28 Oct 2019
Karen Perry
Job Title
Image: illuminaphotographic / Adobe Stock
OA is the most commonly encountered musculoskeletal disorder and results in a complex pain state involving both nociceptive and neuropathic mechanisms. Treatment aims to palliate the painful symptoms associated with the condition; however, despite conscientious employment of multimodal strategies, many dogs continue to experience chronic pain, sometimes necessitating aggressive surgical management. A large unmet need persists for additional therapeutic options in the battle against OA-related pain. Extensive research is in process in this regard.
In this, the final of a three-part series looking at treatment and management protocols for canine OA, some promising treatments for the future are discussed – namely, anti-nerve growth factor antibody; agonists of the transient receptor potential cation channel V1, such as resiniferatoxin; and cannabinoids.
In part one of this three-part series, the complex and variable pathophysiology of OA-related pain was discussed with respect to the challenges that can result secondary to this when it comes to managing patients with OA.
In part two, a case example was explored, which demonstrated a common scenario – a failure of non-surgical management to satisfactorily palliate the symptoms of OA, necessitating salvage surgical techniques. Both these articles highlighted the considerable unmet need for additional therapeutic approaches for OA.
The therapeutic approaches for OA are limited, as no drugs are available to control the disease progression and, as can be appreciated from the case detailed in the second article in this series, analgesic treatment has restricted efficacy (La Porta et al, 2014). Pain is a subjective experience, unique to each individual.
While our recent increased understanding regarding the pathophysiology of OA-related pain has highlighted the need for tailored, multimodal treatment strategies adjusted to the clinical characteristics of each individual, even in the face of such protocols, many dogs continue to suffer chronic pain and new, effective treatments are certainly required. Many alternative options are being investigated – far too many to discuss here.
The following are three of the novel treatments showing promise in ongoing clinical trials, which may become additional weapons in our armoury against OA-related pain in the future.
The activation and sensitisation of peripheral nociceptors by inflammatory and hyperalgesic mediators, such as cytokines, is recognised as one of the main peripheral mechanisms responsible for joint pain in OA (Wojdasiewicz et al, 2014).
In parallel with an increased understanding of the role of the cytokines, chemokines, and neurotrophins in joint pathology and pain (Wojdasiewicz et al, 2014), growing interest has occurred in the use of monoclonal antibody (mAb) therapy to target these molecules (Khan and Sadroddiny, 2015).
Nerve growth factor (NGF) is one of the cytokines (Bonini et al, 2003) that has received significant attention as a key regulator involved in both inflammatory and neuropathic pain (Isola et al, 2011). Preclinical and clinical research has clearly demonstrated the important role of NGF in nociceptor sensitisation in a wide variety of both acute and chronic pain states, including OA-related pain (Mantyh et al, 2011; McKelvey et al, 2013; Bannwarth and Kostine, 2014; Chang et al, 2016).
The rationale for using anti-NGF therapy in several pain conditions – particularly OA-related pain – is strong. Evidence has indicated anti-NGF mAb therapy has positive analgesic effects, and is well tolerated for up to three months in dogs and cats suffering from OA-related pain.
Additionally, the efficacy of a single injection appears to last four to six weeks and the magnitude of effect appears to be the same as, or greater than, that expected with an NSAID. Therefore, anti-NGF mAb therapy could be an alternative, or additive, to pharmacological pain management options available.
Further studies are needed to better understand the level of analgesic effect and the duration, and also what adverse events and immunogenicity may occur (Enomoto et al, 2018).
Specific targeting of nociceptic primary afferents using agonists of the transient receptor potential cation channel V1, such as resiniferatoxin (RTX), has been shown to block most clinically relevant pain while sparing protective pain sensations (Bates et al, 2010; Brown et al, 2015, 2005; Karai et al, 2004; Sapio et al, 2018). In rodents, local injections of RTX have shown strong efficacy for burn (Salas et al, 2017), surgical incisional (Raithel et al, 2018) and arthritic pain models (Kim et al, 2016; Mapp et al, 1996).
A study demonstrated a single intra-articular injection of RTX produced suppression of pain, improvement in gait and weight bearing based on force platform analysis, and improvement in dogs’ activities of daily living lasting four months or longer (Iadarola et al, 2018). No adverse events were encountered.
