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Cannabis for the treatment of ulcerative colitis

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Abstract

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

Our objective is to assess the benefits and harms of cannabis for the treatment of patients with ulcerative colitis.

Background

Cannabis or marijuana is often promoted as a treatment for various illnesses including cancer and autoimmune disorders (Hill 2015). It is a common recreational drug that alters sensory perception and elicits feelings of euphoria (Tibirica 2010). Cannabis is known to affect pain and discomfort via psychotropic effects (Tibirica 2010). However, cannabis also modulates the endocannabinoid system which acts on the nervous system and immune cell function (Klein 2006). It is hypothesized that cannabis and its derivatives may work through this pathway to exert a therapeutic effect on ulcerative colitis (Schicho 2014; Tibirica 2010).

There is a higher prevalence of cannabis use among patients with IBD compared to the general population (Weiss 2015). Cannabis may relieve symptoms of ulcerative colitis such as abdominal pain, reduced appetite, and diarrhea (Lal 2011; Weiss 2015). However, it is not known if these potential benefits are related to centrally acting psychotropic effects or to anti‐inflammatory properties as suggested by animal studies (Hasenoehrl 2016; Klein 2006; Singh 2012). Studies looking at UC in animal and laboratory models have found benefit in attenuating inflammation (Borrelli 2009i; Leinwand 2017). However, in humans, there is evidence that cannabis may be associated with harm and adverse effects such as dizziness and diarrhea (Whiting 2015).

Preliminary results from the first randomized, double‐blind, placebo‐controlled study in humans looking at the use of a cannabinoid in ulcerative colitis were published in 2015 (Irving 2015). This study posed important questions regarding whether cannabis and its derivatives can ameliorate symptoms of ulcerative colitis. For example, can cannabis objectively reduce inflammation in UC? If so, is this benefit clinically significant in the absence of psychotropic effects? Further, what is the safety and side‐effect profile associated with these agents?

Description of the condition

Ulcerative colitis is a chronic immune‐mediated disorder that causes mucosal inflammation in the colon and rectum. UC is associated with significant morbidity and a decreased quality of life (Lahat 2012). In North America, the prevalence of UC is estimated to be 37 to 246 cases per 100,000 person‐years (Friedman 2012). In Europe, the prevalence of ulcerative colitis ranges from 21.4 to 243 cases per 100,000 person‐years (Friedman 2012). Outside of these areas, IBD is less common with the exception of Israel, Australia, and South Africa (Friedman 2012). However, the incidence of ulcerative colitis is rapidly rising in places such as Hong Kong, Japan, South Korea, Singapore, northern India, and Latin America (Friedman 2012). Mortality in ulcerative colitis is highest during the initial years of disease activity (Friedman 2012). However, in the long‐term mortality in ulcerative colitis is due to an increased risk of colon cancer (Friedman 2012).

Patients with UC may have a genetic predisposition to this disease and the pathophysiology of this condition is multifactorial (Friedman 2012). The pathophysiology involves a dysregulated immune response towards commensal microbiota and dietary contents in the gastrointestinal tract (Friedman 2012). This immune response leads to an inflammatory cascade of activated T cells secreting excessive pro‐inflammatory cytokines including interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), and tumour necrosis factor‐alpha (TNF‐α) antibodies resulting in inflammation and damage to previously healthy tissues (Friedman 2012). UC is a relapsing remitting disorder and symptoms may include diarrhea, rectal bleeding, tenesmus, passage of mucus, and abdominal pain (Friedman 2012). Treatment options include anti‐inflammatory and immunosuppressant agents (Friedman 2012). Common first line agents include 5‐aminosalicylates, corticosteroids, thiopurines (e.g. azathioprine or 6‐mercaptopurine), and biologic therapies including TNF‐α antagonists and vedolizumab (Friedman 2012).

Description of the intervention

Cannabis is derived from the leaves and flowering tops of the plant and is prepared in various forms such as cigarettes, hash oil and edible formulations (Mello 2012). Cannabis contains over 400 compounds and has numerous derivatives called cannabinoids (Mello 2012). Although delta 9‐tetrahydrocannabinol (THC) is the main psychotropic derivative of cannabis, there are other derivatives such as cannabidiol that show anti‐inflammatory effects in animal models without psychotropic effects (Klein 2006). Cannabis is rapidly absorbed into the body due to its lipophilic nature, but then it is sequestered into tissues and very slowly cleared from the body through feces (Mello 2012). While there are data identifying an increase in associated short‐term adverse effects of cannabinoids such as dizziness and diarrhea, there is a paucity of studies and data regarding the long‐term benefits and harms of cannabinoids (Whiting 2015).

