Targeting Chemosensory Ion Channels in Peripheral Swallowing-Related Regions for the Management of Oropharyngeal Dysphagia.

Oropharyngeal dysphagia, or difficulty in swallowing, is a major health problem that can lead to serious complications, such as pulmonary aspiration, malnutrition, dehydration, and pneumonia. The current clinical management of oropharyngeal dysphagia mainly focuses on compensatory strategies and swallowing exercises/maneuvers; however, studies have suggested their limited effectiveness for recovering swallowing physiology and for promoting neuroplasticity in swallowing-related neuronal networks. Several new and innovative strategies based on neurostimulation in peripheral and cortical swallowing-related regions have been investigated, and appear promising for the management of oropharyngeal dysphagia. The peripheral chemical neurostimulation strategy is one of the innovative strategies, and targets chemosensory ion channels expressed in peripheral swallowing-related regions. A considerable number of animal and human studies, including randomized clinical trials in patients with oropharyngeal dysphagia, have reported improvements in the efficacy, safety, and physiology of swallowing using this strategy. There is also evidence that neuroplasticity is promoted in swallowing-related neuronal networks with this strategy. The targeting of chemosensory ion channels in peripheral swallowing-related regions may therefore be a promising pharmacological treatment strategy for the management of oropharyngeal dysphagia. In this review, we focus on this strategy, including its possible neurophysiological and molecular mechanisms.

Osteoarthritis year in review 2019: epidemiology and therapy.

Over the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1st, 2018 to April 19th, 2019; the final selection of articles was subjective. Specifically those articles considered to be presenting novel insights and of potential importance for clinical practice, are discussed. Further evidence has emerged that OA is a serious disease with increasing impact worldwide. Our understanding of development of pain in OA has increased. Detailed studies investigating widely used pharmacological treatments have shown the benefits to be limited, whereas the risks seem higher than expected, suggesting further studies and reconsideration of currently used guidelines. Promising new pharmacological treatments have been developed and published, however subsequent studies are warranted. While waiting for new treatment modalities to appear joint replacement is an effective alternative; new data have become available on how long they might last.

Aural stimulation with capsaicin prevented pneumonia in dementia patients.

OBJECTIVE: In the present study, we examined the effects of daily application of capsaicin ointment to the external auditory canal for 6 months on the development of pneumonia in elderly dementia patients at high risk of aspiration. METHODS: Twenty-nine oldest-old bedridden dementia inpatients at high risk of aspiration were enrolled in the present study. Ointment containing 0.025% capsaicin was applied to each external auditory canal with a cotton swab alternatively once a day for 6 months. RESULTS: The incidence of pneumonia during the 6 months before the intervention was 1.80±0.37 in these patients. However, this incidence significantly decreased to 0.40±0.29 (p<0.01) during the 6 months of the alternative application of capsaicin ointment to each auditory canal. No adverse effect such as otalgia was observed. CONCLUSION: These findings suggest that daily long-term aural stimulation with capsaicin ointment enhanced the cough reflex via Arnold's ear-cough reflex as a glottis protective measure, resulting in the reduction of incidence of pneumonia in elderly dementia patients at high risk of aspiration. The daily aural stimulation with capsaicin ointment may be a safe and promising intervention to prevent aspiration pneumonia in elderly people, especially those who cannot undergo swallowing exercise.

Response to bronchodilator and clinical, pathophysiological features in patients with nonasthmatic eosinophilic bronchitis.

INTRODUCTION: Whether nonasthmatic eosinophilic bronchitis (NAEB) shows response to bronchodilator (RB) remains unclear. OBJECTIVES: To investigate the RB and its relationship with clinical and pathophysiological features in NAEB. METHODS: Fifty-one patients with NAEB were assigned in a 2:1 ratio to receive oral bambuterol hydrochloride (n = 34, 10 mg, once daily, for 3 days) or matched placebo (n = 17) randomly, of whom 48 patients (32 with bronchodilator and 16 with placebo) completed the study. Sputum induction, spirometry and cough reflex sensitivity were measured. RB was considered when cough Visual analogue scale (VAS) score decreased 30% or more after treatment. Cough reflex sensitivity was defined as the lowest concentration of capsaicin inducing five coughings or more (C5), and presented as Log C5. RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (34.4% vs 6.3%, P < 0.05). The VAS score decreased significantly in patients with bronchodilator (median: 6.0-3.0, P < 0.01). There was a significantly higher median Log C5 (2.7 vs 1.3, P < 0.05), and a higher trend of decline in FEV1 % predicted and MMEF% predicted after bronchial provocation in patients with RB as compared with patients without RB. No significant differences in baseline percentages of sputum eosinophil were found between patients with RB and that without RB. CONCLUSIONS: One third of patients with NAEB respond well to bronchodilator treatment, which are related with lower cough reflex sensitivity and increased airway responsiveness. The relationship between NAEB and asthma needs to be investigated further.

