(Second in a two-part series on pain in cattle)
The cattle industry is increasingly being asked to address issues of animal welfare, of which pain management in livestock is an important component. Though there are no FDA-approved drugs for pain management in cattle, there are veterinary drugs available that can be administered (in an extra-label manner) either pre-emptively before painful stimuli, or during a pain process in cattle.
There are two categories of pain in cattle, surgical and disease pain. “With minor and major surgical procedures, this is where pre-emptive analgesia is extremely important and effective,” says Paul Walz, DVM, PhD, Auburn University. “Where it is difficult to control pain with the tools we have in a practical manner is the management-induced or naturally occurring pain such as obstetrics, lameness and abdominal pain.”
Pre-treatment in anticipation of a painful event provides more analgesia than treatment with the same drug and dosage after robust pain sensations develop, Walz says. “Unfortunately, pain associated with management and infectious diseases are much more difficult to treat and sometimes it is impossible to relieve pain associated with chronic disease processes such as lameness, peritonitis, pleuritis, chronic pneumonia, and chronic arthritis.”
Pharmacologic agents used in cattle
Five general classes of drugs exist to treat pain, and mainly four of them are used in ruminants. These include the opioids, ketamine, the non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics, and the alpha-2 adrenergics. The following are pharma-cologic agents that can be used in cattle for the relief of pain. See the chart on page 17 for dosage and withdrawal information.
Opioids may exist as pure agonists such as morphine, hydromorphone, and oxymorphone. Buprenorphine is considered a partial agonist. Butorphanol is used quite frequently and is considered an opioid agonist and antagonist because it has multiple opioid effects.
Morphine is a drug Walz has used in a veterinary hospital situation. Morphine is a heavily restricted drug, but it’s fairly inexpensive. Walz notes that in ruminants, morphine is not that great of a drug because it has poor analgesic properties and this is believed to be due to very few receptors in the central nervous system or ineffective disposition of morphine in the central nervous system. “An additional drawback of opioids is that they have a ceiling effect,” Walz explains. “There are a finite number of opioid receptors in the central nervous system, and once all receptors are occupied, very little benefit is achieved by giving more drug.” Use opoids to a dosage and do not use them in excess because negative effects may occur. Administer morphine parenterally; do not give it orally in ruminants. Treatment needs to be given every 4–6 hours to maintain therapeutic blood concentrations.
Side effects with morphine administration can include bradycardia, respiratory depression, hypotension, constipation, and retention of urine. High doses may cause excitement. An additional side effect is hyperthermia.
Morphine exerts the most benefit in the spinal cord, thus epidural administration puts morphine right in the area of the receptors. The duration of activity is 12 hours. Morphine is a very hydrophilic drug, so it takes a long time to diffuse into the spinal cord but once in, it stays there for longer durations. “I’ve used morphine epidurally in cows, and pain mitigation does not seem to occur in a small percentage of cases,” Walz says. Retention of urine and constipation are observed side effects even when administered epidurally.
Morphine has been shown to be beneficial in the relief of pain for the perineum (obstetrical cases), the posterior abdomen, intestinal disease, and for rear-limb disease. Morphine may be given in the sacrococcygeal epidural space. The morphine can be followed by saline in order to move the morphine forward to the lumbar area. Alternatively, the morphine can be administered in the lumbosacral epidural space as well. Of paramount importance is to deliver the morphine epidurally rather than intrathecally. Dosages for epidural morphine are higher than for intrathecal administration, and signs of toxicity may be observed if the dura mater is punctured.
Probably the most common opioid drug used is butorphanol. Walz has used it frequently for pain management; however, he says recently it has become quite expensive. Butorphanol has mixed properties so it’s an agonist and antagonist; therefore, it will not be as potent of an analgesic as other opioids.
