1.0 Osteoarthritis (OA)
Osteoarthritis (OA) is a significant cause of pain, lameness and morbidity in dogs, cats and many other species across the world. It is one of the leading factors in premature euthanasia of dogs.
It is a multi‐factorial, progressive, degenerative disease of synovial joints, affecting not only the articular cartilage but also other structures within the specific synovial joint. Degradation of articular cartilage, subchondral bone sclerosis, osteophytosis, varying degrees of synovitis, meniscal and ligament degeneration are all characteristics of the disease process (Pye et al. 2022).
1.1 Osteoarthritis (OA) Prevalence
The period prevalence of osteoarthritis in dogs is reported in the literature with conflicting values; the estimates have ranged from 6.6% based on primary-care data to 20% based on referral data in the UK dog population. Historically, referral setting tends to show higher prevalence than primary care. A retrospective UK study found a prevalence of 2.5% in UK dogs attending primary care practice, although they do note limitations in their data collected, perhaps providing a conservative estimate. Estimates from a North American study reported age-specific prevalence values ranging from the aforementioned 20% in dogs older than one year up to 80% in dogs older than eight years. Furthermore, evidence is emerging relating to the prevalence of OA in the young dog population, in one study by Enomoto et al (2024), dogs aged 8 months to 4 years were assessed for radiographic OA (rOA) and clinical OA (cOA) . Overall, 39.8% of dogs had rOA in ≥ 1 joint, and 16.3% or 23.6% dogs had cOA, depending on the cut-off value of joint pain; moderate (2), or mild (1), respectively.
In cats, prevalence data is more difficult to obtain, OA is reportedly a relatively common problem in cats, being formally diagnosed in 2.0% of cats, but because overt lameness is not its most common clinical feature, feline patients tend to be under diagnosed; prospective cohort studies have provided prevalence statistics as high as 61%-90%. For each one year increase in cat age, the expected total degenerative joint disease score increased by an estimated 13.6% (Lascelles et al 2010).
Given that prevalence is apparently high in our pet populations, and certainly in our ageing pet populations, where comorbidities are increased, there are ever growing attempts to discover new analgesic medications to help manage the clinical signs of OA and improve quality of life. This drive in furthering the possible treatment options has led to the formulation of anti-nerve growth factor monoclonal antibody therapies in cats and dogs.
2.0 Targets and new targets in OA pain
As one of the most common diseases veterinary professionals may encounter (in numerous species) in first opinion and some referral specialties, over the years there has been extensive research work towards understanding of the biology and pain mechanisms underpinning osteoarthritis.
As this evidence-base grows, so do the number of treatments available to manage the condition. Over the last decade, as well as an increasing number of clinical trials investigating the efficacy of pre‐existing treatments, there have also been a number of advances in the pharmaceutical treatment options available for dogs with osteoarthritis.
Those patients experiencing OA can elicit an inflammatory, neuropathic and nociceptive pain response (Pye et al 2022), as well as peripheral and central sensitisation, hyperalgesia and allodynia.
OA is therefore best managed using case appropriate, multimodal management plans. This includes, but is not limited to, medication therapy including Non Steroidal Anti-inflammatory Drugs (NSAIDs), Gabapentinoids, Piprants, Paracetamol, opioids, N‐methyl d‐aspartate (NMDA) receptor antagonists, and more (Pye et al 2022). Other interventions such as physiotherapy, surgical intervention, hydrotherapy, and evidence-based supplements may also be considered.
A recent addition is the use of Anti-Nerve Growth Factor monoclonal antibody therapy. Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a fully caninised monoclonal antibody (mAb), binds NGF and inhibits its interaction with trkA and p75 neurotrophin receptors. Similarly, Frunevetmab, a felinised anti-nerve growth factor monoclonal antibody, effectively decreases osteoarthritis (OA) pain in cats.
3.0 Nerve Growth Factor (NGF)
Nerve growth factor (NGF) is an insulin-like protein, it is a member of a family of growth and survival factors known as neurotrophins and plays a role in nociception and numerous other organ systems.
3.1 Nerve Growth Factor role
NGF is essential for the development and phenotypic maintenance of neurons in the peripheral nervous system (PNS) and for the functional integrity of cholinergic neurons in the central nervous system (CNS).
