Low Dose Naltrexone: Motility Effects 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 Motility effects of endorphins, short-acting narcotics and naltrexone are counterintuitive

Topics Brief Review of LDN Brief Review of LDN Opioid Receptors and Functions Opioid Receptors and Functions Opioids and Endorphins on MMC (important for SIBO) Opioids and Endorphins on MMC (important for SIBO) Anti-opiates in Humans in Constipation Anti-opiates in Humans in Constipation

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 fold

Endorphins: Functions  Regulate 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 – ?

Opioid Receptors in GI Tract Activation slows motility by continuous contraction Activation causes constipation by increased absorption and decreased secretion

Endogenous Opioid Activity and Constipation

Opioid Receptors Experimental inflammation in mice: Experimental inflammation in mice: Increase gut μ-opioid receptors Increase gut μ-opioid receptors Enhances potency of opioids to slow GI transit Enhances potency of opioids to slow GI transit Abdominal surgery leads increase in endomorphin in humans 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 Opioid receptor antagonists normalize pathologic inhibition of gut function that arises from opioid upregulation and/or over- activity Holzer. Regul Pept 2009;155:11.

Endogenous Opioids Thought to play a role in the fine tuning of digestion 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 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 Distention-evoked peristalsis can be facilitated by naloxone in 4 animal models Holzer, P. Regul Pept 2009; 155: 11–17.

Morphine and MMC - Dogs In normal fasted dogs, morphine initiated phase III of the MMC in the duodenum which propagated distally 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 This effect of morphine was blocked by the opioid receptor antagonists naloxone Telford. Am J Physiol 1985;249:G557.

Morphine and MMC: Man Healthy subjects given MS (100 mcg/kg IV bolus) Healthy subjects given MS (100 mcg/kg IV bolus) Stimulated migrating bursts of phasic activity (similar to phase III of MMC) Stimulated migrating bursts of phasic activity (similar to phase III of MMC) Morphine stimulated ileal flow Morphine stimulated ileal flow Borody. Gastroenterology 1985;89:562.

Endorphins and MMC: Chickens Phase III of MMC studied in chickens Phase III of MMC studied in chickens EMG study in stomach and entire small intestine EMG study in stomach and entire small intestine Met-enkephalin infused i.v. Met-enkephalin infused i.v. Triggered an intestinal migrating activity concurrent with gastric inhibition Triggered an intestinal migrating activity concurrent with gastric inhibition Migrating activity started in distal duodenum and propagated to ileum - effects partially blocked by naloxone Migrating activity started in distal duodenum and propagated to ileum - effects partially blocked by naloxone Jimenez. Life Sci 1992;50:465. ?

Enkephalin and MMC: Man Met-enkephalin analogue studied in 17 humans 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) 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 Their theory: M-E induced an inhibition of the inhibitory nervous system Jians et al. Gastroenterology1987;93: – “fine tuning” – “fine tuning”

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.

Methyl-Naltrexone: opioid naive MNTX twice daily for 4 days and MNTX twice daily for 4 days and MNTX plus morphine for 6 days in horses MNTX plus morphine for 6 days in horses Frequency of BM, weight of feces, moisture of feces content, intestinal transit time Frequency of BM, weight of feces, moisture of feces content, intestinal transit time MNTX increased daily fecal weight in both groups MNTX increased daily fecal weight in both groups MNTX partially prevented the effects of morphine on all four scores MNTX partially prevented the effects of morphine on all four scores Boscan. Am J Vet Res 2006;67:998.

Naloxone and CIC: Case Reports Two pts with CIC requiring high dose laxatives were treated with naloxone (single-blind crossover basis) 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 Both responded to naloxone - increased frequency and weight of BM Positive response with oral and IV: 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 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.

LDN and Chronic Constipation (my observations) N=12; Open-label Rx 2.5 mg twice a day N=12; Open-label Rx 2.5 mg twice a day 58% markedly improved 58% markedly improved 1% moderately improved 1% moderately improved 25% mildly improve 25% mildly improve 1% unchanged 1% unchanged Subsequently – approximately 20 more pts are maintained on LDN for constipation Subsequently – approximately 20 more pts are maintained on LDN for constipation Ploesser J, Weinstock LB, Thomas E. Internat J Pharm Compound 2010:

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.

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?