Low Dose Naltrexone Motility Effects Leonard Weinstock MD

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 counterintuitiv e

Topics • Brief Review of LDN • Opioid Receptors and Functions • Opioids and Endorphins on MMC (important for SIBO) • 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 12 -15 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 TH 2 to TH 1 immunity § Motility effects – ?

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

Endogenous Opioid Activity and Constipation

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.

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.

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: G 557.

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.

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 • 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 • 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. Gastroenterology 1987; 93: 114 -20.

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 five consecutive days Anselmi, et al. Naunyn Schmiedebergs Arch Pharmacol

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

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.

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.

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?