Treatment of painful bladder syndrome/interstitial cystitis with botulinum toxin A: why isn’t it effective in all patients?

Botulinum toxin A (BTA) is currently used to treat a variety of painful disorders, including painful bladder syndrome/interstitial cystitis (PBS/IC). However, BTA is not consistently effective in all patients. This may be due to the disparity of causes of pain, but this may also relate to the processes by which BTA exerts anti-nociceptive effects. This review discusses mechanisms by which BTA may inhibit pain and studies of the use of BTA in PSB/IC patients. It is doubtful that any single treatment will effectively control pain in PBS/IC patients, and it is highly probable that multiple strategies will be required, both within individual patients and across the population of PBS/IC patients. The purpose of this review is to discuss those mechanisms by which BTA acts, with the intent that alternative strategies exploiting these mechanism, or work through alternative pathways, can be identified to more effectively treat pain in PBS/IC patients in the future.     

Review of intravesical therapies for bladder pain syndrome/interstitial cystitis

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic pain condition characterised by urinary frequency, urgency and pain or discomfort which the patient attributes to the bladder. It is a complex condition to manage and treat and requires a multi-disciplinary and multi-modal approach. As well as lifestyle and behavioural modifications, physical therapy and oral medications, intravesical treatments can be used in the treatment algorithm for BPS/IC. A number of intravesical agents are reviewed in this paper along with the available evidence for their use.     

Optimal acupoint and session of acupuncture for patients with chronic prostatitis/chronic pelvic pain syndrome: a meta-analysis

BackgroundThe study aims to perform a meta-analysis of published trials and evaluate the efficacy of acupuncture on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) by symptom score reduction, optimal acupuncture session, and most frequently used acupoints.MethodsA literature search was performed for randomized controlled trials (RCTs) comparing efficacy of acupuncture with sham acupuncture or standard medication on CP/CPPS. The primary outcome was the reduction of National Institute of Health-Chronic Prostatitis Index (NIH-CPSI) total score and its subscales. The optimal acupuncture session to reach its clinical efficacy and most common compatibility rule of acupoints were also evaluated.ResultsTen trials involving 770 participants were included. Meta-analysis showed compared with sham acupuncture, acupuncture yielded significant reduction in NIH-CPSI total score [weighted mean difference (WMD): 7.28, 95% confidence interval (95% CI): 5.69–8.86), and provided better pain relief (WMD: 3.57, 95% CI: 2.07–5.08), urinary symptoms improvement (WMD: 1.68, 95% CI: 1.13–2.22), and quality of life (QOL) (WMD: 2.38, 95% CI: 1.41–3.36). Compared with standard medication, acupuncture were more efficacious in reducing NIH-CPSI total score (WMD: 3.36, 95% CI: 1.27–5.45), also showed significant greater pain relief (WMD: 2.36, 95% CI: 1.67–3.06), marginal advantage in improving QOL (WMD: 0.98, 95% CI: 0.12–1.83) but no difference in reducing urinary symptom (WMD: −0.03, 95% CI: −1.30 to 1.24). Four acupuncture sessions were the minimum “dose” to reach clinical efficacy, and prolonged acupuncture sessions continuously improved urinary symptoms and QOL. The majority of acupoint selection strategies were based on the combination of any three acupoints from CV3, CV4, BL32, SP6, and SP9.ConclusionsAcupuncture has promising efficacy for patients with CP/CPPS, especially category IIIB, in aspects of relieving pain and urinary symptoms and improving the QOL. Acupuncture may serve as a standard treatment option when available, and a tailored comprehensive treatment strategy for CP/CPPS is the future trend.     

