Painful Inflammatory Disorders Research Articles

The analgesic effect of low-dose radiotherapy in treating benign musculoskeletal painful disorders using different energies: A retrospective cohort study

Abstract Introduction: This retrospective cohort study tries to determine if there is a correlation between the effectiveness of low-dose radiotherapy (LDRT) in treating painful inflammatory or degenerative musculoskeletal disorders (MSDs) and the applied radiotherapy energy. Patients and Methods: Between September 2019 and January 2020, a total of 91 patients with either painful inflammatory or degenerative MSDs were treated with LDRT. The inclusion criteria were patients older than 40 years with either painful inflammatory disorders such as epicondylitis humeri, plantar fasciitis or degenerative osteoarticular disorders of the wrist or ankle joints. All patients were treated with a single dose of 0·5 Gy and a total dose of 6·0 Gy (2 to 3 fractions weekly). Patients were divided into two groups. Orthovolt group was treated with 200 Kv, 15 mA and 1 mm copper filtration with different tubes according to the site to treatment using direct fields. The second group included patients treated with Linac machines with opposing fields using energies between 6 and 18 MV. The pain was evaluated before and on the last day of treatment and 4–6 months later using the Numerical Rating Scale. Results: 91 patients compatible with the inclusion criteria were identified with a median of 60 years. The median duration of symptoms was 6 months. 46% of patients were males, and 54% were females. The Orthovolt group included 49% of the patients and the Megavoltage group 51%. Most of the patients (98%) were previously treated with other methods such as local corticosteroid injection, painkillers or physiotherapy. At the end of the treatment, 60% of the patient’s showed subjective pain relief and only 6% had a complete response. The follow-up conducted 4 to 6 months after the treatment showed that 65% of patients had a complete response and 8% had an improvement. The comparison between both studied groups shows that the used energy does not affect the response either at the end of the treatment or at the second control. The relationship between the aetiology and the early and late responses shows no difference in the early response but a better late response in patients suffering from inflammatory diseases with a p-value of 0·015. The response according to the treated location shows that patients with osteoarthritis of the ankle joint have a worse response in comparison to other examined joints and plantar fasciitis. Conclusion: LDRT is an effective analgesic treatment option for both inflammatory and degenerative MSDs. There is no difference in response according to the used energy, and most of the patients show late responses 4 to 6 months after the treatment.

Analgesic, anti-inflammatory and acute oral toxicity profile of leaf and bark extracts of Albizia procera

BackgroundPain and inflammation are associatory events in cancer, diabetes, cardiovascular diseases, arthritis and other chronic diseases. Corticosteroids, non-steroidal anti-inflammatory drugs exert potential side effects on long term use. This study was aimed to investigate the acute oral toxicity, anti-inflammatory and analgesic activities of leaf and bark extracts of Albizia procera in experimental animal models.MethodsEthyl acetate, ethanol, and hydroalcoholic extracts of Albizia procera (leaf and bark) were subjected for acute oral toxicity, anti-inflammatory and analgesic screening. Carrageenan and cotton pellet granuloma models were used to assess acute and chronic anti-inflammatory effects, respectively. Intraplanar formalin test was used to assess the analgesic activity.ResultsAll the extracts of Albizia procera were found to be well-tolerated up to 2000 mg/kg in female rats. Ethanolic leaf (ETLE) and bark (ETBE) of Albizia procera showed anti-inflammatory actions. But, only ETBE produced significant protection in chronic inflammation and analgesic activity.ConclusionIn summary, Albizia procera possess significant anti-inflammatory and analgesic properties. This study adds evidence on the traditional use of Albizia procera plant for treating painful inflammatory disorders.

Inhibition of Spinal Interleukin-33 Attenuates Peripheral Inflammation and Hyperalgesia in Experimental Arthritis.

