Beyond bute and banamine-equine analgesic update (Proceedings)

Nonsteroidal anti inflammatory drugs, particularly phenylbutazone and flunixin meglumine, have been the primary analgesics used in equine medicine for decades. There is much to recommend these agents; they are inexpensive, convenient to give, and generally efficacious. There are two primary reasons why a practitioner might look elsewhere for effective pain relief. First, the NSAIDs produce a finite degree of pain control. Giving twice the recommended dose does not produce twice the analgesia. Secondly, the therapeutic window for NSAID is fairly narrow, and there are a number of severe (at times fatal) side effects that are caused by overdosing.

Most of these are GI tract problems including oral and gastric ulceration, right dorsal colitis, and cecal rupture. Renal failure is a concern in dehydrated horses receiving higher doses of NSAIDs. Giving more than one NSAID at the same time, sometimes referred to as “stacking”, gives the equivalent pain relief as giving a larger dose of any single NSAID, and does not prevent the development of complications. Very small ponies, miniature horses, and foals are prone to develop NSAID toxicity, probably because they are easy to overdose due to overestimation of their weight.

Many other classes and types of analgesics can be used in horses. All have specific advantages as well as drawbacks. The intent of this session to introduce practitioners to some of the options available for pain relief in horses.

Cox II inhibitors

Firocoxib (trade name Equioxx®), a NSAID specifically targeting the cyclooxygenase-2 (COX-2) enzyme, has been recently approved by the FDA for use in the horse. The COX-2 enzyme is induced with inflammation, thus COX2 inhibitors may be superior to conventional NSAIDs as they inhibit the mediators that occur with inflammation, but not inhibit normal actions of prostaglandin. This, in turn, would lead to fewer side effects. At the recommended dosage of 0.1 mg/kg every 24 hours, firocoxib provides a level of analgesia comparable to 2 mg/kg phenylbutazone.

Alpha-2 Agonists

Although this class of drugs are commonly thought of as sedatives, the alpha-2 agonists such as xylazine, detomidine, and clonidine are also potent analgesics. Along with their sedative and analgesic properties, they also cause marked bradycardia with heart arrhythmias, ataxia, decreased GI motility, and hypertension. When given IV they have short half lives and wear off relatively quickly.

The duration of action is prolonged when given IM.  Analgesia without many of the side effects can be achieved when they are given as spinal analgesia. Xylazine at a dose of 0.17 mg/kg given in a volume of 10 ml provides 1 to 2 hours analgesia of the perineal and rear limb regions when given as a spinal. Spinal administration of detomidine at a dose of 20-40 µk/kg in a volume of 5 to 10 ml provides up to 2 hours of analgesia.

Continuous rate infusion

Many drugs which are efficacious but have relatively short durations of action can be given for prolonged effect by administering them as continuous rate infusions. Administration of a CRI can seem daunting to a practitioner, but with some practice anyone who regularly gives IV fluids can become comfortable using this technique. Lidocaine is probably the most frequently used CRI agent. It has the advantage of being a non-controlled substance, inexpensive, readily available, and relatively safe. Intravenous lidocaine was originally used as a prokinetic in post-operative colic patients. It was theorized to block the sympathetic tone that prevented GI motility in some cases.

Lidocaine  also appears to provide a fair degree of pain control, as animals with other painful conditions such as myositis and laminitis also appear to benefit from its use. Other drugs that can be used either alone or in combination with others as CRI are opiate agents such as morphine and hydromorphone, as well as ketamine, xylazine or detomidine. Leaving opiates as a CRI in an open stable is problematic, but they afford a degree of analgesia that cannot be easily met other ways.

Giving drugs by CRI is easily accomplished if one has a fluid pump available where one can precisely set the ml given per minute. It is possible to give CRI infusions of drugs in larger volumes of fluids without a pump. Careful attention should be paid to the rate, and the amount of fluids that are given within an hour should be recorded. The rate of administration can then be increased or decreased as needed if the desired volume was not delivered over 60 minutes. The calculations needed to determine the volume of drug to be put into the fluid bags and rate of administration can be painful at first, but as only simple math is involved it gets much easier as one practices.

A quick short cut for administration of lidocaine IV is to first give 1.3 mg/kg as a bolus, then place 450 ml of 2% lidocaine into a 3-liter bag of fluids. This can then be given at a rate of 1 ml per kg per hour. In a typical 500 kg horse, this would be 500 ml per hour. Thus, the 3,000 ml bag would last 6 hours. Signs of toxicity include ataxia and other neurologic signs. If a horse exhibits these signs while on a lidocaine CRI, the infusion should be stopped immediately. It can be restarted at a slower rate once the signs of toxicity resolve.

