Endocannabinoid system modulation for visceral abdominal pain in inflammatory bowel disease and irritable bowel syndrome: A protocol for systematic review and meta-analysis

Visceral abdominal pain in IBS and IBD

Chronic visceral abdominal pain is a cardinal diagnostic criterion of irritable bowel syndrome (IBS)¹, and affects up to 60% of patients with inflammatory bowel disease (IBD) irrespective of their disease activity^2,3. In addition to the negative impact of chronic pain itself⁴, the health-related quality of life of these patients is further impacted by highly prevalent comorbidities of chronic pain, including anxiety and depression^5–7, and fatigue^8–10. There is a sex dimorphism in visceral pain in IBS and IBD, with IBS more prevalent in females¹¹, and female sex an independent risk factor for pain in IBD¹². Adequate treatment of abdominal pain remains challenging¹³. Adverse effects of commonly used analgesics (e.g., aspirin and other non-steroidal anti-inflammatory drugs, opioids) on the gastrointestinal tract are of particular concern in these patient populations^14,15. Furthermore, chronic use of some analgesics, such as opioids, could lead to dependence and opioid-induced hyperalgesia¹⁶. The overlap between IBS and IBD with regards visceral pain and its treatment is apparent, as is the utility of taking the lead from the IBS research, which has investigated promising avenues for pain management like anti-spasmodic (e.g. hyoscyamine), anti-convulsant (e.g. gabapentin, pregabalin) and psychopharmacological agents (e.g. tricyclic-antidepressants, selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors)^17,18. For both IBS and IBD, a holistic approach to pain management is ultimately required, one that incorporates new pharmacological therapies that target the underlying pain pathophysiology, alongside a tailored selection of dietary, psychological, and lifestyle interventions^19,20.

The Endocannabinoid System (ECS)

Modulation of the sexually dimorphic ECS²¹, an endogenous pain control system, presents a novel avenue for management of pain and negative affective comorbidities in IBS and IBD^22–24. The ECS consists of G_i/o-coupled cannabinoid receptors 1 and 2 (CB₁ and CB₂)^25–27, their endogenous lipid ligands ‘endocannabinoids’ anandamide (AEA)²⁸, and 2-arachydonyl glycerol (2-AG)^29,30, related-lipids N-oleoylethanolamide (OEA), and N-palmitoylethanolamide (PEA)^28–30 and a plethora of catabolic and anabolic enzymes, for example, fatty acid amide hydrolase (FAAH) which degrades AEA, PEA, and OEA³¹, and monoacylglycerol lipase (MGL) which degrades 2-AG³². The ECS is situated at peripheral, spinal and supra-spinal levels of the pain pathways²². It is also present in neuronal and non-neuronal tissue of the gastrointestinal tract where it functions to maintain homeostasis, regulating processes such as visceral sensitivity, inflammation, motility, and secretion³³. Importantly, individuals with IBS and IBD have been shown to have significant alterations in their ECS compared to healthy controls, making this system a key target for treatment of their visceral pain. These alterations range from variation in genes encoding cannabinoid receptors and endocannabinoid-metabolising enzymes^34–36, to differing expression of mRNA^24,37–41 and proteins related to the ECS³⁷ and differing levels of circulating endocannabinoids^24,38,40.

Cannabis, cannabinoids and cannabis-based medicines

There are a variety of natural and synthetic compounds that can modulate the ECS. The natural compounds are derived from Cannabis sativa plant material including herbal cannabis/marijuana, pharmaceutical grade medicinal cannabis, or extracts, and include individual phytocannabinoids (most notably, delta 9-tetrahydrocannabinol [THC]⁴² and cannabidiol [CBD]⁴³). Certain extracts with specific concentrations of THC and/or CBD have regulatory approval and are classified as ‘cannabis-based medicines’ (CBMs, e.g., nabiximols⁴⁴, CBD⁴⁵). The synthetic compounds, some of which are still under development, include a variety of ECS modulators: cannabinoid receptor agonists (e.g., nabilone⁴⁶, dronabinol⁴⁷, CT-3⁴⁸), cannabinoid receptor antagonists (e.g., Rimonabant⁴⁹), and enzyme inhibitors (e.g., PF-00457845⁵⁰).

