12 Apr 2022
Nuria Quesada Vicent comprehensively covers the various pharmaceutical and non-pharmaceutical therapies currently available to vets.
Nuria Quesada Vicent
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This article is kindly sponsored by Chanelle Pharma, Ireland’s largest indigenous generic pharmaceutical manufacturer of both medical and veterinary products, serving customers in 96 countries worldwide.Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. Pain physiology, as well as its classification, is complex, and involves the peripheral and central nervous systems, signalling pathways, and a myriad of receptors and neurotransmitters.
Pain is dynamic and can evolve from acute pain (also known as nociceptive, physiological or adaptive pain) that protects our body from further damage, to chronic (or maladaptive) pain that is harmful itself and requires a multimodal approach to be under control.
Acute pain: Pain that develops after tissue damage, and ceases within a few days or weeks.
Chronic pain: Pain that persists for a long period of time (normally more than three months), beyond the expected healing time.
Somatic pain: Pain that originates from skin, muscles, bones, joints or connective tissue. It is described as “sharp”, “throbbing” or “cramping”.
Visceral pain: Pain that arises from visceral organs located in the abdomen or thoracic cavities. It is described as a “deep squeeze” or “aching”, and it is normally referred to as vague and diffuse, or being difficult to localise.
Neuropathic pain: Pain that originates from nerve damage or an impaired nervous system. It is described as “shooting” or “burning” pain. It is associated with chronic pain.
Peripheral sensitisation: Increased sensitivity and responsiveness of nociceptors in the peripheral nervous system.
Central sensitisation: Increased responsiveness of nociceptors in the central nervous system.
Allodynia: Pain response to a non-painful stimulus.
Hyperalgesia: Increased pain response to a painful stimulus.
This article aims to review the current pharmacological and non-pharmacological therapies available to treat different types of pain. For a better comprehension of the text, some definitions are provided in Panel 1.
Opioids are the prototype of analgesics, normally used as a first-line treatment for acute pain.
Opioids bind to opioid receptors mu (µ), kappa (κ) or delta, widely located throughout the body (brain, spinal cord, gastrointestinal tract, skin or immune cells, among others). Methadone is also an antagonist of the N-methyl-D-aspartate (NMDA) receptors located in the central nervous system (CNS).
Depending on the effect elicited and the receptor bound, opioids can be classified as: full µ agonists (such as morphine, methadone, fentanyl, remifentanil, alfentanil, meperidine or hydromorphone), partial µ agonists (such as buprenorphine), κ agonist/µ antagonist (such as butorphanol) or µ antagonists (such as naloxone and naltrexone).
Full agonist opioids activate the receptors until a maximum effect is achieved; however, partial agonist opioids reach a plateau at a lower level, therefore, providing less analgesia. Opioid antagonists displace the full opioids from the receptor, not providing any analgesic effect.
Opioids can be administered before or after the noxious stimulus has occurred, as a single bolus or a CRI, and via multiple routes: IV, IM, SC, oral transmucosal (OTM), epidural or transdermal.
Common side effects of opioids include: salivation; nausea; vomiting; ileus; sedation/euphoria; respiratory depression; mydriasis (cats) or miosis (dogs); altered thermoregulation; and emesis.
Table 1 summarises the main opioids used in veterinary medicine, their receptor, onset and duration of action, route of administration, and main considerations.
Tramadol is a synthetic opioid, an analogue of codeine, that has been used to treat mild to moderate acute pain in dogs and cats.
Tramadol is a serotonin-norepinephrine reuptake inhibitor. It is metabolised by the liver, producing the active metabolite O-desmethyltramadol or M1, which is a µ opioid receptor agonist. Individual variability of its metabolism and the production of M1 metabolite has been reported in some dogs (McMillan et al, 2008). This can lead to a variable analgesic effect in some patients.
A recent systematic meta-analysis (Donati et al, 2021) that included 26 randomised controlled trials reviewed the efficacy of tramadol in the control of postoperative pain in dogs when compared with placebo or other analgesic drugs.
