Leonard Weinstock MD Disclosures Speakers Bureaus Salix Entera Health Forrest Off label use of medications Low Dose Naltrexone Motility Effects Unexpected effect on endorphins by being an opioid blocker ID: 917170
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Slide1
Low Dose Naltrexone: Motility Effects
Leonard Weinstock, MD
Slide2Disclosures
Speakers Bureaus
Salix
Entera
Health
Forrest
Off label use of medications
Low Dose Naltrexone: Motility Effects
Unexpected effect on endorphins by being an opioid blocker
Motility effects of endorphins, short-acting narcotics and naltrexone are counterintuitive
Slide4Topics
Brief Review of LDN
Opioid Receptors and Functions
Opioids and Endorphins on MMC (important for SIBO)
Anti-opiates in Humans in Constipation
Slide5LDN: 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
fold
Slide6Endorphins: 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 – ?
Slide7Opioid Receptors in GI Tract
Activation slows motility by continuous contraction
Activation causes constipation by increased absorption and decreased secretion
Slide8Endogenous Opioid Activity
and Constipation
Slide9Opioid 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.
Slide10Endogenous 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.
Slide11Morphine 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.
Slide12Morphine 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.
Slide13Endorphins 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.
?
Slide14Enkephalin 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”
Slide15Methyl-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.
Slide16Methyl-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
.
Slide17Naloxone 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.
Slide18LDN 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.
Slide19High 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.
Slide20Naltrexone
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?