Opioids as Analgesics in Animals
Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic activity. Despite some well-known adverse effects and disadvantages, opioids are the most effective analgesics available for the systemic treatment of acute pain in many species.
Opioid receptors are part of a large superfamily of membrane-bound receptors that are coupled to G proteins. Each opioid receptor has a unique distribution in the brain, spinal cord, and periphery. Opioids combine reversibly with these receptors and alter the transmission and perception of pain. In addition to analgesia, opioids can induce other CNS effects that include sedation, euphoria, dysphoria, and excitement.
The clinical effects of opioids vary between the mu opioid receptor agonists (eg, morphine, hydromorphone, fentanyl), partial mu agonists (ie, buprenorphine), and agonist-antagonists (eg, butorphanol). Species and individual differences in the response to opioids are marked, necessitating the careful selection of opioid and adjustment of dose for different species. The clinical effect of an opioid depends on additional patient factors, including the presence or absence of pain, health status of the animal, concurrent drugs administered (eg, tranquilizers), and individual sensitivity to opioids.
Recent information regarding the peripheral endogenous opioid system (PEOS) has presented a unique opportunity to use the powerful analgesic effect of opiates while minimizing unwanted systemic effects. The PEOS includes peripheral opioid receptors (PORs) and peripheral leukocyte-derived opioids (PLDOs): endomorphins, endorphins, enkephalins, and dynorphins. To activate the PEOS, tissue must have sufficient numbers of leukocytes able to secrete PLDO as well as functional POR in sufficient numbers.(1 References Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic... read more )
Inflammation due to tissue damage results in accumulation of PLDO-secreting leukocytes at the site of injury. Inflammation also increases the number and efficiency of PORs. These receptors, inactive under normal conditions and expressed on primary sensory neurons, are synthesized in the dorsal root ganglion and transported distally to peripheral sensory nerve endings due to tissue injury and inflammation. Experimental trials and clinical studies show that peripheral opiates are effective, particularly in the presence of inflammation. For example, preservative-free morphine can be instilled into canine and equine joints after arthroscopy or arthrotomy to provide analgesia via local receptors.
Machelska H, Celik MO. Advances in Achieving Opioid Analgesia Without Side Effects. Front Pharmacol. 2018;9.
Nonsteroidal Anti-inflammatory Drugs and Corticosteroids as Analgesics in Animals
NSAIDs are useful adjuncts in the treatment of postsurgical pain in a variety of species, because they block prostaglandin synthesis mediated by inhibition of cyclooxygenase (COX). Decreasing inflammation after surgery or trauma can greatly improve analgesia. Inflammation is a key component in both peripheral and central sensitization leading to wind-up. Early and aggressive control of wind-up is critical in the prevention of chronic pain syndromes.
NSAIDs appear to confer synergism when administered in combination with opioids and may demonstrate an opioid-sparing effect. Notable advantages of NSAIDs include availability, a relatively long duration of action, low cost, and relative ease of administration. Lack of CNS alteration (sedation or dysphoria) makes NSAIDs ideal for treating acute and chronic pain in animals. Careful patient selection is critical.
Although a number of NSAIDs have been approved for use in dogs and horses, only meloxicam and robenacoxib are FDA approved for use in cats in the US. Meloxicam is approved for a single dose and robenacoxib for up to 3 days. As with all analgesic agents, special attention to drug withdrawal times is necessary when using NSAIDs in production animals.
Corticosteroids also decrease inflammation and provide analgesia. Depending on the product, they can be administered PO, IV, IM, SC, or intra-articularly. Corticosteroids are administered less frequently in the postoperative period because of the potential to decrease immune function and because of other well-known adverse effects (eg, polyphagia, polydipsia, polyuria) after repeated dosing. However, they are administered occasionally in chronic pain syndromes, including PO for degenerative disc disease in dogs and intra-articularly for unresponsive osteoarthritis Disorders of Joints in Animals Articulations are divided into synarthrodial joints and diarthrodial joints. Synarthrodial joints are osseous components united by fibrous tissue or cartilage. Synarthrodial joints are practically... read more . Corticosteroids and NSAIDs should not be administered concurrently.
