Comprehensive Effect Of Low-dose Amitriptyline On Refractory Diarrhea-predominant IBS And Its Mechanism

Background and ObjectiveIrritable bowel syndrome（IBS）is a common functional gastrointestinal disorderswith chronic symptoms. The pathogenesis of IBS is complicated, it now consideredmay be related with abnormal motility, visceral hypersensitivity, psychological,immune system and endocrine system disorders, brain-gut axis dysfunction.Nowadays the IBS therapies focused mostly on regulating the intestinal flora,spasmolytic and antidepressants. Refractory IBS is patients who failure to respond toconventional therapy, including education, dietary advice, spasmolytic, laxative andantidiarrheal administered minimum of3months in gastroenterology outpatient, thesymptom score is still more than50points. Refractory IBS patients often complainedsymptoms persistent repeated attack and hard to recover, quite influence the patient’slife quality and increase health care costs significantly. Therefore Refractory IBSpatients gradually become digestive physician focus on group in recent years.Amitriptyline (AMT) as a representative drug of the tricyclic antidepressant, hadbeen used to treat IBS for many years by high doses (100mg/day), but it limited to beused due to the larger adverse event. In recent years, many studies had found that theeffect of low-dose AMT on IBS is pretty good, so low-dose AMT has been receivedwidespread attention at home and abroad. There is not yet any research literaturetargeting the effect of low-dose AMT on Refractory diarrhea-predominant IBS(D-IBS), and its withdrawal follow-up research reports was never reported before.At present, it is not clear how AMT contributes to IBS. But some found that effects of AMT occur at lower doses than its antidepressant effects, so theyconsidered the effect of AMT in IBS is independent of its antidepressant effects. Inour previous study, we found that low-dose AMT could significant improve visceralsensitivity and reduced ororectal transit time. In this paper, we obtain from the severalaspects of pathogenesis of IBS, to discuss the possible action mechanism of low-doseAMT on refractory D-IBS.The aim of our study was to investigate the effects of low dose AMT on clinicalsymptoms, sleep, quality of life and serum levels of interleukin-6(IL-6),tumornecrosis factor-α(TNF-a)，interleukin-10(IL-10)，5-hydroxytryptamine (5-HT)，neuropeptide Y (NPY)，D-lactic acid in refractory D-IBS patients. We aim to clarifycomprehensive effect of low-dose AMT on refractory D-IBS and its possiblemechanisms, thus provide reference for clinical application.MethodThe subjects of this study were consecutive refractory D-IBS patients fromgastroenterology outpatient of Guangzhou First People’s Hospital Nansha Hospital,the hedong branch of Guangzhou First People’s Hospital, Guangdong provinceSecond People’s Hospital between December2011and March2013. A multi-center,self-control and follow-up study (Clinical trial registration number﹕ChiCTR-TRC-12001969) was conducted. The study was admitted by the hospital ethicscommittee and patients.Part one: Comprehensive effect of low-dose amitriptyline on refractorydiarrhea-predominant IBS and follow-up study.114patients with refractory D-IBSpatients were received25mg AMT before bedtime and conventional treatment(compound lactobacillus acidophilus0.5g tid) for4wk and1year follow-up aftertreatment. The main efficacy endpoint was assessed by Irritable bowel syndromesymptom severity score (IBS-SSS) and main symptom relief rate；Secondary efficacyendpoint included Pittsburgh Sleep Quality Index (PSQI) and IBS quality of life(IBS-QOL). All patients entering this study recorded the side effect. The IBS-SSS andmain symptom scores was evaluated at week2, week4, three months after treatmentand1year after treatment respectively. IBS-QOL was evaluated at baseline, threemonths after treatment and1year after treatment, the others indexes was evaluated at baseline and at week4respectively. After finishing4weeks treatment, those patientswho responses from AMT therapy with drug withdrawal were observed1yearfollowing up. Those patients who after finishing treatment and after recurrenceretreatment during follow-up period is invalid instead of taking SSRI or otherantidepressants, but those patients do not count towards the effective number ofstatistics.Part two: Analysis for the effect mechanism of low-dose amitriptyline onrefractory diarrhea-predominant IBS. All patients were collected10ml fasting cubitalvein blood before and after4wk of treatment respectively. All samples whichcollecting the supernatant were packaged in epoxy epoxide tubes through3000g for15minutes. We used ELISA (Enzyme-linked immunosorbent assay) Kits for detectingserum levels of IL-6, TNF-a, IL-10,5-HT, NPY, D-lactic acid. The operation iscarried out in strict accordance with the operating instructions in the kits.ResultsPart one:99patients completed course of4weeks. After finishing4weekstreatment,25patients taked other drugs and3patients were lost to follow-up, so71patients of them completed therapy and1year follow-up study afterwithdrawal.⑴A fter4wk of treatment,the number of effective patients were84cases,the total effective rate was84.8%, the relief rate of abdominal pain, diarrhea were89.9%,82.8%respectively; the proportion of moderate to severe symptoms patientwas significantly reduced（86.9%vs35.4%）which compared with those beforetreatment (all P﹤0.05); The scores of the PSQI questionnaire were significantlyimproved which compared with those before treatment (all P﹤0.05).⑵The mostcommon side effects were dry mouth, constipation, drowsiness, dizziness, but thedegree were mild.⑶84patients who response from AMT therapy with drugwithdrawal were observed1year following up,3patients were lost to follow-up,25patients (recurrence rate31.1%) out of those patients were symptoms recurrencewithin1year，20case of AMT retreatment patients among them,15case sensitive toAMT treatment (retreatment effective rate was75%).⑷The scores of the IBS-SSSwere significantly improved at week2, week4,3-month follow-up and1year follow-up; After2wk and4wk of treatment, main symptom VAS scores（includeabdominal pain, distention, bowel sound hyperfunction, bowel satisfaction）weresignificantly dropped; The scores of the quality of life questionnaire at3-monthfollow-up (except body image and food avoiding) and the scores of the quality of lifequestionnaire at1year follow-up were significantly improved which compared withthose before treatment.Part two:32patients completed blood before and after treatment. The plasmaconcentration of5-HT、NPY were statistically difference which compared with thosebefore treatment (all P﹤0.05), but D-lactic acid, IL-6, TNF-a and IL-10were nostatistically difference which compared with those before treatment (all P＞0.05).Conclusion⑴Low-dose AMT was a safe, effective and low side effects therapy forrefractory D-IBS patient, so it was a alternative therapy which was invalid byconventional treatment and a therapy which recurrence after drug withdrawal.⑵The mechanisms of low-dose AMT on IBS may be related to its can reducethe plasma concentration of5-HT and increase the plasma concentration of the NPY...