Topical Nitrates Research Articles

Nontopical Nitrates in Flap Perfusion and Delay Phenomenon.

Topical nitrates have demonstrated efficacy in improving flap perfusion. However, evidence for nontopical nitrates in modulation of flap perfusion dynamics has yet to be consolidated. Here, we review evidence regarding the use of intravascular, sublingual, and oral nitrates in modulating flap perfusion. We performed a review of the literature for evidence linking nontopical nitrates and flap perfusion, and included clinical studies, animal studies, and in vitro studies. Evidence suggests that intravascular, sublingual, and oral nitrates exert vasodilatory properties, which may be harnessed for identification of perforators and improved flap perfusion. We also found evidence suggesting nitrates may facilitate ischemic preconditioning while reducing ischemia-reperfusion injury. Nitrates delivered intravascularly, sublingually, or orally may increase flap perfusion and serve as a method for ischemic preconditioning, particularly in the intraoperative setting.

Anal fissures: An update on treatment options.

Anal fissure (AF) is the second most common anorectal complaint in healthcare settings. The presentation might be acute or chronic, characterised by severe pain with defaecation that persists for one to two hours. Non-surgical and surgical interventions are available based on the severity and persistence of the fissure. The aim of this article is to review the pathophysiology, clinical presentation andmanagement of AF under current guidelines. The aetiology of AF is unclear, although it is commonly associated with local trauma or associated chronic conditions. Acute AF is first treated with conservative therapy, including dietary fibre and sitz baths. Addition of topical nitrates, topical calcium channel blockers or botulinum toxin injection is indicated with failure of conservative treatment or at medical discretion. Surgical options are considered if AF persists despite treatment. Most present as hypertonic, but special consideration is needed for hypotonic or secondary presentations.

A Pilot, Prospective, Randomized-Controlled Study to Evaluate the Efficacy and Safety of Arsha Hita™ in the Treatment of Anal Fissures.

Introduction Anal fissures are tears in the anal canal that cause pain, bleeding, and spasms. They can be treated with non-operative options such as sitz baths, local anesthetics, topical nitrates, oral fiber, and calcium channel blockers, but some patients require surgery. Topical nitrates have side effects such as severe headaches, while topical calcium channel blockers can cause itching. There is a need to explore alternative treatments with fewer side effects. This proof-of-concept pilot study aimed to compare the efficacy and safety of a combination of Arsha Hita™ tablets and ointment (Shree Dhootapapeshwar Limited, Mumbai Maharastra, India) (test treatment) with a combination of lidocaine 1.5% w/w + nifedipine 0.3% w/w cream for local application and Isabgol powder (6 g) orally as an active comparator (standard treatment), which is the standard treatment of anal fissures as per the Association of Colon and Rectal Surgeons of India (ACRSI) guidelines. Methodology This study was a single-center, prospective, randomized-controlled study conductedin Karnataka, India. Participants were screened for anal fissures and randomized to receive either standard treatment (Group A) or test treatment (Group B) for 14 days, and were re-evaluated after two, four, and six weeks. The study assessed signs and symptoms related to anal fissures, such as pain post-defecation on Visual Analog Scale (VAS), bleeding per anus grading, wound healing grade, stool consistency, and stool frequency. Compliance, inter-current illness, and concomitant therapy were noted at each visit. The study used independent sample t-tests to compare variables at baseline and chi-square or Fisher's exact tests to compare the number/proportion of participants achieving primary and secondary endpoints. Mann-Whitney U test was used to compare median composite scores at baseline and Visit 4, and Friedman's two-way analysis of variance was used to compare median composite scores across the four visits (p < 0.05 was considered significant). Descriptive analysis was used to assess VAS, bleeding, and healing grades. Results The study included 53 participants with anal fissures, of which 25 out of 27 allocated in Group A (two drop-outs) received standard treatment, and all 26 allocated in Group B received Arsha Hita treatment. At the end of the study, 11 participants in Group B achieved a 90% reduction in composite scores compared to only three patients in Group A (p<0.05). Both groups showed improvement in pain on defecation, severity of bleeding, healing of anal fissure wound, and participant's and physician's global impression score. Group B had significantly better results in terms of VAS score, resolution of per-anal bleeding, and physician's global impression score (p<0.05). There were no adverse events in either group during the six-week treatment period. Conclusion The pilot study provides evidence that the combination of Arsha Hita tablets and Arsha Hita ointment may be more effective and safer for treating anal fissures than the standard treatment. The test treatment group experienced greater pain relief, complete resolution of per-anal bleeding, and better global impression scores than the standard treatment group. These findings suggest the need for further research through larger, randomized controlled trials to determine the efficacy and safety of Arsha Hita in treating anal fissures.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anal Fissures.