Alpha-2 Agonists as Analgesics in Animals
The benefits of alpha-2 agonists include sedation, analgesia, and minimum alveolar concentration (MAC) sparing for inhalation anesthetics, Administration can be parenteral, oral, epidural, intrathecal, and intra-articular, because of spinal and supraspinal actions. Combination treatment with alpha2-agonists and opioids induces profound analgesia and sedation that is additive or synergistic as compared with the effects of either drug alone in both large and small animals. The mechanism of action is via G protein–coupled receptors.
Alpha 2A and alpha 2C receptors mediate analgesia. Alpha2-agonists are used as part of multimodal analgesia in the perioperative period in many species. Alpha2-receptors play an important role in the modulation of pain by the CNS. Alpha2-agonists may be used to induce analgesia when administered as anesthetic premedications (preemptive analgesia), as a constant-rate infusion intraoperatively, and as a supplement to postoperative analgesia. In general, postoperative doses of alpha2-agonists are considerably lower than would be required preoperatively.
Even at relatively low doses, these agents cause profound reductions in cardiac output and may cause marked arrhythmias in all species. Ruminants, in particular, require lower doses, and arterial hypoxemia and pulmonary edema have been described in sheep. Careful patient selection is warranted.
Alpha-2 antagonists (eg, atipamezole) can reverse the central and peripheral effects of alpha2-agonists to hasten recovery and minimize cardiopulmonary depression. Once reversed, however, these drugs provide no analgesia.
Ketamine as an Analgesic in Animals
Ketamine has long been known to provide excellent somatic analgesia but rather poor visceral analgesia. Interest in ketamine has increased because of its role in preventing sensitization of central nociceptive pathways. Ketamine's noncompetitive and nonspecific antagonism of the N-methyl D-aspartate (NMDA) receptors provides its analgesic effects. The receptors are activated by two excitatory neurotransmitters (glutamate and glycine) during sustained nociception in the spinal cord dorsal horn. Inhibition of the NMDA receptors prevents or decreases central sensitization and cumulative depolarization (wind-up) in laboratory animals and humans.
Ketamine also interacts with mu-opioid, muscarinic, monoaminergic, and gamma-aminobutyric acid (GABA) receptors. Ketamine may be incorporated into the anesthetic protocol either as a bolus or a constant-rate infusion to prevent the development of exaggerated or chronic pain states.
Other Analgesic Agents Used in Animals
Tramadol, a synthetic codeine analogue, is a weak mu opioid receptor agonist. In addition to opioid activity, it inhibits neuronal reuptake of norepinephrine and 5-hydroxytryptamine (serotonin) and may facilitate serotonin release. Because of its inhibitory effects on serotonin uptake, tramadol should not be used in animals that may have received monoamine oxidase inhibitors such as selegiline, animals on selective serotonin reuptake inhibitors, or animals with a recent history of seizure activity.
In humans, the principal active metabolite (O-desmethyl tramadol, M1) is more active at mu receptors than the parent drug. Cats produce substantial amounts of M1, whereas dogs produce minimal amounts. Oral bioavailability is 93% in cats but only 65% in dogs. Dogs eliminate and clear tramadol more rapidly than cats, so the dosing interval must be adjusted in cats. Adverse effects include decreased seizure thresholds, nausea/vomiting, and in some animals, altered behavior.
There are few clinical studies examining the use of tramadol in animals. However, it has been shown to decrease minimum alveolar concentration of sevoflurane in cats and is reported to have an analgesic effect after ovariohysterectomy similar to that of morphine in dogs. Tramadol may be used alone to treat mild pain or as an adjunct in a multimodal plan to treat moderate to severe pain.
Gabapentin was originally developed and licensed as a human anticonvulsant agent and has been approved by the FDA since 1993. Reports of its antihyperalgesic effects in rodent experimental pain models and case reports involving human patients suffering from neuropathic pain suggest increasing evidence for its use in neuropathic pain. Gabapentin binds to the calcium channel alpha2-delta proteins, modulates neurotransmitter activity, and blocks the development of hyperalgesia and central sensitization.