While there are a variety of compounds or formulations, few have been thoroughly tested in randomised controlled clinical trials (RCTs), and even fewer are approved by regulatory authorities for pain management, as clinical evidence for their effectiveness is limited⁵¹. Study of ECS modulators is further complicated by the large variety of formulations, doses, and routes of administration available (e.g., oral, oromucosal, inhaled), making comparisons between trials difficult. Despite this, use of ECS modulators (mostly medicinal cannabis) is common amongst patients with pain, including those with IBS and IBD^52–54.

Importance of this review

Previous reviews in this area have investigated the impact of ECS modulators for IBS or IBD generally^55–58, but there has been very little recognition of pain as a key outcome measure, despite the heavy burden this symptom places on patients and its relationship with emotional and physical functioning and quality of life scores. This review will place pain at the forefront, with keen attention also paid to comorbidities of chronic pain. Furthermore, previous reviews have had quite selective search terms, thus focusing on subsets of ECS modulators^56,57 rather than assessing all types of ECS modulators, as this review aims to do. Finally, this review, in compiling the literature on ECS modulators across both IBS and IBD, may reveal important findings with regards similarities and differences in the response to ECS modulators between the different, yet related, populations.

Criteria for considering studies

Studies

We will include RCTs conducted in any care setting, in any part of the world, in this systematic review.

Participants

We will include participants, of any age, sex, or ethnicity, with a diagnosis of IBS as defined by ROME III/IV guidelines¹ and/or IBD as defined by ECCO-ESGAR guidelines⁶¹.

Interventions and comparisons

We will include any type of cannabis, cannabinoid, CBM or ECS modulator, at any dose, delivered by any route of administration, for any duration. We will also include any trials that administer cannabis, cannabinoids, CBMs or ECS modulators as part of a combination treatment, with one another or with other drugs. We will include any control; placebo, or pharmacological/psychological/dietary interventions.

We will base comparisons on the interventions grouped as follows:

We will differentiate between interventions that have a sole aim of reducing pain intensity, and those that aim to improve IBS/IBD health outcomes more generally.

Outcomes

Table 1 provides a summary of the outcome measures for each of the outcome domains listed below.

Primary outcomes

Secondary outcomes

Exclusion criteria

We will exclude: (1) studies that are not RCTs (e.g. cohort studies, case-control studies, cross-sectional studies), (2) grey literature, conference abstracts or case reports, (3) studies not published in the English language, or where the full text is not available in the English language.

Search methods for identification of studies

We will search the literature using a staged approach. We will search CENTRAL, MEDLINE, PubMed, EMBASE, and Web of Science databases from inception to present for peer-reviewed publications with limit to publications available in the English language (see extended data for search strategy). We will search the World Health Organisation International Clinical Trials Registry Platform and the ClinicalTrials.gov online clinical trials registries. We will conduct reference checking and citation searching of included publications to search for further trials. If we identify systematic reviews in the field, we will search their reference lists. We will not search for non-RCT studies (e.g., cohort studies, case-control studies, cross-sectional studies), grey literature or conference abstracts. We will endeavour to match selected RCTs with their trial identifier.

Selection of studies

Two authors will independently decide which of the identified trials will be selected for screening based on their titles and abstracts. Disagreements will be resolved by discussion between the two authors, or with a third author if necessary. We will retrieve the full text of any publications or reports identified as potentially relevant. Two authors will independently screen the full texts for inclusion against eligibility criteria. Disagreements will be resolved by discussion between the two authors, or with a third author if necessary. We will include any peer-reviewed publication or online trial registration that investigated the therapeutic effects of cannabis, cannabinoids, CBMs or other ECS modulators, given by any dose or route of administration, for any duration, compared with placebo, or active pharmacological, psychological, or dietary intervention, for improving health outcomes in IBS and/or IBD patients, irrespective of reported measures. We will manage the results of our search using the Rayyan online systematic review software package (this is a proprietary tool; open access alternatives are provided in the Software Availability section). We will document our screening and selection process in sufficient detail to complete a PRISMA flow chart and ‘Characteristics of excluded studies’ table. We will include trials that are registered but not yet published as ‘awaiting classification’ and describe them separately to the included studies.