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anal Fissures.

Review of Medical and Surgical Management of Chronic Anal Fissure

To determine which treatment modality has the best outcome for chronic anal fissures in terms of pain relief, fissure healing, and recurrence. The main symptoms are pain while the passage of stools is acute in primary fissures but often persists in case of longstanding fissures causing significant discomfort to the patient. The management of anal fissure has progressed immensely in the last decade due to a better understanding of its pathophysiology. The main aim of the treatment is to reduce the spasm of the internal anal sphincter, thereby reducing the anal canal pressure. The Conservative approach consists of topical nitrates, calcium channel blockers, and calcium channel blockers. It is often preferred over surgical alternatives as it is not invasive. Surgeries for chronic anal fissures include anal dilatation, posterior mid-line sphincterotomy, lateral internal sphincterotomy, fistulectomy, sphincterolysis, and advancement flap repair. This narrative review article aims to review all the existing and newer complex modalities available for the management of chronic anal fissures. Currently the initial management of fissures is pharmacological therapy with topical nitroglycerin or diltiazem or botulinum toxin A injection. The following line of treatment is surgical, which is lateral internal sphincterotomy. Non-surgical therapy often proves ineffective in providing relief and healing, frequently culminating in the recurrence of fissures. On the other hand, surgical therapy has postoperative drawbacks like intestinal incontinence, commonly gas, loose stool or rarely hard stool. There is inadequate data on the latest treatment modalities like fistulotomy, sphincterolysis, flap procedures, etc. They may be considered only when conventional therapy fails to provide relief.

A Network Meta-Analysis of Randomized Controlled Trials Directed at Treating Lateral Epicondylalgia

Abstract Background: Lateral epicondylosis is the most prevalent cause of lateral elbow pain, occurring in 4 per 1000 patients. The aim of most treatments is to reduce inflammation even with histological evidence demonstrating that lateral epicondylosis is a non-inflammatory condition. Objective: To determine the relative merits of the different regimens used to diminish lateral epicondylosis pain using a mixed treatment comparison/network meta-analysis (NMA). Methods: A thorough literature search was performed. The eligibility criteria for this mixed treatment comparison were: randomized controlled clinical trials; human subjects; working age population (16 to 70 years); the outcome measure was an objective pain assessment; measured at a 1- to 3-month follow-up. The NMA were performed using the GeMTC user interface for automated NMA utilizing a Bayesian Hierarchical Model of random effects. The evaluation of confidence in the findings from NMA was performed using a semi-automated platform called CINeMA (Confidence in Network Meta-Analysis). Results: The model suggests that articulation technique is the most effective measure for decreasing lateral epicondylalgia followed by topical nitrates, acupuncture, kinesiology taping and low-level laser therapy, respectively. Muscle energy technique, local corticosteroid injection, prolotherapy and counterforce bracing displayed a trend toward being less effective than placebo. Conclusions: The results suggest that the most effective modalities for improving lateral epicondylalgia are those that decrease muscle tone and those that improve circulation, while measures meant to decrease inflammation appear to be of no or limited benefit.

A systematic review and meta-analysis of the efficacy of topical sphincterotomy treatments for anal fissure.