Tramadol reduced the need for rescue analgesia when compared with no treatment, and increased it when compared to methadone or COX inhibitors. However, the authors highlighted the need for more studies, as many of these trials used a low number of cases and showed a low quality of evidence.
Tramadol has been ineffective in the treatment of osteoarthritis pain in dogs (Budsberg et al, 2018). However, it has shown a positive effect in cats with osteoarthritis (Monteiro et al, 2017; Guedes et al, 2018).
Tramadol can be administered IV, SC, IM or orally at a dose of 5mg/kg to 10 mg/kg by mouth every eight hours in dogs, and 1mg/kg to 2mg/kg by mouth every 8 to 12 hours in cats. Its bitter taste might result in a difficult administration in cats.
As a serotonin reuptake inhibitor, its administration in combination with other selective serotonin reuptake inhibitor agents, tricyclic antidepressants or meperidine is contraindicated due to the risk of developing serotonin syndrome, which causes fever, seizures, muscle tremors/fasciculations, hyperthermia and salivation.
Reported side effects of tramadol include: sedation, mydriasis, vomiting and diarrhoea, mild euphoria and/or dysphoria, and decreased appetite (Monteiro et al, 2017; Guedes et al, 2018).
NSAIDs are anti-inflammatory, analgesic and antipyretic drugs, mainly used to treat acute inflammatory pain and osteoarthritis pain.
NSAIDs inhibit cyclooxygenase (COX) enzymes, which catalyse the conversion of arachidonic acid into prostaglandins and thromboxanes. Two isoforms of COX exist: COX-1 (also known as constitutive) and COX-2 (as called inducible).
COX-1 catalyses the formation of prostaglandins involved in physiologic processes such as platelet function, gastrointestinal protection and kidney homeostasis, while COX-2 is synthesised after tissue damage and catalyses prostaglandins involved in the inflammatory processes. Therefore, modern NSAIDs (coxibs) aim to selectively inhibit COX-2 and spare COX-1, in order to reduce undesirable adverse effects.
Examples of selective coxib drugs are: firocoxib, deracoxib, robenacoxib and mavacoxib, while meloxicam and carprofen are considered preferential coxibs. In cats, only meloxicam and robenacoxib are approved by the European Medicines Agency for short-term use.
NSAIDs can be administered IV, SC, by mouth or transdermal, and are contraindicated in hypovolaemic animals, liver and kidney dysfunction, gastrointestinal disease, coagulopathy or concomitant administration with corticosteroids.
Adverse effects include: gastrointestinal disease (anorexia, vomiting, diarrhoea, gastric ulceration), kidney and liver injury, and decreased platelet function.
Grapiprant is classified as an NSAID, but unlike them, it does not inhibit COX-enzymes.
It specifically antagonises prostaglandin E2 receptor 4, in an aim to reduce the side effects produced by other NSAIDs. Therefore, grapiprant has anti-inflammatory and analgesic properties, but it is not considered an antipyretic drug.
Its administration is only approved for dogs as an oral formulation, and it is indicated to treat pain associated with inflammation and osteoarthritis (Rausch-Derra et al, 2016). Nevertheless, a study showed lower efficacy in acute arthritis in comparison with firocoxib (de Salazar et al, 2019).
Paracetamol is an analgesic and antipyretic agent. It is used to treat acute pain. It has been proved to be as effective as meloxicam and carprofen for the treatment of postoperative pain in bitches undergoing ovariohysterectomy (Hernández-Avalos et al, 2020).
Similarly to NSAIDs, it also inhibits prostaglandin synthesis; however, it does not have any anti-inflammatory properties, so it cannot be classified as an NSAID. Its exact mechanism of action remains uncertain. However, it has been proposed to act on the descending serotonergic pain inhibitory and cannabinoid pathways. It is also an inhibitor of the isoenzyme COX-3.
