18 May 2021
Companion animal analgesia: updates and innovations
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Image: © teamjackson / Adobe Stock
In veterinary medicine, pain is defined as “an aversive sensory and emotional experience representing an awareness by the animal of damage or threat to the integrity of its tissues… It changes the animal’s physiology and behaviour to reduce or avoid damage, to reduce the likelihood of recurrence and to promote recovery” (Molony and Kent, 1997).
As perception of pain stimulus may change over time, new and improved analgesic therapies have been discovered over the years. Literature in human medicine about pain has exponentially grown, and veterinary medicine is almost simultaneously achieving that knowledge and its application.
The following article reviews and summarises three analgesic therapies that will become very important in the near future for pain management in veterinary medicine.
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Cannabinoid therapy
The use of cannabinoids (CBs) for therapeutic properties (headache, fever, diarrhoea, infections, malaria and rheumatic pain) were previously reported in ancient China, medieval Persia and during the 19th century in Europe.
However, during the 1960s the isolation, characterisation and synthesis of tetrahydrocannabinol (THC) – a major ingredient of cannabis – allowed the enhancement of developing more synthetic compounds and researching well-founded therapeutic potentials.
The endocannabinoid system
Basically, the endocannabinoid system (ECS) consists of the following components:
CB receptors: during the past decades, multiple research led to the discovery of two subtypes of CB receptors – CB1 and CB2 – which belong to a new family of G‑protein‑coupled receptors. Both CB receptors have been found in mammals, reptiles, birds and fish.
- The CB1 receptors are mostly present in the CNS and play an important role for pain modulation, movement and memory processing. Also, they could be allocated to a lesser extent in peripheral tissues (cardiovascular, immune, gastrointestinal, renal, respiratory and reproductive system). Although the CB1 receptor in humans is not prevalent in the organs responsible for the vital autonomic activity (breathing and heartbeat), this is not the same for dogs and, therefore, the likelihood of overdose is higher.
- CB2 receptors are located in the peripheral tissues, mostly in the cells from the immune system (natural killer cells and B-cells), spleen and tonsils. Although the number of CB2 receptors in the CNS is very low, “non‑haemostatic” situations (inflammation, neurodegenerative diseases and/or cancer) could increase their presence in astrocytes, microglial and cerebrovascular endothelial cells. The activation of CB2 receptors is responsible for the modulation of cytokine release, as well as the inhibition of adenylyl cyclase in B-cells and T-cells, and a minor response of the immune system to an insult.
Endocannabinoids (eCBs): endogenous compounds that bind to the CB receptors, activating them to produce similar THC biological processes. Elevated intracellular calcium ion levels are responsible for the endogenous production of eCBs from the phospholipids located in the cell membrane. The released postsynaptic neuron eCBs target the CB receptors on the presynaptic neuron, in which they inhibit the influx of calcium ions, and, therefore, the inhibition of gamma-aminobutyric acid and glutamate release. The most well-studied eCBs are N-arachidonoylethanolamine (anandamide), 2-arachidonoylglycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), O-arachidonoylethanolamine (virodhamine) and N-arachidonoyl dopamine. The pharmacokinetic profile of the eCBs showed a fast‑acting, short and intermittent lifetime.
Enzymes: a specific group of enzymes from the phospholipid membrane is responsible for the biosynthesis or degradation of the eCB levels (known as “the eCB tone”). Both the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the most prominent. For example, the cleavage by a phospholipase D of the N-arachidonoyl phosphatidylethanolamine is the precursor of the anandamide. Subsequently, anandamide is degraded by the FAAH into arachidonic acid (AA) and ethanolamine. Both diacylglycerol lipase and phospholipase C activities produce 2-AG using an AA precursor. Later, 2-AG is degraded into glycerol and AA by MAGL.
Phytocannabinoids
Phytocannabinoids (PhyCBs), or plant-derived CBs, are chemicals produced by botanical sources with the ability to interact with the ECS.
PhyCBs differ from eCBs in their pharmacokinetics, as they have shown a long lifetime. The most studied PhyCBs are the 113 cannabinoids derived from female plants of Cannabis sativa.
Most of these cannabinoids are analogues of the following:
- THC is the best-known CB and responsible for the psychoactive properties (mental euphoria, increased appetite and slow cognitive function) of cannabis due to its interaction with CB1 receptors.
- THC precursor, tetrahydrocannabinolic acid, is a non-psychotropic compound with modulation properties in specific transient receptor potential (TRP) channels (TRP ankyrin 1 agonism and TRP melastatin 8 antagonism), cyclooxygenase (COX)‑1 and COX‑2 inhibition, and tumour necrosis factor reduction (in vitro).
- Cannabinol is derived from THC degradation with weak potency to activate CB receptors.