Butorphanol has a relatively short duration of activity. “It’s a very effective drug at providing pain relief especially for those management cases where you have pain already existing and you want to provide some relief after the painful stimuli has already been there,” Walz says. Butorphanol may increase appetite. There are reports of it causing a kind of compulsive walking or tremoring. Like morphine usage, this drug also is restricted.
Ketamine is an effective analgesic and blocks N-methyl-D-aspartate (NMDA), whose receptors in the dorsal horn of the spinal cord are important in the transmission of painful impulses from the peripheral to the central nervous system. Ketamine is not a practical pain management drug because it needs to be given constantly and doesn’t have long-term pain relief effects. It needs to be given by a constant rate infusion, making it impractical for cattle.
“It would be nice if it had some residual and long-lasting activity because the actual compound is very important for central sensitization of pain and secondary hyperalgesia,” Walz explains. “When animals hurt all over, it is because of NMDA receptor activity. Activation of NMDA receptors by neuromodulators induces ‘wind-up’ of the CNS and subsequent prolonged and exaggerated central responses to pain. Ketamine may prevent this ‘windup’ phenomena that is secondary hyperalgesia.”
One advantage is that microdoses are used compared to the high doses used for anesthesia, but it must be given IV at a constant rate of infusion. This drug is also heavily restricted.
Non-steroidal anti-inflammatory drugs (NSAIDs) have the ability to work in a painful stimuli pre-emptively, and are antipyretic, analgesic, and anti-inflammatory. Most NSAIDs inhibit the enzyme cyclooxygenase (COX), and ketoprofin is an NSAID that has purported lipoxygenase activity in addition to cyclooxygenase inhibition. The cell membrane phospholipids are broken down during inflammation to arachidonic acid. Minimizing the prostaglandins and their effects is very important for pain management. Prostaglandin E2 is important with respect to pain and tissue trauma.
Thromboxane is important because of the effects on platelets. With damaged tissue comes platelet aggregation, and this in turn results in thrombosis. Ultimately this causes tissue devitalization, Walz says. Minimizing these effects can be quite beneficial. But, you have to get to these fairly early because once all this material is present in the damaged tissue, it’s difficult to modulate pain using non-steroidals.
Flunixin meglumine is the NSAID that is most frequently used since it is approved as an anti-inflammatory and antipyretic in the US. It may result in central analgesia or central inhibition of pain responses. Walz says research indicates there may be some effects similar to opioids, affecting some of the opioid receptors in the central nervous system. “Flunixin meglumine needs to be given IV,” Walz explains.
Walz has not used aspirin as much for the control of pain. It purportedly has some analgesic properties like the other non-steroidals. “I don’t have a lot of experience or real opinion whether it is really effective for managing pain in cattle,” Walz says. Although aspirin is not approved for use in food animals by the FDA, aspirin may be used orally at a dose of 100 mg/kg of body weight.
Phenylbutazone has been used for musculoskeletal conditions, but probably isn’t used as much because of concerns with withdrawals. Walz uses it occasionally, but provides lengthy withdrawals, usually six-months depending upon the amount and duration given. “For the initial single treatment, we usually have a withdrawal of 45 days followed by an additional 5 days for every subsequent dose given. Since phenylbutazone treatment is often repeated, withdrawal periods can become quite lengthy.” The main problem with the withdrawal is that it’s extensively protein-bound and has a very long half-life. Remember that phenylbutazone is illegal to use in dairy cattle 20-months of age and older.
a2 adrenergic drugs (agonists)
Xylazine is the most common of the a2 adrenergic agonists and provides muscle relaxation and analgesia. It is a very potent sedative and causes profound central depression in cattle. However, the analgesia is much shorter-lived than the actual sedation, so animals can be heavily sedated but don’t have analgesia associated with xylazine.
Xylazine receptors are present in the dorsal horn of the spinal cord and this region is important in sensitization of pain. Xylazine is synergistic with opioids because it acts at a different area than the opioids do, so they can be used in combination.