Sample Calculation:

500 kg horse to receive lidocaine at 0.05 mg/kg/min over 12 hours in a 5L bag of saline.  Lidocaine comes as a 2% solution

0.05 mg/kg/min X 500 kg X 60 min/hr = 1500 mg/hr lidocaine

1500 mg/hr X 1ml/20mg lidocaine = 75 ml/hr

75 ml/hr X 12 hr = 900 ml Lidocaine total to be added to the 5 L bag

900 ml + 5000ml = 5900 total volume horse is to get over 12 hours

5900ml/12h  = 491 ml/hr X 1hr/60 min = 8 ml/min

Opiates

The class of drugs that provides the best level of analgesia is the opiate class. There are several problems inherent with these drugs use, however. They are relatively expensive compared to other classes of analgesic and, as scheduled drugs, require special handling such as being kept in a secure location and meticulous record keeping. Horses can react to the pure agonists such as morphine with excitation. Side effects from opiates include muzzle tremors, twitching, head pressing, and compulsive locomotion.

Using an alpha-2 agonist or acepromazine at the same time will prevent most of these from occurring. Side effects are relatively mild with the use of opiate agonist-antagonists such as butorphanol, although some degree of switching and head movement often persists. Butorphanol does not affect GI motility, which makes it an attractive analgesic in horses with colic or other intestinal disease. Morphine, on the other hand, causes increased segmentation and severely decreased GI motility. For this reason, its use in patients with GI disease is contraindicated. Morphine does provide excellent analgesia when given as spinal anesthesia at a dose of 0.05-0.2 mg/kg in a total volume of 10 to 20 ml.

Analgesia in the Laminitis Patient

For many practitioners, the horse with laminitis is the most difficult patient to manage. Because of the severity of lameness, powerful analgesics are often needed. Because of the chronicity of the pain, however, analgesia must be safe and allow for some degree of normal behaviors such as adequate eating and drinking over a 24-hour period. The pain a horse experiences from laminitis has several sources.

The actual damage to structures within the hoof capsule produces a great deal of pain. The instability and imbalance in the foot is also painful. Changes in the joint capsule, bone lysis, and the development of neuromas all contribute to a horse's discomfort during the acute stages of the disease. One cannot keep a horse asleep on its feet with CRI of ketamine or morphine for weeks and weeks, but during the acute phase of the disease, use of opiates, lidocaine, and ketamine may be of benefit.

Once the foot has stabilized, use of oral NSAID may be all that is needed to keep the horse comfortable. If labeled doses of NSAID are not sufficient, giving higher amounts is not likely to improve comfort. In these instances, use of other agents is sometimes attempted.  Both gabapentin and amitriptiline have been used. Their pharmacokinetics are poorly understood in horses, and both may lead to sedation or unwanted side effects. The use of fentanyl patches may provide relief, although the ability of fentanyl to penetrate equine skin is not well studied. Two large patches every 48 hours should reach effective blood levels in most horses

Analgesic Drugs in Equine Medicine Class Drug Dose Interval Notes NSAID           Phenylbutazone 4.4 mg/kg IV or PO SID or BID     Flunixin Meglumine 1.1 mg/kg IV or IM SID or BID     Ketoprofen 2.2 mg/kg IV SID or BID     Aspirin 100 mg/kg PO SID Not an effective analgesic   Meclofenamic acid 2.2 mg/kg PO SID or BID     Carprofen 0.7 mg/kg IV, 1.4 mg/kg PO SID     Meloxicam 0.6 mg/kg PO SID     Naproxen 10 mg/kg PO or IV SID     Firocoxi 0.1 mg/kg PO SID Cox2 Opiates           Butorphenol 0.01 mg/kg IV, 0.2 mg/kg/hr CRI As needed     Morphine 0.1 mg/kg IV or IM QID May need to add sedative   Fentanyl 5-10 µg/kg/hr IV or as patch       Hydromorphone 0.02 mg/kg/hr CRI   First dose as bolus   Pentazocine 2.2 mg/kg IV       Tramadol 2-5 mg/kg PO BID   Alpha-2 Agonists           Detomidine 0.02 mg/kg IV or IM As needed     Xylazine 0.5-1.1 mg/kg IV or IM As needed     Clonidine 0.025 mg/kg IV As needed   NMDA Receptor Antagonists           Ketamine 0.02 mg/kg/min IV CRI     Local Anesthetics           Lidocaine 2% 1.3 mg/kg loading dose, then 0.05 mg/kg/min IV CRI     Tricyclic antidepressant           Amitriptiline 25-75 mg PO SID Side effects common GABA analog           Gabapentin 2.5 -10 mg/kg PO BID