TABLE 3.

a Trials of ECP related to visceral hypersensitivity
Referen ce	Method Score	Intervention	Study Design	Study Size (n)	Mean Age	F/M	Duration	Outcome Measure	Patients characteristics	Results	Safety Analysis
49 Cannon et al.	4	Clonidine 0.1 mg BID or Imipramine 50 mg QHS or Placebo BID	Double-blind, placebo controlled crossover	60	50	40/20	10 weeks	CPF and CPI Change in frequency (number of episodes) and intensity from baseline	ECP+, [Manometry (54, 90% tested); 22 (41%) had motility disorder], no pH metry, +ve Bernstein test (41%), −ve coronary angiogram, and −ve stress test	Imipramine decreased CPF in 52% and 1% placebo (p=0.03) and 39% clonidine. CPI was lower in Imipramine (p<0.001) and in Clonidine (p<0.002) vs Placebo	Imipramine: prolonged QT interval
50 Clous e et al.	3	Trazadone 100– 150 mg QD or Placebo QD	Double-blind, placebo controlled	29	48	21/8	6weeks	Global i mprovement in Chest Pain, r esidual distress, manometric changes	ECP+, Dysmotility (DES, Nutcracker, IEM)(manometry ) −ve esophagogram, no pH test −ve stress test, or – ve cardiac catheterization	Trazadone improved global Symptoms of Chest Pain vs Placebo p= 0.002 No change on manometry vs Placebo	Sedation
51 Varia et al.	4	Sertraline 50 mg QD or Placebo	Double-blind placebo controlled	, 30			8 wks	VAS, CPS, BDI, SF36 Change in VAS (baseline-end Rx)	ECP+, GERD not ruled out (no pH test), no manometry −ve angiogram and/or −ve stress test	Sertraline decreased daily pain in 20% (VAS) per week (p<0.03), no effect on BDI or SF36	Sertraline: nausea, restlessness, decreased libido, delayed ejaculation (all mild)
52 Keefe et al.	5	CST + sertraline, CST + placebo, Sertraline alone or placebo alone	Double-blind, placebo controlled	115	48	77/3 8	34 weeks	CPS on a VAS (0– 100. BDI, Rate of Change in outcomes	ECP+ GERD not ruled out (no pH test), no manometry, −ve stress test or −ve coronary angiogram	CST + Sertraline showed highest response (p<0.001) followed by CST (p< 0.002) and Sertraline alone (p<0.001). No differences in anxiety and catastrophising	Dry mouth Diarrhea Sexual side effects Nausea, Headache
53Lee et al.	5	Venlafaxine 75 mg or placebo	Double-blind, placebo controlled crossover	43	24	6/37	4 weeks	CPF and CPS Composite score (Frequency x severity) > 50% improvement	ECP+ −ve EGD, −ve pH metry, −ve manometry, 4-weeks off-PPI, −ve cardiac stress test −ve coronary angiogram.	Venlafaxine vs Placebo >50% improvement: 52% vs 4% SF 36(bodily pain,emotional role) improved significantly p<0.002 in venlaflaxine group	Sleep disturbance, loss of appetite ( 1 withdrew) Prevalence of any adverse events: 52% venlafaxine vs 12% placebo
54 Dorais wamy et al.	5	Paroxetine 10– 50mg daily vs placebo	Double-blind placebo controlled	50	53	42/8	8 weeks	Physcian Rated Clinical Global Impression Scale + Patient Rated Score	Cardiac testing: NA	Patient rated Chest Pain no change Paroxetine vs Placebo NS Physcian Rated Scale Impoved Proxetine vs Placebo= p<0.05	Fatigue and dizziness
55 Spinh oven et al.	5	Paroxetine 10– 50mg. daily vs placebo	Randomize d Double-blind, placebo controlled	95	55	48/4 7	16 week	NCCP and HADS	ECP+, no pH metry, no manometry, no EGD, −ve coronary angiography, or −ve stress test, or −ve cardiac history	Paroxetine was no more effective than placebo Change in chest pain score paroxetine vs placebo =22 vs 24 p=NS	Similar number of adverse events between paroxetine and placebo n=22
56 Praka sh et al	1	Amitriptyline, Imipramine, Nortriptyline, Desipramine (20–75 mg/day)	Open-label retrospective review	21	50	14/7	0.8–8.6 (mean 2.7) years	Likert Scale (0= no mprove, 3 clinical remission) responders ≥ 2 after treatment and 3 for remission Chest pain Index Freq x severity CPF,CPI	ECP +, Use of tricyclic antidepressants and 6 month follow-up, −ve EGD, −ve pH metry, −ve PPI response, no cardiac tests	81 % symptomatic response or remission. 29% maintain response and 41 % required continuous treatment. TCA decreased CPI and distress (p<0.01) at follow-up	Sedation, anticholi-nergic symptom
57 Raoet al.	1	Theophylline 150–250mg. bid	Open-label	12	46	10/2	12 weeks	(VAS) Global chest pain improvemen t =>50% improvemen t	ECP+, −ve EGD, −ve pH metry, −ve manometry,+ve EBDT, −ve coronary angiography, or −ve stress thallium study.	8 completed study 2 lost follow up 2 adverse events 7/8 improved with Theophylline	2 side effects Nausea palpitation, tremor
58 Rao et al.	5	Theophylline SR 200 mg bid or placebo	Double-blind, placebo controlled	25	46	18/7	8 weeks	CPF, CPI Change in number of days with chest pain Global assessment (better, same, worse)	ECP+, −ve EGD, −ve pH metry, −ve anometry,+v e EBDT,-stress test, or −ve coronary angiography.	Median number of days with chest pain was lower (p<0.014) and severity (p<0.03) decreased with theophylline vs placebo. Global assessment: theophylline vs placebo Better: 58% vs 6%, Same: 21% vs 68% Worse: 21 % vs 26% (p<0.027).	Theophylli ne: nausea, insomnia, tremor, and lightheaded ness; Placebo: palpitations, insomnia

b Quality assessment of trials on visceral hypersensitivity for ECP
Reference	Randomization	Blinding	Statement on Withdrawals	Total Score
Cannon et al. (49)	2	2	0	4
Clouse et al. (50)	1	1	1	3
Varia et al. (51)	1	2	1	4
Keefe et al. (52)	2	2	1	5
Lee et al. (53)	2	2	1	5
Spinhov et al. (55)	2	2	1	5
Prakash et al. (56)	0	0	1	1
Rao et al. (57)	0	0	1	1
Rao et al. (58)	2	2	1	5
Doraiswamy et al. (54)	2	2	1	5

CPF=Chest Pain Frequency, CPI=Chest Pain Intensity, DES=Diffuse Esophageal Spasm, IEM=Ineffective Esophageal Motility, CST=Coping Skills Treatment, BDI=Beck Depression Inventory, SF36=Quality of Life Measure, EBDT: Esophageal Baloon Distention Test, SR: Slow Release, NS: Not Significant