It is highly toxic in cats (a toxic dose ranges from 10mg/kg to 40mg/kg), so its administration in this species is not recommended.
In dogs, it is only licensed for oral administration, although it can be also administered IV off-label. It is administered at a dose of 10mg/kg to 15mg/kg twice or three times daily, not exceeding 200mg/kg (toxic dose). Paracetamol overdose produces acute liver failure, haemolytic anaemia, methaemoglobinaemia and kidney injury (MacNaughton, 2003).
Local anaesthetics (LA) are analgesic drugs that block the transmission of nociceptive signals to the CNS. LAs act on ion voltage-gated channels (mainly sodium, but also potassium and calcium), impairing the creation of action potentials and, therefore, nerve transmission.
Structurally, LAs are divided into amino amides (lidocaine, mepivacaine, prilocaine, bupivacaine, ropivacaine and levobupivacaine) and amino esteres (cocaine, procaine, tetracaine, chloroprocaine and benzocaine), and their pharmacokinetic properties (such as acid strength, solubility and protein binding) will provide varying onsets of action, potency, duration and toxicity.
LA can be administered topically, as an infiltration, epidurally/spinally, or can be deposited close to a peripheral nerve using an appropriate locoregional technique. LAs are cardiotoxic drugs, so the IV route is contraindicated (except for lidocaine in dogs).
LA can be administered alone or combined with vasoconstrictive agents (such as adrenaline or α2 adrenergic agonists) to increase the duration of action of the block, or in combination with opioids (such as morphine epidurally) or corticosteroids (such as dexamethasone for chronic pain treatments). The mixture of two different local anaesthetics to improve their physcochemical characteristics (like shorter onset of action and prolonged duration) is no longer recommended, as it has been proven that the opposite occurs (Jacobsen et al, 2011).
An exception is the eutectic mixture of lidocaine and prilocaine (such as EMLA cream), which is used as a topical anaesthetic to facilitate intravenous catheter placement (Van Oostrom et al, 2018).
Voltage-gated ion channels are also found in the heart and CNS. When toxic plasma concentrations are reached, neuron and cardiac sodium channels are blocked, producing neurological (tremors, seizures) and cardiovascular (arrhythmias, hypotension) signs.
If LA toxicity is suspected, an intravenous lipid emulsion (such as Intralipid) should be initiated immediately (Figure 1). The recommended dose (1.5ml/kg IV bolus over one minute followed by 0.25ml/kg/min during 30 to 60 minutes) is extrapolated from human guidelines (Fernandez et al, 2011).
Lidocaine is an amino amide local anaesthetic with analgesic, anti-arrhythmic, anti-inflammatory anti-endotoxic and prokinetic properties.
It is the only local anaesthetic that can be administered IV as a single bolus or constant infusion. It can also be administered topically to desensitise a cat’s larynx before anaesthetic induction or as a transdermal patch in dogs.
Transdermal patches of lidocaine did not show any benefit or provide any additional postoperative analgesia in dogs undergoing hemilaminectomy (Re et al, 2019) or ovariohysterectomy (Merema et al, 2017).
If lidocaine is administered IV in cats, care must be taken, and close monitoring of the animal is required. A lower dose and shorter duration of the infusion is recommended to avoid toxic plasma concentrations (Corrêa et al, 2021; Pypendop and Ilkiw, 2005).
Nocita is the veterinary commercial name for a long-acting bupivacaine. Bupivacaine molecules are encapsulated in microscopic multivesicular liposomes that are surrounded by a phospholipid membrane.
This layer slowly degrades, releasing the drug over a period of time. It has a reported duration of action of up to 72 hours after stifle surgery in dogs (Lascelles et al, 2016).
This product is not currently available in the UK.
Alpha-2-adrenergic receptor agonists are potent sedative drugs with analgesic properties. Three types of α2-adrenergic receptors exist, located in the cerebral cortex and brainstem (α2a), the spinal cord (α2b and α2c), and the vascular endothelium (α2b).
