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. 2014 Apr;9(2):197-276.
doi: 10.2217/ijr.14.10.

Future directions for the management of pain in osteoarthritis

Nidhi Sofat, Anasuya Kuttapitiya

Future directions for the management of pain in osteoarthritis

Nidhi Sofat et al. Int J Clin Rheumtol. 2014 Apr.

Abstract

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future.

Keywords: NSAIDs; analgesia; bone marrow lesions; cartilage; opiates; osteoarthritis; pain; quantitative sensory testing; subchondral bone; synovium.

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Figures

Figure 1
Figure 1. Histological features of tissue damage in osteoarthritis
(A) There is abundant staining of proteoglycans within cartilage with chondrocytes visible within this section of normal cartilage stained with toluidine blue. (B) Early osteoarthritic cartilage showing loss of cartilage extracellular matrix staining, reduction in chondrocytes and early fibrillation of the articular surface of cartilage; stained with fast green and toluidine blue. (C) Severely damaged osteoarthritic cartilage showing profound loss of proteoglycans staining and fissuring of the cartilage articular surface. The section is stained with toluidine blue. Osteoarthritis samples (B) and (C) were obtained at the time of joint replacement surgery from patient with osteoarthritis. Normal cartilage was obtained from a donor undergoing surgery for osteosarcoma. Full informed consent was obtained for all studies.
Figure 2
Figure 2. Radiographic features of tissue damage in osteoarthritis
(A) Example of osteophytes (white arrows) shown in the anterior lumbar vertebral bodies. (B) MRI with T2-weighted sequences demonstrating cartilage loss (white arrow) in patient with osteoarthritis. (C) MRI with T2-weighted sequences demonstrating bone marrow lesions localized to the knee patella (white arrow) in a patient with osteoarthritis. Image acquisition paradigm for MRIs courtesy of Franklyn Howe (St George’s University, London, UK).
Figure 3
Figure 3. Molecular mechanisms of pain in osteoarthritis (see facing page)
(A) Left: normal joint structure; right: changes taking place in the synovial joint during the development of OA. (B) Bone cells (osteoblasts. osteoclasts and osteocytes), fibroblasts, macrophages and mast cells from the SCB invade the CC and the NCC, via microfractures in the bone–cartilage interface. The disruption of the osteochondral junction promotes production of enzymes, growth factors and molecules (ADAMTS-4, ADAMTS-5, AGEs, BMPs, FGF-18, MMP-3, MMP-13, NGF, TGF-β and VEGF) by the invading cells and chondrocytes stimulating innervation and vascularization ultimately recruiting NVBs (BV and PNF) from the HC. (C) Inflammation in the synovium or synovitis causes joint swelling and effusion. Hyperplasia is seen in the synovial tissue resulting in the formation of a HSL followed by the infiltration of inflammatory cells – possibly owing to a systemic response or secondary to cartilage degradation or bone marrow lesion formation. Factors, enzymes and cytokines (GM-CSF, IL-1 family, IL-6 family, MMPs, NGF, TNF-α, and VEGF) stimulated via the cells encourage innervation and angiogenesis (NVB: BV and PNF). (D) Peripheral inflammation, cartilage degradation and bone marrow lesions produce numerous inflammatory mediators (e.g., sensitisers: bradykinin, a peptide which causes blood vessels to dilate; E2 stimulates osteoblasts to release factors that stimulate bone resorption by osteoclasts; PGE2; substance P, a neuropeptide belonging to tachykinin neuropeptide family; and TNFR-α) and growth factors (e.g., GDNF and NGF) activating their subsequent receptors (bradykinin receptor B2, EP2, GDNF-α, NK1, TNFR1 and TRKA). The sensitizers work by phosphorylating TRPs: TRPA1 and TRPV1, facilitating the trafficking of the channels to the membrane of the PT. Once in the membrane of the PT, TRPA1 modulates calcium exchange with TRPV1 enhancing the nociceptive activity of both channels. The growth factors are transported down the neuron towards the DRG. Altered sensitization of such signaling pathways decreases the pain threshold in OA patients (RPT). (E) During ST, growth factors (GDNF and NGF) are transmitted into the cell body of the DRG, where they facilitate intracellular signaling pathways, for example, the MAPK cascade upregulating the expression of TRP channels (TRPA1/TRPV1), which are then transported via the neuron into the PNF and PT. Changes in this pathway during OA can switch the activity of the neurons to an altered state encouraging peripheral sensitization and RPT at the impaired site. Signaling pathways activated in the DRG then take effect in central processes. AGE: Advanced glycation end product; BMP: Bone morphogenetic protein; BV: Blood vessel; CC: Calcified cartilage; DRG: Dorsal root ganglion; EP2: Prostaglandin E2 receptor; GM-CSF: Granulocyte macrophage colony-stimulating factor; HC: Haversian canal; HSL: hyperplastic synovial lining; MMP: Matrix metalloproteinase; NCC: Noncalcified cartilage; NVB: Neurovascular bundle; OA: Osteoarthritis; P: Phosphorylation; PGE2: Prostaglandin E2; PNF: Perivascular nerve fiber; PT: Peripheral terminal; RPT: Reducing the pain threshold; SCB: Subchondral bone; ST: Signal transduction; TRP: Transient receptor potential cation channel. Image courtesy of Gayanthi Perera.
Figure 4
Figure 4. Sensitisation in osteoarthritis
Summary of types of studies that have provided information regarding evidence for features of sensitization in osteoarthritis from brain neuroimaging and quantitative sensory testing studies. BOLD: Blood–oxygen level dependent.
Figure 5
Figure 5. Complex nature of pain in osteoarthritis
Graph demonstrating potential contributing factors to OA pain. The multiple trajectories are shown to highlight that the relation between cartilage degradation, osteophytes, synovitis, bone marrow lesions, osteochondral cysts, muscle/ligament damage, psychosocial factors and comorbidity do not always appear to be linearly correlated from emerging studies. OA: Osteoarthritis.
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