Gabapentin dosage varies widely and the drug can be administered to effect. Some animals may require continuous administration for weeks to months before their pain resolves. The dose must be tapered down to avoid rebound pain. Adverse effects are usually mild and self-limiting (drowsiness, fatigue, and weight gain with chronic administration).
Amantadine, an antiviral agent developed to inhibit the replication of influenza A in human patients, has efficacy in the treatment of drug-induced extrapyramidal effects and in treatment of Parkinson disease (increases CNS dopamine concentration). Amantadine is not an effective analgesic when used alone. It exerts its analgesic effects via antagonism of NMDA receptors by stabilizing these channels in the closed state rather than blocking the channel as ketamine does.
Amantadine seems most efficacious in the management of chronic neuropathic pain with clinical signs of hyperalgesia and allodynia. Amantadine may be beneficial for animals suffering from opioid tolerance. A 2008 study demonstrated improved activity in dogs with NSAID-refractory osteoarthritis when amantadine was added to meloxicam.(1 References Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic... read more )
Acetaminophen is not approved for use in animals; however, it has been used effectively for the treatment of breakthrough pain in dogs at a dosage of 10–15 mg/kg, every 12 hours, for as long as 5 consecutive days. The exact mechanism of action is unclear, although recent evidence suggests indirect activation of the cannabinoid CB (1) receptor. The so-called COX-3, a splice variant of COX-1, has been suggested as an additional mechanism for acetaminophen in dogs.
Acetaminophen is not considered a classic NSAID partly because of its low anti-inflammatory action; as such, the risk of thrombocytopenia, bleeding, and GI adverse effects is minimal. Hepatopathy is of concern, and routine serum chemistry evaluation is warranted. Acetaminophen should not be used in cats because of inadequate cytochrome P450–dependent hydroxylation (glucuronidation) and subsequent fatal methemoglobinemia.
Maropitant is administered to prevent and treat vomiting in cats and dogs. It is a neurokinin (NK-1) receptor agonist, blocking the receptors in the area of the brain that controls emesis, the chemoreceptor trigger zone (CTZ), and the vagal afferents. Maropitant blocks substance P from binding to NK-1 receptors, which are located throughout both the peripheral and central nervous systems, exerting an analgesic effect. The drug provides visceral analgesia for conditions such as pancreatitis, cholangitis, and painful GI disorders.
Monoclonal antibodies (mAbs) for pain control are monovalent antibodies which specifically bind targets including cytokines, receptors or other cells (Liu 2014). Frunevetmab is an felinized immunoglobulin G monoclonal antibody that binds to block NGFs effects. In 2022, Frunevetmab was approved by the FDA for use in cats as a monthly SC injection to alleviate osteoarthritis pain. In a pre-approval field trial., owners observed an improvement in mobility in treated cats. Adverse effects include vomiting, diarrhea and alopecia.(2 References Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic... read more , 3 References Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic... read more , 4 References Opioids continue to be the cornerstone of effective pain management in veterinary medicine. Opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic... read more )
Lascelles BDX, Gaynor JS, Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med. 2008;22(1):53-59.
Liu JKH. The history of monoclonal antibody development - Progress, remaining challenges and future innovations. Ann Med Surg (Lond). 2014;3(4):113-116.
Gruen ME, Myers JAE, Lascelles BDX. Efficacy and Safety of an Anti-nerve Growth Factor Antibody (Frunevetmab) for the Treatment of Degenerative Joint Disease-Associated Chronic Pain in Cats: A Multisite Pilot Field Study. Front Vet Sci. 2021; 8:610028. Published 2021 May 28. doi:10.3389/fvets.2021.610028
Gruen ME, Myers JAE, Tena JS, Becskei C, Cleaver DM, Lascelles BDX. Frunevetmab, a felinized anti-nerve growth factor monoclonal antibody, for the treatment of pain from osteoarthritis in cats. J Vet Intern Med. 2021 Nov;35(6):2752-2762. doi: 10.1111/jvim.16291. Epub 2021 Nov 1. PMID: 34724255; PMCID: PMC8692178.