Relief of acute and chronic pain in animals is an important part of the practice of veterinary medicine. Human pain medications frequently are used in small-animal and equine practice. However, food-animal practitioners must follow the Animal Medicinal Drug Use Clarification Act (AMDUCA), which limits extra-label drug use to treatment when an animal's health is threatened, it is suffering or death might result from failure to treat.
Pain research in animals can be difficult to perform. Pain responses in animals vary greatly, and the severity of clinical signs does not always match the severity of a lesion. Techniques used in humans, such as pain-score verbalization, cannot be performed in animals. Concealing pain is a survival instinct for cattle, since they are a prey species, which further hampers research. For all of these reasons, development of a consistent pain model for cattle is difficult. And without a reliable pain model, it's hard to critically evaluate the efficacy of pain medications on these patients.
With this in mind, the scarcity of clinically relevant studies on pain responses and pain relief in cattle is not surprising. The good news is research is being conducted. Dr. Hans Coetzee and his colleagues at Kansas State University are one group trying to find answers to some of these questions.
Adaptive responses to pain make chronic pain more difficult to treat than acute pain. The longer the duration and/or the more intense the pain, the more difficult it is to treat, requiring higher and/or more frequent doses of analgesics.
Preventive pain management is preferred and can be performed for most elective and emergency surgical procedures. Local and general anesthetics, some tranquilizers and sedatives can alleviate much of the immediate pain associated with surgical procedures, but the effects are short-lived and do not address the longer-term post-operative pain associated with inflammation following surgery. Proper use of non-steroidal anti-inflammatory drugs (NSAIDs) can greatly reduce longer-term post-operative pain.
Although preventive pain management in cattle is preferred, more often practitioners are faced with making decisions about managing patient pain following an injury or presentation of disease. The drug classes used systemically for treating pain are opioids, alpha-2 adrenergic agonists and NSAIDs. Since the mechanism of analgesia is different for drug classes, combinations should be considered for systemic drugs or systemic and local analgesia.
Opioids used commonly in veterinary practice are buprenorphine, butorphanol, fentanyl, meperidine, methadone, morphine and oxymorphone. These drugs have a short duration of action and disappointing analgesic properties in ruminants compared to other species, so they are not widely used systemically in food animals. They frequently are used for local anesthesia. Opioids are controlled substances and are not approved for use in food-producing animals, so the tenets of AMDUCA have to be met before they are selected. Opioids can inhibit rumenoreticular contractions, and some cause abnormal behaviors such as propulsive walking and hypersensitivity/hyperexcitability, which can be dangerous for animals and personnel.
Butorphanol is the most widely used opioid in food animals. The recommended dose is 0.05 mg/kg subcutaneously every four hours to six hours. Butorphanol might be indicated for short-term analgesia for acute, severe post-operative pain. Suggested meat and milk withdrawals are four days and 72 hours, respectively. There are anecdotal reports of increased appetite following butorphanol administration.
Transdermal fentanyl is used in other animal species, but absorption and analgesic efficacy in cattle is unknown. Rumenosalivary recycling of this drug might prolong the effects but can pose problems with establishment of withdrawal times. Constant-rate infusion techniques of analgesic cocktails have been used in food animals and might benefit animals with severe, acute pain.
Alpha-2 adrenergic agonists
For food animals, the drug most commonly used in this class is xylazine. It has analgesic and sedative effects. The analgesic effects are short lived (less than one hour), but the sedative effects can last greater than 24 hours, which makes them poor choices for long-term pain management. Xylazine might be indicated alone or in combination with butorphanol for post-operative pain, especially if sedation is a desired outcome.
NSAIDs are used for analgesic, antipyretic and anti-inflammatory properties. They produce most of their therapeutic effects through inhibition of prostaglandin synthesis. There is some evidence that they produce analgesic effects by central mechanisms other than inhibition of prostaglandin synthesis. In most instances, they have good oral bioavailability, making the oral route of administration a feasible alternative. There are significant differences in clearance between animal species and age groups. They have therapeutic indexes that are relatively close to their toxic indexes. For these reasons, extrapolation of drug dosage regimens between species can be dangerous.
