Expert opinion on emerging drugs: chronic low back pain

Hsu, Eugene; Murphy, Sunberri; Chang, David S.; Cohen, Steven P.

doi:10.1517/14728214.2015.993379

Cited by 11 publications

(11 citation statements)

References 172 publications

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“…It is also associated with enormous socioeconomic and personal costs to the affected individuals, their families and society (Hsu et al, 2015). Rodent models that more closely mimic individual human pain conditions are invaluable for gaining new insight on the specific pathobiology underpinning each condition.…”

Section: Discussionmentioning

confidence: 99%

“…Globally, chronic low back pain (LBP) is a leading cause of disability that is notoriously challenging to treat ( Hsu et al, 2015 ). In the adult population, chronic LBP ranked first for disability of 291 conditions in the Global Burden of Disease 2010 study ( Hoy et al, 2014 ) and sixth in terms of overall socioeconomic burden in disability-adjusted life years ( Murray et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the adult population, chronic LBP ranked first for disability of 291 conditions in the Global Burden of Disease 2010 study ( Hoy et al, 2014 ) and sixth in terms of overall socioeconomic burden in disability-adjusted life years ( Murray et al, 2012 ). Additionally, chronic LBP has a global point prevalence of 9.4% and a lifetime prevalence of 50–90% ( Hoy et al, 2014 ; Hsu et al, 2015 ). Currently available drug treatments for the relief of chronic LBP are paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and opioids ( Hsu et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods

et al. 2017

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Chronic low back pain (LBP), the leading cause of disability globally, is notoriously difficult to treat. Most rodent models of LBP mimic lumbar radicular pain rather than mechanical LBP. Here, we describe establishment of a new rat model of mechanical LBP that is devoid of a neuropathic component. Groups of adult male Sprague Dawley rats were anesthetized and their lumbar L4/L5 and L5/L6 intervertebral disks (IVDs) were punctured (0.5 mm outer diameter, 2mm-deep) 5 (LPB-5X), or 10 (LBP-10X) times per disk. Sham-rats underwent similar surgery, but without disk puncture. Baseline noxious pressure hyperalgesia of lumbar axial deep tissues, mechanical allodynia in the hindpaws and gait were assessed prior to surgery and once-weekly until study completion on day 49. The model was also characterized using pharmacologic and histologic methods. Good animal health was maintained for ≥ 49 days post-surgery. For LBP- but not sham-rats, there was temporal development of noxious pressure hyperalgesia in lumbar axial deep tissues at days 14–49 post-surgery. Importantly, there were no between-group differences in von Frey paw withdrawal thresholds or gait parameters until study completion. On day 49, significant histologic changes were observed in the L4/L5 and L5/L6 IVDs for LBP-10X rats, but not sham-rats. In LBP-10X rats, single bolus doses of morphine produced dose-dependent relief of primary and secondary mechanical hyperalgesia in lumbar axial deep tissues at L4/L5 and L1, respectively. In conclusion, our new rat model has considerable potential for providing novel insight on the pathobiology of mechanical LBP and for analgesic efficacy assessment of novel compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods

et al. 2017

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“… 6 , 7 Thus, although there has been a myriad of pain targets proposed over the past several decades, the majority of these pharmacotherapies for treating skeletal pain have failed to come to market. 8 – 10 …”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur

et al. 2017

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Sequestration of nerve growth factor (NGF) significantly attenuates skeletal pain in both animals and humans. However, relatively little is known about the specific cell types that express NGF or its cognate receptors tropomyosin receptor kinase A (TrkA) and p75 in the intact bone and articular cartilage. In the present study, antibodies raised against NGF, TrkA, and p75 (also known as CD271) were used to explore the expression of these antigens in the non-decalcified young mouse femur. In general, all three antigens displayed a remarkably restricted expression in bone and cartilage with less than 2% of all DAPI+ cells in the femur displaying expression of any one of the three antigens. Robust NGF immunoreactivity was found in mostly CD-31− blood vessel-associated cells, a small subset of CD-31+ endothelial cells, an unidentified group of cells located at the subchondral bone/articular cartilage interface, and a few isolated, single cells in the bone marrow. In contrast, p75 and TrkA were almost exclusively expressed by nerve fibers located nearby NGF+ blood vessels. The only non-neuronal expression of either p75 or TrkA in the femur was the expression of p75 by a subset of cells located in the deep and middle zone of the articular cartilage. Understanding the factors that tightly regulate the basal level of expression in normal bone and how the expression of NGF, TrkA, and p75 change in injury, disease, and aging may provide insights into novel therapies that can reduce skeletal pain and improve skeletal health.

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“…Taken together, the current gold standard preclinical pain measures have failed to find analgesics with clinically meaningful efficacy in the last decades (Hsu, Murphy, Chang, & Cohen, ; Kissin, ). Accordingly, analgesic candidates selected by such preclinical pain measures have been far from fulfilling the expected profile for innovative analgesics, i.e., showing significant efficacy in patients with chronic pain resistant to existing drugs.…”

Section: Introductionmentioning

confidence: 99%

Giving priority to preclinical pain measures resistant to existing drugs for developing innovative analgesics

Nagakura

2018

Drug Development Research

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Preclinical Research & Development Chronic pain is a major health and socioeconomic burden because of its high prevalence, negative influence on patients' physical and/or emotional conditions, and huge costs to society. The responses of chronic pain patients to analgesic therapies vary substantially from individual to individual, and no more than a minority of chronic pain patients with various etiologies such as neuropathy and inflammation are, in fact, successfully relieved by existing drugs including opioid analgesics, nonopioid analgesics, antiepileptics, and antidepressants. The large primary unmet medical need would therefore be the patient domain that does not respond well to existing drugs. Accordingly, the expected profile for innovative analgesics would not be efficacy in the responder patient domain, but significant efficacy in patients with existing drug-resistant chronic pain. Meanwhile, the current gold standard in preclinical pain measures for the screening of analgesic candidates is existing drug-sensitive pain measures in animal models of chronic pain. Analgesic candidates screened using such preclinical pain measures during the last decades have been far from fulfilling the expected profile for innovative analgesics. Given that it is unlikely that such existing drug-sensitive pain measures are the best approach to developing innovative analgesics, one of the other approaches would be giving priority to existing drug-resistant pain measures in preclinical research. This review introduces potentially applicable existing drug-resistant pain measures published so far and suggests that the use of them would lead to the development of innovative analgesics.

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Expert opinion on emerging drugs: chronic low back pain

Cited by 11 publications

References 172 publications

Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods

Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods

Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur

Giving priority to preclinical pain measures resistant to existing drugs for developing innovative analgesics

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