The peripheral site of action, long duration of analgesia, apparent safety and retention of coordination, all resulting from a single dose, suggested intra-articular RTX may be an effective intervention for OA-related pain with few or no side effects leading to an improved quality of life (Iadarola et al, 2018).
Recent medical interest in alternative therapies and modalities for pain relief has led many pet owners to seek hemp-related products rich in cannabinoids. Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for OA-related pain.
Indeed, pharmacological studies have shown the anti-nociceptive effects of cannabinoids in different rodent models of OA and compelling evidence has suggested an active participation of the endocannabinoid system in the pathophysiology of this disease (La Porta et al, 2014).
The ubiquitous distribution of cannabinoid receptors – together with the physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function – further support the therapeutic interest of cannabinoids for OA (La Porta et al, 2014).
The endocannabinoid receptor system is known to play a role in pain modulation and attenuation of inflammation (Di Marzo et al, 2004; Ben-Shabat et al, 2006; Maione et al, 2011). Cannabinoid receptors (CB1 and CB2) are widely distributed throughout the central and peripheral nervous system (Herkenham et al, 1990; Galiègue et al, 1995; Cabral et al, 2008) and are also present in the synovium (Richardson et al, 2008).
However, the psychotropic effects of certain cannabinoids prevent extensive research into their use as single agents for pain relief (Di Marzo et al, 2004; Rapaka and Makriyannis, 1987).
The cannabinoids are a group of as many as 60 different compounds that may or may not act at CB receptors. One class of cannabinoids, cannabidiol (CBD), may actually be an allosteric, non-competitive antagonist of CB receptors (Zhornitsky and Potvin, 2012).
In lower vertebrates, CBD is also reported to have immunomodulatory (Sacerdote et al, 2005), anti-hyperalgesic (Costa et al, 2004; Comelli et al, 2008), antinociceptive (Shiue et al, 2017; Cui et al, 2011) and anti-inflammatory actions (Di Marzo et al, 2004; Malfait et al, 2000), making it an attractive therapeutic option in dogs with OA. Several companies distribute nutraceutical derivatives of industrial hemp, rich in cannabinoids for pets, yet little scientific evidence regarding safe and effective dosing exists. A study assessed the safety and analgesic efficacy of a CBD-based oil in dogs with OA, as well as evaluating basic oral pharmacokinetics (Gamble et al, 2018).
Pharmacokinetics revealed an elimination half-life of 4.2 hours at doses of both 2mg/kg and 8mg/kg, and no observable side effects; 2mg/kg was chosen as the dosage for the clinical component of the study due to the cost prohibitive nature of 8mg/kg dosing for larger patients, the impractical nature of more frequent dosing, the volume of oil necessary and anecdotal reports surrounding 0.5mg/kg to 2mg/kg dosing recommended by other vendors.
Canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity with CBD oil. Veterinary assessment demonstrated decreased pain during CBD treatment. No side effects were reported by owners; however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment.
Based on this study, it was suggested 2mg/kg of CBD twice daily may help increase comfort and activity levels in dogs with OA. The short-term effects of CBD-rich industrial hemp treatment appear to be positive, but further studies are necessary to investigate 24-hour pharmacokinetics with different dosing regimens.
Studies with larger numbers of dogs are also required in addition to studies investigating the effect of different delivery vehicles and the long-term effects of CBD.
In summary, pain in OA is driven both by structural joint changes and abnormal excitability in peripheral and central pain pathways. A growing amount of evidence has suggested neuropathic pain is at least partially responsible for the pain in OA.
The deeper understanding of multiple mechanisms of OA pain has led to the use of centrally acting medicines that may have a benefit on alleviating OA-related pain (Dimitroulas et al, 2014). However, the evidence base demonstrating efficacy of such medications is weak and despite their use, many dogs continue to suffer chronic pain, in some cases necessitating salvage surgery.
New, effective treatments are certainly needed, representing a vast area of ongoing research. The frequently ineffective pain management and high rates of debilitation associated with OA mandate ongoing research and subsequent changes in our treatment paradigm.