Of the NSAIDs commonly used in large-animal practice, only two are approved for use in food animals. These are flunixin meglumine and aspirin. Flunixin meglumine has gone through the Food and Drug Administration's (FDA) approval process for use in food-producing animals. Aspirin is "generally regarded as safe and efficacious" (GRAS and GRAE) by the FDA and was grandfathered in as an approved compound for food animals. Other veterinary products used in an extra-label manner in food animals are phenylbutazone and ketoprofen. Dipyrone use in food animals is prohibited.
Aspirin is considered effective for fever and for minor joint/muscle pain. Higher doses are required on a per kg basis in ruminants compared to other species due to a high clearance and a low volume of distribution. The current labels have no withdrawal times listed, but the Food Animal Residue Avoidance Databank (FARAD) previously recommended a 24-hour slaughter and milk withdrawal.
Flunixin meglumine is approved for pain in horses, but not cattle. It is approved for use in beef and lactating dairy cattle for fever and inflammation associated with respiratory disease and endotoxemia. The approved dose is 1.1 mg/kg (BID) -2.2 (SID) mg/kg IV for up to three days. The label slaughter and milk withdrawal times are four days and 36 hours, respectively. This dose has not been evaluated for its pain-relief effectiveness.
Phenylbutazone is not approved for use in food-producing animals and is prohibited for use in dairy cattle older than 20 months. Since flunixin meglumine is approved for use in food animals, even though not necessarily for pain, and aspirin is GRAS and GRAE, these should be considered first. However, many practitioners consider phenylbutazone a superior analgesic for chronic osteoarthritis. Phenylbutazone has a long half-life in cattle (about 30-80 hours) compared to other large-animal species including goats and sheep (half-life of about 15-20 hours). Due to the long half-life, a loading dose is required to reach therapeutic levels more quickly. The recommended dose in cattle based on pharmacokinetic and clinical trials in lame bulls is 17-25 mg/kg loading dose, followed by 4-6 mg/kg once a day, or 10-14 mg/kg every other day. My clinical experience is that the once-daily dosage regimen is more effective for pain control than every other day. The long half-life dictates the use of extended withdrawal times. Past recommendations for slaughter withdrawal were of a minimum 45 days for the first dose, with another five days added for each day of therapy beyond the first. A one-month course of phenylbutazone at this withdrawal would be more than six months. Since phenylbutazone poses serious human-health risks, and a very long withdrawal period, make this a drug to use with extreme caution. If used at all, phenylbutazone should be reserved for valuable beef breeding stock with chronic osteoarthritis where slaughter is not an option (for example, temporary relief of pain for embryo or semen collection followed by euthanasia and carcass disposal).
Ketoprofen is not approved for use in food animals and offers no benefits over flunixin meglumine. It should be avoided in food animals.
Gastrointestinal (GI) ulceration is the most commonly described side effect of NSAID therapy, but it is rare in animals that are eating. The first sign of GI trouble is anorexia followed by mild diarrhea, which should subside when the NSAID is discontinued. Renal toxicity has been described following NSAID administration. Most often, this only occurs in severely hypovolemic animals or in those receiving other potentially nephrotoxic drugs concurrently. As long as animals are rehydrated before or immediately after administration, nephrotoxicity should not be a concern.
Other considerations for pain management
Analgesic therapy is a critical part of pain management, especially if the animal is in enough pain to prevent it from eating. However, when pain is managed in animals with severe musculoskeletal injuries, excessive movement should be controlled with proper confinement.
Veterinarians can help producers control animal pain in other ways too. Obviously you should treat the conditions causing pain, but teach your producers to spot painful symptoms or conditions early. Assess cow comfort and the patient's ease of access to clean water and palatable feed. In addition, level surfaces with good footing and soft bedding should be provided.
Dr. Navarre works as an extension veterinarian with Louisiana State University's Department of Veterinary Science.