Vet Times The website for the veterinary profession https://www.vettimes.co.uk Pain management: advances and possible complications Author : Celia Marr Categories : Equine, Vets Date : August 22, 2016 ABSTRACT Equine vets use analgesic drugs most commonly for managing horses with abdominal and musculoskeletal pain. In sick horses, pathophysiological processes relating to the primary condition may complicate drug side effects. When used at low and moderate doses, side effects from longterm NSAID therapy are relatively rare in horses with chronic musculoskeletal conditions, but higher doses increase the risk. A multimodal approach is indicated in horses with severe musculoskeletal pain. It is important not to focus exclusively on drugs and consider if therapy aimed at stabilising the underlying musculoskeletal condition, or weight bearing reduction strategies, may help. Pain management in horses can be challenging. In colic, at the initial evaluation, analgesics with mild or moderate efficacy are usually selected, as the response to analgesia is an important diagnostic tool. In sick horses, hypovolaemia and systemic inflammatory response syndrome (SIRS) complicate management. Gastrointestinal and renal side effects of NSAIDs must be considered and drugs such as lidocaine are often added to the therapeutic plan. NSAIDs in low and moderate doses are used effectively with chronic, low-grade musculoskeletal pain. If musculoskeletal pain is severe, avoiding supporting limb laminitis is critical and multimodal analgesia, combined with physical strategies to reduce weight bearing, becomes important. Many clinical conditions lead to pain, but, in horses, perhaps the most commonly encountered are gastrointestinal problems and lameness. With gastrointestinal problems in particular, it can be difficult to determine whether complications relate directly to the antinociceptive and analgesics 1 / 11
given, or whether they are due to the primary underlying disease process at play. Often, both may be contributing. Complications in managing abdominal pain Figure 1a. Fluid pumps, as well as syringe drivers, are the most precise way to ensure continuous administration of appropriate doses of drugs such as lidocaine, which can cause significant neurological side effects if doses are too high. The focus of initially assessing horses with acute colic is to decide whether the case requires further investigation and, potentially, surgery. Estimates of the prevalence of surgical colic vary, but a large-scale study in the UK suggested about a quarter of cases that fail to respond to simple medical treatment are likely to require hospitalisation for more intensive therapy and/or surgery (Curtis et al, 2015a). The initial physical examination, particularly the evaluation of cardiovascular status (including heart 2 / 11
rate, appearance of the mucous membranes, capillary refill time and assessment of skin turgor) and assessment of gastrointestinal sounds, is ideally performed before administering any drugs because analgesics can rapidly change these parameters. Response to analgesia is the most frequently used diagnostic test in the primary evaluation of colic, more commonly used than rectal examination and nasogastric intubation (Curtis et al, 2015b). It is often helpful to give drugs with both sedative and analgesic actions to facilitate transrectal palpation and passage of a nasogastric tube to detect gastric reflux. As a general rule, it is helpful to match the analgesic potency to the degree of pain the horse is showing. In fact, it can be useful, diagnostically, to find out if a milder drug is sufficient to resolve the problem. Very potent drugs are usually avoided for fear of masking declining clinical status in a horse that would be best served by surgical exploration, rather than controlled with analgesics to the point surgery is delayed with a negative impact on outcome. For this reason, most referral hospital clinicians prefer cases are not given full (for example, 1.1mg/kg IV) doses of flunixin before admission. More appropriate options for first-line treatment of colic include hyoscine butylbromide with metamizole, phenylbutazone or lower doses of flunixin. The impact of the analgesic on gastrointestinal motility must be considered. Hyoscine and alpha 2 adrenergic agonists will all, to some extent, reduce gastrointestinal motility. This can help in some cases and, provided repeated doses are not given, is not generally a major complication. However, this side effect should be considered where reduced gastrointestinal motility might be counterproductive; for example, in horses with pelvic flexure impaction or sand enteritis. In critically ill horses with gastrointestinal disease, the presence of hypovolaemia and SIRS requires more care in the selection of analgesic and monitoring for complications. NSAIDs can lead to renal tubular damage of varying extents, intestinal mucosal damage and/or impede mucosal recovery following ischaemia. 3 / 11
