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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.

In theabstract, there were mistakes in the first sentence of the Results section which was incorrectly written as “MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord.” The incorrect sentence read “All measurement timepoints for these complex protocols were chosen on the basis of our experience and data available in literature on the different pathophysiological parameters of the model (Blom et al., 2007; Baragi et al., 2009; Walsh et al., 2007a; Xie et al., 2012).” The incorrect sentence read “The most prominent MIA-induced alterations of the subchondral trabecular bone microarchitecture were bone resorption (indicated by decreased volume density and trabecular number), increased trabecular separation and pattern factor, and cortical erosions (indicated by increased open pore space volume and open porosity compared to the contralateral side) (Figures 6A–F.

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).

Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, imaging, and morphological techniques. Knee OA was induced by intraarticular MIA injection (0.5 and 0.8 mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20 mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period. MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density. SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5 mg.

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.

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.

Transient receptor potential subfamily V, member 1 (TRPV1) is a nonselective cation channel expressed in both the peripheral and central nervous systems (CNS). TRPV1 protein levels in rat tissues were determined under normal and pain states using enzyme-linked immunosorbent assay. In naive rats, brain TRPV1 protein concentrations ranged from 1.5 to 4 ng/mg in hippocampus, cortex, hypothalamus, and cerebellum. Rat spinal cord TRPV1 protein levels were 40–50 ng/mg in L1–L5 of the lumbar regions, but increased to 97 ± 9.3 ng/mg toward the end of the lumbar region (L6–S1). In the complete Freund’s adjuvant (CFA)-induced inflammatory pain model, TRPV1 protein level significantly increased on both the contralateral (36.5 %, p  < 0.05) and ipsilateral (31.4 %, p  < 0.05) L4–L6 dorsal root ganglia (DRG). TRPV1 protein levels also increased 33.3 % ( p  < 0.05) on the ipsilateral sciatic nerve, but no significant change in the lumbar spinal cord of CFA rats. In the monoiodoacetate-induced rat knee joint pain model, TRPV1 protein level was significantly reduced in the ipsilateral L3–L5 DRG (33.3 %, p  < 0.01), no significant difference was detected in the lumbar region of the spinal cord. Quantitative determination of TRPV1 protein levels may help to elucidate the TRPV1 physiological roles and regulatory mechanisms in various pain states.

This chapter contains sections titled: Introduction Pain in OA Role of Transient Receptor Potential Vanilloid 1 (TRPV1) in Joint Pain Conclusions References

Osteoarthritis (OA) is one of the most commonly occurring forms of arthritis in the world today. It is a debilitating chronic illness causing pain and immense discomfort to the affected individual. Significant research is currently ongoing to understand its pathophysiology and develop successful treatment regimens based on this knowledge. Animal models have played a key role in achieving this goal. Animal models currently used to study osteoarthritis can be classified based on the etiology under investigation, primary osteoarthritis, and post-traumatic osteoarthritis, to better clarify the relationship between these models and the pathogenesis of the disease. Non-invasive animal models have shown significant promise in understanding early osteoarthritic changes. Imaging modalities play a pivotal role in understanding the pathogenesis of OA and the correlation with pain. These imaging studies would also allow in vivo surveillance of the disease as a function of time in the animal model. This review summarizes the current understanding of the disease pathogenesis, invasive and non-invasive animal models, imaging modalities, and pain assessment techniques in the animals.

Pain is one of the most common symptoms among patients with end-stage renal disease (ESRD), and is often under recognized and not adequately managed in hemodialysis (HD) patients. Barriers to adequate pain management include poor awareness of the problem, insufficient medical education, fears of possible drug-related side effects, and common misconceptions about the inevitability of pain in elderly and HD patients. Caregivers working in HD should be aware of the possible consequences of inadequate pain assessment and management. Common pain syndromes in HD patients include musculoskeletal diseases and metabolic neuropathies, associated with typical intradialytic pain. Evaluating the etiology, nature, and intensity of pain is crucial for choosing the correct analgesic. A mechanism-based approach to pain management may result in a better outcome. Pharmacokinetic considerations on clearance alterations and possible toxicity in patients with ESRD should drive the right analgesic prescription. Comorbidities and polymedications may increase the risk of drug–drug interactions, therefore drug metabolism should be taken into account when selecting analgesic drugs. Automedication is common among HD patients but should be avoided to reduce the risk of hazardous drug administration. Further research is warranted to define the efficacy and safety of analgesic drugs and techniques in the context of patients with ESRD as generalizing information from studies conducted in the general population could be inappropriate and potentially dangerous. A multidisciplinary approach is recommended for the management of complex pain syndromes in frail patients, such as those suffering from ESRD.