Accumulating evidence indicates that the continuous and intense nociceptive from inflamed tissue may increase the excitability of spinal dorsal horn neurons, which can signal back and modulate peripheral inflammation. Previous studies have demonstrated that spinal interleukin (IL)-33 contributes to the hyperexcitability of spinal dorsal horn neurons. This study was undertaken to investigate whether spinal IL-33 can also influence a peripheral inflammatory response in a rat model of arthritis. Lentivirus-delivered short hairpin RNA targeting IL-33 (LV-shIL-33) was constructed for gene silencing. Rats with adjuvant-induced arthritis (AIA) were injected intrathecally with LV-shIL-33 3days before the complete Freund's adjuvant (CFA) injection. During an observation period of 21days, pain-related behavior and inflammation were assessed. In addition, the expression of spinal proinflammatory cytokines and the activation of spinal extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB) pathways were evaluated on 9days after CFA treatment. The existence of tissue injury or inflammation in rats with AIA resulted in the upregulation of spinal IL-33, which is predominantly expressed in neurons, astrocytes, and oligodendrocytes. Intrathecal administration of LV-shIL-33 significantly alleviated hyperalgesia, paw swelling, and joint destruction, and attenuated the expression of proinflammatory cytokines [IL-6, IL-1β, and tumor necrosis factor-α (TNF-α)], as well as the activation of ERK and NF-κB/p65 in the spinal cord. Our data suggest that spinal IL-33 contributes to the development of both peripheral inflammation and hyperalgesia. Thus, interference with IL-33 at the spinal level might represent a novel therapeutic target for painful inflammatory disorders.

Exploring Access to Surgical Interventions for Hidradenitis Suppurativa: Retrospective Population-Based Analysis.

Hidradenitis suppurativa (HS) is a painful inflammatory disorder that confers significant distress to patients, with surgery as an integral treatment modality. To inform improvements in care, patterns in HS surgery were assessed. A retrospective population-based analysis was performed on Ontario billing claims for HS surgery across a period of 10 years from January 1, 2008 to December 31, 2017. HS surgery was defined as the excision of inguinal, perineal, or axillary skin and sweat glands for hidradenitis. The top 5 billing specialties, including general and plastic surgery, were analyzed. The total number of procedures performed as well as the number performed per physician were investigated. Patient and physician locations were compared. A total of 7195 claims for the excision of inguinal, perineal, or axillary skin and sweat glands for HS were submitted across the study period. Annual HS surgery claims showed an increasing trend across 10 years, ranging between 4.9 and 5.8 per 100,000 population. However, overall, for every additional year, the number of claims per 100,000 population only increased slightly, by 0.03 claims. The number of providers steadily decreased, ranging between 1.7 and 1.9 per 100,000, with approximately twice as many general than plastic surgeons. However, again overall, for every additional year, the number of providers per 100,000 population decreased slightly, by 0.002 physicians. The mean annual number of procedures per physician rose from 2.8 to 3.1. In rural areas, analyzed per claim, general surgeons performed the majority of surgeries (1318/2003, 65.8%), while in urban areas, surgeries were more equally performed by general (2616/5192, 50.4%) and plastic (2495/5192, 48.1%) surgeons. Of HS surgery claims, 25.7%-35.9% were provided by a physician residing in a different area than the patient receiving care. No significant improvements in access to HS surgery were seen across the study period, with access potentially worsening with annual HS claims rising overall and number of providers decreasing, with patients travelling further to access surgery. System barriers across the continuum of HS diagnosis and management must be evaluated to improve access to surgical care.

Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity

BackgroundPain is reported as the leading cause of disability in the common forms of inflammatory arthritis conditions. Acting as a key player in nociceptive processing, neuroinflammation, and neuron-glia communication, the chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how the CCL2/CCR2 system in the dorsal root ganglion (DRG) contributes to the peripheral inflammatory pain sensitization.MethodsRepeated intrathecal (i.t.) administration of the CCR2 antagonist, INCB3344 was tested for its ability to reverse the nociceptive-related behaviors in the tonic formalin and complete Freund’s adjuvant (CFA) inflammatory models. We further determined by qPCR the expression of CCL2/CCR2, SP and CGRP in DRG neurons from CFA-treated rats. Using DRG explants, acutely dissociated primary sensory neurons and calcium mobilization assay, we also assessed the release of CCL2 and sensitization of nociceptors. Finally, we examined by immunohistochemistry following nerve ligation the axonal transport of CCL2, SP, and CGRP from the sciatic nerve of CFA-treated rats.ResultsWe first found that CFA-induced paw edema provoked an increase in CCL2/CCR2 and SP expression in ipsilateral DRGs, which was decreased after INCB3344 treatment. This upregulation in pronociceptive neuromodulators was accompanied by an enhanced nociceptive neuron excitability on days 3 and 10 post-CFA, as revealed by the CCR2-dependent increase in intracellular calcium mobilization following CCL2 stimulation. In DRG explants, we further demonstrated that the release of CCL2 was increased following peripheral inflammation. Finally, the excitation of nociceptors following peripheral inflammation stimulated the anterograde transport of SP at their peripheral nerve terminals. Importantly, blockade of CCR2 reduced sensory neuron excitability by limiting the calcium mobilization and subsequently decreased peripheral transport of SP towards the periphery. Finally, pharmacological inhibition of CCR2 reversed the pronociceptive action of CCL2 in rats receiving formalin injection and significantly reduced the neurogenic inflammation as well as the stimuli-evoked and movement-evoked nociceptive behaviors in CFA-treated rats.ConclusionsOur results provide significant mechanistic insights into the role of CCL2/CCR2 within the DRG in the development of peripheral inflammation, nociceptor sensitization, and pain hypersensitivity. We further unveil the therapeutic potential of targeting CCR2 for the treatment of painful inflammatory disorders.

A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities.

Endometriosis is a painful inflammatory disorder affecting ~10% of women of reproductive age. Although chronic pelvic pain (CPP) remains the main symptom of endometriosis patients, adequate treatments for CPP are lacking. Animal models that recapitulate the features and symptoms experienced by women with endometriosis are essential for investigating the etiology of endometriosis, as well as developing new treatments. In this study, we used an autologous mouse model of endometriosis to examine a combination of disease features and symptoms including: a 10week time course of endometriotic lesion development; the chronic inflammatory environment and development of neuroangiogenesis within lesions; sensory hypersensitivity and altered pain responses to vaginal, colon, bladder, and skin stimulation in conscious animals; and spontaneous animal behavior. We found significant increases in lesion size from week 6 posttransplant. Lesions displayed endometrial glands, stroma, and underwent neuroangiogenesis. Additionally, peritoneal fluid of mice with endometriosis contained known inflammatory mediators and angiogenic factors. Compared to Sham, mice with endometriosis displayed: enhanced sensitivity to pain evoked by (i) vaginal and (ii) colorectal distension, (iii) altered bladder function and increased sensitivity to cutaneous (iv) thermal and (v) mechanical stimuli. The development of endometriosis had no effect on spontaneous behavior. This study describes a comprehensive characterization of a mouse model of endometriosis, recapitulating the clinical features and symptoms experienced by women with endometriosis. Moreover, it delivers the groundwork to investigate the etiology of endometriosis and provides a platform for the development of therapeutical interventions to manage endometriosis-associated CPP.