Figure 1b. Syringe drivers are another precise method of ensuring continuous administration of appropriate doses of drugs such as lidocaine, which can cause significant neurological side effects if doses are too high. Selective cyclooxygenase-2 (COX-2) inhibitors should, in theory, have less impact on mucosal recovery, but the evidence to support that assertion is conflicting (Salem et al, 2016). Firocoxib, a COX-2 inhibitor, did not retard mucosal recovery in ischaemia-injured intestine, whereas flunixin did (Cook et al, 2009). One study suggested concurrent administration of systemic lidocaine reduced the negative effects of flunixin on the mucosal barrier (Cook et al, 2008). Flunixin is more effective at reducing pain scores (Naylor et al, 2014) and remains the most frequently used NSAID following colic surgery by US and European diplomates (Lefebvre et al, 2015; 2016). Critically ill horses are also at risk of renal injury. Both phenylbutazone and meloxicam attenuated diuresis and natriuresis, and reduced glomerular filtration rate, compared to results for the control solution, when horses were treated with furosemide as a model for volume depletion (Raidal et al, 2014). In addition to the pathophysiological mechanisms at play, such as hypovolaemia, the clinical 4 / 11
situation is often complicated by concurrent use of other drugs that may affect the kidneys, such as aminoglycosides. These are not reasons to not use NSAIDs in the postoperative colic patient, but they do justify careful monitoring of serum creatinine and urine. Lidocaine (along with flunixin) is commonly used to treat postoperative ileus by US and European diplomates (Lefebvre et al, 2015; 2016). This drug has potential analgesic effects by preventing propagation of action potentials, thereby interfering with neural pathways that mediate pain. It may also have prokinetic and anti-inflammatory properties (Sanchez and Robertson, 2014). Clinical signs of toxicity in conscious horses include skeletal muscle tremors, altered visual function, anxiety, ataxia and collapse. Seizures are also possible. The therapeutic index for this drug is narrow and it must be given by a carefully controlled infusion, ideally using a fluid pump, syringe driver or drip counter (Figures 1 and 2). Early side effects can be difficult to discern in a patient already depressed due to its primary condition. Complications in managing chronic musculoskeletal pain Extremely potent drugs are not commonly required for chronic musculoskeletal pain, but long-term administration can increase the risk of complications. NSAIDs are the main class of drugs used. COX-2 selective drugs are appealing, but, in theory, many horses appear to tolerate long-term administration of NSAIDs at low to moderate doses and the additional costs of the COX-2 given long term may be difficult to justify. With long-term use, the most important side effects relate to the gastrointestinal tract, and NSAIDs have been implicated in the pathogenesis of right dorsal colitis and glandular gastric ulcer disease (Sykes et al, 2015). Flunixin, phenylbutazone and ketoprofen at doses 50 per cent higher than typically recommended induced gastric ulceration (MacAllister et al, 1993). Given for 15 days at clinical doses, phenylbutazone and suxibuzone did not induce gastric ulcers (Andrews et al, 2009). Early studies comparing suxibuzone with phenylbutazone suggested suxibuzone might be less ulcerogenic (Monreal et al, 2004), a surprising observation given suxibuzone is a prodrug rapidly converted to phenylbutazone by a first-pass mechanism in the liver (Delbeke et al, 1993). Subsequent studies have not confirmed this observation (Andrews et al, 2009) and it is likely little difference exists between the two drugs in respect to gastrointestinal side effects. Phenylbutazone has been linked to pancytopenia and bone marrow suppression (Lavoie et al, 1987), and ulcerative cystitis (Aleman et al, 2011). The dosage may influence the likelihood of complications; phenylbutazone at 8.8mg/kg orally once a day for 21 days induced hypoalbuminaemia, neutropenia and changes in the blood flow to the right dorsal colon (McConnico et al, 2008), highlighting the importance of monitoring serum albumin 5 / 11
concentrations and neutrophil counts in horses requiring analgesic administration at this level. The effects of NSAIDs on the gut are mediated by prostaglandin; therefore, administration of the prostaglandin analogue misoprostol, together with removal of the NSAID, can lead to resolution of the problem. Unfortunately, in some cases, removing the NSAID leaves the vet unable to control the pain relating to the primary condition. Tramadol is not specifically licensed for use in the horse, but it shows some clinical potential, particularly where an oral preparation is required for multimodal analgesia or where side effects are limiting the use of NSAIDs. A fairly high dose is required in horses, but a study has shown tramadol given orally at 10mg/kg twice a day reduced signs of forelimb discomfort, whereas 5mg/kg did not (Guedes et al, 2016). Gabapentin may have some benefit for treatment in neuropathic pain, which may be involved in chronic laminitis (Davis et al, 2007). Gabapentin has poor bioavailability (Terry et al, 2010) and the optimal dose remains to be defined. Re-evaluating whether any potential solutions to reduce pain exist by changing the horse s farriery is also prudent. 6 / 11