Although NGF is essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development, it is also known to function throughout the life of an animal, in various capacities, including playing a pivotal role in the modulation of nociception in adulthood.
NGF plays a prominent role in nociception because its selective receptor (tropomyosin receptor kinase A, trkA) is expressed primarily on nociceptors. Studies have demonstrated that it sensitises the response to nociceptive stimuli via acute post-transcriptional mechanisms and by changing expression of numerous genes. Blockade of NGF has been shown to be efficacious in many preclinical models of pain, including joint pain in rat autoimmune arthritis, and more recently in feline and canine studies.
4.0 Rodent models
4.1 Inflammation
One 2010 study by McNamee et al concluded that NGF is an important mediator of OA pain but also suggests that, unlike post-operative pain, induction of pain in OA may not necessarily be driven by classical inflammatory processes.
NGF is up-regulated in human and rodent osteoarthritic joints and is associated with inflammatory cell infiltration of the synovium and subchondral bone.
Although originally defined by its actions in the peripheral and central nervous systems, data indicates the presence of extensive interactions between NGF and the endocrine and immune systems. Steroid hormones are able to modulate the neurosomal expression of NGF, while functional NGF receptors have been detected on cells of the immune system, and increased levels of NGF protein are found during the acute phase of diseases with a significant inflammatory component. Moreover, NGF appears to have a regulatory role in inflammatory processes, with receptor downregulation (a marker of tolerance) being associated with chronic inflammatory disorders.
4.2 Central Nervous System
A study, published in 1984 suggested the presence of NGF and/or its receptors in the CNS. Subsequent investigations demonstrated that NGF administration directly into the brain can be transported to the basal forebrain cholinergic neurons (BFCN), where it can improve experimentally induced cholinergic dysfunctions (cholinergic dysfunction relating to or denoting nerve cells in which acetylcholine dysfunctions.)
4.3 Pain
In OA models, intra-articular NGF injection augmented pain-related behaviours; mice with enhanced NGF-mediated signalling showed enhanced nociceptive behaviours. Neutralisation of NGF reduced pain even at late phases suggesting that this mediator is essential in chronic pain conditions.
One study by Bryden et al (2015) found that burrowing behaviour provides an objective, non-reflexive read-out for pain-related behaviour in the MIA model that has predictive validity in detecting analgesic efficacy. The researchers found that at the 3 day time point ibuprofen, celecoxib and an anti-nerve growth factor (NGF) monoclonal antibody (mAb) were able to significantly reinstate burrowing behaviour.
5.0 Human trials and discussion
5.1 Pain
TRPV1 (transient receptor potential vanilloid 1) is an ion channel that plays a crucial role in pain sensation. NGF enhances currents through TRPV1, and reduces the threshold of thermal excitation (a marker of increased nociceptor sensitivity). Long-term exposure to NGF upregulates the expression of TRPV1, bradykinin receptors, purinergic P2X receptors, and the synthesis of putative nociceptive transmitters such as substance P and CGRP in DRG neurons. NGF was also shown to induce priming of nociceptors; priming describes the phenomenon that after previous exposure to NGF or other compounds, the neuron is more responsive e.g., to prostaglandins.
NGF is required for the structural and functional integrity of nociceptors and generates hyperalgesia, partly by direct effects on neurons, partly by stimulation of inflammatory cells to release inflammatory mediators. Exogenous administration of small doses of NGF to adult animals and humans can produce pain and hyperalgesia.
5.2 Osteoarthritis
In humans and horses, NGF was increased in serum of patients with osteoarthritis compared with healthy controls (Kendall et al 2023) and in dogs with chronic lameness when compared to healthy dogs (Isola et al 2011).
NGF can be produced by chondrocytes, mast cells and macrophages. NGF is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans. The actual mechanisms underlying the persistent effects of NGF are not fully understood.
Injections of a monoclonal antibody against NGF relieved pain up to 56 weeks in a dose-dependent fashion and improved function in moderate to severe OA, with a low incidence of side effects. Two systematic reviews have each confirmed that inhibition of NGF through targeted monoclonal antibody therapy effectively relieves pain and improves function in OA (Schnitzer et al 2015, Kan et al 2016).
6.0 Veterinary trials
Currently, two monoclonal antibody drugs are available on the market to block the action of NGF in dogs and cats for the relief of pain associated with OA. Bedinvetmab and Frunevetmab are, respectively, fully canine and felinised anti-nerve growth factor monoclonal antibodies (mAbs).