Association of Cannabis Use with Pancreatitis

Introduction: Acute and chronic pancreatitis (AP and CP) are painful inflammatory disorders causing substantial public health burden. The etiology of pancreatitis is clustered into three groups: alcohol, gallstones, and others (non-gallstones-non-alcohol). Containing potent anti-inflammatory cannabinoids, cannabis use (CU) could suppress pancreatitis, has shown in murine models. Furthermore, conflicting results are reported in other studies where cannabinoids have aggravated pancreatitis. However, human data are lacking, besides few reported cases. Therefore, we conducted a more extensive and detailed assessment of the impact of CU on pancreatitis. Methods: We collected data from 2012-2014 of the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (NIS) discharge records of patients 18-years and older, and identified three populations: those with gallstones (379,125); abusive alcohol drinkers (762,356); and non-gallstones-non-alcohol users (15,255,464). Within each population, CUsers were identified and matched by age, race, and gender to records without CU. Adjusted Odds Ratio (AOR) of having AP and CP were measured with conditional logistic models (SAS 9.4). Results: Concomitant cannabis among abusive alcohol use was associated with reduced odds of AP and CP (aOR: 0.50[0.48-0.53] and 0.77[0.71-0.84]). Strikingly, for individuals with gallstones, additional CU did not impact the incidence of AP or CP. Amongst non-gallstones-non-alcohol users, CU was associated with increased likelihood of CP, but not AP (1.28[1.14-1.44] and 0.93[0.86-1.01]). Conclusion: Our findings suggest reduced odds of only alcohol-associated pancreatitis with CU. Our results emphasize the urgent need for further studies to elucidate the modulatory effect of cannabis on pancreatitis among different risk groups.

A therapeutic role for potassium (K) to reduce pain and complications related to the cardiovascular system and bone in rheumatoid arthritis (RA): A clinical research perspective

Rheumatoid arthritis is a painful inflammatory disorder. Patients seek relief mostly with analgesics and anti-inflammatory drugs which are rife with life-threatening side effects. Alterations in the body’s potassium (K) status may be one such factor. K along with sodium is critical to cellular homeostasis and the electrophysiology of nerve impulses. This review is based on the premise that K can be used therapeutically to reduce joint pain and inflammation in RA and co-morbidity. K ion channel inhibition was shown to cause persistent nerve stimulation (a prelude to pain sensation) and altered immunity (T cells) in experimental studies. Diets rich in K (with normal/reduced salt intake) have to reduce hypertension in several large population studies. Premature atherosclerosis-related cardiovascular disorders and osteoporosis are important complications of RA. The third National Health and Nutrition Examination Survey (1994) carried out in the USA also reported hypokalemia in several RA patients. A diet deficient in K in RA patients was recently reported by an Indian study. In a controlled clinical trial (Iran), K supplementation (diet-based) led to a significant reduction in pain and arthritis in women suffering from seropositive RA. Some of the benefits of K in RA were postulated to be due to an improved cortisol status. K is not a known therapeutic agent in the treatment of RA. Vegetables and fruits are rich sources of K and provide a safe option for intervention. The existing data on the potential therapeutic role of K in RA is encouraging and merits further research.

Systemic Drug-induced Chronic Paronychia and Periungual Pyogenic Granuloma.

Paronychia is a painful inflammatory disorder of the nail fold. Periungual pyogenic granuloma – a benign vascular tumor of the capillaries – can develop as a complication of paronychia. We report both, paronychia and periungual pyogenic granuloma, as possible adverse events during systemic drug-therapy. The following groups of systemic drugs have been considered: taxanes, epidermal growth factor-receptor (EGFR) inhibitors, EGFR tyrosine kinase inhibitors, tyrosine kinase inhibitors, inhibitors of MEK/ERK, BRAF inhibitors, CD20 antagonists, vascular endothelial growth factor inhibitors, and retinoids. Recommendations for prevention and treatment are given. Since paronychia is a painful inflammatory disorder that has a negative impact on daily activities, early recognition and adequate treatment improve adhesion to treatment and quality of life.

One compound of saponins from Disocorea zingiberensis protected against experimental acute pancreatitis by preventing mitochondria-mediated necrosis.

Acute pancreatitis (AP) is a painful inflammatory disorder of the exocrine pancreas, ranking as the most common gastrointestinal reasons for hospitalization with no specific therapy currently. Diosgenyl saponins extracted from natural products and diosgenin or its derivatives have been shown to exert anti-inflammatory effects in various diseases. However, the therapeutic effects of diosgenyl saponins from Dioscorea zingiberensis C. H. Wright in AP have not yet been determined. Five compounds were extracted and screened for taurocholate-induced necrosis in mouse pancreatic acinar cells. Particularly, 26-O-β-d-glucopyranosyl-3β, 22α, 26-trihydroxy-25(R)-furosta-5-en-3-O-[α-L-rhamnopyranosyl-(1 → 4)]-β-d-glucopyranoside (compound 1) exhibited the best protective effects with no toxicity observed. Next, we showed compound 1 concentration-dependently inhibited necrotic cell death pathway activation and 2.5 mM compound 1 also prevented the loss of mitochondrial membrane potential, adenosine triphosphate production, and reactive oxygen species generation in mouse pancreatic acinar cells. Finally, we showed compound 1 protected against three clinically representative murine models of AP and significantly improved pancreatitis-associated acute lung injury. These data provide in vitro and in vivo evidence that one compound of diosgenyl saponins can be potential treatment for AP. This study suggests natural saponins may serve as fruitful sources for exploring/identifying potential therapies for inflammatory diseases.

Unusual Complications Associated with Gout.

The deposits of urate crystals known as gout can result in acute and chronic arthropathy and bone erosion. The most common site of this painful inflammatory disorder is the base of the big toe—the first metatarsophalangeal joint. Although gout is painful, it is usually only sporadically debilitating and is not often associated with serious orthopaedic complications. However, this month’s “Case Connections” highlights three examples from JBJS Case Connector in which urate crystals agglomerated into calcified tophi, causing unusually serious problems for patients’ bones and joints. In the September 24, 2014 JBJS Case Connector , Kim et al. report on a young soldier with no prior history of gout who experienced an acute pathologic fracture of the fibular sesamoid, which was likely caused by gouty tophi. The twenty-three-year-old soldier’s right forefoot pain began during a military march. He reported having similar but less intense pain in the past. Upon examination, the foot was swollen and tender on the lateral side of the first metatarsophalangeal joint. Laboratory values, including erythrocyte sedimentation rate, were normal, but radiographs and CT revealed a “completely disrupted” fibular sesamoid …

Activation of spinal NF-κB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis.

It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-κB/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-κB/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). Lentiviral vectors encoding short hairpin RNAs that target NF-κB/p65 (LV-shNF-κB/p65) were constructed for gene silencing. The spines of rats with AIA were injected with LV-shNF-κB/p65 on day 3 or day 10 after treatment with Freund's complete adjuvant (CFA). During an observation period of 20 days, pain-related behavior, paw swelling, and joint histopathologic changes were evaluated. Moreover, the expression levels of spinal tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and cyclooxygenase 2 (COX-2) were assessed on day 14 after CFA treatment. The presence of peripheral inflammation in rats with AIA induced an increase in NF-κB/p65 expression in the spinal cord, mainly in the dorsal horn neurons and astrocytes. Delivery of LV-shNF-κB/p65 to the spinal cord knocked down the expression of NF-κB/p65 and significantly attenuated hyperalgesia, paw edema, and joint destruction. In addition, spinal delivery of LV-shNF-κB/p65 reduced the overexpression of spinal TNFα, IL-1β, and COX-2. These findings indicate that spinal NF-κB/p65 plays an important role in the initiation and development of both peripheral inflammation and hyperalgesia. Thus, inhibition of spinal NF-κB/p65 expression may provide a potential treatment to manage painful inflammatory disorders.

AB1274 Lumbar facet joint effusion on 3-D MR myelography: A sign of rheumatoid back pain?

BackgroundThe articular hydropsy of knee is very popular clinical conditions. And, lumbar facet joint effusion is also very frequency disorders of spine, particularly those involved in RA, thoracic or lumbar...

Necrotizing scleritis in a patient positive for both c- and p-ANCA without underlying systemic vasculitis

Scleritis is a painful inflammatory disorder of the outer coating of the eye. Any form of scleritis associated with a systemic disease is more likely to be aggressive [1], and it is now recognized that antineutrophil cytoplasmic antibody (ANCA)-associated active scleritis tends to have more severe inflammation and requires more aggressive therapy [2]. Here, we report a case of necrotizing scleritis positive for both cytoplasmic pattern ANCA and perinuclear staining pattern ANCA without underlying systemic vasculitis, which was successfully treated with intravenous pulse cyclophosphamide therapy.

Gastro-protective effect of Crossopteryx febrifuga in Wistar rats.

Preparations of Crossopteryx febrifuga (Afzel.) Benth. (Rubiaceae) are widely used in Northern Nigeria in the therapeutic management of trypanosomiasis, malaria and painful inflammatory disorders. Previous studies have shown that the methanolic stem bark extract of Crossopteryx febrifuga possesses significant analgesic and anti-inflammatory properties possibly mediated via Non-selective inhibition of cyclo-oxygenase pathways. In the present study, the methanolic stem bark extract of Crossopteryx febrifuga was evaluated against ethanol- and piroxicam-induced ulceration in rats. Histopathological studies of the rat stomach tissues were also carried out in order to determine its safety profile on the gastrointestinal tract (git). The extract (25, 50 and100 mg extract/kg body weight) significantly (P<0.05) and dose-dependently reduced ulcer index induced by ethanol (24 - 92%) and piroxicam (81.81- 98.60%). Histopathology of the rat stomach tissues from control and extract-treated groups at 25 mg/kg body weight extract showed mild inflammation characterized by infiltration of inflammatory cells, while the extract treated groups at 50 and 100mg/kg body weight and 200 mg misoprostol/kg body weight group showed no obvious lesions. These results showed that the extract had no deleterious effects and was cytoprotective on the gastrointestinal tract (git). It can thus be developed as a safe alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs) for the management of painful inflammatory disorders.

Sclérites : quand évoquer une pathologie systémique ?

Scleritis is typically a severe painful inflammatory disorder of the eye. This process may involve the sclera but also the cornea, adjacent episclera, and underlying uvea and therefore threaten vision. Careful clinical history taking, detailed ocular examination, appropriate investigation for systemic disease, and timely intervention with the use of immunosuppressive drugs when necessary has improved the long-term outcome of patients with scleritis.

Changing Referral Trends of Acute Pancreatitis in Children: A 12‐year Single‐center Analysis

Acute pancreatitis is a painful inflammatory disorder known to occur in children. Recent reports, primarily on the basis of adult data, have suggested an increasing incidence. However, pediatric studies are limited. The study was performed to examine the frequency of acute pancreatitis in a pediatric population from 1994 to 2007 and to characterize etiologies by age subsets. In this retrospective study, cases of pancreatitis were identified by ICD-9 codes and subjected to inclusion criteria. Two hundred and seventy-one cases of pancreatitis met inclusion criteria. Mean age of the subjects was 13.1 +/- 5.6 years. The recurrence rate was 15.3%. Biliary disease was the most common etiology (32.6%). Acute pancreatitis cases evaluated at a single tertiary care center increased 53% between 1995 to 2000 and 2001 to 2006 (P < 0.02). However, when cases were normalized by all annual pediatric emergency department visits for all medical reasons, the increase was reduced to 22% and lost statistical significance (P = 0.16). The rise was not associated with a change in etiologies or body mass index (BMI). This is the first report demonstrating that an increase in pediatric pancreatitis may in part be due to growing referrals to tertiary care centers. The data on etiologies, particularly with regard to differing ages, may be helpful in managing children who present with acute pancreatitis.