Figure 2. Drip counters are an inexpensive alternative to fluid pumps and syringe drivers. They have to be monitored carefully to ensure the right dose is given. 7 / 11
Figure 3. Epidural catheters are useful for administering morphine in severe hindlimb lameness and can be maintained for many days. 8 / 11
Figure 4. With severe musculoskeletal pain, clinicians should look beyond drugs to help manage pain. Slings may help reduce weight bearing, relevant in preventing and managing supporting limb laminitis. This system takes a variable proportion of the horse s bodyweight and is mounted on a gantry, which allows the horse to move around the stable. It is also designed so the horse can lie down and get up voluntarily, so is ideal for long-term use. Complications in managing severe musculoskeletal pain Supporting limb laminitis represents an important challenge when dealing with horses with severe musculoskeletal injuries. Although uncommon in general, the prevalence of supporting limb laminitis was as high as 12 per cent in horses treated with half limb, full limb or transfixation pin cases (Virgin et al, 2011). Increased bodyweight was a risk factor in the study, but the presence of fracture, whether the primary problem was forelimb or hindlimb and breed of horse were not. The duration of lameness, but not bodyweight, was shown to be a risk factor in another case control study (Peloso et al, 1996). Improved methods of surgically stabilising fractures and management of other forms of non-weight bearing laminitis have lead to a reduction in prevalence of supporting limb laminitis (Orsini, 2014). Prevention is the key to overcoming supporting limb laminitis and analgesia has a critical role. A multimodal approach is indicated. In addition to NSAIDs, use of combinations of drugs, such as ketamine, lidocaine and the more potent opiate morphine, is often appropriate frequently in combination with sedatives and tranquillisers. 9 / 11
Epidural administration of analgesics, such as morphine, can be effective with severe hindlimb lameness and catheters can be placed in the epidural space to facilitate long-term dosing (Figure 3). However, strategies to minimise pain and reduce load bearing should look beyond drugs and include encouraging the horse to lie down by providing deep bedding, and the use of support shoes and, in some cases, slings to bear some of the horse s weight (Figure 4). References Some drugs mentioned are used under the cascade. Aleman M, Nieto JE and Higgins JK (2011). Ulcerative cystitis associated with phenylbutazone administration in two horses, J Am Vet Med Assoc 239(4): 499-503. Andrews FM, Reinemeyer CR and Longhofer SL (2009). Effects of top-dress formulations of suxibuzone and phenylbutazone on development of gastric ulcers in horses, Vet Ther 10(3): 113-120. Cook VL, Jones Shults J, McDowell M, Campbell NB, Davis JL and Blikslager AT (2008). Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine, Equine Vet J 40(4): 353-357. Cook VL, Meyer CT, Campbell NB and Blikslager AT (2009). Effect of firocoxib or flunixin meglumine on recovery of ischaemic-injured equine jejunum, Am J Vet Res 70(8): 992-1,000. Curtis L, Burford JH, Thomas JSM, Curran ML, Bayes TC, England GCW and Freeman SL (2015a). Prospective study of the primary evaluation of 1,016 horses with clinical signs of abdominal pain by veterinary practitioners, and the differentiation of critical and non-critical cases, Acta Vet Scand 57: 69. Curtis L, Trewin I, England GCW, Burford JH and Freeman SL (2015b). Veterinary practitioners selection of diagnostic tests for the primary evaluation of colic in the horse, Vet Rec Open 2(2): e000145. Davis JL, Posner LP and Elce Y (2007). Gabapentin for the treatment of neuropathic pain in a pregnant horse, J Am Vet Med Assoc 231(5): 755-758. Delbeke FT, Vynckier L and Debackere M (1993). The disposition of suxibuzone in the horse, J Vet Pharmacol Ther 16(3): 283-290. Guedes A, Knych H and Hood D (2016). Plasma concentrations, analgesic and physiological assessments in horses with chronic laminitis treated with two doses of oral tramadol, Equine Vet J 48(4): 528-531. Lavoie JP, Morris DD, Zinkl JG, Lloyd K and Divers TJ (1987). Pancytopenia caused by bone marrow aplasia in a horse, J Am Vet Med Assoc 191(11): 1,462-1,464. Lefebvre D, Hudson NPH, Elce YA, Blikslager A, Divers TJ, Handel IG, Tremaine WH and Pirie RS (2015). Clinical features and management of equine post operative ileus (POI): survey of diplomates of the American Colleges of Veterinary Internal Medicine (ACVIM), Veterinary Surgeons (ACVS) and Veterinary Emergency and Critical Care (ACVECC), Equine Vet J, Epub ahead of print: 10.1111/evj.12520. 10 / 11
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