There are some published clinical trials that evaluate the efficacy of single intravenous injection of the monoclonal antibody ranevetmab, a compound that was successfully converted the rat anti-NGF mAb (αD11) into caninised and felinised anti-NGF mAbs with the goal of managing pain states, including OA.
Both studies required a two-week withdrawal period of NSAIDs prior to the study starting, and NSAIDs were not permitted to be used throughout the study period, in order to best assess efficacy of the anti-NGF therapy. In a randomised and double-blind study where all dogs received ranevetmab, the safety and clinical effect was examined using an owner completed questionnaire—the Canine Brief Pain Inventory (CBPI) score. Results of the study by Webster et al (2014) suggested the evaluated anti-NGF mAb decreased pain severity (PS) and pain interference (PI) scores for 4 weeks after administration. This treatment may be effective for alleviation of signs of pain in dogs with osteoarthritis for up to 4 weeks. The other study, by Lascelles et al (2015), stated that these pilot data demonstrate a positive analgesic effect of anti-NGF antibody in dogs suffering from chronic pain.
There was pilot data demonstrated by Gruen et al (2016) showing a 6-week duration positive analgesic effect of this fully felinised anti-NGF antibody in cats suffering from degenerative joint disease (DJD) associated pain.
Furthermore, a multisite pilot field study by Gruen et al (2021) using an owner questionnaire found results showed significant improvement in frunevetmab-treated cats [compared to placebo]; at Days 42 and 56. This clearly has limitations as a subjective owner assessment, with the benefit that is was placebo compared and objectively found that there was a less marked decreased in activity in those treated; all groups had decreased objectively measured weekly activity from baseline; frunevetmab-treated cats had a mean decrease of 0.9%, while placebo-treated cats had a mean decrease of 9.3%. Frunevetmab was further assessed by Greun et al (2021) in a randomised, placebo-controlled, parallel-group, double-blind, superiority study. Frunevetmab and placebo treated cats were enrolled and received at least 1 treatment. Significant improvement with frunevetmab over placebo occurred at days 28 and 56 for the client specific outcome measures (CSOM) questionnaire; at days 28 and 56 for owner-assessed global treatment response; and at days 56 and 84 for veterinarian-assessed joint pain. The researchers concluded that Frunevetmab has the potential to address a critical gap in the treatment of pain because of osteoarthritis in cats.
Additionally, in a prospective, randomised, blinded, placebo-controlled multisite clinical study of bedinvetmab the authors Corrall et al (2021) found that the percentage treatment success was significantly greater in the bedinvetmab group than in the placebo group from day 7 through all assessed time points. Treatment success continued through days 56 and 84 in the bedinvetmab group and was < 25% in the placebo group at all time points. Sustained efficacy was demonstrated in the continuation phase. Treatment with bedinvetmab demonstrated a significant effect on all three components of CBPI—pain interference, pain severity, quality of life. It was concluded that this study demonstrated the effectiveness and safety of bedinvetmab administered monthly for up to 9 months at 0.5–1.0 mg kg–1 for alleviation of pain associated with canine osteoarthritis.
7.0 Adverse events and adverse drug reactions
An adverse drug reaction is defined by the World Health Organization (WHO) as: ‘a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function’. They also state that ‘Pharmacovigilance is defined by the World Health Organization as the science related to the detection, assessment, understanding and prevention of adverse events (AEs).’
The safety, quality and efficacy of marketed veterinary medicinal products are assessed before a marketing authorisation is granted. Pre approval studies are typically short in duration and include only a small number of animals that are not as diverse as the target population. Premarketing safety and efficacy studies therefore cannot detect all AEs that may occur once a product is used in a wider population. For this reason, post marketing pharmacovigilance in the detection and mitigation of emerging ADRs is essential.
It is common after a new drug is released to see active engagement in adverse effect (AE) reporting. It is important to remember that not all AEs thought to be connected to administration of medication will be caused by the medication, correlation doesn't always equal causation. Post marketing surveillance of adverse drug events carries on continually, but typically engagement is highest during the initial stages of use in the field and there is an inverse association with how long the drug has been on the market for and reporting (Hunt et al 2015). Post marketing drug monitoring actions deal with two pharmacology fields: pharmacovigilance and pharmacoepidemiology. All adverse events will have a background event rate (i.e. the frequency with which such events happen in an untreated population) and so it is important to understand that background event rate, and to compare the event rate within treated populations to see if that event rate is significantly higher.
