Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0-10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (- 1.91 ± 0.35, p < 0.0001), average pain (- 1.92 ± 0.35, p < 0.0001) and maximum pain (- 1.97 ± 0.34, p < 0.0001) (data represent mean reduction on a 0-10 NPRS scale ± standard error of the mean (SEM)). A significant increase in grip strength in the treated hand (p < 0.0001) was observed although self-reported functionality did not improve. There were significant (p < 0.005) improvements in three QoL measures: fatigue, stiffness and anxiety. CBD and its metabolites were detected at low concentrations in all urine samples. Measured reductions in pain and increases in grip strength seen during treatment reverted back towards baseline during the washout phase. In summary, pain, grip strength and QoL measures, using smartphone technology, was shown to improve over time following transdermal CBD application suggesting feasibility of this intervention in relieving osteoarthritic hand pain. Proof of efficacy, however, requires further confirmation in a placebo-controlled randomised trial.Trial registration: ANZCTR public trials registry (ACTRN12621001512819, 05/11/2021).

Resiniferatoxin (RTX) is an ultrapotent capsaicin analog with a unique spectrum of pharmacological actions. The therapeutic window of RTX is broad, allowing for the full desensitization of pain perception and neurogenic inflammation without causing unacceptable side effects. Intravesical RTX was shown to restore continence in a subset of patients with idiopathic and neurogenic detrusor overactivity. RTX can also ablate sensory neurons as a \"molecular scalpel\" to achieve permanent analgesia. This targeted (intrathecal or epidural) RTX therapy holds great promise in cancer pain management. Intra-articular RTX is undergoing clinical trials to treat moderate-to-severe knee pain in patients with osteoarthritis. Similar targeted approaches may be useful in the management of post-operative pain or pain associated with severe burn injuries. The current state of this field is reviewed, from preclinical studies through veterinary medicine to clinical trials.

The role of spinal glia in the development and maintenance of chronic pain has become over the last years a subject of increasing interest. In this regard, toll-like receptor 4 (TLR4) signaling has been proposed as a major trigger mechanism. Hence, in this study we explored the implications of TLR4 inhibition in the periphery and primarily in the CNS, focusing on the impact this inhibition renders in pain development and glia activation in the dorsal horn in two models of pain. Making use of a synthetic cluster of differentiation 14 (CD14)/TLR4 antagonist, the effect of TLR4 blockade on tactile allodynia and heat hyperalgesia was evaluated in osteoarthritic and postoperative rat models. An in vitro parallel artificial membrane permeation assay was performed to determine the proneness of the drug to permeate the blood-brain barrier prior to systemic and central administration. Findings suggest a dominant role of peripheral TLR4 in the model of incisional pain, whilst both peripheral and central TLR4 seem to be responsible for osteoarthritic pain. That is, central and peripheral TLR4 may be differently involved in the etiopathology of diverse types of pain what potentially seems a promising approach in the management of pain.

Knee osteoarthritis (OA) is the most common form of arthritis worldwide. The incidence of this disease is rising and its treatment poses an economic burden. Two early targets of knee OA treatment include the predominant symptom of pain, and cartilage damage in the knee joint. Current treatments have been beneficial in treating the disease but none is as effective as total knee arthroplasty (TKA). However, while TKA is an end-stage solution of the disease, it is an invasive and expensive procedure. Therefore, innovative regenerative engineering strategies should be established as these could defer or annul the need for a TKA. Several biomaterial and cell-based therapies are currently in development and have shown early promise in both preclinical and clinical studies. The use of advanced biomaterials and stem cells independently or in conjunction to treat knee OA could potentially reduce pain and regenerate focal articular cartilage damage. In this review, we discuss the pathogenesis of pain and cartilage damage in knee OA and explore novel treatment options currently being studied, along with some of their limitations.

Chronic osteoarthritis pain is accompanied by several comorbidities whose treatment has not been completely resolved. The anti-inflammatory, analgesic, and antidepressant effects of slow-releasing hydrogen sulfide (H2S) donors during osteoarthritic pain have been shown, but their actions in the accompanying memory impairment and anxious-like behaviors have not yet been demonstrated. Using female mice with chronic osteoarthritic pain, the effects of natural, diallyl disulfide (DADS) or synthetic, morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex (GYY4137) slow-releasing H2S donors, on associated cognitive and grip strength deficits and anxiodepressive-like behaviors, were assessed. Their effects on specific brain areas implicated in the modulation of pain and emotional responses were also determined. Results demonstrated an improvement in memory and grip strength deficits, as well as in the anxious-like behaviors associated with chronic pain in GYY4137 and/or DADS treated mice. The painkiller and antidepressant properties of both treatments were also established. Treatment with DADS and/or GYY4137 inhibited: oxidative stress in the amygdala; phosphoinositide 3-kinase overexpression in the amygdala, periaqueductal gray matter, and anterior cingulate cortex; protein kinase B activation in the amygdala and infralimbic cortex; up-regulation of inducible nitric oxide synthase in the amygdala, periaqueductal gray matter and infralimbic cortex and apoptotic responses in the amygdala. These results might explain the recovery of memory and grip strength and the inhibition of allodynia and associated anxiodepressive-like behaviors by these treatments. In conclusion, this study revealed new properties of slow-releasing H2S donors in cognitive impairment and affective disorders linked with chronic osteoarthritis pain and their effects on the central nervous system.

