CAM & Common GI Complaints: Objectives

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1 Complementary and Alternative Medicines (CAM) for Common GI Complaints Brian E. Lacy, Ph.D., M.D., FACG Professor of Medicine i Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology & Hepatology Director, GI Motility Laboratory Dartmouth-Hitchcock Medical Center Lebanon, NH CAM & Common GI Complaints: Objectives What is CAM? How prevalent is CAM use? What is the evidence to support CAM use in: GERD Functional Dyspepsia IBS 1

? Once alternative, many Tx now mainstream

2 How to define CAM? Definition keeps changing Confined to medications only? Should it include diet, cognitive therapy, hypnotherapy, manipulation therapy, etc.? Once alternative, many Tx now mainstream Probiotics i Medical treatments not commonly considered to be a part of conventional medicine CAM use in the US 2

cost (real or perceived) Natural factor Perception of better

3 Prevalence of CAM use by Age Why is CAM use so prevalent? Ease of access No need dfor an office visit it or an Rx Lower cost (real or perceived) Natural factor Perception of better safety profile Often used prn? Improved efficacy Traditional therapy has failed 3

4 CAM and GERD Acupuncture: Basic Principles TCM targets the state of disharmony, any imbalance in the yin-yang and its connecting qi. Yang Yin 4

session; combinations varying during a course of sessions Acupuncture: Basic Principles

5 Acupuncture: Basic Principles 365 traditional acupuncture points on 14 main channels (meridians) Each point has defined therapeutic actions 5-15 needles are used in a session; combinations varying during a course of sessions Acupuncture: Basic Principles After puncturing the skin needles are moved back & forth Needles are left in place for minutes 5

6 480 GERD Pts GERD & Acupuncture Electroacupuncture Q d x 6 weeks combined with zhizhukuanzhong capsules Not placebo controlled; not blinded Symptoms, ph, endoscopy, SF-36 QoL measured pre- and post-treatment treatment Symptoms, QoL, 24-hr ph and endoscopic findings all improved after 6 weeks (p <.01) Zhang et al, Chin J Intergr Med 2012; 32: GERD & Acupuncture GERD Pts with persistent Sx despite daily PPI 33 Pts; EGD (-); characterized as NERD Randomized, prospective, comparative b.i.d. PPI (20 mg omeprazole) vs. acupuncture 10 sessions over 4 weeks; 5 acupuncture points Only day-time HB improved in PPI group Day-time HB, night-time HB, regurgitation, dysphagia and CP all better in acupuncture group Acupuncture more effective than doubling the PPI dose Dickman et al, Aliment Pharmacol Ther 2007; 26:

7 Melatonin Synthesized in the GI tract 500x more than in the pineal gland Produced by enterochromaffin cells Production and release stimulated by eating Increases PGE 2, which may minimize oxidative stress to the esophagus Increases NO, which hmay improve microcirculation Minimizes acid-induced esophagitis in mice 60 GERD Pts Melatonin & GERD Randomized to 3 mg melatonin vs. 20 mg omeprazole vs. melatonin and omeprazole LES resting Pressure Pretreatment = 10.3 mm Hg 8 weeks Tx PPI group = 10.5 mm Hg vs mm Hg in melatonin and the melatonin-ppi group Kandil et al, BMC Gastroenterol 2010; 10: 7. 7

Melatonin & GERD Melatonin + nutrient capsule compared to 20 mg omeprazole Nutrient capsule tryptophan, folic acid, betaine, methionine, and vitamins B6 and B12 Primary outcome length of time to

8 Melatonin & GERD Melatonin + nutrient capsule compared to 20 mg omeprazole Nutrient capsule tryptophan, folic acid, betaine, methionine, and vitamins B6 and B12 Primary outcome length of time to become asymptomatic Not blinded; no placebo group Pereira, J Pineal Res 2006; 41: Melatonin & GERD 176 Pts on melatonin-nutrient nutrient vs. 175 on PPI 90% on melatonin asymptomatic at 7 days 66% on PPI asymptomatic at 9 days At 40 days, 100% of Pts on melatonin-nutrient were asymptomatic At 40 days, 66% on PPI were asymptomatic AE: somnolence in 156 of 179 melatonin Pts 8

9 Esomeprazole vs. raft-forming agent: on demand Tx for GERD 77 GERD Pts (44% women; mean age = 47 yrs) 9 outpatient clinics; consecutive Pts Sx > 3 months; > 2 days out of 7 ~ 35% NERD; 50% LA Grade A esophagitis Randomized to 20 mg esomeprazole or pectinbased, raft forming agent (RFA), to be used prn At 6 weeks, satisfaction, symptoms, and preference all significantly better for esomeprazole (p <.0019 for all) Farup et al, BMC Compl Alt Med 2009; 9: CAM & Functional Dyspepsia 9

