Low Dose Naltrexone: - PowerPoint Presentation

Slide1

Low Dose Naltrexone: Motility Effects

Leonard Weinstock, MDSlide2

Disclosures

Speakers Bureaus

Salix

Entera

Health

Forrest

Off label use of medications

Slide3

Low Dose Naltrexone: Motility Effects

Unexpected effect on endorphins by being an opioid blocker

Motility effects of endorphins, short-acting narcotics and naltrexone are counterintuitiveSlide4

Topics

Brief Review of LDN

Opioid Receptors and Functions

Opioids and Endorphins on MMC (important for SIBO)

Anti-opiates in Humans in ConstipationSlide5

LDN: mechanism of action

LDN

displaces endorphins from

opioid receptors

for 4 hours

Cells

sense opioid deficiency and rebound

via

a

positive feedback mechanism

Receptors

increased

Met-

enkephalin

production x 12-15

foldSlide6

Endorphins: FunctionsRegulate cell growth

Decrease inflammation

Decrease vascular permeability

Stabilize Toll-like receptors

Decrease microglia activation (reduce pain)

Decrease cytokine release

Shift from

TH2 to TH1

immunity

Motility effects – ?Slide7

Opioid Receptors in GI Tract

Activation slows motility by continuous contraction

Activation causes constipation by increased absorption and decreased secretionSlide8

Endogenous Opioid Activity

and ConstipationSlide9

Opioid Receptors

Experimental

inflammation

in mice:

Increase gut μ-opioid receptors

Enhances potency of opioids

to

slow

GI transit

Abdominal

surgery leads

increase

in

endomorphin

in

humans

Opioid receptor

antagonists

normalize pathologic

inhibition of gut function that arises from

opioid upregulation

and/or

over-activity Holzer. Regul Pept 2009;155:11. Slide10

Endogenous Opioids

Thought

to play a role in the fine tuning of

digestion

Endogenous

opioid peptides

participate

in

neural

control of peristalsis

by dampening

peristaltic performance via activation of

mu and kappa receptors

Distention-evoked peristalsis can be facilitated by naloxone in 4 animal

models

Holzer

, P.

Regul

Pept

2009; 155: 11–17. Slide11

Morphine and MMC - Dogs

In

normal fasted

dogs,

morphine

initiated

phase III of the

MMC

in the

duodenum which propagated distally

This

effect of morphine was blocked by the opioid receptor antagonists

naloxone

Telford

. Am J

Physiol

1985;249:G557.Slide12

Morphine and MMC: Man

Healthy subjects given MS

(100

mcg/kg IV bolus)

Stimulated

migrating bursts of phasic activity (similar to phase III of

MMC)

Morphine stimulated

ileal

flow

Borody

. Gastroenterology 1985;89:562.Slide13

Endorphins and MMC: Chickens

Phase

III of MMC

studied in chickens

EMG study in stomach and entire small intestine

Met-

enkephalin

infused

i.v

.

Triggered an

intestinal migrating activity concurrent with gastric

inhibition

M

igrating

activity started in

distal

duodenum and propagated to

ileum - effects partially

blocked by

naloxone

Jimenez

. Life

Sci 1992;50:465.

?Slide14

Enkephalin and MMC: Man

Met-

enkephalin

analogue

studied

in

17 humans

M-E induced

a premature phase III of the

MMC starting

in the duodenum

that migrated

distally at a significantly higher velocity than a spontaneous phase

III

(potential role for LDN)

Their theory: M-E induced an

inhibition of the inhibitory nervous

system

Jians

et al.

Gastroenterology1987;93:114-20

.

– “fine tuning”Slide15

Methyl-Naltrexone: opioid naive

Compared

effects of

MNTX

in naïve vs. opiate chronically treated

guinea

pigs

MNTX blocked

the inhibitory effect of acute

morphine

at any

dose

MNTX did

not affect GI transit in naïve guinea pigs when administered acutely or for five consecutive

days

Anselmi

, et al.

Naunyn

Schmiedebergs Arch Pharmacol 2013;386:279. Slide16

Methyl-Naltrexone: opioid naive

MNTX twice

daily for 4

days and

MNTX plus morphine for

6

days in

horses

Frequency of BM,

weight of

feces, moisture of feces

content, intestinal transit

time

MNTX

increased daily fecal

weight in both groups

MNTX

partially prevented the effects of morphine on

all four scores

Boscan

.

Am J Vet Res

2006;67:998

.Slide17

Naloxone and CIC: Case Reports

Two pts

with

CIC requiring high dose laxatives were

treated with

naloxone (single-blind

crossover

basis)

Both responded

to

naloxone - increased frequency and weight of BM

Positive

response

with oral and IV:

Primary

effect of naloxone is at

receptor

sites in the

myenteric

plexus and other neural and endocrine cells of the intestinal

wall

Kreek

et al.

Lancet 1983;1:261.Slide18

LDN and Chronic Constipation(my observations)

N=12; Open-label Rx 2.5 mg twice a day

58% markedly improved

1% moderately improved

25% mildly improve

1% unchanged

Subsequently – approximately 20 more pts are maintained on LDN for constipation

Ploesser

J, Weinstock LB, Thomas E.

Internat

J Pharm Compound 2010:171-173.Slide19

High Dose Naltrexone in IBS-c

Study of

tegaserod

alone

and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with

IBS-c

N = 48

randomized to

tegaserod

alone, naltrexone alone or in combination with

tegaserod

or placebo for 6

days. Small bowel and colon studied by nuclear testing

Tegaserod

increased small bowel

and

colon transit

Naltrexone

did not accelerate colonic transit relative to

placebo

Combination

treatment did not significantly accelerate transit relative to

tegaserod

alone

Foxx-Orenstein

et al.

Neurogastroenterol

Motil

2007;19:821. Slide20

Naltrexone

Improve

GI motility – via

fine tune blocking

endogenous opioids

?

Prevent SIBO by increasing endorphins which increase MMC?

Reduce inflammation with a secondary effect of normalizing motility?

Reduce pain of IBS via Toll-receptor activity and allow for better motility?