Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks ...when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.
Chronic pain is one of the most common, yet poorly studied, complaints in people suffering from Ehlers–Danlos syndromes (EDS). This heterogeneous group of heritable connective tissue disorders is ...typically characterized by skin hyperextensibility, joint hypermobility, and generalized connective tissue fragility. Most EDS types are caused by genetic defects that affect connective tissue biosynthesis, thereby compromising collagen biosynthesis or fibrillogenesis and resulting in a disorganized extracellular matrix. Even though chronic pain is a major source of disability, functional impairment, and psychosocial suffering in EDS, currently used analgesics and other treatment strategies provide inadequate pain relief and thus represents an important unmet medical need. An important contributor to this is the lack of knowledge about the underlying mechanisms. In this narrative review, we summarize the current understanding of pain and the associated mechanisms in EDS based on clinical studies focusing on questionnaires and experimental pain testing as well as studies in animal models of EDS. In addition, we highlight the challenges, gaps, and opportunities in EDS‐pain research.
Chronic pain continues to be a significant global burden despite the availability of a variety of nonpharmacologic and pharmacologic treatment options. Thus, there is a need for new analgesics with ...novel mechanisms of action. In this regard, antibodies directed against nerve growth factor (NGF-Abs) are a new class of agents in development for the treatment of chronic pain conditions such as osteoarthritis and chronic low-back pain. This comprehensive narrative review summarizes evidence supporting pronociceptive functions for NGF that include contributing to peripheral and central sensitization through tropomyosin receptor kinase A activation and stimulation of local neuronal sprouting. The potential role of NGF in osteoarthritis and chronic low-back pain signaling is also examined to provide a mechanistic basis for the observed efficacy of NGF-Abs in clinical trials of these particular pain states. Finally, the safety profile of NGF-Abs in terms of common adverse events, joint safety, and nerve structure/function is discussed.
Objective
To analyze disease burden in osteoarthritis (OA) according to Multidimensional Health Assessment Questionnaire (MDHAQ)/Routine Assessment of Patient Index Data 3 (RAPID3) scores at the ...initial visit and the 6‐month follow‐up visit, compared with rheumatoid arthritis (RA) as a benchmark for high disease burden.
Methods
All patients with all diagnoses at the Rush University Medical Center Division of Rheumatology complete a paper MDHAQ at all visits, saved as a PDF in the electronic health record. MDHAQ 0–10 scores for physical function, pain, and patient global assessment (compiled into RAPID3 0–30 scores) and additional scales at the initial and 6‐month follow‐up visits, for new OA and RA patients seen from 2011 to 2017, were compared. OA and RA patients were classified as self‐referred or physician‐referred, and RA patients were classified as disease‐modifying antirheumatic drug (DMARD)–naive or having prior‐DMARD treatment. Patient groups were compared using t‐tests and analysis of variance, adjusted for age, disease duration, body mass index (BMI), education, and ethnicity.
Results
Compared with RA patients, OA patients had higher age, BMI, and disease duration. At initial visit, the mean RAPID3 did not differ significantly in OA versus DMARD‐naive RA patients, whether self‐ or physician‐referred (range 14.8–16.4 P = 0.38), or in all OA patients versus DMARD‐naive RA patients versus prior‐DMARD RA patients (15.0, 15.7, and 15.8, respectively P = 0.49). After 6 months, RAPID3 was improved to 13.3, 10.3, and 10.8, respectively, which represented substantially greater improvement in RA patients than OA patients (P < 0.001). Similar results were seen for most self‐reported measures and in adjusted analyses.
Conclusion
MDHAQ/RAPID3 scores are similar in OA and RA patients at the initial visit, but higher in OA patients than in RA patients 6 months later, reflecting superior RA treatments. The same MDHAQ/RAPID3 allows comparisons of disease burdens in different diseases.
Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. We undertook ...this study to characterize age-associated changes in knee OA, pain-related behaviors, and dorsal root ganglion (DRG) molecular phenotypes in mice of both sexes.
Male or female C57BL/6 mice 6 or 20 months of age were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 DRG immune characterization via flow cytometry. DRG gene expression in older mice and humans was also examined.
Male mice at 20 months of age had worse cartilage degeneration than 6-month-old mice. Older female mouse knees showed increased cartilage degeneration but to a lesser degree than those of male mice. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male mouse DRGs showed increased expression of Ccl2 and Ccl5, and older female mouse DRGs showed increased Cxcr4 and Ccl3 expression compared to 6-month-old mouse DRGs, among other differentially expressed genes. Human DRG analysis from 6 individuals >80 years of age revealed elevated CCL2 in men compared to women, whereas CCL3 was higher in DRGs from women.
We found that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of OA therapies.
Objective
To determine whether selected damage‐associated molecular patterns (DAMPs) present in the osteoarthritic (OA) joints of mice excite nociceptors through Toll‐like receptor 4 (TLR‐4).
Methods
...The ability of S100A8 and α2‐macroglobulin to excite nociceptors was determined by measuring the release of monocyte chemoattractant protein 1 (MCP‐1) by cultured dorsal root ganglion (DRG) cells as well as by measuring the intracellular calcium concentration (Ca2+i) in cultured DRG neurons from naive mice or from mice that had undergone surgical destabilization of the medial meniscus (DMM) 8 weeks previously. The role of TLR‐4 was assessed using TLR‐4–/– cells or a TLR‐4 inhibitor. The Ca2+i in neurons within ex vivo intact DRGs was measured in samples from Pirt‐GCaMP3 mice. Neuronal expression of the Tlr4 gene was determined by in situ hybridization. DMM surgery was performed in wild‐type and TLR‐4–/– mice; mechanical allodynia was monitored, and joint damage was assessed histologically after 16 weeks.
