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Managing Osteoarthritis-associated Pain
Declaration of sponsorship Pfizer and Lilly

Emerging therapies

Declaration of sponsorship Pfizer and Lilly
Read time: 20 mins
Last updated:4th Feb 2022
Published:10th Nov 2020
  • therapies targeting nociceptive and inflammatory pathways that promote OA pain
  • disease-modifying osteoarthritis drugs (DMOADs) that may also reduce pain
  • the challenges in conducting and interpreting clinical trials on OA treatment

Emerging therapies for osteoarthritis pain

Traditional pharmacological strategies for managing pain in osteoarthritis (OA) include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular treatments and, for severe pain, opioid analgesics. Updates to guidelines, while strongly recommending NSAIDS, have downgraded (or withdrawn) recommendations for paracetamol use, and recommend opioids only as a last resort as there is insufficient evidence of efficacy and the likelihood of adverse reactions1–3. These treatments are often inadequate, particularly in older patients that are less able to deal with adverse reactions or who possess comorbidities that mean some treatments are contraindicated. Adverse reactions include paracetamol-induced hepatotoxicity, gastrointestinal toxicities from NSAIDs, and the risk of falls, delirium and dependency from opioids4.

Long-lasting, effective and tolerable medical treatments for OA pain are required if core first-line therapies such as exercise and lifestyle changes prove insufficient. Current data suggest that joint damage, inflammation, and peripheral and central sensitisation to pain all contribute to OA pain, which may partly explain the relative incongruence between structural damage and perceived pain in patients with OA5.

Therapies targeting inflammation

There has been a shift in interest towards therapies that target nociceptive and inflammation pathways, both of which are implicated in OA pain; increasing evidence points to cross-talk between these pathways6–9. Therapies that target inflammation, such as intra-articular glucocorticoids, are already used in the clinic to treat OA pain. However, there has been limited success in targeting individual proinflammatory mediators, such as tissue necrosis factor (TNF) or members of the interleukin family9, with biologics5,9,10. Some evidence suggests that long-term treatment (>12 months) with anti-TNF can protect against joint damage but that TNF is less involved in pain mechanisms5.

Other inflammatory cytokines are being investigated as potential treatment targets in OA. Therapies that facilitate intra-articular delivery of genes encoding anti-inflammatory cytokines may overcome the problem of delivering large biologic molecules into the joint. Currently, multiple experimental therapies that target the cross-talk between the inflammation and nociceptive pathways are under investigation, including the granulocyte–macrophage colony-stimulating factor (GM-CSF)–CC-chemokine ligand 17 (CCL17) chemokine axis5,9.

Methotrexate is an accepted treatment for rheumatoid arthritis. A pragmatic phase III trial showed methotrexate significantly reduced knee OA pain and improved the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for stiffness and function, but the analgesic effect was clinically borderline11. An ongoing randomised controlled trial (RCT) is examining the effect of methotrexate on pain and synovitis in patients with moderate-to-severe knee OA12, but more evidence is required for a possible role of methotrexate in relieving OA pain.

Therapies targeting the nociceptive pathway

Investigative therapies associated with the nociceptive (pain) pathway aim to dampen nociceptive signalling in various ways13

Nerve growth factor as a target

Nerve growth factor (NGF) is released during injury or inflammation and regulates neuronal survival and pain signalling by binding to and activating tropomyosin kinase A (TrkA) (Figure 1). NGF also binds to the p75NTR receptor that triggers a cellular signalling cascade known to be associated with mechanical hyperalgesia13. Both NGF and p75NTR appear to be overexpressed in the serum and synovial fluid of patients experiencing pain from conditions such as OA14. Investigative therapeutic strategies aimed at disrupting NGF-induced pain, therefore, include antibodies and small molecule inhibitors against NGF, TrkA and p75NTR 13(Figure 1).

OA_T4_Fig_1_redraw.png

Figure 1. Pathways of investigative drugs targeting pain in osteoarthritis (Adapted). NGF, nerve growth factor; TrkA, tropomyosin kinase A; TRPV1, transient receptor potential vanilloid 1 (ion channel).

Anti-NGF antibodies

Currently, only one anti-NGF monoclonal antibody, fasinumab, is still being explored in Phase III clinical trials. Trials with two other candidates, fulranumab and tanezumab15, have been discontinued because of safety concerns, including osteonecrosis and rapidly progressive OA5.

Fasinumab is a fully human IgG4 monoclonal antibody. In randomised, double-blind Phase III clinical trials, OA patients treated with fasinumab at different doses from 1 to 9 mg experienced less knee and hip pain and displayed better physical function than the placebo group5,16. In a Phase II-III trial, 9 mg of subcutaneous fasinumab every 4 or 8 weeks improved pain and function in patients with chronic low back pain at 16 weeks17. However, the incidence of arthropathies also increased in both these trials, suggesting that joint-related adverse reactions are a class effect of NGF inhibitors. Data from a long-term safety study of fasinumab (NCT02683239) are expected in 202218.

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Challenges in interpreting findings of clinical trials on therapies for osteoarthritis pain

Several characteristics of pain in general, and osteoarthritis (OA) pain in particular, increase the challenges of interpreting the results of clinical trials exploring potential new therapies5,10:

  • Pain is a subjective experience and so is challenging to measure. The numerous methods of measuring pain that are used in clinical trials (visual analogue scales, numeric rating scales, functional assessments, patient-reported outcome measures) make comparing the results of trials difficult. A further complication is the varying degrees of psychometric robustness of the measures30.
  • The biopsychosocial model of pain recognises that physical, psychological, behavioural and social factors can modulate an individual’s experience/perception of pain31. The interrelationships of these factors may confound the outcomes of clinical trials if the measurement of pain used fails to account for key domains.
  • OA is heterogenous in both clinical and pathophysiological terms – it affects multiple joints through different processes and varies substantially in its clinical and radiographic presentation. Thus, OA in different joints, and in different patients, may respond differently to the same treatment, confounding trial results. 'Pain phenotyping' of patients would help overcome this, but is very challenging5.
  • OA can progress at different rates. For example, knee OA often progresses slowly. Therefore, if clinical trials of disease-modifying drugs have follow-ups of <12 months, they may miss meaningful changes in structure and possible translation into clinical benefits5.
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References

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