Anal fissure is a common condition that can be treated medically or surgically. Chemical sphincterotomy is often used before surgical intervention. This study aims to evaluate the effectiveness of topical agents for chemical sphincterotomy on healing of anal fissures and side-effects. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant systematic review was performed using MEDLINE, EMBASE, Scopus, and CENTRAL databases. Eligible studies included randomized controlled trials which compared topical sphincterotomy agents with topical placebo agents or each other. Studies that included surgical treatments were excluded. Overall evidence was synthesized according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Thirty-seven studies met the study selection criteria. Seventeen studies show that glyceryl trinitrate (GTN) was significantly more likely to heal anal fissure than placebo (relative risk (RR) = 1.96, 95% confidence interval (95%CI) = 1.35-2.84, I2 = 80%). Eleven studies showed a marginally significant difference between healing rates for diltiazem vs GTN, RR = 1.16, (1.01-1.33) I2 = 48%. There was no significant difference in healing between diltiazem and placebo, RR = 1.65, (0.64-4.23), I2 = 92%. GTN significantly reduced pain on the visual analog scale compared to the placebo group, MD-0.97 (-1.64 to -0.29) I2 = 92%. There was high certainty of evidence that GTN was significantly more likely to cause headache than placebo (RR = 2.73 (1.82-4.10) I2 = 58%) and diltiazem RR = 6.88 (2.19-21.63) I2 = 17%. There is low certainty evidence topical nitrates are an effective treatment for anal fissure healing and pain reduction compared to placebo. Despite widespread use of topical diltiazem, more evidence is required to establish the effectiveness of calcium channel blockers compared to placebo.

Regional Differences in Early BP Management After Acute Ischemic Stroke in the ENCHANTED International Randomized Controlled Trials.

Background and Aims: Epidemiological studies show significant variations in hypertension management within and between countries. The level of regional variation in early blood pressure (BP) management after acute stroke is uncertain.Methods: Data are from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), a partial-factorial, international randomized controlled trial of thrombolysis-eligible acute ischemic stroke (AIS) patients with elevated systolic BP (SBP >150 mmHg) assigned to intensive (target SBP 130-140 mmHg) vs. guideline-recommended (SBP <180 mmHg) treatment; BP management was compared among four regions: Western countries (Italy/United Kingdom/Spain/Australia), China (mainland), other Asia (Hong Kong/Taiwan/Singapore/Thailand/Vietnam/India), and South America (Chile/Brazil/Colombia).Results: These analyses included 2,196 AIS [38% women, mean age 67 (12) years] patients. Commonly used intravenous BP-lowering agents were labetalol, nitroglycerin, and topical nitrates in Western countries; urapidil and sodium nitroprusside in China; nicardipine in other Asian countries; and sodium nitroprusside and labetalol in South America. Chinese patients were less likely to receive BP-lowering treatment in the first 24 h and be treated with multiple agents although they had smaller magnitude of SBP reduction and lower SBP variability.Conclusion: Regional variations in early BP management in acute stroke translated into differences in early BP control parameters.

Evaluation of clinical effectiveness of topical 0.2% glyceryl trinitrate, topical 2% diltiazem and their combination in the treatment of chronic anal fissure

Background: The longitudinal tear or defect in the epithelial lining of the anal canal distal to the dentate line is called anal fissure. It is of two types: acute and chronic. The break in the cycle of pain, spasm and ischemia is essential for successful treatment of anal fissure. Among multiple non-surgical treatment approaches, the appropriate approach with good patient compliance might be the use of topical agents as chemical sphincterotomy. However, the effectiveness of these agents has not been evaluated widely.&#x0D; Objectives: To evaluate clinical effectiveness of topical 0.2% glyceryl trinitrate, topical 2% diltiazem and their combination in the treatment of chronic anal fissure.&#x0D; Methodology: The study was prospective comparative type including total 158 patients. Initially, they were given first line therapy followed by chemical sphincterotomy agents. The study drugs were given to 84 patients (three groups - 0.2% glyceryl trinitrate, 2% diltiazem and their combination) who were not healed after initial therapy. Patients were assessed for pain using visual analogue scale and other symptoms prior to and after two and six weeks of therapy.&#x0D; Results: Complete healing rate was higher with combination (92.86%) than individual agents. The reduction of visual analog scale score within each group and between the groups in the period between before and after treatment was found to be statistically significant. Headache and hypotension were the common side effects seen during study.&#x0D; Conclusion: Anal fissures can be successfully managed by chemical sphincterotomy. The topical nitrates and calcium channel blockers in combination are found to be effective choice rather than individual agents.

