Trials and Studies with LDN for Crohn's
Segal D1, Macdonald JK, Chande N. , Low dose naltrexone for induction of remission in Crohn's disease., Cochrane Database Syst Rev. 2014 Feb 21;2:CD010410. doi: 10.1002/14651858.CD010410.pub2. https://www.ncbi.nlm.nih.gov/pubmed/19453963
BACKGROUND: Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn'sdisease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy.
OBJECTIVES: The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease.
SEARCH METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Register was performed from inception to February 2013 to identify relevant studies.
Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also reviewed.
SELECTION CRITERIA: Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included.
DATA COLLECTION AND ANALYSIS: Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.2). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria.
MAIN RESULTS: Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study.
GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data).
AUTHOR'S CONCLUSIONS: Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children. One study is currently ongoing (NCT01810185).
Smith JP1, Field D, Bingaman SI, Evans R, Mauger DT. , Safety and tolerability of low-dose naltrexone therapy in children with moderate to severeCrohn's disease: a pilot study., J Clin Gastroenterol. 2013 Apr;47(4):339-45. doi: 10.1097/MCG.0b013e3182702f2b. https://www.ncbi.nlm.nih.gov/pubmed/19453963
BACKGROUND: There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells.
AIMS: The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease.
METHODS: A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey.
RESULTS: Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035).
CONCLUSIONS: Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity. Comment In: Avoiding narcotics in Crohn's disease. [J Clin Gastroenterol. 2013]Avoiding narcotics in Crohn's disease. Jackson WE, Rizk M, Lashner BA. J Clin Gastroenterol. 2013 Apr; 47(4):293-5. Naltrexone therapy for Crohn's disease and ulcerative colitis. [J Clin Gastroenterol. 2014]
Shannon A, Alkhouri N, Mayacy S, Kaplan B, Mahajan L. , Low-dose naltrexone for treatment of duodenal Crohn's disease in a pediatric patient., Inflamm Bowel Dis. 2010 Sep;16(9):1457. doi: 10.1002/ibd.21185. https://www.ncbi.nlm.nih.gov/pubmed/19453963
Ploesser J, Weinstock LB Md, Thomas E Pharmd., Low Dose Naltrexone: Side Effects and Efficacy in Gastrointestinal Disorders., Int J Pharm Compd. 2010 March/April;14(2):171-173. Int J Pharm Compd. 2010 March/April;14(2):171-173. Abstract, Use of low dose naltrexone has been advocated for a variety of medical problems. Only a few articles published in peer review journals have documented side effects of low dose naltrexone. The purpose of this study was to determine the frequency of adverse effects of low dose naltrexone in patients who have been treated for a variety of gastrointestinal disorders. The secondary purpose was to determine global efficacy in a retrospective survey. Patients (206) form a single gastroenterologist's clinical practice who had been prescribed naltrexone were mailed a survey to evaluate the side effects and efficacy of naltrexone. Patients had either irritable bowel syndrome without evidence for small intestinal bacterial overgrowth, chronic idiopathic constipation, or inflammatory bowel disease. Patients with diarrhea were given 2.5 mg daily, constipation 2.5 mg twice daily, and inflammatory bowel disease 4.5 mg daily. In the patients who returned the survey, 47/121 (38.8%) had no side effects. Of the 74/121 (61.2%) patients who had side effects, 58 had one or more neurological complaints, and 32 had one or more gastrointestinal side effects. In the patients with side effects, 24/74 (32.4%) had short lived symptoms. Low dose naltrexone was terminated owing to side effects in 20/74 patients (27.0%). In 13 patients with idiopathic irritable bowel syndrome, 2 were markedly worse. In 85 patients with irritable bowel syndrome-small intestinal bacterial overgrowth, 15 were markedly improved, 32 were moderately worse, and 1 was markedly worse. In 12 patients with chronic constipation, 7 were markedly improved, 1 was moderately improved, 1 was mildly improved, and 4 were unchanged. Low dose naltrexone frequently has side effects but in most is tolerable. It appears to be helpful for a member of patients with gastrointestinal disorders.
Smith JP1, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. , Low-dose naltrexone therapy improves active Crohn's disease., Am J Gastroenterol. 2007 Apr;102(4):820-8. Epub 2007 Jan 11. https://www.ncbi.nlm.nih.gov/pubmed/1945396
OBJECTIVES: Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues. In an open-labeled pilot prospective trial, the safety and efficacy of low-dose naltrexone (LDN), an opioid antagonist, were tested in patients with active Crohn's disease.
METHODS: Eligible subjects with histologically and endoscopically confirmed active Crohn's disease activity index (CDAI) score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day. Infliximab was not allowed for a minimum of 8 wk prior to study initiation. Other therapy for Crohn's disease that was at a stable dose for 4 wk prior to enrollment was continued at the same doses. Patients completed the inflammatory bowel disease questionnaire (IBDQ) and the short-form (SF-36) quality of life surveys and CDAI scores were assessed pretreatment, every 4 wk on therapy and 4 wk after completion of the study drug. Drug was administered by mouth each evening for a 12-wk period.
RESULTS: Seventeen patients with a mean CDAI score of 356 +/- 27 were enrolled. CDAI scores decreased significantly (P= 0.01) with LDN, and remained lower than baseline 4 wk after completing therapy. Eighty-nine percent of patients exhibited a response to therapy and 67% achieved a remission (P < 0.001). Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were noted. The most common side effect was sleep disturbances, occurring in seven patients.
CONCLUSIONS: LDN therapy appears effective and safe in subjects with active Crohn's disease. Further studies are needed to explore the use of this compound.
Kariv R1, Tiomny E, Grenshpon R, Dekel R, Waisman G, Ringel Y, Halpern Z. , Low-dose naltreoxone for the treatment of irritable bowel syndrome: a pilot study., Dig Dis Sci. 2006 Dec;51(12):2128-33. Epub 2006 Nov 1. https://www.ncbi.nlm.nih.gov/pubmed/17080248
Abstract; Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate antagonist, can block excitatory opioid receptors without affecting inhibitory opioid receptors, resulting in analgesic potency without side effects. The present study assessed the efficacy and safety of PTI-901 (low-dose NTX) treatment in Irritable bowel syndrome (IBS) patients. Forty-two IBS patients participated in an open-label study. Participants received 0.5 mg PTI-901/day for 4 weeks and were evaluated during baseline, during treatment, and at 4-week follow-up. Patients recorded degree of abdominal pain, stool urgency, consistency, and frequency. Primary outcomes were number of pain-free days and overall symptom relief, evaluated by a global assessment score. Data were analyzed per protocol. Global assessment improved in 76% of 42 patients. During treatment, the mean weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14 (P=0.011). There were no significant adverse reactions. PTI-901 improves pain and overall feeling, and is well tolerated by IBS patients. A large, randomized, double-blind, placebo-controlled study is justified.