After the launch of the anti-NGF antibodies, there have been anecdotal reports, predominantly online, of adverse events that are not currently on the data sheet (see VMD: Librela and Solensia for current data)
7.1 Cognitive decline or cognitive adverse events
There have been some anecdotal reports of cognitive decline in veterinary patients administered anti-NGF monoclonal antibody therapy. NB, this is not currently on the applicable data sheets and is speculative only at the time of writing.
As the aim for this therapy is to reduce the NGF in patients with pain relating to OA, for which NGF is found in higher concentrations in affected joints, there is concern that systemic use can also impact NGF levels in the CNS and brain – resulting in cholinergic degeneration, inability to regenerate and other mechanisms resulting in cognitive decline.
Let us investigate this hypothesis:
7.1.2 Central Nervous System
Within the Central Nervous System (CNS), the greatest amount of NGF is produced in the cortex, hippocampus and pituitary gland, although significant quantities of this neurotrophin are also produced in other areas, including the basal ganglia, thalamus, spinal cord and CNS-adjacent areas areas such as the retina.
Based on the evidence, possible clinical application for NGF in human neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson disease (PD) has been proposed. NGF regulates the development and the phenotypic maintenance of cholinergic neurons in the basal forebrain and the striatum, as well as of noradrenergic neurons in the hypothalamus. Because the degeneration of basal forebrain cholinergic nuclei (BFCN) and the decline of cognitive abilities are hallmarks of Alzheimer’s disease it was hypothesised that the addition and application of NGF (NB not the use of anti-NGF therapy) might be of therapeutic value for AD patients.
The synthesis/release of NGF from cortical neurons and glia as well as NGF-regulated functions in selected neuronal populations, i.e. the synthesis of acetylcholine in BFCNs, could be markedly affected in brain neurodegenerative disorders. Basal forebrain cholinergic neurons are highly dependent on NGF supply for the maintenance of their cholinergic phenotype as well as their cholinergic synaptic integrity; exogenous administration of NGF was found to be able to protect degenerating neurons.
NGF administration directly into the brain can be transported to the basal forebrain cholinergic neurons (BFCN), where it can improve experimentally induced cholinergic dysfunctions (cholinergic dysfunction relating to or denoting nerve cells in which acetylcholine dysfunctions.)
However, what is the evidence for systemic administration of anti-NGF monoclonal antibodies and the impact on the brain and thus its impact on cognition?
7.1.3 Blood Brain Barrier and Cognitive Decline
When administering NGF related therapies, there is a major difficulty in delivering NGF directly to brain neurons, due to the poor permeability of NGF to the blood–brain barrier (BBB) when injected systemically. It has been shown that molecules with neurotrophic activity can bypass the BBB, however these routes include intra-nasal, via the nasal-spinal pathway, and ocular administration.
Permeability of frunevetmab and bedinvetmab across the BBB to reduce NGF in the CNS/brain has not been studied at the time of writing. As monoclonal antibodies are large, we can assume that they also have poor permeability across the BBB. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. Although there is no specific data for anti-NGF monoclonal antibodies in this formulation, this evidence could suggest that when anti-NGF monoclonal antibodies is administered systemically the uptake via the BBB is limited, and therefore is not of great concern in relation to cognitive decline. More evidence is needed in this area to draw firm conclusions.
7.2 Ataxia
One of the discussions has been around ataxia and weakness following anti-NGF mAbs and the significance of this. This is currently stated as a 'rare' (1 to 10 animals / 10,000 animals treated) side effect.
This is noteworthy as we need to consider: 1) are anti-NGF mAbs contraindicated in any conditions; 2) is it possible to see more adverse events in a patient that has comorbidities alongside OA, or if OA has been misdiagnosed and the patient has a spinal/neurological issue alongside or instead of OA, which is presenting in similar ways; or 3) is the ataxia and weakness a direct result of the medical treatment?