Epidural xylazine is an effective mechanism for providing analgesia locally and in less concentration. There seems to be variability with the effect of xylazine epidurals. “Some animals will have good analgesia within 5–10 minutes, some will take longer,” Walz says. “The other thing that happens is the sedation effects are quite variable, as some animals may become sedate and recumbent while others do not, so you have to be extremely aware of that when you are using xylazine epidurals in cattle while restrained in a chute.” Other negative effects that have been described include paralysis following epidural usage due to demyelination of the spinal cord.
Walz uses local anesthetics frequently because they are easily administered, not restricted for use, inexpensive, and have limited toxicity in cattle. Walz says signs of toxicity are not usually observed in cattle unless the dose exceeds 10 mg/kg of body weight, so for a 1,000-lb. animal, up to 250 ml of lidocaine may be used without demonstrating toxicity.
Lidocaine is relatively short-lived with one- to two-hour duration of activity.
Epinephrine may be incorporated in the lidocaine block to prolong the duration of analgesia. Lidocaine blocks action potentials along the nerve roots, and it has no preference for sensory or motor neurons. The motor neurons that control fine movement of the muscles are blocked preferentially to the sensory nerves.
Local anesthetics available for use are lidocaine, mepivicaine and bupivicaine. Most are acidic and even more acidic if epinephrine is added.
Xylocaine is available as a lidocaine/ epinephrine combination. It is extremely acidic, and causes pain upon injection. Walz says lidocaine may be buffered 10:1 with 8.4% bicarbonate which will elevate the pH of the lidocaine so there is less “burning” underneath the skin. It doesn’t appear to alter the effect on analgesia even if buffered to a pH level of 7.4. “Once lidocaine is buffered, it needs to be used quickly, within several hours,” Walz cautions. Lidocaine remains stable in an acidic solution. Once lidocaine is injected in the tissues, the alkaline environment of the tissues makes it effective.
Local anesthetic blocks or intravenous regional blocks are extremely easy to perform on distal extremities, Walz notes and can be performed by using several different veins. “I like to use the dorsal pedal vein which is also referred to as the dorsal metatarsal or dorsal metacarpal veins,” Walz says. Place a tourniquet on the limb, and the vein can be found distal to the tourniquet. At the level of the fetlock at a 30-degree angle, a 19-gauge butterfly needle is used to catheterize the vein. “Once you get flashback, inject the lidocaine and 3–4 minutes later there is analgesia to the foot. With this form of analgesia, digits may be amputated.”
Walz also uses this for diagnostic purposes in examinations. If you anticipate considerable debridement and hoof wall resection with a severe toe abscess, perform the block right away, he suggests. It probably doesn’t provide long-term analgesia, but it provides enough short-term analgesia to perform procedures easily and effectively.
There are also abaxial vessels called palmar or plantar abaxial veins located approximately a finger-width from the edge of the dewclaw. “Usually you have to go deeper in that area but this is another vein that works very well for providing analgesia,” Walz says.
Local anesthetics can also be given parenterally. “Lidocaine given intravenously has analgesic properties especially when we’re dealing with the central sensitization of pain.” Central sensitization is where an animal essentially hurts all over. Providing them intravenous lidocaine or local anesthetics can be pretty beneficial, however, the problem is they are not practical because you have to give them by a constant-rate infusion.
Effective pain relief may be achieved by using combinations of agents. “In our individual patients, we often use butorphanol combined with an NSAID, or opioids combined with local anesthetics,” Walz explains. “Using different drugs that act upon different receptors and different mechanisms of action allows one to use smaller doses, safer doses, with less sedation.”
There is a term called neurolept analgesia. The classic example is Demerol, which makes people indifferent to pain or problems, combined with an opioid. For cattle use, Walz uses xylazine and/or opioids combined with local anesthetics, which work very well for relief of pain. “Using multiple different modes of analgesia combined together, you can do a lot of different surgical procedures for controlling pain,” Walz says.