Interstitial cystitis/painful bladder syndrome: the influence of modern diagnostic criteria on epidemiology and on Internet search activity by the public

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic debilitating condition that is characterised by suprapubic pain and urinary symptoms such as urgency, nocturia and urinary frequency. The prevalence of the condition is increasing due to more inclusive diagnostic criteria. Herein, we review the evolving epidemiology of IC/PBS and investigate health seeking behaviour for the condition through Internet search activity. Study selection was performed in accordance with PRISMA. In addition, global search trends for the terms ‘Interstitial Cystitis’ and ‘Painful Bladder Syndrome’ from 2005 to 2015 were also evaluated using the ‘Google Trends’ search application. The mean search activity per month was recorded and mean activity at annual intervals calculated. Regional search activity by country and city was also measured. Prevalence rates for IC/PBS vary according to diagnostic criteria and range from 2% to 17.3% among the general population. Increased prevalence is associated with female gender and females with one first-degree relative affected. There has been an increase in global mean search activity for IC/PBS on an annual basis since 2005. The greatest increase in search activity was in USA, Canada, United Kingdom, Australia, Ireland and India respectively. The top five cities for search activity for IC/PBS were in the USA. As diagnostic criteria for IC/PBS continues to become more inclusive it is likely that the prevalence will continue to increase. This is particularly true for the USA and Canada as these regions have demonstrated the greatest increase in Internet search activity for IC/ PBS.     

Paving the way for a better management of pain in patients with spinal cord injury: An exploratory study on the use of Functional Electric Stimulation(FES)-cycling

Context/objective:Chronic pain is common in patients with spinal cord injury (SCI), for whom it negatively affects quality of life, and its treatment requires an integrated approach. To this end, lower limb functional electrical stimulation (FES) cycling holds promise.Objective:To investigate pain reduction in a sample of patients with SCI by means of lower limb rehabilitation using FES cycling.Design, setting and participants:Sixteen patients with incomplete and complete SCIs, attending the Neurorobotic Unit of our research institute and reporting pain at or below the level of their SCI were recruited to this exploratory study.Interventions:Patients undertook two daily sessions of FES cycling, six times weekly, for 6 weeks.Outcome measures:Pain outcomes were measured using the 0–10 numerical rating scale (NRS), the Multidimensional Pain Inventory for SCI (MPI-SCI), and the 36-Item Short Form Survey (SF-36). Finally, we assessed the features of dorsal laser-evoked potentials (LEPs) to objectively evaluate Aδ fiber pathways.Results:All participants tolerated the intervention well, and completed the training without side effects. Statistically significant changes were found in pain-NRS, MPI-SCI, and SF-36 scores, and LEP amplitudes. Following treatment, we found that three patients experienced high pain relief (an NRS decrease of at least 80%), six individuals achieved moderate pain relief (an NRS decrease of about 30–70%), and five participants had mild pain relief (an NRS decrease of less than 30%).Conclusion:Our preliminary results suggest that FES cycling training is capable of reducing the pain reported by patients with SCI, regardless of American Spinal Injury Association scoring, pain level, or the neurological level of injury. The neurophysiological mechanisms underlying such effects are likely to be both spinal and supraspinal.     

Complementary and alternative medical therapies for interstitial cystitis: an update from the United States

The diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) has shifted from organ-specific to a multifactorial, multidisciplinary and individualized approach. Patients with refractory and debilitating symptoms may respond to complementary and alternative medical treatments (CAM). Through CAM therapies, practitioners assist the patient to be at the center of their care, empowering them to be emotionally and physically involved. Multi-disciplinary care, including urology, gynecology, gastroenterology, neurology, psychology, physiotherapy and pain medicine, is also identified to be the crux of adequate management of patients with chronic pelvic pain because of its variable etiology. The purpose of this review is to emphasize these changes and discuss management strategies.     

Interstitial cystitis/painful bladder syndrome: diagnostic evaluation and therapeutic response in a private urogynecology unit

Background

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a spectrum of pelvic, bladder or urethral pain, as well as irritative voiding symptoms. The term interstitial cystitis (IC) is reserved for patients with typical cystoscopic features. Diagnosis and management of this syndrome may be difficult. The aim of this study was to describe endoscopic features and our experience on the treatment of this syndrome in Urodifem de Occidente S.C., a private urogynecology unit.