Data extraction and management

Two authors will independently extract the following data from the included trials using a data extraction spreadsheet on Microsoft Excel:

Disagreements will be resolved by discussion between the two authors, or with a third author if necessary. We will contact study authors of trials included in the review if required to obtain further data or to confirm aspects of the data available. One author will enter all extracted data into the Review Manager (RevMan) web platform (this is a proprietary tool; open access alternatives are provided in the Software Availability section). A second author will independently check the entered data for accuracy.

Risk of bias (quality) assessment of included studies

Two authors will independently assess the risk of bias of included trials using the Cochrane Risk of Bias Tool (RoB2) (Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International License)⁶³. Disagreements will be resolved by discussion between the two authors, or with a third author if necessary. We will report our judgements with supporting quotes and justifications on the following risk of bias domains in a risk of bias table: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias) and blinding of outcome assessment (detection bias); completeness of outcome data (attrition bias), selective outcome reporting (reporting bias), and study size (bias of small size). Our judgements on a trial being of high, low, or some concern for risk of bias will follow criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions⁶⁴ and in the Cochrane Pain, Palliative, and Supportive Care Review Group template for intervention review⁶⁵.

Synthesis methods

We will tabulate two descriptive summaries of the extracted data from individual trials: one for IBS trials, and one for IBD trials. These tables will include participant characteristics, post-treatment N, length of follow up, and descriptions of interventions, comparators, duration, and outcome measures of interest for this review, including adverse event description and frequency. We will stratify by IBS and IBD classification (IBS-C/IBS-D/IBS-M and CD/UC/IC, respectively), and intervention type (cannabis, cannabinoid, CBM, other pharmacological ECS modulator), if possible. We will narratively compare the effects of ECS modulation for outcomes relevant to both IBS and IBD populations (e.g., pain intensity, physical and emotional functioning, quality of life, fatigue, sleep, adverse events). This will enable us to identify similarities and differences between the included trials for each condition and across both conditions.

We will combine data comparing ECS modulation versus control for IBS or IBD respectively in meta-analysis if sufficient data on similar outcomes from homogenous studies are available. Two authors will independently select studies suitable for inclusion in meta-analysis, with any disagreements resolved by discussion with a third author. We will only include studies with greater than 30 participants post-treatment per group in the meta-analysis, as small sample sizes can inflate effect estimates^51,66. We will use Review Manager (RevMan) for meta-analysis. We will calculate standardised mean differences with 95% confidence interval (CI) for continuous outcomes, and risk ratio with 95% CI for dichotomous outcomes. We will also calculate risk ratios with 95% confidence intervals for adverse events. We will perform statistical analysis using a random effects model to account for any within-study and between study-variation. We will assess statistical heterogeneity using the I² statistic. We will conduct sensitivity analysis to examine the impact of risk of bias and certainty of evidence. If the data allows, we will perform the following subgroup analysis:

If meta-analysis is not possible due to the nature of the data available, we will synthesize the literature narratively and will create effect direction plots for our outcomes of interest.

Certainty of the evidence assessment (GRADE)

Two authors will assess the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, and the GRADEpro GDT tool (Standard Licence)^67,68. The GRADE approach deems the certainty of evidence for each outcome to be ‘high’, ‘moderate’, ‘low’ or ‘very low’ based on 5 considerations: study limitations, unexplained heterogeneity or inconsistency, imprecision, indirectness and publication bias. Disagreements will be resolved by discussion between the two authors, or with a third author if necessary.