Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

Review of systematic reviews of non-pharmacological interventions to improve quality of life in cancer survivors.

OBJECTIVES: Over two million people in the UK are living with and beyond cancer. A third report diminished quality of life. DESIGN: A review of published systematic reviews to identify effective non-pharmacological interventions to improve the quality of life of cancer survivors. DATA SOURCES: Databases searched until May 2017 included PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO. STUDY SELECTION: Published systematic reviews of randomised trials of non-pharmacological interventions for people living with and beyond cancer were included; included reviews targeted patients aged over 18. All participants had already received a cancer diagnosis. Interventions located in any healthcare setting, home or online were included. Reviews of alternative therapies or those non-English reports were excluded. Two researchers independently assessed titles, abstracts and the full text of papers, and independently extracted the data. OUTCOMES: The primary outcome of interest was any measure of global (overall) quality of life. ANALYTICAL METHODS: Quality assessment assessing methdological quality of systematic reviews (AMSTAR) and narrative synthesis, evaluating effectiveness of non-pharmacological interventions and their components. RESULTS: Of 14 430 unique titles, 21 were included in the review of reviews. There was little overlap in the primary papers across these reviews. Thirteen reviews covered mixed tumour groups, seven focused on breast cancer and one focused on prostate cancer. Face-to-face interventions were often combined with online, telephone and paper-based reading materials. Interventions included physical, psychological or behavioural, multidimensional rehabilitation and online approaches. Yoga specifically, physical exercise more generally, cognitive behavioural therapy (CBT) and mindfulness-based stress reduction (MBSR) programmes showed benefit in terms of quality of life. CONCLUSIONS: Exercise-based interventions were effective in the short (less than 3-8 months) and long term. CBT and MBSR also showed benefits, especially in the short term. The evidence for multidisciplinary, online and educational interventions was equivocal.

Sacral nerve stimulation for faecal incontinence and constipation in adults.

BACKGROUND: Faecal incontinence (FI) and constipation are both socially-embarrassing and physically-disabling conditions that impair quality of life. For both, surgery may be required in a minority of people when more conservative measures fail. However, the invasiveness and irreversible nature of direct surgery on bowel and sphincter muscles, poor long-term outcomes and well-established compIications makes such procedures unappealing for these benign conditions. A less-invasive surgical option to treat faecal incontinence and constipation is direct, low-voltage stimulation of the sacral nerve roots, termed sacral nerve stimulation (SNS). SNS has become the first line surgical treatment for FI in people failing conservative therapies. Its value in the treatment of constipation is less clear. OBJECTIVES: To assess the effects of sacral nerve stimulation using implanted electrodes for the treatment of faecal incontinence and constipation in adults. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, ClinicalTrials.gov, the World Health Organization (WHO) ICTRP and handsearched journals and conference proceedings (searched 5 February 2015), EMBASE (1 January 1947 to 2015 Week 5), and the reference lists of retrieved relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials assessing the effects of SNS for faecal incontinence or constipation in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed the methodological quality of the included trials, and undertook data extraction. MAIN RESULTS: Six crossover trials and two parallel group trials were included.Six trials assessed the effects of SNS for FI. In the parallel group trial conducted by Tjandra, 53 participants with severe FI in the SNS group experienced fewer episodes of faecal incontinence compared to the control group who received optimal medical therapy (mean difference (MD) -5.20, 95% confidence interval (CI) -9.15 to -1.25 at 3 months; MD -6.30, 95% CI -10.34 to -2.26 at 12 months). Adverse events were reported in a proportion of participants: pain at implant site (6%), seroma (2%) and excessive tingling in the vaginal region (9%).In the parallel group trial carried out by Thin, 15 participants with FI in the SNS group experienced fewer episodes of FI compared with the percutaneous tibial nerve stimulation (PTNS) group (MD -3.00, 95% CI -6.61 to 0.61 at 3 months; MD -3.20, 95% CI -7.14 to 0.74 at 12 months). Adverse events were reported in three participants: mild ipsilateral leg pain during temporary testing (n = 1); and stimulator-site pain following insertion of neurostimulator (n = 2).In the crossover trial by Leroi 7 of 34 recruited participants were excluded from the crossover due mainly to complications or immediate device failure. Twenty-four of the remaining 27 participants while still blinded chose the period of stimulation they had preferred. Outcomes were reported separately for 19 participants who preferred the 'on' and five who preferred the 'off' period. For the group of 19, the median (range) episodes of faecal incontinence per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of five, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period. Four of 27 participants experienced an adverse event resulting in removal of the stimulator.In the crossover trial by Sørensen and colleagues, participants did not experience any FI episodes in either the one-week 'on' or 'off' periods.In the crossover trial by Vaizey, participants reported an average of six, and one, episodes of faecal incontinence per week during the 'off' and 'on' periods respectively in two participants with FI. Neither study reported adverse events.In the crossover trial by Kahlke, 14 participants with FI experienced significantly lower episodes of FI per week during the stimulator 'on' (1 (SD, 1.7)) compared with the 'off' period (8.4 (SD, 8.7)). Adverse events reported include: haematoma formation (n = 3); misplacement of tined lead (1); and pain at stimulator site (n = 1).Two trials assessed SNS for constipation. In the Kenefick trial, the two participants experienced an average of two bowel movements per week during the 'off' crossover period, compared with five during the 'on' period. Abdominal pain and bloating occurred 79% of the time during the 'off' period compared with 33% during the 'on' period. No adverse events occurred. In contrast, in the trial by Dinning with 59 participants, SNS did not improve frequency of bowel movements and 73 adverse events were reported, which included pain at site of the implanted pulse generator (32), wound infection (12), and urological (17) events. AUTHORS' CONCLUSIONS: The limited evidence from the included trials suggests that SNS can improve continence in a proportion of patients with faecal incontinence. However, SNS did not improve symptoms in patients with constipation. In addition, adverse events occurred in some patients where these were reported. Rigorous high quality randomised trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.

Percutaneous tibial nerve stimulation for fecal incontinence: a video demonstration.

BACKGROUND: Fecal incontinence is an increasingly common condition with significant negative impact on quality on life and health care resources. It frequently presents a therapeutic challenge to clinicians. Emerging evidence suggests that percutaneous tibial nerve stimulation is an effective treatment for fecal incontinence with the added benefit of being minimally invasive and cost effective. METHOD: Pursuant to the preliminary report of our early experience of percutaneous tibial nerve stimulation in patients with fecal incontinence published in this journal in 2010, in this dynamic article, we now describe and demonstrate the actual technique that can be performed in a nurse-led clinic or outpatient or community setting. CONCLUSION: Percutaneous tibial nerve stimulation is a technically simple procedure that can potentially be performed in an outpatient or community setting. The overall early success rate of 68% following its use reported by our unit compares favorably with the success rate following other forms of neuromodulation, including sacral nerve stimulation. When completed, our long-term outcome data will provide further information on the efficacy of tibial nerve stimulation in a larger cohort of patients (n > 100). Future studies, including our currently planned randomized controlled trial of percutaneous tibial nerve stimulation vs sham stimulation, will provide controlled efficacy data and may provide information on its exact mechanism of action.