Methods

Observational, retrospective analytic study of 25 treated patients from 33 with diagnosis of IC/PBS between January 2001 and March 2015. The diagnosis was done by clinical, cystoscopic and urodynamic approach. Treatment was based on bladder instillation of dymetilsulfoxido (DMSO), dexamethasone and heparin. Oral pentosan polysulphate was prescribed for at least 1 year.

Results

Cystoscopic findings showed petechial hemorrhages in 32%, Hunner’s lesions in 28%, glomerulations in 28% and bladder pain in absence of lesions in 12%. The basic treatment included one instillation once a week for 6 weeks, twice a month for 2 months and four monthly instillations. Three cases had complete remission of their symptoms, 21 had significant improvement and we have only one failure.

Conclusions

We recommend the combined use of DMSO instillation and pentosan polysulphate (PPS) in cases of IC/PBS.     

硝普钠阴茎海绵体内注射治疗阳萎的临床研究

本研究选择４２例阳萎患者，采用硝普钠进行阴茎海绵体注射（ＩＣＩ），并选择罂粟碱／酚妥拉明进行对照，结果表明，硝普钠ＩＣＩ后：（１）阴茎外形性状（长度、周径等）明显改变。（２）Ｖｉｒａｇ硬度计点表明硝普钠与罂粟碱／酚妥拉明效果之间无明显差别。（３）所有测试患者无一例出现低血压或局部不适等副反应，与罂粟碱／酚妥拉明相比各有优劣，但总体差异不大，这充分表明，硝普钠作为一种ＮＯ供体可导致阴茎平滑肌松弛，血窦充盈阴茎勃起，其副反应较小，有其临床应用之价值。     

Acid‐sensing ion channel 3 or P2X2/3 is involved in the pain‐like behavior under a high bone turnover state in ovariectomized mice

We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain‐like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid‐sensing nociceptor, improved the threshold value of pain‐like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H⁺‐ATPase, known as an proton pump, (ii) an antagonist of acid‐sensing ion channel (ASIC) 3, as another acid‐sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP‐ligand nociceptor, on pain‐like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain‐like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:566–573, 2016.     

Clinical presentation and treatment of bladder pain syndrome/interstitial cystitis (BPS/IC) in India

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease characterized by pelvic pain urgency and frequency. Patients with severe symptoms lead a very miserable life. North American, European and Asian guidelines have been recently promulgated but they differ on many important issues. There is no consensus on its name, definition, investigations and management. Indian guidelines have also been developed and they give more importance to the symptoms in relation to micturition. Though initially believed to be rare or non-existent in India the situation has changed. In Indian patients the presentation is more or less same as the rest of the world but a large percentage have obstructive symptoms and unusual urinary symptoms. Anal discomfort is also common. In India the commonest investigation in all cases of lower urinary tract (LUT) dysfunction is ultrasonography of kidney ureter and bladder with measurement of the post void residual urine volume. Cystoscopy is also done in all the cases to rule out presence of tuberculosis or carcinoma in situ. Bladder pain syndrome/interstitial cystitis (BPS/IC) is not considered to be a clinical disease as it is difficult to rule out all differential diagnosis only from history. Hunner’s lesion is very rare. Cystoscopy with hydro distension, oral therapy, intravesical therapy and surgical therapy form the back bone of management. It is difficult to know which treatment is best for a given patient. A staged protocol is followed and all the treatment modalities are applied to the patients in a sequential fashion—starting from the non-invasive to more invasive. Intravesical botox has not been found to be effective and there is no experience with interstim neuromodulation.     

Enhanced recovery strategies after penile implantation: a narrative review

Optimizing pain management strategies in penile implantation has historically been a challenge to urologists assuming care of patients post-operatively. In addition to the complex pathophysiology of male genital pain, the responsibility of opioid stewardship in the face of the ongoing narcotics epidemic presents its own set of challenges to experienced implanters. Recent innovations in pre- and intra-operative analgesia have provided some improvement in patient-reported pain outcomes. When used together in protocols spanning each phase of operative care, multimodal analgesia (MMA) regimens provide superior patient pain control and successfully decrease opioid usage compared to traditional opioid-based pain control. This review will systematically present literature that discusses interventions in the preoperative and intraoperative spaces aimed at optimally controlling pain. We will also highlight surgical techniques that have been demonstrated to help ameliorate post-operative pain in penile implant recipients. We will discuss the impact of MMA protocols across urology and further explore its larger impact on reducing opioid burden in the ongoing epidemic.     