Modern Therapeutic Approaches to the Treatment of Anal Fissure

Anal fissure (AF) is one of the most common coloproctological diseases which causes reduction in quality of life. The incidence of anal fissure is 2,1 - 2,3% or 21-23 cases per 1000 working-age people in Russian Federation. Fissures occur most frequently in the posterior midline of the anal canal and associated with the poor blood supply to this area. In some cases, AFs are seen in the anterior midline and rarely seen laterally in the anal. The exact etiology of anal fissures is not entirely clear. However, there is a clear association with the increased pressure within the anal canal. Anal fissures may be acute and chronic. Up to 87% of AFs are resolved with conservative management which includes sitz baths, laxatives, increased intake of fluid and fiber. Patients with chronic anal fissures require the addition of medical treatment. First line therapy includes application of calcium channel blockers (CCB) or topical nitrates in addition to increasing dietary fiber. Medical management is usually effective in 65-95%. However, the range of worldwide approved drugs containing CCBs ornitrates is still very poor. If fissures do not resolve after 6-8 weeks of first line therapy, referral to secondary care (botulinum toxin injections and surgical sphincterotomy) is made. The healing rate in case lateral internal sphincterotomy is close to 100%, however, the fecal incontinence rate ranges from 8% to 30%. In this regard, the development of new effective drugs with the minimum side effects is still a critical task.

Abstract WP390: Regional Differences in Blood Pressure Management After Acute Stroke in International Randomized Controlled Trials

Background and Aims: Epidemiological studies show significant variations in hypertension management within and between countries. The level of regional variation in early blood pressure (BP) management after acute stroke is uncertain. Methods: Data are from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), a partial-factorial, international randomized controlled trial (RCT) of thrombolysis-eligible acute ischemic stroke (AIS) patients with systolic BP (SBP &gt;150 mmHg) assigned to intensive (target SBP 130-140 mmHg) vs. guideline-recommended (SBP &lt;180 mmHg) treatment; and INTERACT2, an international RCT of patients with spontaneous intracerebral hemorrhage (ICH) (&lt;6 hours) with elevated SBP randomized to intensive (target SBP &lt;140 mmHg) or guideline-recommended (SBP &lt;180 mmHg) treatment. BP management was compared between five participating regions of these RCTs: west (Europe/Australia/US), China, other Asia (South Korea, Singapore, Thailand, Vietnam), India (India and Pakistan), and South America (Argentina, Chile, Brazil, Colombia). Results: There were 2196 AIS (38% women, mean age 67[12] years) and 2829 acute ICH (37% women, mean age 63[13] years) patients in these analyzes. Commonly used intravenous BP lowering agents are labetalol, nitroglycerin, and topical Nitrates in western countries; mannitol, urapidil, and sodium nitroprusside in China; nicardipine in other Asian countries; and sodium nitroprusside and labetalol in South America. Western patients were more likely to receive BP lowering treatment in the first 24 hours and treated with multiple agents, and had larger magnitude of SBP reduction and greater SBP variability. BP control parameters over 2-7 days were comparable between regions. Conclusion: Regional variations in early BP management in acute stroke translated into differences in magnitude of SBP reduction and SBP variability in patients.

Recent advances in the workup and management of Raynaud’s phenomenon

Raynaud phenomenon (RP) is defined as recurrent, reversible episodes of vasospasm involving peripheral small vessels, typically in the fingers and toes. Primary (idiopathic) RP is common (it occurrs in about 5% of the general population) and is usually benign. Secondary RP accounts for 10% to 20% of all RP cases and may be associated with complications such as tissue loss, ulcers, and gangrene. Systemic sclerosis (SSc) or, more rarely, other connective tissue diseases are the main underlying conditions. A detailed clinical history and careful physical examination may be helpful in identifying the cause. Routine investigations include a full blood count, measurement of erythrocyte sedimentation rate, C‑reactive protein, antinuclear antibody levels, biochemical profile, thyroid function tests, protein electrophoresis, chest X‑ray, and nailfold capillaroscopy. Capillaroscopy can facilitate a very early diagnosis of SSc. Doppler ultrasound is recommended to evaluate the risk of pathologies in large to medium-sized arteries. Lifestyle modifications may be sufficient to control primary RP, but some patients, and most with secondary RP, require pharmacologic treatment. Several medications are proposed to manage RP and its complications, such as calcium channel blockers, phosphodiesterase type 5 inhibitors, intravenous prostanoids, and topical nitrates. However, scientific evidence for the use of these drugs is still weak to moderate. Despite the lack of efficacy of bosentan in RP treatment, this medication is approved for the secondary prevention of digital ulcers in patients with SSc. In conclusion, the management of RP still represents a challenge. Collaboration between healthcare professionals, patient organizations, and the society could encourage earlier medical assessment of people at risk of SSc.

