Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats

Tawfik, Dina Ibrahim; Osman, Ashraf; Tolba, Hedayat; Khattab, Aida Abdalla; Abdel‐Salam, Lubna O.; Kamel, Mahmoud M.

doi:10.1016/j.npep.2016.06.003

Cited by 19 publications

(17 citation statements)

References 55 publications

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“…Together, these results suggest that the combinations of agonists and antagonists used clinically may have benefits beyond their intended applications (e.g., naloxone reducing the abuse potential and risk of overdose for buprenorphine). These benefits to gut health may overlap with the other clinical uses of naltrexone, including relief from opioid-induced constipation, the potential promotion of gut mucosal healing for Crohn's disease, and anti-inflammatory applications for treating chronic pain [21][22][23][24][25] . However, the mechanisms of naltrexone's action in Crohn's disease are the subject of some debate, and the dose of naltrexone used in these applications is lower than the dose recommended for craving management in alcohol and OUDs 23,25 .…”

Section: Discussionmentioning

confidence: 99%

“…Naltrexone is used to manage cravings for both alcohol and OUDs 20 . It is also used to relieve opioid-induced constipation and is thought to mitigate gut mucosal injury from Crohn's disease, suggesting that it may modulate gut barrier function [21][22][23][24][25] . It is unknown whether the formulation of naltrexone used to manage cravings for opioid and alcohol use disorders similarly modulates gut barrier function and/or whether this modulation of gut barrier function has a possible role in craving management.…”

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confidence: 99%

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Opioid agonist and antagonist use and the gut microbiota: associations among people in addiction treatment

Gicquelais

Bohnert

Thomas

et al. 2020

Sci Rep

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Murine models suggest that opioids alter the gut microbiota, which may impact opioid tolerance and psychopathology. We examined how gut microbiota characteristics related to use of opioid agonists and antagonists among people receiving outpatient addiction treatment. Patients (n = 46) collected stool samples and were grouped by use of opioid agonists (heroin, prescription opioids), antagonists (naltrexone), agonist–antagonist combinations (buprenorphine–naloxone), or neither agonists nor antagonists within the month before enrollment. We sequenced the V4 region of the 16S rRNA gene using Illumina MiSeq to examine how alpha diversity, enterotypes, and relative abundance of bacterial genera varied by opioid agonist and antagonist exposures. Compared to 31 participants who used neither agonists nor antagonists, 5 participants who used opioid agonists (without antagonists) had lower microbiota diversity, Bacteroides enterotypes, and lower relative abundance of Roseburia, a butyrate producing genus, and Bilophila, a bile acid metabolizing genus. There were no differences in gut microbiota features between those using agonist + antagonists (n = 4), antagonists only (n = 6), and neither agonists nor antagonists. Similar to murine morphine exposure models, opioid agonist use was associated with lower microbiota diversity. Lower abundance of Roseburia and Bilophila may relate to the gut inflammation/permeability and dysregulated bile acid metabolism observed in opioid-exposed mice.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Opioid agonist and antagonist use and the gut microbiota: associations among people in addiction treatment

Gicquelais

Bohnert

Thomas

et al. 2020

Sci Rep

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“…A controlled study using a rat model of indomethacin-induced CD showed significant improvements following LDN treatment. 21 …”

Section: Discussionmentioning

confidence: 99%

The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study

Raknes

Simonsen²,

Småbrekke

2018

Journal of Crohn's and Colitis

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Background and AimsLow-dose naltrexone [LDN] is a controversial off-label treatment used by many Crohn’s disease [CD] and ulcerative colitis [UC] patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We sought to examine whether initiation of LDN therapy by patients with inflammatory bowel disease [IBD] was followed by changes in dispensing of relevant medication.MethodsWe performed a quasi-experimental before-and-after study following a sudden increase in LDN use in the Norwegian population in 2013. IBD patients were identified from among all the patients who had at least one LDN prescription recorded in the Norwegian Prescription Database [NorPD] in 2013. Drug dispensing 2 years before and after the first LDN prescription was compared.Results: We identified 582 IBD patients who had received LDN. Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [–12%], [ii] intestinal anti-inflammatory agents [–17%], [iii] other immunosuppressants [–29%], [iv] intestinal corticosteroids [–32%] and [v] aminosalicylates [–17%]. In subgroups of identified CD and UC patients, there were significant reductions in the number of users of intestinal corticosteroids [CD: –44%, UC: –53%] and systemic corticosteroids [UC: –24%]. No significant differences in cumulative defined daily doses were observed.Conclusions: Our findings imply that the initiation of LDN in IBD is followed by reduced dispensing of several drugs considered essential in the treatment of CD and UC.

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“…Other studies investigating the potential mechanism of LDN on inflammation have focused on immune cell cytokine production. Elevated TNFα, IL-6 and IL-12 levels have been reported to be reduced by Naltrexone in chemically induced mouse colitis models [ 15 , 16 ]. In contrast, others have found that LDN enhances dendritic cell maturation and stimulates their TNFα and IL-12 production, whereas in the current study, no effect of Naltrexone on either epithelial induced IL-8 production or IL-8 and TNFα serum levels in IBD patients was observed.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the use of LDN in clinical settings is gaining interest, with Crohn’s disease, multiple sclerosis and fibromyalgia described as potential targets for treatment with LDN [ 12 – 14 ]. In both mouse and rat models of IBD, LDN alleviated inflammation, in part by reducing pro-inflammatory cytokine production [ 15 , 16 ]. Interestingly, we and others have shown that endoplasmic reticulum (ER) stress in intestinal Paneth cells is one of the contributing factors in IBD [ 17 – 19 ], and it was recently reported that Naltrexone attenuates inflammation in a mouse liver injury model by reducing ER stress [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients

et al. 2018

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BackgroundAround 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function.MethodsPatients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples.ResultsLow dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected.ConclusionsNaltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1427-5) contains supplementary material, which is available to authorized users.

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Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats

Cited by 19 publications

References 55 publications

Opioid agonist and antagonist use and the gut microbiota: associations among people in addiction treatment

Opioid agonist and antagonist use and the gut microbiota: associations among people in addiction treatment

The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients

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