Clinical effectiveness of microsurgical subinguinal varicocelectomy with enhanced recovery after surgery for varicocele

BackgroundVaricocele (VC) is one of the most common causes of infertility in men, and microscopic varicocelectomy is currently the major surgical procedure for VC. We assessed the clinical effectiveness of microsurgical subinguinal varicocelectomy (MSV) with enhanced recovery after surgery (ERAS) in the treatment of VC in terms of semen quality improvement rate, pregnancy rate, pain relief rate, recurrence rate, and complication rate after MSV and explored the indications for VC surgery.MethodsIn total, 216 patients undergoing MSV in our center between June 2019 and July 2020 were enrolled in this study. All patients received the surgery under local anesthesia and were admitted and discharged within 24 hours. All patients were followed up for more than 6 months, and the rates of semen quality improvement, pregnancy, pain relief, recurrence, and postoperative complications were recorded. We can evaluate the pain degree of patients through the numerical rating scale (NRS). (I) 0 points for painless; (II) 1–3: mild pain; (III) 4–6: moderate pain; (IV) 7–10 points are severe pain. 0 is the most slightly, indicating comfort, and 10 is the most painful and unbearable.ResultsThe sperm concentration, total sperm count, progressive motility rate, sperm viability, and morphology were significantly improved after the surgery (all P values <0.05). The rate of semen quality improvement was 88.2%, and the semen indicators returned to normal in 26.6% of the patients. Among the patients who were followed up for 1 year, the natural conception rate reached 27.1% and was accompanied by a 95.5% pain relief rate, a 0.5% VC recurrence rate, and a 2.3% postoperative complication rate.We obtained data through laboratory examination of semen DNA fragments index (DFI). Compared with preoperative and postoperative DFI, postoperative DFI was improved, and the pregnancy outcome was improved.ConclusionsMSV under local anesthesia increases the rates of semen quality improvement, pregnancy, and pain relief while lowering the rates of recurrence and postoperative complications. MSV may also help to improve the pregnancy outcomes in patients with VC accompanied by sperm DNA fragmentation or nonobstructive azoospermia, but this should be verified by further investigation.     

Tomoscintigraphy of the lumbar spine: Prospects and clinical application

Summary In an in vivo prospective study, we examined the lumbar spine of 18 patients presenting with a first episode of acute low-back pain with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Scintigraphic activity at L2 was considered 100%, and the other levels were quantified in relation to L2. MRI scans were rated for disc signal intensity on T2-weighted images. The results show that an abnormal intervertebral MRI signal corresponds with an abnormal image on tomoscintigraphy. On tomoscintographic profiles, the disappearance of the discal dip corresponds well with degeneration on MRI. Furthermore, a positive MRI at one level appears to influence other levels at which a significantly higher scintigraphic activity was observed. Of patients with acute LBP 50% had a normal disc SPECT; it is concluded that in these cases a non-discal origin for the pain must be sought.Read at the annual meeting of the International Society for the Study of the Lumbar Spine, Marseilles, 1993     

Oddi括约肌测压术在慢性胆胰疾病诊治中的应用价值

目的评价Oddi括约肌测压术(sphincter of Oddi manometry,SOM)在慢性胆胰疾病诊治中的应用价值。方法回顾分析我院2005年5月~2009年1月11例慢性上腹痛疑似Oddi括约肌功能紊乱(sphincter of Oddi dysfunction,SOD)在ERCP检查时接受SOM的临床资料,分析测压结果、ERCP诊治情况,并随访远期疗效。结果SOM结果正常2例(18.2%),均为胆囊切除术后腹痛待查患者,未行乳头括约肌切开术(endoscopic sphincterotomy,EST),长期随访腹痛无加重,未再因此就医。5例复发性胰腺炎和4例腹痛伴胆总管增宽的SOM均存在不同程度的异常:Oddi括约肌基础压力为(52.7±19.2)mm Hg(34~96.5mm Hg);蠕动压力为(167.3±24.8)mm Hg(140~200mm Hg)。9例SOM结果异常者均接受EST治疗,术后随访7例(77.8%)获得良好效果,2例复发性胰腺炎再次行ERCP并放置胰管支架后获满意疗效。结论SOM有助于评价Oddi括约肌功能,尤其适用于胆囊切除术后腹痛怀疑为SODⅢ型的患者,可以帮助明确诊断SOD,指导ERCP治疗。     