Effects of capsaicin on swallowing function in stroke patients with dysphagia: A randomized controlled trial.

BACKGROUND/AIMS: Dysphagia is a common complication after acute stroke. While there are several innovative treatments being tested to improve the swallowing function of stroke patients with dysphagia, our aim is to explore the use of readily available natural capsaicin in stroke patients with dysphagia. STUDY DESIGN: A randomized, double-blind study. METHODS: Sixty-nine hospitalized stroke patients were enrolled in this study. The capsaicin intervention group received thermal tactile stimulation with supplementation of natural capsaicin and additional nectar viscosity boluses. The control group received stimulation and boluses with placebo. Swallowing function was evaluated before and after the 3-week treatment, using Volume-Viscosity Swallow Test, Eating Assessment Tool, Standardized Swallowing Assessment, and Water Swallow Test. RESULTS: The score decreases in the Eating Assessment Tool and Standardized Swallowing Assessment of the capsaicin intervention group were significantly greater than that of the placebo control group (P < .01). Among the 60 patients, the capsaicin intervention group exhibited effectiveness in a higher number of patients (n = 27, 90%) than the placebo group (n = 9, 30%, P < .001). CONCLUSIONS: Regular use of natural capsaicin could promote the recovery of swallow function in stroke patients with dysphagia. The ample availability of natural capsaicin could provide a low cost, easily accessible, and safe alternative method to address dysphagia in stoke patients.

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time.

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9-T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

Up-date on Clinical Management of Postherpetic Neuralgia and Mechanism-Based Treatment: New Options in Therapy.

Patients with postherpetic neuralgia may experience various sensory signs and symptoms of pain. Despite this, the recommendations for medicinal treatment do not differ accordingly. In order to find the appropriate treatment options for postherpetic neuralgia, several attempts have been made in the past. The crucial obstacle to these attempts was insufficient or no subgrouping of patients according to their sensory phenotype, mostly resulting in an unsatisfactory treatment response. Recently, a new concept of retrospective stratification according to the patients' sensory phenotype has been made in a large cohort of pain patients. This new stratification tool allows a predictive validity for treatment response in subgroups of patients and might be of potential value in determining the optimal treatment in postherpetic neuralgia patients.

Topical therapies for knee osteoarthritis.

BACKGROUND: Symptomatic knee osteoarthritis (OA) involves millions of adults around the world. PURPOSE: To analyze the effectiveness and tolerability of topical therapies and their contemporary placement in knee OA management criteria. METHODS: A Cochrane Library and PubMed (MEDLINE) search related to the role of topical therapies in knee OA was carried out. RESULTS: Many types of local therapy have been reported, including nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac and ketoprofen; capsaicin, cream containing glucosamine sulfate, chondroitin sulfate, and camphor; nimesulide; civamide cream 0.075%; menthol; drug-free gel containing ultra-deformable phospholipid vesicles (TDT 064); 4Jointz utilizing Acteev technology; herbal therapies; gel of medical leech (Hirudo medicinalis) saliva extract; and gel prepared using Lake Urmia mud. One systematic review showed that topical diclofenac and topical ketoprofen can alleviate pain. However, another systematic review found that topical diclofenac and ketoprofen had limited efficacy in knee OA at 6 to 12 weeks. Many studies with a low level of evidence have reported some pain mitigation using the rest of aforementioned topical therapies. CONCLUSIONS: Although some controversy exists on the role of topical NSAIDs, current management guidelines advise topical NSAIDs as an option and even first-line therapy for knee OA treatment, particularly among elderly patients. Topical NSAIDs may be contemplated as similar options to oral NSAIDs and are associated with fewer gastrointestinal complications when compared with oral NSAIDs. Caution should be taken with the use of both topical and oral NSAIDs, including close adherence to dosing regimens and monitoring, especially for patients with previous complications of NSAIDs. The role of other topical therapies needs further research.