Results
DRG neurons from both naive and DMM mice expressed Tlr4. Both S100A8 and α2‐macroglobulin stimulated release of the proalgesic chemokine MCP‐1 in DRG cultures, and the neurons rapidly responded to S100A8 and α2‐macroglobulin with increased Ca2+i. Blocking TLR‐4 inhibited these effects. Neurons within intact DRGs responded to the TLR‐4 agonist lipopolysaccharide. In both of the calcium‐imaging assays, it was primarily the nociceptor population of neurons that responded to TLR‐4 ligands. TLR‐4–/– mice were not protected from mechanical allodynia or from joint damage associated with DMM.
Conclusion
Our experiments suggest a role of TLR‐4 signaling in the excitation of nociceptors by selected DAMPs. Further research is needed to delineate the importance of this pathway in relation to OA pain.
Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in accordance with a global ...aging population. In addition to affecting patients' physical lives, chronic pain also adversely affects patients' mental wellbeing. However, there remain no pharmacologic interventions to slow down the progression of OA and pain-alleviating therapies are largely unsuccessful. The presence of low-level inflammation in OA has been recognized for many years as a major pathogenic driver of joint damage. Inflammatory mechanisms can occur locally in joint tissues, such as the synovium, within the sensory nervous system, as well as systemically, caused by modifiable and unmodifiable factors. Understanding how inflammation may contribute to, and modify pain in OA will be instrumental in identifying new druggable targets for analgesic therapies. In this narrative review, we discuss recent insights into inflammatory mechanisms in OA pain. We discuss how local inflammation in the joint can contribute to mechanical sensitization and to the structural neuroplasticity of joint nociceptors, through pro-inflammatory factors such as nerve growth factor, cytokines, and chemokines. We consider the role of synovitis, and the amplifying mechanisms of neuroimmune interactions. We then explore emerging evidence around the role of neuroinflammation in the dorsal root ganglia and dorsal horn. Finally, we discuss how systemic inflammation associated with obesity may modify OA pain and suggest future research directions.
Abstract
There is a big need for the development of novel therapies for the safe management of chronic pain associated with OA. Here we reviewed PubMed (2015 onward) and ClinicalTrials.gov for ...ongoing and recently completed trials where pain in OA is the primary outcome measure. Three broad categories were identified: biological therapies, small molecules and cryoneurolysis. The most promising new strategy is blockade of nerve growth factor with antibodies. Two anti-nerve growth factor antibodies, tanuzemab and fasinumab, are in active development after the 2010 hold on trials was lifted in 2015. In addition, several active clinical trials are testing distinct mechanism-based interventions, including cytokine inhibition, selective μ, δ or κ opioid receptor agonists, zoledronate and intra-articular capsaicin. In addition to pharmacological approaches, cryoneurolytic strategies that directly target peripheral nerves may play a role in OA pain management, but efficacy profiles and long-term effects of such treatments need more study. Clearly, the therapeutic landscape for OA pain is rapidly expanding. Since symptomatic OA is a heterogeneous disease, the challenge will be to identify patients that will benefit the most from specific approaches.
Objective
To determine the ability of drugs that activate inhibitory G protein–coupled receptors (GPCRs) expressed in peripheral voltage‐gated sodium channel 1.8 (NaV1.8)–positive sensory neurons to ...control osteoarthritis (OA)–associated pain.
Methods
We used designer receptors exclusively activated by a designer drug (DREADD) technology, which employs engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand clozapine N‐oxide (CNO). NaV1.8‐Pdi C57BL/6 mice were generated to express the inhibitory DREADD receptor Pdi in NaV1.8‐expressing sensory neurons. Destabilization of the medial meniscus (DMM) surgery was performed in 10‐week‐old male mice. Four, 8, 12, or 16 weeks after surgery, knee hyperalgesia or hind paw mechanical allodynia was tested. Subsequently, CNO or vehicle was administered, and the effect on pain‐related behaviors was measured by a blinded observer. Morphine was used as a control.
Results
Immunohistochemistry and electrophysiology confirmed functional expression of the inhibitory DREADD receptor Pdi by NaV1.8‐positive sensory neurons. Acute inhibition of NaV1.8‐expressing neurons in mice treated with CNO reduced knee hyperalgesia 4 weeks after DMM surgery and reduced mechanical allodynia 8 weeks after DMM surgery. Inhibition had no effect on pain‐related behaviors 12 and 16 weeks after DMM surgery. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage of experimental OA.
Conclusion
Chemogenetic inhibition of NaV1.8‐expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental OA, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic OA pain.
Animal models of osteoarthritis are extensively used for investigating disease pathways and for preclinical testing of novel therapies. Their predictive utility, however, has often been questioned, ...mainly because preclinical efficacy of novel therapeutics is poorly translated in clinical trials. In the current narrative review, we consider the preclinical models that were used to support undertaking clinical trials for disease-modifying osteoarthritis drugs, and compare outcomes between clinical and preclinical studies. We discuss this in light of the 1999 Food and Drug Administration draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis, which raised five considerations on the usefulness of osteoarthritis models. We systematically discuss what has been learnt regarding these five points since 1999, with emphasis on replicating distinct risk factors and subtypes of human osteoarthritis, and on comprehensive evaluation of the disease in animals, including pathology of all joint tissues, biomarker analysis, and assessment of pain and joint function. Finally, we discuss lessons learnt and propose some recommendations for how the evidence from preclinical research might be strengthened with a view to improving success in clinical translation.
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