针刺阳陵泉、胆囊穴治疗急性胆囊炎胆绞痛的临床疗效观察

目的 观察针刺阳陵泉、胆囊穴对急性胆囊炎胆绞痛的临床镇痛疗效。方法 收集2015年1月至2016年1月就诊于我院普外科的急性胆囊炎胆绞痛患者共60例,随机平均分成针刺组及药物组。在治疗前后对患者进行疼痛评分,并检测患者外周血浆C反应蛋白（C-Reactive Protein）、β-内啡肽（β-Endorphin,β-EP）、胆囊收缩素（Cholecystokinin,CCK）水平。结果 两组患者的术前临床资料无统计学差异（P>0.05）,治疗后5、10及15 min这三个时间点,针刺组的疼痛治疗有效率明显优于药物组（P<0.05）,而在治疗后20、25及30 min,两组的疼痛治疗有效率无统计学差异（P>0.05）。针刺组在降低血浆CRP方面优于药物组,有统计学差异（P=0.004）,但血浆β-EP及CCK的变化无统计学差异（P>0.05）。结论 此次研究证实针刺对于急性胆囊炎胆绞痛治疗效果优于麻醉镇痛药联合抗胆碱能药物的镇痛效果,具有起效快、效果好、持续久的优势,同时能降低胆绞痛患者的CRP水平,安全可靠。     

Effect of dexmedetomidine combined with local infiltration analgesia on postoperative wound complications in patients with total knee arthroplasty: A meta-analysis

Dexmedetomidine has been demonstrated to be effective in the management of pain in total knee replacement (TKA). Nevertheless, a combination of a local anaesthetic and a dose of dexmedetomidine might be a better choice for post-operative pain management of TKA. The aim of this research is to determine if the combination of a local anaesthetic with dexmedetomidine during a knee replacement operation can decrease the post-operation pain. Furthermore, the effectiveness and security of dexmedetomidine combined with topical anaesthetic were evaluated for the management of post-operative TKA. Based on the research results, the author made a research on the basis of four big databases. The Cochrane Handbook on Intervention Systems Evaluation has also evaluated the quality of the literature. Seven randomized controlled trials have been established from this. It was found that the combination of local anaesthesia and dexmedetomidine had a greater effect on postoperative pain in 4 h (mean difference [MD], −0.9; 95% CI, −1.71, −0.09; p = 0.03), 8 h (MD, −0.52; 95% CI, −0.66, −0.38; p < 0.0001), 12 h (MD, −0.72; 95% CI, −1.04, −0.40; p < 0.0001), 24 h (MD, −0.49; 95% CI, −0.83, −0.14; p = 0.006), 48 h (MD, −0.51; 95% CI, −0.92, −0.11; p = 0.01). Nevertheless, because of the limited number of randomized controlled trials covered by this meta-analysis, caution should be exercised with regard to data treatment. More high quality research will be required to confirm the results.     

