using anti-depressants in the ibs patient anti-depressants in the ibs patient philip schoenfeld, md,...

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1 Using Anti-Depressants in the IBS Patient Philip Schoenfeld, MD, MSEd, MSc (Epi) Associate Professor of Medicine Director, Training Program in GI Epidemiology U. of Michigan School of Medicine

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1

Using Anti-Depressants

in the IBS Patient

Philip Schoenfeld, MD, MSEd, MSc (Epi)

Associate Professor of Medicine

Director, Training Program in GI Epidemiology

U. of Michigan School of Medicine

2

• Abdominal cramping/bloating & frequent loose,

watery stools with urgency or

hard, pellet-like stools with straining

• Associated nausea/dyspepsia/gerd sxs

are commonly present

• Has had multiple diagnostic tests-all normal

• Has tried fiber, lactose-free diet, elimination of

some foods

• Tried anti-spasmodic agents in low doses (e.g., Bentyl®

10 mg bid),laxative (Miralax® 17gm/day) or anti-

diarrheal (Imodium®) prescribed to use “as needed”

My “Average” Severe IBS Patient

3

Is this patient a candidate for

anti-depressant therapy?

What medication should be used?

4

• TCAs and SSRIs are more effective than placebo at

relieving global IBS symptoms, and appear to reduce

abdominal pain

• There are limited data on the safety and tolerability of

these agents in patients with IBS

• For IBS-D, use TCAs

• For IBS-C, use SSRIs

Antidepressants: ACG Recommendations

Brandt LJ et al. Am J Gastroenterol. 2009;104 Suppl 1:S1-35.

5

0

20

40

60

80

100

ITT n=201

Desipramine Placebo

TCA vs. Placebo for Moderate

to Severe FGIDs

Drossman DA et al. Gastroenterology. 2003;125:19-26.

Halpert, Am J Gastroenterol. 2005;100:664-669.

P=0.13

(12 weeks) %

Resp

on

ders

60

47

6

TCA vs. Placebo for

Moderate to Severe FGIDs

Drossman, Gastro 2003;125:19

*Halpert, Am J Gastroenterol 2005;100:664

60

73

47 49

0

20

40

60

80

100

ITT n=201 PP n=153

Desipramine Placebo

P=0.13

P=0.006

NNT=4

26% of pts d/c

Desipramine due

to side effects:

constipation,

fatigue

% R

esp

on

ders

(12 wks)

7

TCA vs. Placebo for

Moderate to Severe FGIDs

Drossman, Gastro 2003;125:19

*Halpert, Am J Gastroenterol 2005;100:664

Best response in patients with IBS-D!

60

73

47 49

0

20

40

60

80

100

ITT n=201 PP n=153

Desipramine Placebo

P=0.13

P=0.006

NNT=4

26% of pts d/c

Desipramine due

to side effects:

constipation,

fatigue

% R

esp

on

ders

(12 wks)

8

Meta-analysis: TCAs in IBS

Total events: 132 (treatment), 153 (control)

Test for heterogeneity: X2 = 10.92, df=8, (p=.21), I2 = 26.9%

Test for overall effect: Z=3.86 (p=.0001)

Ford AC et al. Am J Gastroenterol. 2009;104:1831-1843; quiz 1844.

Study

or sub-category

Treatment

n/N

Control

n/N RR (random)

95% CI

Weight

%

RR (random)

95% CI

Heefner 1978

Myren 1982

Nigam 1984

Boerner 1988

Bergmann 1991

Vij 1991

Drossman 2003

Talley 2008

Vahedi 2008

10/22

5/30

14/21

16/42

5/19

14/25

60/115

0/18

8/27

12/22

10/31

21/21

19/41

14/16

20/25

36/57

5/16

16/27

Subtotal (95% CI) 319 256 67.56 0.68 (0.56-0.83)

5.94

2.66

14.74

7.63

3.82

10.67

16.77

0.33

5.02

0.83 (0.46 to 1.51)

0.52 (0.20 to 1.33)

0.67 (0.49 to 0.90)

0.82 (0.50 to 1.36)

0.30 (0.14 to 0.65)

0.70 (0.47 to 1.04)

0.83 (0.63 to 1.08)

0.08 (0.00 to 1.36)

0.50 (0.26 to 0.97)

Tricyclic Antidepressants

9

Efficacy of SSRIs in Relieving

Global IBS Symptoms*

*Significant heterogeneity among studies may limit conclusions. Study duration ranged from 6 weeks to 12 weeks.

Ford AC, et al. Gut. 2009;58:367-378.