They are responsible for sedation, cardiovascular effects (bradycardia and hypertension) and supraspinal and spinal analgesia.
Alpha-2-adrenergic receptor agonists can be administered IV (as a bolus or infusion), IM, SC or OTM, and they are used perioperatively to treat acute pain.
Combined with opioids, α2-adrenergic receptor agonists create a synergistic effect, enhancing their analgesia (Chabot-Doré et al, 2015); while in combination with a local anaesthetic, they increase the duration of the locoregional block (Agarwal et al, 2014).
Due to their strong sedative and cardiovascular properties, their use is limited to the clinical and hospital settings.
Ketamine is a phencyclidine derivative, used to induce general anaesthesia and provide analgesia. It is classified as a “dissociative anaesthetic agent”, as people report a detachment from reality (such as hallucinations, out-of-body experiences, nightmares or delirium).
Ketamine is a non-competitive antagonist of the NMDA receptors, which prevent central sensitisation in dorsal horn neurons. It also enhances the descending inhibiting serotoninergic pathways, interacting with opioid, monoaminergic and muscarinic receptors, as well as voltage-gated calcium channels. It can be administered IV (single dose or constant infusion), IM, SC or OTM.
Over the past years, interest has grown in the use of ketamine to treat neuropathic chronic pain.
Although several studies have been conducted in human medicine, and the results seem to be positive, more high-quality and standardised clinical trials are needed before drawing conclusions (Shteamer et al, 2019).
In veterinary medicine, ketamine improved the management of postoperative pain in a forelimb amputation (Wagner et al, 2002) and mastectomy (Sarrau et al, 2007) surgeries.
Although a promising drug in the control of neuropathic pain, randomised controlled trials are needed to assess the efficacy, and establish dosage, routes and duration of treatments.
Maropitant is a neurokinin-1 (NK-1) receptor antagonist, commonly used as an antiemetic. NK-1 is the receptor for substance P, a neurotransmitter involved in pain modulation in the spinal cord, among other physiological functions.
It has been proposed that the inhibition of substance P could provide some form of analgesia.
In a recent study, in which maropitant was co-administered with lidocaine and ketamine infusions in dogs undergoing radical mastectomy, a reduced postoperative rescue analgesia and a significant inhibition of peripheral sensitisation was obtained in the maropitant group (Soares et al, 2021).
Similarly, in cats undergoing ovariohysterectomy, maropitant administered intraoperatively in a continuous infusion (100mcg/kg/h), showed a reduction in postoperative rescue analgesia (Corrêa et al, 2019).
However, when maropitant (administering 1mg/kg SC) was compared to morphine (administering 0.5mg/kg SC) in dogs undergoing ovariohysterectomy, it did not seem to provide enough postoperative analgesia, as most of the dogs in both groups required rescue analgesia during the recovery period (Marquez et al, 2015).
Gabapentinoids are anticonvulsant drugs with a structure similar to the gamma-aminobutyric acid (GABA) neurotransmitter, although they do not interact with GABA receptors.
Gabapentinoids inhibit the presynaptic calcium channels, impairing calcium influx and the release of excitatory neurotransmitters in the CNS. Gabapentinoids are administered orally, in the form of capsules, tablets or liquid.
Gabapentin is only licensed as an anticonvulsant agent in veterinary medicine. However, in the past few years, it has also been used off-label as an analgesic drug to treat chronic pain, postoperative pain, or even as an alternative to NSAIDs whenever these are contraindicated (Reader et al, 2021).
Some studies have evaluated gabapentin as an adjuvant drug in the management of postoperative pain in dogs undergoing forelimb amputation (Wagner et al, 2010), intervertebral disc surgery (Aghighi et al, 2012) and mastectomy (Crociolli et al, 2015). In none of these studies, postoperative pain scores differed from those in the control or placebo groups, indicating a lack of benefit of gabapentin in the treatment of postoperative pain.
However, an inadequate dosage or frequency of administration of the drug, a low sample size or the concomitant administration with potent analgesics are some reasons provided that could also explain these results.
In cats undergoing ovariohysterectomy, gabapentin in combination with buprenorphine provided similar postoperative analgesia than buprenorphine combined with meloxicam. (Steagall et al, 2018). In geriatric cats with osteoarthritis, gabapentin (10mg/kg by mouth twice daily) when compared with placebo showed an improvement in owner perceived mobility impairment, despite cats in the gabapentin group showing decreased activity levels, likely to be due to the sedative effects. (Guedes et al, 2018).
If gabapentin is used in long-duration treatments, dosage and frequency of administration should be titrated to effect, while side effects, such as sedation, ataxia or muscle tremors, should also be monitored.
Pregabalin (also known by the commercial name Lyrica) is an anticonvulsant drug used to treat seizures that are refractory to gabapentin.
Two clinical studies have evaluated the use of pregabalin in neuropathic pain associated with Chiari-like malformation and syringomyelia in Cavalier King Charles spaniels (Sanchis-Mora et al, 2019; Thoefner et al, 2020).
In Thoefner´s study, pregabalin (13mg/kg to 19mg/kg by mouth twice daily) reduced the spontaneous scratching and improved the quality of life of the animals, according to their owners. Ataxia and increased appetite were the main side effects encountered.
In Sanchis-Mora et al’s study, pregabalin (5mg/kg by mouth twice daily) improved daily pain scores, according to the dogs’ owners, and significantly reduced hyperalgesia and allodynia, by increasing the mechanical thresholds and cold latency compared to placebo and baseline values.
Amantadine is an NMDA receptor inhibitor in the CNS. Originally, it was formulated as an antiviral drug, but it has been used to alleviate some Parkinson’s disease symptoms in people. In veterinary medicine, amantadine is used as part of a multimodal analgesic therapy to treat moderate to severe chronic pain non-responsive to an adequate analgesia treatment.
It has shown positive results as an adjuvant analgesic in dogs suffering from osteoarthritis refractory to NSAIDs (Lascelles et al, 2008) and in cats with osteoarthritis pain (Shipley et al, 2021).
It is administered orally at a dose of 3mg/kg to 5mg/kg once or twice daily, with a minimum duration recommended of at least 21 days.
Tricyclic antidepressants (TCAs) are serotonin and norepinephrine reuptake inhibitors, although they also exhibit antihistaminic and anticholinergic effects, as well as α1 and α2 adrenergic antagonism.
Amitriptyline, clomipramine, desipramine, doxepin, imipramine and nortriptyline are some drugs included in this group.
In veterinary medicine, amitriptyline has been used to treat behavioural disorders and feline idiopathic lower urinary tract disease. As an analgesic, amitriptyline has been used for the treatment of hyperaesthesia syndrome in cats (Amengual Batle, 2019) and in three cases where neuropathic pain was suspected in dogs (Cashmore et al, 2009), as part of a multimodal management approach.
The side effects reported are sedation and ataxia, weight gain, urinary retention, mydriasis, tachycardia and cardiac arrhythmias.
The combination of TCAs with monoamine oxidase inhibitors, meperidine and selective serotonin reuptake inhibitors is contraindicated due to the risk for developing serotonin syndrome, as already explained.
Bedinvetmab (dogs) and frunevetmab (cats) are species-specific monoclonal antibodies that target nerve growth factor, a cytokine that plays a major role in inflammatory and neuropathic pain.
They have been recently launched to the veterinary market, with the commercial names Librela (dogs) and Solensia (cats), to treat osteoarthritis pain.
Bedinvetmab (0.5mg/kg to 1mg/kg SC injected monthly for up to nine months) showed to be effective in dogs with osteoarthritis when compared to placebo. Furthermore, no adverse health events were reported (Corral et al, 2021).
Frunevetmab (1mg/kg to 2.8mg/kg either IV or SC monthly) was evaluated over a period of 42 days in cats with degenerative joint disease. Frunevetmab resulted in an improvement in the mobility compared to placebo, according to owners’ questionnaire and accelerometry parameters.
Adverse events were reported in both groups and included: skin dermatitis (associated with the accelerometry devices), renal insufficiency and gastrointestinal diseases (Gruen et al, 2021).
The term “nutraceutical”, coined by Stephen DeFelice in 1989, is a combination of the words “nutrition” and “pharmaceutical”. Nutraceuticals are substances derived from food that possess pharmaceutical properties and have a beneficial impact on health.
Their beneficial effects have been evaluated in allergies, cardiovascular diseases, cancer, diabetes, immune system diseases or inflammatory states.
Some of the substances specifically used for osteoarthritis are omega-3 and omega-6, chondroitin sulfate, S-adenosylmethionine, glucosamine sulfate and methylsulfonylmethane.
A recent meta-analysis (in humans) reviewing 42 randomised controlled trials showed beneficial effects of nutraceutical products on pain and physical function when used for hip and knee osteoarthritis (Aghamohammadi et al, 2020).
In veterinary medicine, several studies have assessed the use of dietary supplements in dogs suffering from osteoarthritis pain with positive results (Gupta et al, 2012; Musco et al, 2019).
In cats with degenerative joint disease, Dasuquin (chondroitin and glucosamine sulfate) did not provide any pain relief compared to placebo. In addition, the authors concluded that a strong placebo effect was found (Cunningham et al, 2021).
The wide variety of substances, formulations, manufacturers, regimens, duration of treatment and so forth make it difficult to compare the studies and extract conclusions about the benefits of these compounds (Bhathal et al, 2017).
Cannabinoids are substances that bind the cannabinoid receptors.
It was not until mid 1990s when the endocannabinoid system was discovered. The endocannabinoid system is formed by:
The cannabinoid receptors (CB1 and CB2), localised in the central and peripheral nervous system, as well as immune system, cardiovascular system or gastrointestinal system.
The endogenous ligands or endocannabinoids (anandamide and 2-arachidonoyl glycerol), which are arachidonic acid derivatives.
The endocannabinoid system is involved in the regulation of multitude physiological, homeostatic and cognitive functions, such as glucose metabolism, sleep, mood, blood pressure, immune function, pain modulation and memory, among others.
It also plays a role in neuropathic pain, decreasing hyperalgesia and allodynia.
Cannabidiol (CBD) is commercialised as a nutraceutical, in the form of oil. Unlike the delta-9-tetrahydrocannabinol (THC), CBD does not exert psychoactive effects.
Several studies have assessed the efficacy of CBD oil in osteoarthritis pain in dogs (Gamble et al, 2018; Verrico et al, 2020; Brioschi et al, 2020).
However, similar to nutraceuticals, a standardisation on the composition and formulation of the oil is also needed.
Physical therapy can be applied in combination with pharmacological therapy with the goal of reducing postoperative pain, as well as analgesic drugs consumption and their side effects.
These techniques decrease pain and inflammation through different mechanisms of action.
Cryotherapy consists in the application of a cold surface, such as ice packs (Figure 2), cold compression therapy or ice massages that create vasoconstriction, decreasing swelling and inflammation.
Pulsed electromagnetic field therapy uses an electromagnetic field in painful areas to decrease inflammation. Some specific devices ultimately release nitric oxide, a potent vasodilatory agent.
Transcutaneous electrical nerve stimulation applies low-voltage electrical impulses through different electrodes located in the skin. These impulses release endogenous opioids.
Light amplification by stimulated emission of radiation or photobiomodulation.
Photons are absorbed by the mitochondria, initiating a biological response and releasing adenosine triphosphate, beta-endorphins, nitric oxide and acetylcholine, which will have an inflammatory effect.