- Cannabidiol (CBD) is the second most studied in the past years. The application of CBD in human and veterinary medicine has shown promising results in epileptic diseases and as an antitumoral agent.
- CBD precursor, cannabidiolic acid, has shown anti-inflammatory effects as a selective COX‑2 inhibitor.
- Tetrahydrocannabivarin has shown weaker analgesic and cataleptic effects in animals compared to THC.
- Cannabigerol (CBG) is a low‑potency CB with relative partial agonist for CB receptors. CBG has shown good results in humans as a treatment of glaucoma and colon cancer, and as an anti‑inflammatory for inflammatory bowel disease.
Analgesic CB therapy in veterinary medicine
The oral administration of an industrial hemp and its clinical effects has been studied in dogs with chronic OA. The mixture contained a proprietary hemp strain using ethanol and heat extraction, with the final desiccated product reconstituted into an olive oil base containing approximately 10mg/ml of CBD as an equal mix of CBD and carboxylic acid of CBD, 0.24mg/ml of THC, 0.27mg/ml of cannabichromene and 0.11mg/ml of CBG; all other CBs were less than 0.01mg/ml.
CBD was administered at 2mg/kg every 12 hours for a period of four weeks. A significant decrease in pain and an increase in activity based on validated scales (Canine Brief Pain Inventory [CBPI] and Hudson scale) were reported at weeks two and four during the CBD treatment compared to baseline parameters and a placebo group (Gamble et al, 2018).
To the author’s knowledge, only one case report exists about the administration of CBD in equine medicine. CBD was orally administered at 0.33mg/kg to 0.5mg/kg every 12 hours in a four-year-old quarter horse mare with a chronic history of mechanical allodynia over the caudal neck and withers region. Although previous treatment with dexamethasone, gabapentin, magnesium/vitamin E, prednisolone and acupuncture was administered, the symptoms did not improve. Nevertheless, clinical signs resolved after two days following CBD therapy (Ellis and Contino, 2021).
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Nerve growth factor activity
In 1954, a nucleoprotein particle isolated from mouse sarcomas 180 and 37, with enhancing properties of growth and differentiation in sensory and sympathetic nerve cells during development stages, was discovered in human medicine – the nerve growth factor (NGF).
However, several studies have shown that after sensory fibres have lost their dependence on NGF for survival, NGF shifts to an important role in the modulation of acute, transient nociceptive responses and in longer-term, chronic pain in adults.
Basic understanding of NGF and pain
NGF belongs to a family of neurotrophins, a target-derived protein responsible for the survival, development and function of specific sensory and sympathetic nerve cells. Their binding to a family of high-affinity receptors, tropomyosin-related kinase receptors (Trks), is the reason for their specificity of activity.
Also, all neurotrophins interact with a second low-affinity receptor, the p75. NGF preferentially binds the Trk A receptor (TrkA), therefore forming the NGF-TrkA complex (NGF/TrkA), which is responsible for the generation and maintenance of several types of acute and chronic pain.
TrkAs are expressed on the following areas:
Inflammatory, immune or Schwann cells: NGF binds to the TrkA during an injury, inflammatory process or a disease, causing degranulation and release of inflammatory mediators (histamine, serotonin, prostaglandin E2, protons and bradykinin), as well as NGF. This phenomenon enhances the sensitisation of polymodal nociceptors.
Peripheral terminals of primary afferent nerve fibres: the cell bodies of these primary sensory nerve fibres are located in the dorsal root ganglia (DRG). The released NGF after an injury, inflammation or disease binds to the TrkA, forming the NGF/TrkA, which is transported to the DRG by retrograde transport.
An increase in the sensitivity of the primary afferent nociceptors to thermal and chemical stimuli is developed after the NGF/TrkA. The activation of the intracellular cascade results in the release of neuropeptides (for example, substance P or calcitonin gene‑related peptide), and increased expression of receptors (transient receptor potential vanilloid 1, acid‑sensing ion channels two and three, endothelin receptors and bradykinin receptors) and channels (voltage-gated sodium, calcium channels and delayed rectifier potassium currents).
These neuropeptides, receptors and ion channels are transported from the DRG to the peripheral tissues and to the terminals in the dorsal horn.
Monoclonal antibodies
Monoclonal antibodies (mAbs) are monovalent antibodies that specifically bind to target molecules including cytokines, receptors or cells.
Murine mAbs are produced from individual B-lymphocyte clones in mice, but immune reactions have been observed when administering purified non-human-derived antibodies to humans. Therefore, recombinant engineering technology has been developed to lower the risk of immune reactions:
Chimeric: mAbs made by fusing the variable region from a murine-derived mAb, with the Ig constant region from a human antibody. These mAbs are 75% human.