Study (Year, Drug, Dose) Treatment

n/N

Control

n/N RR (Random) 95% CI

Kuiken (2003, fluoxetine 20 daily) 9/19 12/21

Tabas (2004, paroxetine 10-40 daily) 25/44 36/46

Vahedi (2005, fluoxetine 20 daily) 6/22 19/22

Tack (2006, citalopram 20-40 daily) 5/11 11/12

Talley (2008, citalopram 40 daily) 5/17 5/16

Subtotal (95% CI) 113 117

RR=0.62

(95% CI=0.45-0.87)

0.2 0.5 1 2 5

Favors Treatment Favors Control

0.1 10

Total events: 50 treatments; 83 controls

Test for heterogeneity: Chi2 = 6.46, df = 4, (P=.17), I2 = 38.1%

Test for overall effect: Z = 2.74 (P=.006)

10

If I prescribe anti-depressants, then

am I implying that the patient is simply

depressed or anxious and that her IBS

symptoms are “just in her head”?

11

IBS is associated with Symptoms of Dysmotility

and Hypersensitivity

Symptoms of

hypersensitivity

may be the result of

changes in the way

the ENS

communicates

with the CNS.

Symptoms of dysmotility are a result of impaired coordination of the muscles and nerves in the GI tract.

Visceral Sensitivity

Motility Secretion

ENS= Enteric Nervous System

Mayer EA, Raybould HE

Gastroenterology 1990; 99:1688

12

Why use Tri-cyclic anti-depressants

(TCA) for IBS-D and use SSRI for IBS-C?

Can I use SSRI for IBS-C?

Can I use TCA for IBS-C?

13

Are TCAs, SSRIs, and SNRIs

Different in IBS?

TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;

SNRI=serotonin-norepinephrine reuptake inhibitor (eg, desvenlafaxine, venlafaxine, duloxetine)

Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.

TCAs SSRIs SNRIs

Peripheral pain

modulation ++ ? ++

Central

antinociception +++ + +++

Anxiolysis + +++ +

Motility ++ + ?

Visceral pain +++ ? ?

Sleep ++ — ?

Psychiatric

comorbidities ++ +++ +++

Potential benefits: A comparison

14

Are TCAs, SSRIs, and SNRIs

Different in IBS?

TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;

SNRI=serotonin-norepinephrine reuptake inhibitor

Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.

TCAs SSRIs SNRIs

Adverse effects

Sedation

Constipation

Dry mouth/eyes

Weight gain

Hypotension

Sexual dysfunction

Insomnia

Diarrhea

Night sweats

Weight loss

Agitation

Sexual dysfunction

Nausea

Agitation

Dizziness

Fatigue

Liver dysfunction

Time to action

Few days to 2 weeks

(low doses)

2-6 weeks (high doses)

3-6 weeks 3-6 weeks

Efficacy Good Moderate Not adequately studied

Dose adjustments Common Usually not needed Common

15

What anti-depressant should I use?

What dose should I use?

16

Available Antidepressants

and Dosages for IBS

TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor;

SNRI=serotonin-norepinephrine reuptake inhibitor

Grover M, Drossman DA. Gastrointest Endoscopy Clin N Am. 2009;19:151-170.

TCAs SSRIs SNRIs

Agents

Amitriptyline

Imipramine

Doxepin

Desipramine

Nortriptyline

Fluoxetine

Sertraline

Paroxetine

Citalopram

Duloxetine

Venlafaxine

Desvenlafaxine

Dose range 10-200 mg 10-100 mg

50-400 mg (desvenlafaxine)

30-90 mg (duloxetine)

75-224 mg (venlafaxine)

17

• For IBS-C, I start with citalopram (Celexa®) 10 mg daily

• For IBS-D, I start with nortiptyline (Pamelor®) 10-25mg

qhs. I choose the initial dosage based on weight of

the patient

How Do I Use Anti-depressants?

(Experience-Based Medicine)

18

• Psychological therapies, including cognitive therapy,

dynamic psychotherapy, and hypnotherapy, but not

relaxation therapy, are more effective than usual care in

relieving global symptoms of IBS (Grade 1B)

Psychological Therapies:

ACG Recommendations

Brandt LJ et al. Am J Gastroenterol. 2009;104 Suppl 1:S1-35.

19

• 20 studies (various psychological therapies),

1278 patients

• Significant heterogeneity and funnel plot asymmetry

Psychological Therapy for IBS:

Meta-analysis

Ford AC et al. BMJ. 2008;337:a2313.

Improvement:

Psychological therapy

(%)

Improvement: “Usual

management” or

control therapy (%)

RR symptoms remain

(95% CI)

49.1 27.5 0.67

(0.57-0.79)

20

• If concurrent nausea: consider ondansetron (Zofran®)

as a scheduled dose (not on-demand)

• Use other meds for neuropathic pain: gabapentin

(Neurontin®) 300mg daily and escalate dose as

tolerated

• If using anti-spasmodics, use higher doses of

dicyclomine (Bentyl®) or hyoscyine (Levsin®) or

consider Librax® (chlordiazepoxide & clinidium bromide)

• The importance of a therapeutic patient-physician

relationship shouldn’t be underestimated

What else can be done?

(Experience-based medicine)