Use of nitroglycerin ointment to treat primary and secondary Raynaud's phenomenon: a systematic literature review.

Raynaud's phenomenon (RP) is a microvascular condition in which reversible ischemic attacks occur in the extremities. Due to the unpredictable nature of these attacks, pharmacologic agents that can be administered on as-needed basis are currently being sought after. Topical nitrates are well suited for as-needed use, and several different formulations have been studied for the treatment of RP, including ointments, gels, patches, and tapes. However, these different dosage forms are not all equal in terms of safety and efficacy, and not every one is commercially available for use in clinical practice. Nitroglycerin ointment is commercially available, and it has less systemic side effects than other topical formulations. Since its role in the treatment of RP has not yet been completely established, we performed a systematic search of Medline, Embase, and the Cochrane Central Register of Controlled Trials to evaluate its safety and efficacy. A total of 1125 studies were identified, and 7 were included in our review. Although the included studies used different measures of efficacy, the majority reported positive responses to nitroglycerin ointment. The benefit of nitroglycerin ointment in the treatment of RP may be further realized through more robust investigation.

A systematic review and meta-analysis of the effects of topical nitrates in the treatment of primary and secondary Raynaud's phenomenon.

Multiple placebo-controlled trials have assessed locally applied topical nitrate preparations in treating Raynaud's phenomenon (RP). The objective of this meta-analysis was to assess the effects of local topical nitrates in primary and secondary RP with respect to a combined end point integrating parameters of digital blood flow and clinical severity. A systematic review was performed using MEDLINE, Embase, and the Cochrane library. Only trials comparing locally applied topical nitrates with placebo comparators were included. Studies were appraised for bias by 2 independent reviewers. A total of 7 placebo-controlled trials including 346 patients were used in the meta-analysis; 4 trials used nitroglycerin ointments, 2 used the nitroglycerin gel vehicle MQX-503, and 1 used compounded nitrite. The meta-analysis results supported a moderate-to-large treatment effect in RP (standardized mean difference [SMD]=0.70; 95% CI, 0.35-1.05; P<.0001). Subgroup analyses showed a large treatment effect in secondary RP (SMD=0.95; 95% CI, 0.25-1.65; P=.008) and moderate effect in primary RP (SMD=0.45; 95% CI, 0.05-0.85; P=.03). Limitations include the inclusion of multiple topical nitrate preparations and integration of different outcomes assessments. Local topical nitrates have significant efficacy in the treatment of both primary and secondary RP.

Botulinum toxin injection vs topical nitrates for chronic anal fissure: an updated systematic review and meta-analysis of randomized controlled trials.

Chronic anal fissures (CAFs) are frequently encountered in coloproctology clinics. Chemical sphincterotomy with pharmacological agents is recommended as first-line therapy. Topical nitrates (TN) heal CAF effectively but recurrences are common. An alternative treatment modality is injection of botulinum toxin (BT) into the anal sphincter. We aimed to perform an updated systematic review and meta-analysis to compare the effectiveness of BT and TN in the management of CAF. PubMed, EMBASE and Cochrane databases were searched for relevant articles from inception until March 2017. All randomized controlled trials (RCTs) that reported direct comparisons of BT and TN were included. Two independent reviewers performed methodological assessment and data extraction. Random effects models were used to calculate pooled effect size estimates. Six RCTs describing 393 patients (194 BT, 199 TN) were included. There was significant heterogeneity among the trials. On random effects analysis there were no significant differences in incomplete fissure healing (OR=0.47, 95% CI 0.13-1.68, P=0.24) or recurrence (OR=0.70, 95% CI 0.39-1.25, P=0.22) between BT and TN, respectively. BT was associated with a higher rate of transient anal incontinence (OR=2.53, 95% CI 0.98-6.57, P=0.06) but significantly fewer total side effects (OR=0.12, 95% CI 0.02-0.63, P=0.01) and headache (OR=0.10, 95% CI 0.02-0.60, P=0.01) compared with TN. BT is associated with fewer side effects than TN but there is no difference in fissure healing or recurrence. Patients need to be warned regarding the risk of transient anal incontinence associated with BT.