TRP Channels and Pain

Preclinical research has identified an array of ion channels in sensory neurons involved in the generation and transduction of pain as potential targets for pharmacological intervention. Paramount among these new targets is the family of thermosensitive transient receptor potential channels, referred to as "thermoTRPs". We detect a wide range of noxious stimuli via a limited number (as of today, six) of thermoTRP channels, four of which (TRPV1-TRPV4) respond to heat and two (TRPA1 and TRPM8) are sensitive to cold. Targeting these thermoTRP channels represents a new and logical strategy in pain relief. Unlike traditional analgesic drugs that either suppress inflammation (e.g. NSAIDs and COX-2 inhibitors) or block pain transmission (e.g. opiates), TRP channel inhibitors aim to prevent pain by blocking a receptor where pain is generated. The archetypal thermoTRP is the vanilloid (capsaicin) receptor TRPV1. TRPV1 has a dynamic threshold of activation. Agents in inflammatory soup, including endogenous TRPV1 agonists (so-called "endovanilloids"), act in concert to reduce the heat activation threshold of TRPV1. In patients, the expression of TRPV1 is up-regulated in a number of painful inflammatory disorders. TRPV1 as a pain target has been validated by genetic deletion and pharmacological inhibition experiments. This area of drug development has been moving rapidly. It took less than a decade from the cloning of TRPV1 to clinical trials with potent small molecule TRPV1 antagonists. This review evaluates current evidence that supports particular TRP channels as targets for novel analgesic drugs, along with potential adverse effects that may limit drug development.

Screening TRPV1 antagonists for the treatment of pain: lessons learned over a decade

Background: The capsaicin receptor TRPV1, a polymodal nociceptor whose expression is up-regulated in a number of painful inflammatory disorders, represents a promising therapeutic target for pain relief. Potent small molecule TRPV1 antagonists are now undergoing clinical trials in patients with inflammatory or neuropathic pain. This review focuses on the multiplicity of factors regulating this channel and on their contributions to the emerging complexity of responses to TRPV1 and partial antagonists. For example, it is now clear that antagonists of capsaicin response can also antagonize, have no effect, or stimulate response to heat or protons. The complexity of TRPV1 regulation affords the potential to optimize agents for a specific therapeutic indication. An encouraging advance is the dissection of therapeutic efficacy of antagonists from induction of hyperthermia, a side effect that initially had raised concerns about the suitability of systemically administered TRPV1 antagonists for therapy. Objectives and methods: To discuss the challenges facing the development of clinically useful TRPV1 antagonists based on our experience and a comprehensive review of the literature. Results/conclusions: TRPV1 is a polymodal receptor. Some antagonists block all modalities of TRPV1 stimulation whereas others are more selective in their pharmacological profile. A number of antagonists can, conversely, potentiate certain modes of TRPV1 activation (e.g., protons and heat). The selectivity of TRPV1 antagonists is species-dependent, posing a problem for extrapolation from animal models to patients. At present, this rich pharmacology of TRPV1 antagonists complicates drug development but for the future it promises great opportunities for drug design.

Effects of Cyclooxygenase inhibitors on bone and cartilage metabolism: A Review

In this era of increeasing use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) for treatment of painful/inflammatory disorders, it is necessary to review the effect of these drugs on bone and cartilage metabolism. Inflammation is an essential component of the healing process in bone, and cyclooxygenase (cox-1 and cox-2) enzymes play important roles in fracture repair. Therefore, there is concern that NSAIDs, which have anti-inflammatory and analgesic properties that are mediated by inhibition of cox-1 and cox-2 may delay the healing of bone injuries. Also as newer drugs, selective cox-2 inhibitors are being developed to avert the gastrointestinal symptoms of the non-specific NSAIDs, it is imperative that these substances are studied for any deleterious effect on bone and cartilage metabolism. Literature on the subject was reviewed using manual library search, articles in journals and internet search. The search words were: NSAIDs and bone metabolism, cyclooxygenase inhibitors and bone metabolism. The search was done using medscape, ortolink and pubmed search engines. The search covered a period of 35 years (1970-2005). NSAIDs can either reversibly or irreversibly block the cyclooxygenase pathway thereby inhibiting prostaglandin synthesis. These cox inhibitors especially the cox-2 have been found to inhibit the production of prostaglandins which are necessary in bone healing. Prostaglandins play a role in both osteoblastogenesis and bone resorption, and so, cox inhibitors suppress these functions. NSAIDs especially the cox-2 inhibitors should be avoided following fractures or implant surgery. They should be reserved for other painful inflammatory disorders in which bone resorption and formation mediated by prostaglandins are not required.