In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour.
MJL was used to induce OA in the right knees of 12-week-old male C57BL/6 mice (40 cycles, 9N, 3x/week for 2 weeks). Mechanical sensitivity thresholds and weight-bearing ratios were measured before loading and at weeks one, three and six post-loading. At these time points, separate groups of loaded and non-loaded mice (n = 12/group) were sacrificed, joints collected, and fur corticosterone levels measured. μCT analyses of subchondral bone integrity was performed before joint sections were prepared for nerve quantification, cartilage or synovium grading (scoring system from 0 to 6).
Loaded mice showed increased mechanical hypersensitivity paired with altered weight-bearing. Initial ipsilateral cartilage lesions 1-week post-loading (1.8 ± 0.4) had worsened at weeks three (3.0 ± 0.6, CI = -1.8-0.6) and six (2.8 ± 0.4, CI = -1.6-0.4). This increase in lesion severity correlated with mechanical hypersensitivity development (correlation; 0.729, P = 0.0071). Loaded mice displayed increased synovitis (3.6 ± 0.5) compared to non-loaded mice (1.5 ± 0.5, CI = -2.2-0.3) 1-week post-loading which returned to normal by weeks three and six. Similarly, corticosterone levels were only increased at week one post-loading (0.21 ± 0.04 ng/mg) compared to non-loaded controls (0.14 ± 0.01 ng/mg, CI = -1.8-0.1). Subchondral bone integrity and nerve volume remained unchanged.
Our data indicates that although the loading induces an initial stress reaction and local inflammation, these processes are not directly responsible for the nociceptive phenotype observed. Instead, MJL-induced allodynia is mainly associated with OA-like progression of cartilage lesions.

Osteoarthritic pain has a strong impact on patients\' quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3-14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991. Together, these results indicate that suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of osteoarthritic pain.

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg).

Osteoarthritis prevalence is expected to increase markedly in the Asia-Pacific region due to rapid population aging. Identifying effective and safe therapeutic options to manage osteoarthritic pain is viewed as a priority. The Asia-Pacific Experts on Topical Analgesics Advisory Board developed consensus statements for use of topical NSAIDs in musculoskeletal pain. Evidence supporting these statements in osteoarthritic pain was reviewed. Best available evidence indicates that topical NSAIDs have a moderate effect on relief of osteoarthritic pain, comparable to that of oral NSAIDs but with a better risk-to-benefit ratio. International clinical practice guidelines recommend topical NSAIDs on par with or ahead of oral NSAIDs for pain management in patients with knee and hand osteoarthritis, and as the first-line choice in persons aged ≥75 years.

BACKGROUND: The source of pain in patellofemoral osteoarthritis is not fully understood. The purpose of this study was to identify the origin of pain using intraosseous pain catheters and to show early results with an osteotomy that is potentially denervating and hydrostatic pressure-relieving.
METHODS: Five patients with patellofemoral osteoarthritis and pain with straight downward patellofemoral compression were included. All underwent arthroscopic placement of two 0.8mm catheters into the medial and lateral patella prior to subsequent patellar facetectomy with an incomplete horizontal patellar osteotomy. The catheters were first flushed with 0.5ml saline, then with local anaesthetic to determine pain response. After a mean of 44months the latest clinical examination was performed.
RESULTS: Instillation of less than 0.5ml of saline provoked sharp pain, which could be localised by all patients as medial or lateral within the patella. Subsequent instillation of local anaesthetic suppressed the mean patellar tenderness during axial compression from VAS 6 to VAS 1. In one of the five patients, patellar osteotomy did not relieve symptoms and further surgical intervention was required. The remaining four patients experienced a clinical improvement with a mean subjective knee value of 55 (range 40 to 65) out of 100.
CONCLUSIONS: This is the first report on intraosseous catheters applying local anaesthetics into bone. There is a surprisingly precise intraosseous spatial resolution of pain perception in the patella and triggering of pain in osteoarthritis appears at least in part to occur through intraosseous increase of hydrostatic pressure.
METHODS: Level IV, Case Series.