Intervention Review

You have free access to this content

Low dose naltrexone for induction of remission in Crohn's disease

  1. Dan Segal1,
  2. John K MacDonald2,
  3. Nilesh Chande3,*

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group

Published Online: 21 FEB 2014

Assessed as up-to-date: 28 FEB 2013

DOI: 10.1002/14651858.CD010410.pub2


How to Cite

Segal D, MacDonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010410. DOI: 10.1002/14651858.CD010410.pub2.

Author Information

  1. 1

    London Health Sciences Centre - University Hospital, London, Ontario, Canada

  2. 2

    Robarts Research Institute, Robarts Clinical Trials, London, Ontario, Canada

  3. 3

    London Health Sciences Centre - Victoria Hospital, London, Ontario, Canada

*Nilesh Chande, London Health Sciences Centre - Victoria Hospital, Room E6-321A, 800 Commissioners Road East, London, Ontario, N6A 5W9, Canada. nilesh.chande@lhsc.on.ca. nchande2@uwo.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 21 FEB 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Smith 2011

MethodsRandomized, double-blinded, placebo-controlled, single centre trial

Centralized pharmacy allocation with block randomization


Participants34 adult patients with moderate to severe Crohn’s disease (CDAI greater than or equal to 220)

Concomitant medications were allowed if patients received stable doses of steroids or aminosalicylates for 4 weeks and thiopurines for 12 weeks prior to entry

Exclusion criteria: use of TNF-alpha antagonists within 8 weeks of entry, on lomotil, pregnant or breastfeeding, ostomy or ileoanal anastomosis, short bowel syndrome, abnormal liver enzymes


InterventionsNaltrexone 4.5 mg or placebo for 12 weeks


OutcomesThe primary outcome was the proportion of subjects with a 70-point or more decline in CDAI from baseline

Secondary outcomes included the proportion of subjects with a 100 point decline in CDAI, endoscopic improvement (5 point decline in CDEIS), endoscopic remission (CDEIS less than 6 or less than 3) and clinical remission (CDAI < 150)

Other secondary outcomes included a histological inflammation score, measures of quality of life (IBDQ and SF36), and adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe method of randomization was not described in the paper

The contact author was able to confirm that randomization was computer generated

Allocation concealment (selection bias)Low riskCentralized randomization

“Assignments were made by the investigational pharmacy department”

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded with identical placebo

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEndoscopist was blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient from each group dropped out do to flare

Selective reporting (reporting bias)Low riskIn the manuscript the proportion of patients with clinical remission was only reported for patients in the LDN group

The contact author provided the proportion of placebo patients who achieved clinical remission

Other biasLow riskThe study appears to be free of other sources of bias

Smith 2012

MethodsRandomized, double-blinded, placebo-controlled, single centre trial

Centralized pharmacy allocation with block randomization


Participants8 children, ages 6 to 17, with moderate to severe Crohn’s disease (PCDAI greater than or equal to 30) for a minimum of six months

Concomitant medications were allowed if patients received stable doses of steroids or aminosalicylates for 4 weeks and thiopurines for 12 weeks prior to entry

Exclusion criteria: use of TNF-alpha antagonists within 8 weeks of entry, on lomotil or diphenoxylate hydrochloride, pregnancy, ostomy or ileoanal anastomosis, abnormal liver enzymes


InterventionsNaltrexone 0.1 mg/kg (maximum 4.5 mg) versus placebo for 8 weeks


OutcomesThe primary outcome was the safety and tolerability of treatment

Secondary outcomes included clinical response (greater than or equal to a 10 point decline in PCDAI) and clinical remission (PCDAI = or <10)

Other outcomes included two quality of life assessments (Impact III survey, Harvey-Bradshaw index)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe method of randomization was not described in the paper

The contact author was able to confirm that randomization was computer generated

Allocation concealment (selection bias)Low riskCentralized randomization

“Randomized by the investigational pharmacy department”

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded with identical placebo

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEndoscopist was blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients appear to have completed the study

Selective reporting (reporting bias)Unclear riskAlthough the primary aim of the trial was to assess safety and tolerability secondary outcomes were incompletely reported

The contact author provided the proportion of placebo patients who achieved clinical remission

Other biasLow riskThe study appears to be free of other sources of bias

 
Characteristics of ongoing studies [ordered by study ID]
NCT01810185

Trial name or titleLow dose naltrexone in symptomatic inflammatory bowel disease

MethodsRandomized, double-blind, placebo-controlled, parallel group trial

ParticipantsConfirmed active Crohn's disease or ulcerative colitis through radiographic, endoscopic or histologic criteria

InterventionsLow dose naltrexone (4.5 mg) daily for 12 weeks or placebo daily for 12 weeks

OutcomesIBDQ

Starting dateEstimated starting date was March 2013

Contact informationErick J Imbertson, M.D., Santa Barbara Cottage Hospital, Santa Barbara, California, United States, 93105

Notes

 
Comparison 1. Low dose naltrexone versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical remission (CDAI < 150)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Clinical response (CDAI change of 70 or greater)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Clinical response (CDAI change of 100 or greater)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Endoscopic remission (CDEIS less than 3)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Endoscopic remission (CDEIS less than 6)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Endoscopic response1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 Withdrawals due to adverse events246Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.23, 10.71]

 8 Specific adverse events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Sleep disturbance
246Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.38, 2.20]

    8.2 Unusal dreams
246Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.33, 4.31]

    8.3 Headache
246Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.32, 4.34]

    8.4 Decreased appetite
246Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.24, 8.14]

    8.5 Nausea
246Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.37, 3.35]

    8.6 Fatigue
246Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.02, 1.47]

 
Summary of findings for the main comparison. Low dose naltrexone versus placebo for induction of remission in Crohn's disease

Low dose naltrexone versus placebo for induction of remission in Crohn's disease

Patient or population: Patients with active Crohn's disease
Settings: Outpatient
Intervention: Low dose naltrexone versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlLow dose naltrexone versus placebo

Induction of clinical remission
CDAI < 150
Study populationRR 1.48
(0.42 to 5.24)
34
(1 study)
⊕⊕⊝⊝
low2,3

188 per 10001278 per 1000
(79 to 985)

Induction of 70-point clinical response
CDAI
Study populationRR 2.22
(1.14 to 4.32)
34
(1 study)
⊕⊕⊝⊝
low3,4

375 per 10001832 per 1000
(427 to 1000)

Induction of 5-point endoscopic response
CDEIS
Study populationRR 2.89
(1.18 to 7.08)
34
(1 study)
⊕⊕⊝⊝
low3,5

250 per 10001722 per 1000
(295 to 1000)

Sleep disturbance (adverse event)Study populationRR 0.92
(0.38 to 2.2)
46
(2 studies)
⊕⊕⊝⊝
low3,7

318 per 10006293 per 1000
(121 to 700)

Withdrawals due to adverse outcomesStudy populationRR 1.57
(0.23 to 10.71)
46
(2 studies)
⊕⊕⊝⊝
low3,8

45 per 1000671 per 1000
(10 to 487)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 The control group risk estimate comes from the control arm of the included study on adult patients.
2 Sparse data (8 events).
3 Wide confidence intervals.
4 Sparse data (21 events).
5 Sparse data (17 events).
6 The control group estimate comes from the control arm of the two included studies.
7 Sparse data (14 events).
8 Sparse data (3 events).