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

  • Protocol
  • Intervention

Authors


Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The primary objective is to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn’s disease.

Background

Description of the condition

Crohn’s disease is a transmural, relapsing inflammatory condition afflicting the gastrointestinal system. It can involve any portion of the digestive tract and numerous extra-intestinal sites. Complications include large and small bowel obstructions, fistulas and intra-abdominal abscesses, and perianal disease (Baumgart 2007). Furthermore patients experience major impacts in employment, relationships, and general well being (Hommes 2012). The pathogenesis of Crohn’s disease remains unclear. In those with certain genetic and environmental factors there may be a loss of balance between immune tolerance and pathogenic response towards the vast luminal microbe environment (Abraham 2009).

The burden of Crohn’s disease is growing in both developing and developed nations. The highest annual incidence of disease is 20.2 per one hundred thousand person-years in North America (Molodecky 2012). Current medical therapies include corticosteroids, immunosuppressives (e.g. azathioprine, 6-mercaptopurine, or methotrexate), and tumour necrosis factor alpha antagonists and other biologics (Burger 2011). Upwards of 30% of patients require major abdominal surgery within five years of diagnosis (Bouguen 2011). However, surgery is not curative and the endoscopic recurrence rate may be as high as 90% within one year of surgery and the clinical recurrence rate may be 30% within two years of surgery (Rutgeerts 1984; Tytgat 1988; Olaison 1992).

Description of the intervention

Naltrexone is a long-acting opioid antagonist (Preston 1993). Its use has been well described for the treatment of alcohol and opioid abuse (Anton 2006; Minozzi 2011). In the gut, opioids affect secretion and motility by interacting with δ-, κ-, and μ- opioid receptors (Holzer 2009). Naltrexone is a potent inhibitor of the µ-opioid receptor (MOR) (Preston 1993), present in the gut as well as the central nervous system, which interacts with endogenous opioid peptides β-endorphin, met-enkephalin, and leu-enkephalin (Holzer 2009). The finding that MOR is overexpressed by CD4+ and CD8+ T lymphocytes in inflamed bowel led to the hypothesis that regulation of the innate opioid axis may be an effective treatment for Crohn’s disease (Philippe 2006).

How the intervention might work

MOR activation by opioid agonists has reduced inflammation in mouse models of colitis with a concomitant reduction in CD4+ T lymphocytes and cytokines including TNF-α and IL-1β (Philippe 2003). The mechanism of action may involve a decrease in inflammatory cell proliferation via tonic inhibition through the opioid axis (Zagon 2011). Naltrexone, a MOR antagonist, when administered in low doses temporarily increases proliferation by blocking the opioid receptor, but up-regulates both ligands and receptors providing a longer period of decreased proliferation once it falls off (Zagon 1989). A small (N = 17), uncontrolled, open label, pilot study found that low dose naltrexone (LDN) may improve quality of life and induce remission in patients with moderate to severely active Crohn's (Smith 2007).

Why it is important to do this review

Crohn’s disease patients still have suboptimal rates of remission and maintenance of remission with contemporary therapies including biologics (Peyrin-Biroulet 2011). Low dose naltrexone has gained attention from the public as a possible treatment for Crohn’s disease despite limited data. This review aims to systematically evaluate the effectiveness of LDN in order to inform the developing debate. 

Objectives

The primary objective is to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn’s disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) will be considered for inclusion.

Types of participants

Participants of any age with active Crohn’s disease defined by a combination of clinical (e.g. Crohn's disease activity index, CDAI > 150), radiographic, endoscopic, and histological criteria will be considered for inclusion.

Types of interventions

RCTs where low dose naltrexone was given by any route versus placebo or an active comparator will be considered for inclusion.

Types of outcome measures

Primary outcomes

The primary outcome will be the proportion of patients achieving remission (e.g. CDAI < 150) as defined by the included studies, and expressed as a percentage of the patients randomized (intention to treat analysis).

Secondary outcomes

Secondary outcome measures will include the proportion of patients with:

A. Clinical response (as defined by the included studies);

B. Endoscopic response or remission (as defined by the included studies);

C. Improvement in quality of life (as defined by the included studies);

D. Adverse events;

E. Withdrawal because of adverse events; and

F. Serious adverse events.

Search methods for identification of studies

Electronic searches

We will search the following databases for relevant trials:

  • MEDLINE (from 1966 to February 2013)

  • PubMed (from 1966 to the February 2013);

  • EMBASE OVID (from 1974 to the February 2013);

  • The Cochrane Library (CENTRAL, February 2013); and

  • The Cochrane Inflammatory Bowel Disease and Functional Bowel Bowel Disorders Review Group Specialised Register (SR-IBD).

The search strategies are listed in Appendix 1.

Searching other resources

We will perform a manual review of conference proceedings including Digestive Disease Week (DDW) and United European Gastroenterology Week (UEGW). Reference lists from retrieved articles will be scanned to identify additional citations that may have been overlooked by the electronic searches.

Data collection and analysis

Selection of studies

All studies identified by the search strategy will be independently assessed by two authors (DS and JKM) for inclusion, according to pre-specified criteria listed above. Studies in abstract form will only be included if the authors can be contacted for further information. Any disagreements will be resolved by consensus. If necessary a third party (NC) will be engaged to resolve any ongoing disagreements.

Data extraction and management

A standardized form will be used to extract relevant data from the included studies. The form will be based on the Cochrane checklist of items to consider for data extraction (Higgins 2011a). Two authors (DS and JKM) will independently extract and record the data. Any disagreements will be resolved by consensus with possible input from a third author (NC). The following data will be extracted:

A. Methods (methods of randomization, allocation, concealment, and blinding; inclusion and exclusion criteria, definition of outcomes);

B. Participants (number, age, gender, disease activity, co-medication);

C. Interventions (formulation, dose, frequency, duration); and

D. Outcomes (clinical remission and response rates, endoscopic remission and response rates, quality of life, adverse events, withdrawals due to adverse events, and serious adverse events).

Assessment of risk of bias in included studies

Two authors (DS and JKM) will independently assess the methodological quality of the included studies using the Cochrane risk of bias tool (Higgins 2011b). Any disagreements will be resolved by consensus with possible input from a third author (NC). Factors to be assessed will include:

A. Sequence generation;

B. Allocation concealment;

C. Blinding of participants and personnel;

D. Blinding of outcome assessment;

E. Completeness of outcome data;

F. Selective reporting; and

G. Other sources of bias.

Studies will be assigned a low risk of bias, high risk of bias, or unclear risk of bias for each category.

The quality of the total body of evidence for the primary outcomes of interest will be assessed using the GRADE criteria (Guyatt 2008; Schünemann 2011). Randomized trials are considered high quality and will be downgraded if the following weaknesses are present: within-study risk of bias, indirectness of evidence, heterogeneity, imprecision of effect estimates, and risk of publication bias. The quality of the body of evidence for a particular outcome will then be graded as:

A. High: Further research is very unlikely to change our confidence in estimate of effect;

B. Moderate: Further research is likely to have an important impact on our confidence in estimate of effect and may change estimate;

C. Low: Further research is very likely to have an important impact on our confidence in estimate of effect and likely may change estimate; and

D. Very low: Any estimate of effect is very uncertain.

Measures of treatment effect

Data will be analyzed using Review Manager (RevMan 5.2). All data will be analyzed on an intention-to-treat basis. For dichotomous outcomes, we will calculate the relative risk and 95% confidence intervals (95% CI). For continuous outcomes with uniform units, we will calculate a mean difference (MD) and the corresponding 95% CI. The standardized mean difference (SMD) and 95% CI will be calculated when different scales are used for the same outcome. 

Unit of analysis issues

The primary analysis will combine data from the trial defined primary observation time-point. For studies that report outcomes at fixed intervals, outcomes will be combined at those time points as well. For a parallel group design a single measurement for each outcome per participant will be collected. For crossover trials, data from the first part of the trial (prior to crossover) will be extracted. For cluster-randomized trials, data will be extracted at the level of the individual. When more than one efficacy or safety event is reported per subject, we will use the proportion of subjects with at least one event as the outcome. If studies allocate subjects to different active treatment arms they will be combined for the primary analysis. In this case, subgroup analysis will be attempted to assess outcomes among different doses of naltrexone. Separate analyses will be conducted for LDN versus placebo, and LDN versus active comparator. 

Dealing with missing data

As the primary analysis will be carried out as intention-to-treat, missing data will be assumed to be negative (treatment failure). Whenever possible, study authors will be contacted to request missing data, or to ascertain the reason for data loss. A sensitivity analysis will be used to assess the impact on the results of the assumption of treatment failure when data are missing. 

Assessment of heterogeneity

Heterogeneity in included studies will be evaluated using the Chi2 test (a P value of 0.10 will be considered statistically significant) and the I2 statistic. Sensitivity analysis will be used as indicated to investigate sources of heterogeneity.

Assessment of reporting biases

If there are a sufficient number of studies publication bias will be assessed by funnel plots (Egger 1997).

Data synthesis

Studies will be pooled for meta-analyses when studies are similar in terms of treatments, comparators, and outcome definitions (determined by consensus). Data will not be pooled for analysis if there is a high degree of heterogeneity (I2 > 75%). A fixed-effect model will be used in the absence of statistically significant heterogeneity; while a random-effects model will be used if there is statistically significant heterogeneity (P < 0.10).

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be undertaken to investigate treatment effects for the following if possible:

A. LDN dose;

B. Disease activity;

C. Duration of treatment;

D. Age; and

E. Gender.

Sensitivity analysis

Sensitivity analyses will be done by repeating the meta-analysis with new data sets that:

A. Exclude lower quality studies; and

B. Incorporate specific assumptions for missing data.

Acknowledgements

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

Appendices

Appendix 1. Search strategies

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R)

1randomized controlled trial.pt.
2controlled clinical trial.pt.
3random allocation/
4randomized controlled trial/
5double blind method/
6single blind method/
7triple blind method/
8or/1-7
9animal/ not human/
108 not 9
11clinical trial.pt.
12exp clinical trials as topic/
13(clin$ adj25 trial$).ti,ab.
14((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
15placebos/
16placebo$.ti,ab.
17random$.ti,ab.
18research design/
19or/11-18
2019 not 9
2110 and 20
22exp Crohn disease/ or exp colon Crohn disease/ or crohn$.mp.
23ibd.mp.
24inflammatory bowel disease$.mp.
2522 or 23 or 24
26naltrexone.mp. or exp Naltrexone/
27naloxone.mp. or exp Naloxone/
2826 OR 27
2921 and 25 and 28

PubMed

#9Search (#6 AND #7 AND #8)
#8Search (Crohn* OR “inflammatory bowel disease*” OR IBD)
#7Search (naltrexone OR naloxone)
#6Search (#1 OR #2 OR #3 OR #4 OR #5)
#5Search (singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo*)
#4Search (single-blind* OR double-blind* OR triple-blind*)
#3Search random*
#2Search controlled clinical
#1Search randomized controlled

Ovid EMBASE

1random$.tw.
2factorial$.tw.
3(crossover$ or cross over$ or cross-over$).tw.
4placebo$.tw.
5single blind.mp.
6double blind.mp.
7triple blind.mp.
8(singl$ adj blind$).tw.
9(double$ adj blind$).tw.
10(tripl$ adj blind$).tw.
11assign$.tw.
12allocat$.tw.
13crossover procedure/
14double blind procedure/
15single blind procedure/
16triple blind procedure/
17randomized controlled trial/
18or/1-17
19exp animal/ or nonhuman/
20exp human/
2119 not 20
2218 not 21
23exp Crohn disease/ or Crohn$.mp.
24ibd.mp.
25 inflammatory bowel disease$.mp.
2623 or 24 or 25
27 naltrexone.mp. or exp naltrexone/ or exp naltrexone derivative/
28 exp naloxone 6 spirohydantoin/ or exp naloxone/ or naloxone.mp. or exp naloxone benzoylhydrazone/
29 27 or 28
30 22 and 26 and 29

Cochrane Library (CENTRAL)

(naltrexone OR naloxone) AND (Crohn* OR IBD OR inflammatory bowel disease*)

SR-IBD

naltrexone OR naloxone

Declarations of interest

Dan Segal has no known declarations of interest. Nilesh Chande has received fees for consultancy from Abbott and Ferring, fees for lectures from Abbott, travel expenses from Merck and has stock/stock options in Pfizer, Glaxo Smith Kline, Procter and Gamble and Johnson and Johnson. All of these financial activities are outside the submitted work. John MacDonald has received fees for consultancy from Tillotts Pharma AG. All of these financial activities are outside the submitted work.