Humanised: mAbs retain only the part of the variable domain from the original murine‑derived mAb that binds to the specific antigen, and are 95% human.
Fully human: mAbs produced through transgenic mice and phage technologies, and with no murine sequences.
Analgesic anti-NGF therapy in veterinary medicine
In a model of inflammatory pain by injection of kaolin into the footpad in 32 dogs, animals were allocated into four groups based on administered medication during seven days’ treatment: placebo, oral administration of meloxicam, canine mAb (called “NV-01”) injected IV once at 0.2mg/kg, and single SC administration of NV-01 at 0.2mg/kg. NV-01 showed significant differences as effective in reducing lameness compared to placebo on days one, three, six and seven in the IV group, and on day seven in the SC single injection (Gearing et al, 2013).
A group of nine dogs with a history of OA were included in a clinical study that evaluated CBPI scores before and after treatment with canine mAb. The CBPI was scored before, and two, four and six weeks after canine mAb was given IV at 0.2mg/kg only at one of three different periods of time (first, second or third week). Independently when canine mAb was administered, significant differences existed in decreasing CBPI scoring two and four weeks after administration. Therefore, an estimated duration of analgesic action of four weeks is attributed to IV administration of canine mAb at 0.2mg/kg in dogs (Webster et al, 2014).
A posterior clinical study was conducted in dogs with degenerative joint disease (DJD) during a 28-day period of treatment after either single IV injection of NV-01 or placebo. The different pain scales revealed an analgesic efficacy and increase in motor activity with NV-01 single treatment in dogs with DJD (Lascelles et al, 2015).
Similar to dogs, 38 cats were recruited for an experimental model of inflammatory pain by injection of kaolin into the footpad. Cats were allocated in two groups: a placebo SC injection group, and a feline mAb (called “NV‑02”) administered SC once at a dose of 2mg/kg. Statistically lower lameness scoring was observed from day two to day seven in the group with NV-02 treatment compared to placebo (Gearing et al, 2016).
In a clinical study, 34 cats with a history of DJD were enrolled in three different groups: placebo, and SC injection of NV-02 at 0.4mg/kg or 0.8 mg/kg. Locomotor activity improved significantly at two and four weeks post‑treatment, and pain scale scoring statically decreased after the third week of treatment compared to the placebo group. Analgesic properties lasted until six weeks later (Gruen et al, 2016).
Radiofrequency ablation
The application of electrical currents by radiofrequency to produce ablation in nearby nociceptive pathways has been studied to manage pain since the 1970s.
Basically, a thermal energy is created through an electrode in targeted areas (nerve fibres responsible for transmission and modulation of pain) to produce an expected necrotic lesion and, therefore, to interrupt the pain sensation.
Nowadays, few types of radiofrequency ablation (RA) exist:
Thermal RA (TRA): thermal energy is produced by the application of an alternating current through a needle electrode, which is insulated along its length except for a short length (2mm to 10mm) at the distal end. The electrical field at the distal tip will oscillate charged molecules, which will generate heat. The temperature is controlled by a thermocouple incorporated in the electrode. The thermal lesion causes “Wallerian degeneration”, characterised by axonal swelling, fragmentation and secondary demyelination distal to the lesion. Previous studies have shown that TRA is a non‑selective (myelinated and unmyelinated fibres) technique for neurotomy.
Pulsed RA (PRA): PRA consists of high‑voltage radio frequency currents (50,000Hz) application in brief pulses (20 milliseconds) at a frequency of 2 seconds. The pause between pulses favours the dissipation of any heat generated and, therefore, no thermal lesion is created. Because PRA produces no lesion (axontomesis or neurotemesis), nerve conduction is reversible blocked, and the technique is reliable to apply in both sensory and motor nerves.
Water-cooled RA (WCRA): a continuous flow of water is applied to the electrode to decrease the temperature at the tissues. The advantage of this technique is the continuous application of RA in larger lesions. WCRA is used when other types of RA have failed, and it is limited to clinical presentations in which pain sensation arises from numerous and variable sources of innervation.
Analgesic RA technique in veterinary medicine
Six beagle dogs were recruited in an experimental model to assess histological and electrophysiological changes, and the clinical effects of both TRA applied in the saphenous nerve and PRA of the sciatic nerve. The lesion in the TRA group showed an extent that may be sufficient to impair conduction between saphenous nerve and the CNS. No motor or neurological deficits were seen in any of the dogs treated with PRA of the sciatic nerve (Boesch et al, 2019).
Authors from the aforementioned study have advised to use with caution the TRA applied in the saphenous nerve in dogs. In a clinical trial with canine patients in which TRA was applied, two dogs seemed to show a worsening of the pain (Boesch et al, 2020).
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