Therapeutic Applications of Capsaicin in Upper Airways.

BACKGROUND: Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the substance responsible of the irritation caused by the contact of chili peppers with the skin or mucous membranes. This protoalkaloid acts by stimulating the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is mainly expressed by nociceptive fibers of peripheral sensory neurons, but is also present in the central nervous system, and in some non-neuronal cells. Following the initial, intense neuronal excitation, a brief refractory period occurs. However, repeated and massive exposures to capsaicin can impair nociceptive fiber function for weeks or months. During this lapse of time, disorders related to the hyperreactivity of peripheral nociceptors are abolished or greatly reduced. Capsaicin has been utilized to treat several diseases of upper airways. OBJECTIVE: The objective of this review was to report the latest findings on the use of Capsaicin in the treatment of upper airway diseases. RESULTS: Capsaicin effectiveness has been proved in non allergic rhinitis. Some studies suggest that this substance may be also effective in nasal polyposis and in the burning mouth syndrome. No clear evidence has been obtained about its use in allergic rhinitis. CONCLUSION: To date, the use of capsaicin to treat upper airway diseases is still limited in clinical practice. This may originate by the lack of strong, conclusive evidences of its effectiveness, by the variety of therapeutic schemes used in literature, and finally by the unpleasant effects of the exposure to capsaicin, which are only partly relieved by the pretreatment with local anesthetics.

Burning mouth syndrome: a systematic review of treatments.

Burning mouth syndrome (BMS) is a chronic oral pain syndrome that primarily affects peri- and postmenopausal women. It is characterized by oral mucosal burning and may be associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. The etiology of the disease process is unknown, but is thought to be neuropathic in origin. The goal of this systematic review was to assess the efficacy of the various treatments for BMS. Literature searches were conducted through PubMed, Web of Science, and Cochrane Library databases, which identified 22 randomized controlled trials. Eight studies examined alpha-lipoic acid (ALA), three clonazepam, three psychotherapy, and two capsaicin, which all showed modest evidence of potentially decreasing pain/burning. Gabapentin was seen in one study to work alone and synergistically with ALA. Other treatments included vitamins, benzydamine hydrochloride, bupivacaine, Catuama, olive oil, trazodone, urea, and Hypericum perforatum. Of these other treatments, Catuama and bupivacaine were the only ones with significant positive results in symptom improvement. ALA, topical clonazepam, gabapentin, and psychotherapy may provide modest relief of pain in BMS. Gabapentin may also boost the effect of ALA. Capsaicin is limited by its side effects. Catuama showed potential for benefit. Future studies with standardized methodology and outcomes containing more patients are needed.

Capsaicin Attenuates Amyloid-ß-Induced Synapse Loss and Cognitive Impairments in Mice.

Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid ß-protein (Aß) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Aß-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Aß. To induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Aß42 (100 µM, 2.5 µl/mouse, i.c.v.). Two weeks after Aß42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Aß42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Aß42-treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Aß42-induced mouse model of AD both structurely and functionally.

Use of High-Concentration Capsaicin Patch for the Treatment of Pelvic Pain: Observational Study of 60 Inpatients.

BACKGROUND: Chronic pelvic, perineal and gluteal neuralgia is often experienced in a similar way to neuropathic pain, in the territories of four nerves: ilio-inguinal, pudendal, inferior cluneal and posterior gluteal nerves. These pains are often refractory to medical treatment based on the use of systemic molecules with disabling adverse effects and surgical procedure may be necessary. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of treatment with a high-concentration capsaicin patch in these indications. STUDY DESIGN: This study was prospective, nonrandomized, and observational. SETTING: Federative Center of Pelvi-Perineology in the University Hospital of Nantes, France. METHODS: Sixty patients with pelvic neuralgia were treated with high-concentration capsaicin patch. The primary endpoint was Patient Global Impression of Change (PGIC) and secondary endpoints included pain intensity on a Numerical Rating Scale (NRS), maximum sitting duration at the end of the day, Medication Consumption Score (MQS), and patient global improvement (from -100% to + 100%). RESULTS: Twenty four percent of the 60 patients included in the study declared that they felt "very much improved" or "much improved" (PGIC = 1 or 2) and these patients reported an average 58% improvement and a 3.4-point reduction on the NRS. Among the "good responder" patients, patients with coccygodynia appear to obtain the bestresults, as 37% of these patients declared that they were much improved with an average 63% improvement No serious adverse effects were observed and treatment was well tolerated. LIMITATION: This study is limited by its relatively small sample size and non-randomized study. CONCLUSION: These results suggest the value of high-concentration capsaicin 8% patch in the treatment strategy for patients with chronic pelvic, perineal and gluteal neuralgia. This treatment would be particularly indicated in the management of coccygodynia.Key words: Pelvic pain, neuropathic pain, pudendal nerve, ilio-inguinal nerve, inferior cluneal nerve, posterior gluteal nerve, capsaicin, capsaicin patch, coccygodynia.