Pain-relieving effects of intravenous ATP in chronic intractable orofacial pain: an open-label study

PURPOSE: Chronic orofacial pain is often refractory to conventional pain therapies. We conducted an open-label study to determine whether adenosine 5'-triphosphate (ATP) could alleviate chronic intractable orofacial pain, and if so, which type of pain could respond to ATP. METHODS: In 8 and 16 patients with non-neuropathic and neuropathic intractable orofacial pain, respectively, ATP was intravenously infused at a rate of 100 microgxkg(-1)xmin(-1) over 120 min. The magnitudes of spontaneous pain and brush-evoked allodynia were graded with a visual analog scale (VAS). When a VAS score for spontaneous pain was decreased by 50% or more by ATP, the patient was classified as a responder. RESULTS: The patients could be clearly divided into 10 responders and 14 non-responders. Ten of the 16 patients (62.5%) with neuropathic pain, but none of the 8 patients with non-neuropathic pain, responded to ATP. In particular, all of 8 patients with neuropathic pain following pulpectomy, with or without subsequent tooth extraction, responded to ATP. In the 10 responders, VAS scores for spontaneous pain decreased slowly but progressively during the infusion period, and eventually, ATP reduced the VAS scores for spontaneous pain and allodynia by 82 +/- 15% and 74 +/- 9%, respectively. In these responders, the analgesic and anti-allodynic effects of ATP outlasted the infusion period for medians of 7 and 12 h, respectively. CONCLUSION: Intravenous ATP did not relieve non-neuropathic orofacial pain. However, it exerted slowly expressed but long-lasting analgesic and anti-allodynic effects in patients with neuropathic orofacial pain, especially in those suffering from neuropathic pain following pulpectomy and/or tooth extraction.     

Evaluation of Effect and Comparison of Superoxidised Solution (Oxum) V/S Povidone Iodine (Betadine)

Wounds expose a patient to serious hazards like wound infection, tissue destruction, disfiguring and disabling scars. Use of superoxidised solution (oxum) in infected wounds, ulcers, diabetic wounds, abcesses, burns reduced morbidity and hospital stay with its early wound healing effect. To evaluate the effect of superoxidised water (Oxum) V/s povidone iodine (Betadine) on similar types of wounds. We retrospectively analysed the records of two hundred patients with different types of wounds who attended Department of Surgery, Guru Nanak Dev Hospital/Govt. Medical College, Amritsar from January 2008 to January 2009. The patients were divided into two groups. Group A where topical management and dressing was done using oxum and group B where topical management and dressing was done using betadine. A standard grading in terms of percentage decrease in wound size, periwound oedema/erythema, pus discharge and percentage increase in granulation, fibrin and epithelisation was noted in various types of wounds in both groups. Oxum treated wounds showed reduction in inflammation and their healing earlier than betadine group. Oxum application was safe having no pain and allergic manifestation.     

Interstitial cystitis/bladder pain syndrome and glycosaminoglycans replacement therapy

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disease characterized by discomfort or recurrent abdominal and pelvic pains in the absence of urinary tract infections. Its symptomatology includes discomfort, increased bladder pressure, sensitivity and intense pain in the bladder and pelvic areas, increased voiding frequency and urgency, or a combination of these symptoms. For these reasons, this pathology has a very negative impact on quality of life. The etiology of IC/BPS is still not well understood and different hypotheses have been formulated, including autoimmune processes, allergic reactions, chronic bacterial infections, exposure to toxins or dietary elements, and psychosomatic factors. The finding of an effective and specific therapy for IC/BPS remains a challenge for the scientific community because of the lack of a consensus regarding the causes and the inherent difficulties in the diagnosis. The last recent hypothesis is that IC/BPS could be pathophysiologically related to a disruption of the bladder mucosa surface layer with consequent loss of glycosaminoglycans (GAGs). This class of mucopolysaccharides has hydrorepellent properties and their alteration expose the urothelium to many urinary toxic agents. It has been hypothesized that when these substances penetrate the bladder wall a chain is triggered in the submucosa. In order to improve the integrity and function of the bladder lining, GAG layer replenishment therapy is widely accepted as therapy for patients with IC/BPS who have poor or inadequate response to conventional therapy. Currently, Chondroitin sulfate (CS), heparin, hyaluronic acid (HA), and pentosan polysulphate (PPS), and combinations of two GAGs (CS and HA) are the available substances with different effectiveness rates in patients with IC/BPS. There are four different commercially available products for GAG replenishment including CS, heparin, HA and PPS. Each product has different concentrations and dosage formulations. Recently, a combination of CS and HA is the latest commercially available product with promising results.