Biologics: the next-generation therapeutics for analgesia?

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Date: Nov. 2011
From: Expert Review of Neurotherapeutics(Vol. 11, Issue 11)
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 5,383 words
Lexile Measure: 1510L

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Author(s): Jonathan P Hatcher 1 , Iain P Chessell 1 , Jane P Hughes [[dagger]] 2

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biologics; interleukin-6; nerve growth factor; pain; tumor necrosis factor

Chronic pain is the leading cause of disability in the developed world, with one in three individuals experiencing pain lasting more than 3 months at some point in their lives, and is the most common symptom for which patients seek medical help. However, current treatments are poorly effective, with approximately only 50% of patients obtaining effective relief of their pain. Unwanted side effects - which include sedation, nausea and vomiting - are common and limit clinical effectiveness. There remains a huge burden of unmet medical need and an urgent requirement for medicines that will provide greater efficacy [1] .

Current approaches

It has been many decades since an analgesic was marketed for the treatment of inflammatory pain that had a truly novel mode of action. For many years treatment has relied on an established treatment ladder that includes the use of drugs such as the NSAIDs or the newer COX2 inhibitors, such as celecoxib, rofecoxib and valdecoxib - all of which target the prostaglandin system - followed by use of drugs targeting the opioid system, such as morphine and oxycodone. Whilst the current market leader, celecoxib [2] , has been reported to show significant clinical activity in many controlled studies, the level of test effectiveness is generally small. For example, Emery et al. reported that following 24 weeks of treatment in a group of rheumatoid arthritis (RA) patients, pain visual analogue scales (VAS) were reduced by only 6.6 mm ([proportional to]6.6%) [3] . Generally it is thought that treatment with celecoxib produces something in the order of a 12-20% improvement on VAS in osteoarthritis patients. In addition to this lack of efficacy in patients, questions have recently been raised about the cardiovascular safety of the coxib class of drugs in general. The increasing risk of heart attacks have raised concerns about their use in the treatment of chronic pain conditions [4,5] and two drugs of this class, rofecoxib and valdecoxib, have now been withdrawn from the market owing to the seriousness of this risk. A raft of new small molecule approaches targeting a range of potential pain mediators, including adenosine receptors and cannabinoid receptors, purinergic approaches, such as P2X7, chemokines, such as fractalkine, cytokines, such as IL-6 and glutamate, as well as sodium and potassium channels have been, and are being, researched with varying degrees of success (for reviews, see [6,7] ), but despite these efforts no novel treatment for inflammatory pain has yet been approved. Over the past few years, the majority of new approaches to the treatment of neuropathic pain have been through the 'off-label'â prescribing of existing drugs, such as gabapentin. A recent analysis of industry-wide failures suggests that while most new treatments fail in preclinical testing, there is an approximate 90% failure rate in Phase II studies with 'lack of efficacy'â being cited as the biggest reason for this failure [8] . This lack of efficacy can be translated...

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Gale Document Number: GALE|A270258624