Raynaud's phenomenon and digital ischaemia--pharmacologic approach and alternative treatment options.

The primary goal of therapy is to reduce the frequency and intensity of Raynaud's attacks and to minimize the related morbidity rather than to cure the underlying condition. Treatment strategies depend on whether Raynaud's phenomenon (RP) is primary or secondary. All patients should be instructed about general measures to maintain body warmth and to avoid triggers of RP attacks. Pharmacologic intervention can be useful for patients with severe and frequent RP episodes that impair the patient's quality of life. Calcium channel blockers are currently the most prescribed and studied medications for this purpose. There has been limited evidence for the efficacy of alpha-1-adrenergic receptor antagonists, angiotensin receptor blockers, topical nitrates or fluoxetine to treat RP. The intravenously administered prostacyclin analogue iloprost can reduce the frequency and severity of RP attacks and is considered a second-line therapy in patients with markedly impaired quality of life, critical digital ischaemia and skin ulcers who are at risk for substantial tissue loss and amputation. Phosphodiesterase inhibitors (e.g., sildenafil) can also improve RP symptoms and ulcer healing whereas endothelin-1 receptor antagonists (e.g., bosentan) are mainly considered treatment options in secondary prevention for patients with digital skin ulcers related to systemic sclerosis. However, their use in clinical practice has been limited by their high cost. Antiplatelet therapy with low-dose aspirin is recommended for all patients who suffer from secondary RP due to ischaemia caused by structural vessel damage. Anticoagulant therapy can be considered during the acute phase of digital ischaemia in patients with suspected vascular occlusive disease attributed to the occurrence of new thromboses. In patients with critical digital ischaemia, consideration should be given to hospitalisation, optimisation of medical treatment in accordance with the underlying disease and evaluation for a secondary, possibly reversible process that is causing or aggravating the clinical symptoms.

Therapeutic Management of Accidental Epinephrine Injection

Objective: To review the literature regarding therapeutic options for accidental epinephrine exposure via EpiPen (Mylan Specialty Inc.) autoinjector devices and to suggest a treatment algorithm based on the most common approaches found therein. Data Sources: A literature search of MEDLINE (1950-March 2012) was conducted, using the search term accidental epinephrine injection in combination with the terms adrenaline, EpiPen, anaphylaxis, autoinjector, and treatment. Case reports, case series, and systematic reviews were evaluated for efficacy and safety data. In addition, the references of the reviewed articles were examined to identify additional reports or data. Study Selection and Data Extraction: All English-language articles describing accidental exposure to epinephrine were identified. Our search included both pediatric and adult patient populations. Articles were excluded if the exposure to epinephrine was purposeful and the EpiPen described in the report was being used as intended or the outcome was not clear. Individual case reports were described in detail whereas case series and systematic reviews were included but were not described in detail. To our knowledge, there have been no clinical trials that describe or compare therapeutic options for accidental exposure to epinephrine. Data Synthesis: Accidental exposure to epinephrine is an underreported phenomenon that could warrant medical attention. The importance of this issue has recently been emphasized with the legislative requirement of many schools to store epinephrine (EpiPen) autoinjector devices. The available therapeutic options can be divided into pharmacologic and nonpharmacologic categories. The most common pharmacologic options described in the literature include phentolamine, subcutaneous terbutaline, topical nitrates, and calcium channel blockers. Nonpharmacologic options include observation and/or warm water soaks. Treatment recommendations in our proposed algorithm were based solely on the available data that we describe in our review. Conclusions: The literature did not provide clear guidance on the most appropriate management of accidental epinephrine injection. However, if pharmacologic therapy is necessary, phentolamine appears to be considered the most effective. Guidelines may be helpful in improving the management of accidental epinephrine injection, as well as in preventing unnecessary therapy.

Painful diabetic neuropathy: an update.

