Naltrexone for the treatment of Crohn s disease

Transcription

1 Naltrexone for the treatment of Crohn s disease DR. NILESH CHANDE COORDINATING EDITOR, IBD REVIEW GROUP; UNIVERSITY OF WESTERN ONTARIO, LONDON, ON CANADA

2 Opioid receptors 3 major types kappa κ delta δ mu µ Found in Bound by endogenous opioids: Dynorphins Enkephalins Endorphins Endomorphins Variety of physiological effects: Regulation of neurologic functions Analgesia

3 Opioid receptors 3 major types kappa κ delta δ Found in Bound by endogenous opioids: Dynorphins Enkephalins Endorphins Endomorphins Affected primarily by opiate drugs: Analgesia Respiratory depression Constipation mu µ Variety of physiological effects: Regulation of neurologic functions Analgesia

4 Opioid receptors in the gut kappa κ delta δ mu µ Expressed by enteric neurons Involvement in: Gut motility Regulation of intestinal secretion Binding leads to: Reduced motility Reduced colonic active Cl - and passive H 2 O secretion

5 Mu opioid receptors in inflamed bowel µ µ CD4 + CD8 + µ µ µ µ µ µ Mu opioid receptors are overexpressed by CD4 + and CD8 + lymphocytes Mouse model of colitis Blocking mu opioid receptor leads to: Reduced CD4 + lymphocytes Reduced cytokines including TNF-α and IL-1β Hypothesis that regulation of the innate opioid axis may be an effective treatment for Crohn s disease

6 Naltrexone o Competitive antagonist at mu opioid receptor o Used for opioid dependence o Used for alcohol dependence (exact mechanism uncertain) o Standard dose 50 mg orally daily o Low dose naltrexone ( LDN ) reported to be effective to treat a variety of diseases Do not confuse with: Methylnaltrexone, naloxegol Peripherally active opioid antagonists do not cross blood-brain barrier Used to treat opioid induced constipation Naloxone Non-selective opioid antagonist - used IM/IV to treat opioid overdose Oral formulation used in combination with oxycodone to prevent constipation

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8 curetogether.com

9 Cochrane Review: Low dose naltrexone for induction of remission in Crohn s Disease Purpose To asses the efficacy and safety of naltrexone for the treatment of CD Databases searched MEDLINE, EMBASE, Pubmed, Cochrane CENTRAL, clinicaltrials.gov, Cochrane IBD specialized register (January 15, 2018) Reference Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD DOI: / CD pub3.

10 Cochrane Review: Low dose naltrexone for induction of remission in Crohn s Disease Inclusion criteria CD patients of all ages Primary outcomes Clinical remission Types of studies Randomized controlled trials Secondary outcomes Clinical response Endoscopic response or remission Quality of life Adverse events Withdrawal due to adverse events Serious adverse events

11 PRISMA flow diagram 123 records identified 106 records after duplicates removed 106 records screened 99 records excluded 7 full text articles assessed 3 records excluded with reasons 4 reports of 2 studies included in metaanalysis

12 Clinical remission (CDAI < 150) at 12 weeks

13 Clinical response (CDAI -70 points) at 12 weeks

14 Endoscopic response (CDEIS -5 points) at 12 weeks

15 Adverse events

16 Summary Opioid receptors are a novel target of therapy for IBD patients Limited evidence suggests LDN may improve symptoms in patients with CD LDN appears to be well-tolerated Further research is required to determine if LDN can be used as primary or adjunctive therapy in patients with IBD

17 Case 3 Naltrexone for the treatment of CD o 42 year old female, cigarette smoker o RLQ pain and diarrhea for 6 months o Colonoscopy showed ileal CD with ulceration without stricturing o MRE showed 10 cm ileal disease o Patient not keen on steroids or immune suppression o Can she be treated with naltrexone? o How do you address patients who request benign, inexpensive therapies for Crohn s disease with unproven efficacy?