EULAR revised recommendations for the management of fibromyalgia.

OBJECTIVE: The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. METHODS: A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. RESULTS: 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). CONCLUSIONS: These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

Effectiveness and Impact of Capsaicin 8% Patch on Quality of Life in Patients with Lumbosacral Pain: An Open-label Study.

BACKGROUND: Capsaicin 8% patch (Qutenza™) is mainly used to treat postherpetic neuralgia and HIV-associated neuropathy. Evidence of the efficacy of Qutenza in other forms of neuropathic pain is lacking. OBJECTIVE: To evaluate the analgesic effect and the impact on quality of life after a single application of the capsaicin 8% cutaneous patch in patients with lumbosacral pain. STUDY DESIGN: Prospective open-label study of capsaicin 8% patch in patients with lumbosacral pain. SETTING: Outpatient Pain and Palliative Care Center. METHODS: All recruited patients were evaluated prior to capsaicin 8% patch administration and were followed-up at 2 weeks, at 8 weeks, and at 12 weeks post administration. Visual analog scale (VAS) was used to record pain intensity and EQ-5D was used to assess the quality of life of the participants. RESULTS: Ninety patients met our inclusion criteria (54.4% men, mean age 59.1 ± 9.2 years). At baseline the mean VAS score of the participants was 7.6 ± 0.7. A statistically significant reduction of the VAS score between baseline and week 2 (mean VAS score 5.6 ± 1.1, P < 0.001) was observed. The therapeutic effect further continued between week 2 and week 8 (mean VAS score 3.2 ± 1.2, P < 0.001) and between week 8 and at endpoint at week 12 (mean VAS score 2.6 ± 1.1, P < 0.001).Between baseline and weeks 2, 8, and 12 (end-point) a significant improvement in all 5 dimensions of EQ-5D (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) was observed (P < 0.001). LIMITATIONS: As it is an open-label study, a prospective randomized placebo-controlled study should be designed to confirm the effectiveness of capsaicin 8% patch in patients with lumbosacral pain. CONCLUSIONS: Administration of the capsaicin 8% patch resulted in a significant relief of neuropathic pain and a significant improvement of the quality of life of patients with lumbosacral neuropathic pain. KEY WORDS: Lumbosacral pain, peripheral pain, Qutenza, neuropathic pain, capsaicin, patch, quality of life, effectiveness.

Treating Painful Diabetic Peripheral Neuropathy: An Update.

Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient's goals and functional status and potential adverse effects of medication when choosing a treatment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medications, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-l-carnitine, primrose oil, and electromagnetic field application lack high-quality evidence to support their use.

Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

An update regarding the treatment of nonallergic rhinitis.

PURPOSE OF REVIEW: The review presents some information on known options for treatment of nonallergic rhinitis (NAR) with introduction to new therapies. The merits and limitations of recent advancements in pharmacotherapy of this common problem are briefly discussed as well. RECENT FINDINGS: Intranasal corticosteroids are first-line therapy for NAR. Fluticasone propionate and beclomethasone remain the only topical corticosteroids approved for NAR. The use of azelastine - another first-line option - has also been found to be effective even though NAR is a nonallergic entity by definition. Combination of fluticasone propionate and azelastine is a promising option in achieving better symptom reduction. Coadministration of intranasal corticosteroid and topical decongestants is an attractive topic that requires additional safety studies before recommending treatment. Although promising, no scientifically valid recommendation can be made for treatment of NAR with capsaicin. Surgical options in patients with refractory NAR are limited. New studies demonstrate a lack of correlation between objective outcome of radiofrequency ablation of the inferior turbinate and subjective patient symptoms. SUMMARY: The heterogeneity in clinical presentation makes NAR treatment a daily challenge for otolaryngologists. The diversity of clinical studies with use of unique outcome measures limit systematic reviews which may be instrumental in providing strong recommendations.