Diabetes, a silent killer, is a leading cause of neuropathy. Around 50% of diabetic patients develop peripheral neuropathy in 25 years. Painful diabetic neuropathy manifests as burning, excruciating, stabbing or intractable type of pain or presents with tingling or numbness. The pathophysiology of this condition is due to primarily metabolic and vascular factors. There is increase in sorbitol and fructose, glycated endproducts, reactive oxygen species and activation of protein kinase C in the diabetic state. All these factors lead to direct damage to the nerves. The first step in the management of painful diabetic neuropathy is a tight glycaemic control. Currently there is no drug which can halt or reverse the progression of the disease. Most of the therapies prevalent aim at providing symptomatic relief. Antidepressants like tricyclic antidepressants (TCAs) and selective norepinephrine reuptake inhibitors (SNRIs) have good efficacy in controlling the symptoms. Selective serotonin reuptake inhibitors have not shown the same consistent results. Anticonvulsants including pregabalin, gabapentin and lamotrigine have shown good results in the control of symptoms whereas same was not found with carbamazepine, oxcarbazepine and topiramate. Topical agents (capsaicin, topical nitrates and topical TCAs) and local anaesthetics have also been used with good results. Use of opioids and non steroidal anti-inflammatory drugs although common but is not preferable. The newer therapies under studies are NMDA antagonists, aldose reductase inhibitors, neurotropic factors, vascular endothelial growth factor, Gamma linolenic acid, protein kinase C beta inhibitors, immune therapy, hyperbaric oxygen and alpha lipoic acid.

Treatment of chronic anal fissure with topical nitroglycerin ointment 0.4%: a prospective clinical study

Of all of the available topical treatments for the treatment of anal fissure, nitroglycerin (NTG) ointment has been the most widely popularised. However, the different studies carried out with this ointment have been with customised compounded prescription medications prepared by pharmacists. There has been a disparity in the results arising from the inconsistency of the product, depending on the pharmacy and the methodology used in the research, namely different means of application, doses and concentrations [1]. Azarnoff et al. [2] have suggested that this heterogeneity of results existed because, to date, the studies that were conducted used formulas prepared in pharmacies (where it is not possible to ensure the exact concentration or the homogeneity of the whole tube), and thus, the dose was not exact. In one study of 24 pharmacies in the USA, it was observed that 46% of the pharmacies failed to comply with the exact formula (concentration and/or dose) prescribed, which created differences in the results reported regarding pain reduction due to NTG ointment and migraine associated with treatment. This problem has been solved with the recent appearance on the market of the first NTG ointment for commercial use Rectogesic (glyceryl trinitrate 0.4%), where both the concentration and the dose (dosifier) are precise. In our experience with Rectogesic in 120 patients, initial fissure healing was achieved in 87 patients (72.5%). In 6 cases, a relapse of the fissure occurred 4 months after treatment was completed. Therefore, the final healing rate was 67.5% (81 patients).There are few articles reported in the literature with this new formula that correct for the methodological defects mentioned above. However, we can assume that the long-term recurrence rate is high since anal pressures in repose revert to the pre-treatment values in the first 8 weeks after healing [3]. Nevertheless, we should expect the treatment to cause an initial improvement in the symptoms in most patients. On occasion, the treatment may produce incapacitating proctalgia with serious effects on quality of life. But, for the majority of patients, this treatment makes it possible to avoid irreversible resection of the internal anal sphincter and the postoperative consequences. Since the introduction of topical nitrates, the number of surgical interventions performed for anal fissure has fallen by 72% in England and 61% in Scotland [4]. As regards side effects, the risk of migraine (20–70%) is four times greater than with the placebo, as observed in the medical literature [5]. Nevertheless, although headaches may be serious, they tend to be temporary or transitory (in the first 30 min) and only necessitate withdrawal from the treatment in approximately 10% of the patients. When headaches do occur, they can be treated with mild analgesics before applying the ointment. To reduce the incidence of this side effect, the product should be applied with the finger protected by a finger cot in order to limit the absorption to the anal area and to reduce the absorption of the product through the skin of the finger. In our sample of 120 patients, headaches occurred in 63 patients (52.5%), but most were self-limiting or were relieved by oral analgesics. We must take into account the fact that the intensity of the migraine is always less than the pain caused by the anal fissure; therefore, it is not common for patients to abandon the treatment as a consequence of this side effect. J. Perez-Legaz A. Arroyo (&) J. Ruiz-Tovar A. Lopez-Delgado A. Frangi P. Moya J. Santos F. Candela R. Calpena Alicante, Spain e-mail: arroyocir@hotmail.com