Capsaicin A component of red pepper (cayenne) Activates nociceptive C fiber sensory afferent neurons Substance P is released & depleted MOA: conflicting results on gastric emptying 30 FD patients

10 Capsaicin A component of red pepper (cayenne) Activates nociceptive C fiber sensory afferent neurons Substance P is released & depleted MOA: conflicting results on gastric emptying 30 FD patients Placebo vs. capsaicin (2.5 gm) qac x 5 weeks Outcome variable: Mean overall weekly scores and individual scores Bortolotti et al, NEJM 2002; 346: Capsaicin for Functional Dyspepsia 5 Placebo, n = 15 Capsaicin, n = 15 4 Score * * * 0 *P < One to two capsules red pepper powder q ac. Epigastric pain and fullness relieved. B Time, weeks Bortolotti et al, NEJM 2002; 346:

volunteers (n = 9) 2 improves gastric accommodation Improves antral contractility 1 Braden et al,

11 Iberogast Iberogast (STW5) Extract of Iberis amara and 8 other herbs Mechanism of action in FD -unknown Does not accelerate gastric emptying FD Pts; 13 C-octanoic breath test In healthy volunteers (n = 9) 2 improves gastric accommodation Improves antral contractility 1 Braden et al, Neurogastro & Motil 2009; 31: Pilichiewicz et al, Am J Gastroenterol 2007; 102:

12 Iberogast (STW5) 315 Rome II FD patients (49 yrs; 67% women) Multicenter, R, PC, DB study 20 drops tid vs. placebo; 8 weeks Primary outcome = change in validated GIS (10 dyspeptic symptoms; 5 point Likert scale) STW group improved 6.9 points vs. 5.9 (p <.05) AE and tolerability was similar in both groups H. pylori status did not affect outcome Von Arnim et al, Am J Gastroenterol 2007; 102: STW 5-II 6 separate herbs (Iberis amara) 120 Rome I FD pts (45 yrs; 71% women) Multicenter, R, DB, PC trial; 3 4-week blocks 4 separate treatment groups; 20 drops t.i.d. Primary outcome: improvement in GIS At 4 and 8 weeks, those on STW 5-II noted improvement in symptoms compared to baseline and placebo (p <.001) No SAEs; AEs were similar Madisch et al, Digestion 2004; 69:

Peppermint oil Used as a digestive aid in ancient Greece Smooth muscle relaxation likely l mediated d by calcium channel antagonism Banned in 1990 by FDA as an OTC drug Sold as a dietary supplement

13 Peppermint oil Used as a digestive aid in ancient Greece Smooth muscle relaxation likely l mediated d by calcium channel antagonism Banned in 1990 by FDA as an OTC drug Sold as a dietary supplement Meta-analysis of 5 IBS studies demonstrated superiority compared to placebo 1 No studies of peppermint oil alone in FD patients 1 Pittler et al, Am J Gastroenterol 1998; 93: Peppermint oil & Caraway oil Caraway oil proposed antimeteoric properties Multicenter, DB, PC trial Combination of peppermint oil (90 mg) and caraway oil (50 mg) in capsule form (PCC) 39 FD patients; 4 weeks; t.i.d. dosing Primary outcomes = pain; global measure Pain (p <.015) and global symptoms (p <.008) were improved in the PCC group compared to placebo May et al, Arzneimittelforschung 1996; 46:

Peppermint Oil & Caraway oil DB, R, multicenter, parallel group study 96 pts (mean age = 51; 67% women) Bid dosing (90 mg peppermint oil & 50 mg caraway oil) x 28 days (PCC) Primary efficacy

14 Peppermint Oil & Caraway oil DB, R, multicenter, parallel group study 96 pts (mean age = 51; 67% women) Bid dosing (90 mg peppermint oil & 50 mg caraway oil) x 28 days (PCC) Primary efficacy variables: pain, fullness, global symptoms 40% reduction in pain in PCC vs. 28% in placebo 67% improvement in global Sx vs. 21% (p<.001) Eructation = most common AE May et al, APT 2000; 14: Artichoke leaf extract (ALE) 247 Rome II FD pts (47 yrs; 64% women) Multicenter, R, DB, PC, 6 week trial 2 capsules t.i.d. (640 mg) vs. placebo Primary outcome: weekly summated scores ALE pts noted greater improvement in symptoms (sum score 8.3) vs. placebo (6.7; p =.007) Fullness and early satiety improved (p <.05) NDI QoL scores improved with ALE (p <.01) Holtmann et al, APT 2003; 18:

Banxiaxiexin Tang: A Meta-analysis of RCTs Commonly used in TCM 7 different ingredients Acts on stomach and spleen (cold and heat) 10 RCTs; all published in Chinese 972 Pts Rome III

Functional Bowel disorders 431 women with functional bowel disorder (FBD) 12 week; multicenter study; Rome I criteria Patients randomized to psychological therapy or medical therapy

15 Banxiaxiexin Tang: A Meta-analysis of RCTs Commonly used in TCM 7 different ingredients Acts on stomach and spleen (cold and heat) 10 RCTs; all published in Chinese 972 Pts Rome III criteria 7 compared to domperidone; 3 to mosapride Significant heterogeneity; poor to low quality; data hard to interpret Gan et al, J Trad Chinese Med 2014; 34: CBT & Functional Bowel disorders 431 women with functional bowel disorder (FBD) 12 week; multicenter study; Rome I criteria Patients randomized to psychological therapy or medical therapy Desipramine vs. placebo CBT vs. education Primary outcome = global measure CBT = 70% responder rate Education = 37% (p <.0001); NNT = 3.1 Drossman et al, Gastroenterology 2003; 125:

and individual symptoms Lacy et al, Aliment Pharmacol Ther 2012

16 Brian E. Lacy, MD, PhD, FACG Behavioral Therapy & FD 3 separate studies (n = 95, 100, 103) 3 different study designs 7, 8, or 10 sessions weeks in duration All studies noted improvement in global and individual symptoms Lacy et al, Aliment Pharmacol Ther 2012 Hypnotherapy Image: A calm river Refocus: No pain Heightened suggestibility Rough water: Severe pain Heavy focus on pain Can t cope 16

17 Hypnotherapy for Functional Dyspepsia % Improvement HT, n = * 26 Support and placebo, n=24 Medical, n = 29 * * * * End of Rx (16 wks) Long-term (56 wks) QOL *P < Hypnotherapy associated with less drug use and fewer visits. Calvert EL et al. Gastroenterology. 2002;123: FD & Acupuncture 68 FD Pts (Rome II); randomized Mean age 35; 79% women 6-point acupuncture vs. nondefined point 3 sessions/week x 2 weeks Nepean Dyspepsia Index pre- and post-tx Results: Both groups had a significant improvement in quality of life scores and symptom scores (p <.001), but no difference between the groups Park et al, J Alt and Complementary Medicine 2009; 15:

18 Acupuncture & FD Rome III FD Pts, yrs (83% F; 37 yrs) Randomized, multicenter; 706 Pts (ITT) 4 week treatment period (5 sessions/week) 12-week follow-up 4 acupuncture groups (specific and non-specific acupoints) vs. sham group vs. itopride (50 mg tid) Primary outcome = NDI 55% of itopride Pts improved; 35% with sham; 50-71% improvement with gastric acupuncture Ma et al, APT 2012; 35: Acupuncture for FD: Summary 7 RCTs eligible for analysis N = 542 (330 women; ages 18-70) 3 studies acupuncture or sham only 4 studies comparator (cisapride, domperidone, itopride) Overall all studies of low or very low quality High risk of bias in all studies Unable to provide any conclusion Cochrane Collaboration, 2014; issue 10 18

19 CAM & IBS Bifidobacteria Infantis for IBS Global Assessment of Relief Answering Yes at We eek 4 (%) P= B Infantis B Infantis B Infantis Placebo 1 x x x 10 6 SGA: (Subjects Global Assessment) a yes/no response to the following question: Please consider how you felt in the past week in regard to your IBS, in particular your general well being, and symptoms of abdominal discomfort or pain, bloating or distension, and altered bowel habit. Compared with the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms? Whorwell PJ, et al. Am J Gastroenterol. 2006;101:

20 Peppermint Oil (Colpermin) Improves Abdominal pain/ discomfort 90 IBS patients in Iran were randomized to enteric-coated, delayed-release peppermint oil (Colpermin) or placebo tid. Week 0 Week 1 Week 4 Week 8 None Placebo 0 (0%) 9 (33%) 11 (41%) 6 (22%) Colpermin 0 (0%) 6 (18%) 14 (42%) 14 (42%) Occasional Placebo 17 (63%) 15 (56%) 10 (37%) 7 (26%) Colpermin 15 (46%) 18 (55%) 11 (33%) 14 (42%) Persistent Placebo 9 (33%) 3 (11%) 6 (22%) 14 (52%) Colpermin 14 (42%) 8 (24%) 7 (21%) 5 (15%) Merat et al. Dig Dis Sci 2010 May;55(5): Psychological Therapies for IBS RR NNT Trials N 95% CI 95% CI Cognitive behavior therapy Relaxation training Dynamic psychotherapy Hypnotherapy Ford, Quigley, Lacy et al. Am J Gastroenterology 2014;

