyle changes. Most analgesics used long term are will be used in an off license fashion so it is important to know if they are safe and effective to use in the cat and how easy they are to administer. Analgesic drugs As a general rule for most drugs mentioned (with the exception of opioids) avoid use in pregnancy and lactation and reduce dose if elderly or if renal disease is present. NSAIDs These are the current mainstay of chronic pain therapy. They act by inhibiting the cyclo-oxygenase (COX) isoenzymes and are analgesic, anti-inflammatory and antipyretic. COX has protective functions in the GI tract and kidney and this is where the main adverse effects are seen (GI ulceration and renal tubular damage). Some of the older NSAIDs (like aspirin) have significant adverse effects if used long term whereas the newer NSAIDs (like meloxicam) are much less likely to cause problems. NSAIDs may interact with other drugs and herbal medicines. 1 NSAIDs have increased risk of toxicity in the cat due the lack of feline hepatic glucorinadation pathways and for this reason they should be used cautiously when administered chronically. The lowest possible dose should be used and ideally patients should be monitored for side effects relating to renal and hepatic function and GI erosions. There are no accepted monitoring guidelines but a standard biochemistry panel, PCV and total protein measurement before starting treatment repeated at 1-4 weeks and then every 4-6 weeks thereafter has been recommended. 2 Regular monitoring should allow the dose to be tailored to the smallest effective amount. Many feline patients for whom chronic NSAIDs might be considered will be those that are geriatric or ill so it is advisable to approach long term NSAID therapy cautiously after discussion with the owner and with careful long term monitoring. Opioids A variety of opioids are used in the treatment of acute pain in cats including morphine, methadone, pethidine, fentanyl, buprenorphine and butorphanol however, with the exception of cancer pain, metanalysis of human patients 3 has demonstrated that opioid medication is less useful for chronic pain (although it may be helpful in acute flare ups within a chronic condition). Buprenorphine (injectable) may be administered buccally in cats ( mg/kg up to 3 to 4 times a day) and butorphanol is available as oral tablets (0.5-1mg/kg every 6-8 hours). Transdermal fentanyl patches are available for use in man and have anecdotally been used in cats (a dose of 2-4μg/kg/hr has been recommended, with the onset time being 6-24 hours and duration of action hours). The smallest patches (25μg/kg/ hr) should be used in cats with the dose titrated by covering part of the patch with non-permeable tape (i.e. to 2

4 Scientific proceedings: companion animals programme deliver 12 μg/kg/hr half the patch area should be covered) the patches should not be cut. Amantidine This is an NMDA antagonist and has been used for veterinary patients suffering from allodynia and opioid tolerance and allows the dose opioids to be decreased in these patients. A suggested dose is 3-5mg/kg PO once daily (available as 100mg capsules and 10mg/ml liquid). Local anaesthetics A local anaesthetic patch is available in humans and may prove to be useful in cats. Gabapentin This is indicated for neuropathic pain in humans. A suggested starting dose in dogs and cats is mg/ kg PO escalating up to 50mg/kg (100mg, 300mg and 400mg tablets available) but this is based on anecdotal evidence and there is no published information as yet. Tricyclic antidepressants Amitriptyline, clomipramine and imipramine can provide analgesia for chronic pain conditions in humans. Amitiptyline at mg/kg (10mg and 25mg tablets) orally once daily has been used to treat feline intersititial cystitis with few side effects. 4 References 1. Robertson S. Managing pain in feline patients. The Veterinary clinics of North America Small animal practice. 2005;35(1): Robertson SA. Assessment and management of acute pain in cats. Journal of Veterinary Emergency and Critical Care. 2005;15(4): Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in chronic non-cancer pain:: An epidemiological study. Pain. 2006;125(1-2): Chew D, Buffington C, Kendall M. Amitryptyline treatment for severe recurrent idiopathic cystitis in cats.. J Am Vet Med Assoc. 1998;213: USE OF BUPRENORPHINE IN SMALL ANIMAL PRACTICE A variety of types of drug are analgesic, these include opioids, NSAIDs, local anaesthetics, alpha 2 agonists, ketamine and nitrous oxide. Unfortunately there is no magic bullet analgesic as pain is a complex process and multiple different pathways involving multiple different receptors are involved in pain initiation, signalling and perception. Opioids exert their analgesic effect primarily through activation of the endogenous mu opiod receptor and are usually used to relieve moderate to severe pain particularly of visceral origin. Buprenorphine is a high affinity agonist which has dissociates slowly from the mu opioid receptors giving a long duration of action. As with most drugs the effectiveness and duration of action depends on the dose administered but in dogs and cats at doses of 20 mcg/kg the effect normally lasts from 6-8 hours; rabbits, rats, guinea pigs, gerbils, ferrets 50 mcg/kg 8-12 hours; mice mcg/kg 8-12 hours. Although laboratory studies in rodent models have demonstrated bell shaped dose response or ceiling effects at very high doses for a number of attributes of buprenorphine (antinociception, respiratory depression) these have not been reported in small animal veterinary species at or above the normal analgesia doses. General Side Effects of Opioids The general side effects of opioids are sedation (at clinical doses), excitement (at very high doses), respiratory depression, vagal mediated CVS effects (bradycardia and vasodilation), GI effects (vomiting, constipation), diuresis (net effect) and possible urinary retention. However, it is often stated that there are no absolute contraindications to the use of opioid (unlike other drugs like NSAIDs) and that cautious use is often possible in all cases requiring analgesia. Buprenorphine at clinical doses appears to give little if any cause for concern and effects on the CVS and respiratory system are generally limited and of little clinical relevance. 1, 2 Buprenorphine is not associated with hyperthermia after administration in cats. Metabolism of Bupremorphine Buprenorphine is metabolised in the liver so impaired liver function may prolong the effect. There is high first pass metabolism so oral administration is less effective however it is well absorbed transmucosally and this is a useful route of administration in cats and dogs. 3, 4 In the rabbit urinary excretion predominates but in other small animals the faeces is the major route of excretion. There can be variable response to opioids so it is important to check that sufficient analgesia has been obtained after administration and further doses may be administered if analgesia is insufficient Analgesia Analgesia is required in ALL companion animals, not just dogs and cats as all mammals suffer pain and re- CHAPTER 2 PAIN MANAGEMENT 3

5 quire analgesia. Most analgesic agents have extensive safety and tolerance data in rabbits and rodents and, although nothing is licensed, suggested analgesic dosages are widely available. In order to safely and accurately dose analgesics in the smaller mammals commercially available drugs need to be diluted e.g. 500g rat administered buprenorphine at 50 mcg/kg = 25mcg = 0.083ml of 0.3mg/ml buprenorphine Buprenorphine is an effective analgesic for most kinds of acute traumatic and surgical pain. It has no effect on biliary smooth muscle so may be the best choice for cats with pancreatitis (as they have a common pancreatic and bile duct). In man opioids are reported to be less effective for sharp pain (as with an unsupported fracture), dental pain and in chronic non cancer pain. In cases where even high doses of buprenorphine do not provide sufficient analgesia multimodal analgesia is required. Pre-emptive Analgesia Pre-emptive Analgesia describes administration of an analgesic agent BEFORE a painful stimulus is applied and as such is generally only useful for surgical analgesia. It prevents the up-regulation of the nervous system (wind-up and central sensitisation) and so can be a more effective way to provide analgesia than waiting until pain is already established. Buprenorphine is an ideal candidate for pre-emptive analgesia and it often administered as part of the anaesthetic premedication regimen where it also has the advantage of potentiating the sedative effects of sedative drugs like acepromazine and medetomidine and being anaesthetic sparing. Multimodal Analgesia Multimodal Analgesia describes administration of two or more analgesic agents each of which acts via different receptors. This may allow decreases in dose of both/ all agents and will maximise overall analgesia and minimise side-effects. Opioids like buprenorphine are often used in this way in combination with NSAIDs and/ or Alpha-2 agonists and Ketamine. It is important not to use two agents which both act at the same receptor such as buprenorphine and another opiod such as morphine as overdosage of opioid will occur. Analgesia examples for general practice Example 1: Perioperative multimodal analgesia (IV/ volatile agent) 1. Premedication with buprenorphine plus sedative (ACP/ midazolam/ dexmedetomidine) plus NSAID (carprofen/ meloxicam) 2. Induction with IV agent (propofol) 3. Maintain with volatile agent in oxygen/ nitrous oxide 4. Local anaesthetic technique (e.g. infiltration/ splash block with lidocaine) 5. Short acting opioid bolus if required or infusion if able to ventilate 6. Assess analgesia in recovery with anything other than minor surgery expect to re-dose with buprenorphine at least once in first 24 hours Example 2: Perioperative multimodal analgesia (IM anaesthesia) 1. Induction of anaesthesia with triple combination of buprenorphine medetomidine and ketamine 2. Intubate and if necessary maintain with volatile agent in oxygen/ nitrous oxide 3. Local anaesthetic technique (e.g. infiltration/ splash block with lidocaine) 4. Administer NSAID (carprofen/ meloxicam) at end of procedure 5. Reverse medetomidine with atipamazole (NB this reverses medetomidine analgesia) 6. Assess analgesia in recovery with anything other than minor surgery expect to re-dose with buprenorphine at least once in first 24 hours Useful resources for pain management generally: Pain management in Animals ISBN Handbook of Veterinary Pain Management ISBN References 1. Martinez E, Hartsfield S, Melendez L, Matthews N, Slater M. Cardiovascular effects of buprenorphine in anesthetized dogs. Am J Vet Res Nov;58(11): Stepien RL, Bonagura JD, Bedarski RM, Muir WW. Cardiorespiratory effects of acepromazine maleate and buprenorphine hydrochloride in clinincally normal dogs Am J Vet Res (1): Robertson SA, Lascelles BDX, Taylor PM, Sear JW. PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. Journal of Veterinary Pharmacology and Therapeutics. 2005;28(5): Abbo LA, Ko JCH, Maxwell LK, Galinsky RE, Moody DE, Johnson BM, et al. Pharmacokinetics of Buprenorphine Following Intravenous and Oral Transmucosal Administration in Dogs. Veterinary Therapeutics 2008 Summer 2008;9(2):. PAIN ASSESSMENT IN DOGS AND CATS Definition of Pain The International Association for the Study of Pain definition of Pain (available from their website) = An un- 4

6 Scientific proceedings: companion animals programme pleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Note: The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. Pain Assessment Pain assessment is important because unrelieved pain is a major stressor and as such affects: Welfare and quality of life Wound healing (poor post-op outcome) Appetite (generally a decrease)poor nutrition Mood (depression is a major consequence in humans) Relationship with owner (often diminished) Relationship with handlers (may become difficult for handlers to manage animal safely) Chronic pain Signs may be less obvious and chronic pain may have an insidious onset and may be interpreted as a sign of age related slowing down: Behavioural changes the she s not herself syndrome Abnormal posture Abnormal Gait Abnormal movement Vocalization Miscellaneous (allodynia/ hyperalgesia/ licking) Response to analgesics may sometimes be the most reliable indicator! Quantifying pain A variety of methods may be used such as: Numerical Rating Scale (NRS) e.g Where 0 = no pain and 10 = worst possible pain CHAPTER 2 PAIN MANAGEMENT In practice pain is best assessed using behavioural changes so it is important to know: What is normal behaviour? What behaviours are indicators of pain? What behaviours MAY be indicators of pain? (but may also be due to something else) If the animal is an inpatient it is important to do more than just look into the cage, you need to handle the animal and encourage it to move to properly assess any discomfort. If the animal is an outpatient good physical examination will pick up areas of discomfort. History taking will also be useful but owners may not necessarily appreciate that some changes (e.g. inappropriate toileting) may be due to pain. Clinical examination Give away signs of pain: Hunched Abdomen tucked in Praying posture Negative reaction on palpation/ manipulation Signs that may indicate pain: Salivation and vomiting Panting or shallow breathing Lying in an abnormal position Standing in an abnormal position Immobile Beware of over interpreting vocalisation(particularly when owner is not present) cats growling is a fairly good sign of fear or discomfort dogs growling - may depend on temperament dogs whining - often indicates need to U+/F+ Visual Analogue Scale (VAS) Similar to NRS but uses a continuous line. Simple Descriptive Scale (SDS) Descriptors are assigned to either a number or category Example 1 0 = No pain: Normal behaviour with response to pressing area 1 = Behaviour normal but some response when wound is pressed (e.g. head turning to look at you/ area pulled away) 2 = Behaviour seems normal but marked response to wound pressure - may be an aggressive response 3 = Some abnormal behaviours seen (e.g. reluctance to move, stretching) with some response to wound pressure 4 = Behavioural changes and marked response to wound pressure Example 2 no pain, mild pain, moderate pain, severe pain Composite pain scoring scales Dogs Glasgow pain scoring system free to use ( ourservices/painmanagementandacupuncture/) Help? Is this animal in pain? Review procedure undertaken/ condition present - would you expect it to be painful? How painful? Review your analgesia so far - don t forget individual variation, response to analgesic is a normal distribution so a proportion of animals will not respond to your analgesic (however good it/they are) Could a drug be causing the problem (e.g. overdose of opioid?) 5

7 Don t forget management (Fluids, food /water, bandages, bedding, U+/F+,nasty dog in next cage, TLC) If you think the animal is in pain GIVE ANALGESICS Sometimes response to analgesia may be the only way of identifying pain. Useful textbooks relating to pain and analgesia: Pain management in Animals ISBN Handbook of Veterinary Pain Management ISBN In Practice Articles 6