7.2.1 Ataxia and comorbidities
Some of the potential clinical signs seen in canine intervertebral disc disease (IVDD) and chronic spinal cord compression, though they may vary with the location and severity of the spinal cord injury, can present as reluctance to go up or down stairs, jump, or go for a walk; these can mirror OA signs. These signs may progress to kyphosis, shaking or trembling, weak (wobbly) legs, or knuckling of the paws but may initially be presumed as a musculoskeletal abnormality rather than spinal. Importantly, if this were the case and an anti-NGF mAb was initiated, it is unlikely to improve the condition (although IVDD pain is also associated with inflammatory and nociceptive pain as well as neuropathic pain). Medical therapy, surgical therapy, or a combination of both seek to alleviate the pain or neurological deficits associated with IVDD. Thus, if anti-NGF mAbs were initiated, and OA was not the cause of the signs, deterioration in the condition is still likely to occur. Other conditions that could cause similar clinical signs include degenerative myelopathy, chronic intervertebral disc protrusion, and tumours. More research is needed in this area, but the possibility of ‘correlation is not causation’ may be important here - a degenerative and progressive (challenging to diagnose) neurological disease not accessing a disease appropriate treatment pathway may result in deterioration while on anti-NGF mAbs because initially the clinical signs may appear very similar to that of OA, this might be natural progression instead of direct cause. The role of NGF in baseline function of spinal neurones has not yet been elucidated; but there is currently no reason to suppose that an NGF deficiency is a significant cause of ataxia in a neurologically intact patient. More evidence is needed before we have any robust conclusions to numerous hypothesis.
7.3 Polyuria and polydipsia and urinary incontinance
One of the adverse drug reactions noted, which is on the data sheet and occurs rarely (1 to 10 animals / 10,000 animals treated) is polyuria and polydipsia (PU/PD) and urinary incontinence.
The mechanism for this is still unknown. Often with PU/PD in animals the questions of ‘which came first?’ must be determined. For example, in diabetes when animals get osmotic diuresis first causing PU which then causes PD, alternatively there are other mechanisms where the thirst centers may be stimulated, thus causing PD primarily and then leading to PU.
It is difficult to speculate what the mechanism of action behind this adverse effect may be. Some have suggested that NGF’s role in smooth muscle and bladder health and integrity could be to blame, which would be the case if it was an ‘incontinence’ rather than PU/PD. NGF is produced by the bladder smooth muscle and the urothelium. Interestingly, several studies on urinary bladder disorders in humans such as overactive bladder, interstitial cystitis, or neurogenic bladder have already indicated the crucial role of the increased levels of NGF in this context. This has been verified by elevated NGF-levels either in the urine or in bladder wall biopsies. NGF also seems to play a significant role in abnormal afferent signalling and in increased bladder sensations. Thus in this context, where increased NGF is impacting bladder function, theoretically, anti-NGF is therefore more likely to see improvements in such urinary bladder disorders than cause a decline in function. In animal models of partial urethral obstruction, chemical cystitis, and spinal cord injury (SCI), pretreatment with antibodies against NGF or its receptor prevents urinary frequency and unstable contractions - suggesting a protective effect.
Alternatively, immune complexing at the glomerular basement membrane may be a factor in low level renal dysfunction; however, widespread evidence of concurrent renal impairment is currently most notable by its absence.
It is hard to gauge a robust conclusion as to the mechanism behind the PU/PD seen, and more data will need to be drawn upon in the future.
7.4 Rapidly Progressive Arthritis
In human discussions, it is understood that OA is not simply a passive ‘wear and tear’ disorder, but rather a complex disease process involving various different effectors, ranging from inflammatory mediators to epigenetic alterations. For example, cellular senescence is a state of stable proliferation arrest of cells, senescent cells can predispose joints to the development and/or progression of OA. Many factors have been shown to decrease or increase the risk of cellular senescence. Exercise prevents diet-induced cellular senescence as well as the senescence-associated secretory phenotype within visceral adipose tissue. Cells undergo senescence in response to various detrimental stimuli, including but not limited to oncogene activation; radiation; oxidative stress; shortened telomeres; and unscheduled DNA replication. Due to the complex nature of OA, inhibiting nociceptive transmission alone (for example, with anti-NGF mAbs) should not, therefore, be seen as a panacea.