Acupuncture in IBS: Clinical Trial 262 IBS patients Sham Acupuncture Needle

weeks of: Acupuncture (3x/wk) Sham acupuncture (3x/wk) Sham non-penetrating

(no visits) Lembo A, Am J Gastroenterol 2009; 104:1489 1497; Acupuncture IBS

21 Acupuncture in IBS: Clinical Trial 262 IBS patients Sham Acupuncture Needle Following a 3 week run-in period of sham acupuncture Pts were randomized to 3 weeks of: Acupuncture (3x/wk) Sham acupuncture (3x/wk) Sham non-penetrating needle non-acupuncture points in vicinity of genuine points Waitlist control (no visits) Lembo A, Am J Gastroenterol 2009; 104: ; Acupuncture IBS Clinical Trial P= P<0.001 Lembo A, Am J Gastroenterol 2009; 104: ; 21

22 Acupuncture in IBS: Meta-analysis 65 studies identified; 17 met criteria 5 trials of acupuncture vs. sham acupuncture 5 trials of acupuncture vs. pharmacologic Tx 5 trials of acupuncture plus pharmacologic therapy vs. pharmacology alone 2 trials of acupuncture vs. Standard Tx Conclusion: significant limitations preclude any recommendation; acupuncture is not better than sham. Manheimer et al, Am J Gastroenterol 2012 Specific Challenges in Performing Acupuncture Trials Inherent bias by the acupuncturist Matching sham control Penetrating, non-penetrating, location Heterogeneity of acupuncture techniques Individuality of treatment according to patterns of disease is difficult to incorporate into a RCT Non-specific effects 22

23 Summary Complementary therapies are common Complementary therapies are no longer alternative they are now mainstream Become familiar with CAM you re patients will ask Assess data using EBM, when available Be cognizant of potential AEs 23

24 Systemic Review of Hypnosis in IBS 14 published studies (N=644) No control group (n=8) vs. control group (n=6) Most studies show favorable outcome Hypnosis consistently produces significant results and improves the cardinal symptoms of IBS in the majority of patients Cochrane Review of Hypnotherapy for IBS 4 studies (n=147) met inclusion criteria 1 study (Whorwell, 1984): hypnotherapy vs. psychotherapy and placebo pill 2 studies (Paulson, 2002; Galvoski, 1998) hypnotherapy vs. waiting-list controls 1 study (Roberts, 2006) hypnotherapy vs. usual medical management. Hypnotherapy > waiting list control or usual medical management abdominal pain, composite primary IBS symptoms AEs not reported in any of the trials. Quality was inadequate to allow any conclusion about the efficacy of hypnotherapy for IBS Webb AN Cochrane Database Syst Rev.2007 Oct 17;(4):CD

Traditional Chinese Medicine Basic Principles of Acupuncture Patterns of energy flow (qi) through the body that are essential to health Disruptions of this flow are believed to be responsible for

25 Traditional Chinese Medicine Basic Principles of Acupuncture Patterns of energy flow (qi) through the body that are essential to health Disruptions of this flow are believed to be responsible for disease Imbalances in qi flow can be corrected at identifiable anatomical locations (i.e., acupuncture points) or by herbs Acupuncture in IBS: Demographics Acupuncture (N=78) Sham acupuncture (N=75) Waitlist (N=77) Mean age Female Caucasian IBS type and duration Constipation i Diarrhea Alternating IBS for>1 year

26 Acupuncture in IBS: Summary Acupuncture/sham acupuncture are superior to Waitlist Control Is sham acupuncture active therapy? Non-specific (i.e., placebo) effects? Recent trials have shown acupuncture to have a small nonsignificant effect on IBS symptoms? If other therapies were added to acupuncture (e.g., cupping, electrical activation) i? Subset of IBS? A larger trial (e.g., n=970) would be needed to adequately power a larger more definitive study Lembo A, Am J Gastroenterol 2009; 104: ; Schneider, 2005 Acupuncture in IBS SAC vs np-sac at non-ap pts Pts (n) Conclusions 43 NS Forbes, 2005 IAC vs p-sac 59 NS Rohrbock, Electro-AC vs p-sac 21 NS 2004 Xiao, 2004 TENS vs sham TENS 104 TENS for dibs Fireman, 2001 Kunze, 1990 AC (single point LI4) vs p-sac Psychotherapy vs AC vs p-sac vs papverin vs placebo med Schneider A. World J Gastroenterol July 7, 2007 Volume 13 Number NS 60 Psychoth > AC and papaverine 26

Functional Dyspepsia

Functional Dyspepsia American College of Gastroenterology Boston Massachusetts, June 2015 Brian E. Lacy, PhD, MD, FACG Professor of Medicine Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology