Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models?

Miller, Rachel E.; Block, Joel A.; Malfait, Anne-Marie

doi:10.1097/bor.0000000000000354

Cited by 82 publications

(79 citation statements)

References 47 publications

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“…However, intrathecal Derm-BOT in the naïve mice reported here, had no effect on baseline mechanical pain sensitivity but only on mechanical thresholds in injury-induced pain states. This suggests that the target for Derm-BOT mediated analgesia was not primary afferents (62,63). The successful use of SP-saporin in rodents and dogs also opens up the possibility that silencing of this pathway with SP-BOT might be sufficient to control chronic pain states in human patients without permanent damage to the spinal cord (11,14).…”

Section: Discussionmentioning

confidence: 99%

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Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

et al. 2018

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Overline: PainOne Sentence Summary: Silencing key neurons with botulinum toxin conjugates exerts long-lasting pain relief in mouse models of chronic pain. 2 AbstractChronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain processing neurons in the spinal cords of mice.We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration.

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Section: Discussionmentioning

confidence: 99%

“…Please note that, as in our previous paper (67), we logged the data of the behavioural testes to ensure a normal distribution since the Von Frey's hairs are distributed on an exponential scale. Mills et al, 2012, recently demonstrated that Log transformation makes more 'mathematical and biological sense' (62).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

et al. 2018

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“…Although strongly expressed on nociceptive neurons, the tissue distribution of these receptors is broader and includes bone and cartilage as well as other non‐neuronal tissues . Biologic agents that specifically block NGF to treat pain may obviate many of the side effects of currently used analgesic medications, such as opioids and nonsteroidal antiinflammatory drugs (NSAIDs), which rely on different mechanisms of action . This new therapeutic could benefit patients experiencing pain from osteoarthritis (OA), a progressive, chronic disease characterized by joint breakdown and functional loss .…”

Section: Introductionmentioning

confidence: 99%

“…Biologic agents that specifically block NGF to treat pain may obviate many of the side effects of currently used analgesic medications, such as opioids and nonsteroidal antiinflammatory drugs (NSAIDs), which rely on different mechanisms of action . This new therapeutic could benefit patients experiencing pain from osteoarthritis (OA), a progressive, chronic disease characterized by joint breakdown and functional loss . However, NGF‐directed therapies exhibit their own unique side effect profile in OA, which includes alterations in peripheral sensation and development of arthropathies .…”

Section: Introductionmentioning

confidence: 99%

“…This new therapeutic could benefit patients experiencing pain from osteoarthritis (OA), a progressive, chronic disease characterized by joint breakdown and functional loss . However, NGF‐directed therapies exhibit their own unique side effect profile in OA, which includes alterations in peripheral sensation and development of arthropathies .…”

Section: Introductionmentioning

confidence: 99%

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The Efficacy, Tolerability, and Joint Safety of Fasinumab in Osteoarthritis Pain: A Phase IIb/III Double‐Blind, Placebo‐Controlled, Randomized Clinical Trial

Dakin

DiMartino

Gao

et al. 2019

Arthritis & Rheumatology

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ObjectiveTo prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti–nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain.MethodsPatients with moderate‐to‐severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow‐up, and if prompted, at the time of active joint symptoms.ResultsOf the 421 patients randomized, 342 completed the 36‐week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging −0.78 to −1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment‐emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab‐treated patients and 1% of placebo‐treated patients) occurred in a dose‐dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab.ConclusionFasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit‐to‐risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA.

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Clinical Management and Pharmacologic Treatment of Pain

McKune

2024

Veterinary Anesthesia and Analgesia

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Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models?

Cited by 82 publications

References 47 publications

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

The Efficacy, Tolerability, and Joint Safety of Fasinumab in Osteoarthritis Pain: A Phase IIb/III Double‐Blind, Placebo‐Controlled, Randomized Clinical Trial

Clinical Management and Pharmacologic Treatment of Pain

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