In humans, a reported risk in clinical testing was an increased incidence of ‘rapidly progressive OA’ and of osteonecrosis (ON) among patients who had received anti-NGF therapy. The risk of developing rapidly progressive OA appeared to be significantly greater when tanezumab (a humanised anti-NGF mAb) was used in conjunction with NSAIDs.
A dose-response relationship was noted between the serious events (progressive OA and reported ON) and doses of tanezumab between 2.5 mg and 10 mg and this has resulted in dose reductions in subsequent trials.
At the time of writing, ‘rapidly progressive OA’ had not been a demonstrated phenomenon in animals, either as a mono-therapy or as part of a polypharmacy approach with NSAIDs.
The SPC states:
‘In clinical trials in humans, rapidly progressive osteoarthritis has been reported in patients receiving humanised anti-NGF monoclonal antibody therapy. The incidence of these events increased with high doses and in those human patients that received long-term (more than 90 days) non-steroidal anti-inflammatory drugs (NSAIDs) concomitantly with an anti-NGF monoclonal antibody. Dogs have no reported equivalent of human rapidly progressive osteoarthritis.’
However, damage could still occur through other means that could result in more rapid deterioration. One hypothesis is that dogs who have been experiencing chronic pain associated with OA related changes have seen positive improvement when administered the medication. Subsequently, animals who have previously been inactive, and as a consequence may have muscle atrophy, joint instability and proprioceptive deficits as a result of disease processes were suddenly much more active. This leaves them vulnerable to injury if exercise,strength and conditioning is not reintroduced in a controlled manner. Thus, the SPC for Librela, as of the time of writing, quotes:
‘Where a dog has not been able to properly exercise prior to treatment due to its clinical condition, it is recommended that the dog is gradually (over a few weeks) allowed to increase the amount of exercise they take (to prevent overexercise by some dogs)’
8.0 Conclusion
All medication therapy carries potential side effects, denying this would be an injustice to the wide range of actions that medications induce both positively and negatively. We are, however, in a more fortunate position as time goes on that we have more and more medications available to use that have been shown to be both effective and generally safe to use.
OA is not necessarily an ‘old’ pet disease, due to emerging evidence of the prevalence of OA in young dogs, notably a study that found 39.8% of dogs aged 8 months to 4 years had rOA in 1 joint (Enomoto et al 2024), age is a significant risk factor, and many pets may start medical therapy in their advanced or geriatric years. As a result of this, we are far more likely to have other comorbidities present that could result in clinical signs that are, sometimes wrongly, attributed to medication. For example, in one prospective, randomised, blinded, placebo-controlled multisite clinical study of bedinvetmab (Corral et al. 2022) adverse health events occurred at similar frequencies in both groups. They were considered typical for a population of dogs with osteoarthritis and not related to study treatment.
Something that impacts one body system has potential to impact another. Anti-NGF monoclonal antibodies, at the time of writing, appear to have very good safety profiles. For bedinvetmab no adverse reactions, except mild reactions at the injection site, were observed in a laboratory overdose study when it was administered for 7 consecutive monthly doses at 10 times the maximum recommended dose. For frunevetmab, no adverse reactions were observed in laboratory overdose studies when it was administered for 6 consecutive monthly doses at 5 times the maximum recommended dose.
However, this does not mean that unusual and unexpected adverse events cannot or will not occur. As a result, adverse events should always be reported to the manufacturer or regulatory body (e.g.VMD in UK), and adverse events should be reported to the company, and then surveillance can be undertaken to assess. Many adverse events could be seen due to other comorbidities, coincidental correlation or by mechanisms we do not yet understand. And conversely, if there are other adverse effects directly linked to the use of anti-NGF mAbs, then good pharmacovigilance and reporting will allow the risks to be quantified to allow us to make better risk:benefit assessments.
Robyn Lowe BSc Hons Dip AVN (Surgery, Medicine, Anaesthesia) Dip HE CVN, RVN
Director: Veterinary Voices UK
Special thanks to John Innes and Mark Lowrie for their oversight on orthopaedics and neurology to ensure that, in areas where data is lacking, that my conclusions were fair and considered. And to David Harris, who has a critical eye for my grammatical errors and ensures some method to the madness of my writing.
Information and research in veterinary medicine is abundant and always changing, this article is updated as on 2025. If you are aware of new research that has come to light that is relevant, please email us.
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Please also note the in text links and citations.
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