How the intervention might work

Cannabis is hypothesized to affect disease activity in ulcerative colitis via the endocannabinoid system (Hasenoehrl 2016). The endocannabinoid system affects the nervous system, peripheral tissues, and the immune system (Tibirica 2010). It is composed of cannabinoid (CB) receptors 1 and 2, endogenous endocannabinoids, and associated enzymes (Hasenoehrl 2016; Klein 2006). It is hypothesized that modulating this system may therapeutically decrease inflammation in the gut (Hasenoehrl 2016).

CB1 receptors are found in the central nervous system, peripheral tissues and gastrointestinal system (Hasenoehrl 2016; Klein 2006). Activation of these receptors may help reduce intestinal transit time and reduce colon propulsion, and enhance epithelial wound closure in the colon (Pinto 2002; Wright 2005). There is evidence that these receptors play a physiologic role in protecting the colon during excessive inflammation (Massa 2004). In the central nervous system, CB1 receptors are associated with effects such as reduction in pain and nausea (Klein 2006; Tibirica 2010).

CB2 receptors are found in the myenteric plexus, immune cells and in epithelial cells in ulcerative colitis (Hasenoehrl 2016; Klein 2006; Marquez 2009). Cannabis is thought to influence immune cells through various pathways. For example, CB2 receptor activation may lead to T‐cell apoptosis, decreased T‐cell proliferation in colitis, decreased recruitment of leukocytes to the inflamed colon, and may also help reduce the release of cytokines ( Klein 2006; Lahat 2012; Singh 2012).

The endocannabinoid system also has other pathways that may be activated by cannabis and cannabinoids. For example, non‐psychotropic cannabinoids such as cannabidiol may reduce inflammation through the peroxisome proliferator‐activated receptors and transient receptor potential cation channels subfamily V receptor pathways (Hasenoehrl 2016).

Why it is important to do this review

This review will help evaluate the evidence supporting the use of cannabis and cannabinoids for the treatment of ulcerative colitis. We intend to assess the efficacy and safety of cannabis and its derivatives for the treatment of ulcerative colitis. This systematic review will help distinguish objective markers of improvement (e.g. endoscopic remission) from subjective scores and will also help identify harms associated with cannabis and cannabinoids.

Objectives

Our objective is to assess the benefits and harms of cannabis for the treatment of patients with ulcerative colitis.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials will be considered for inclusion. Studies published as abstracts will only be included if the authors can be reached for further information to allow for evaluation of quality and main outcomes. Any study duration will be included.

Types of participants

Adult patients (> 18 years of age) with ulcerative colitis (diagnosed by conventional methods) will be considered for inclusion. Patients with clinically active or quiescent ulcerative colitis will be considered for inclusion. Clinical remission or quiescent disease is often defined by the Mayo Score or Disease Activity Index (DAI) for ulcerative colitis. Patients with active (e.g. DAI >2) or quiescent disease (defined as mild or absent symptoms prior to entering the study or by a DAI total score < 2 with no sub score > 1) will be included. We will include patients on all therapies for ulcerative colitis including those with a history of biologic therapy. Patients with surgically‐induced remission will be excluded.

Types of interventions

Studies comparing any form of cannabis or cannabinoid derivatives to placebo or an active therapy for ulcerative colitis will be included. We will include studies that utilize any dosage and method of consumption such as oral supplementation or smoking. For example, we will include cannabidiol derived from non‐THC containing hemp and other sources.

Types of outcome measures

Primary outcomes

The primary outcome will be clinical remission at study endpoint for induction of remission studies (as defined by a DAI total score <=2 with no sub score >1) and relapse (e.g. DAI >2) at study endpoint for maintenance studies. We will include any validated scoring system such as the DAI. We will include all short‐term and long‐term outcome time points.

Secondary outcomes

Secondary outcomes will include:

1. Clinical improvement (as defined by the included studies);

2. Endoscopic remission (as defined by the included studies);

3. Endoscopic improvement (as defined by the included studies);

4. Histological response (as defined by the included studies);

5. Quality of life (as defined by validated instrument or primary study, e.g. the Inflammatory Bowel Disease Questionnaire or IBDQ);

6. CRP and fecal calprotectin measurements;

7. Symptom improvement (e.g. improvement in pain, nausea, or anorexia);

8. Adverse events (i.e. psychological effects, cognitive impairment, personal safety accidents, and GI upset);

9. Serious adverse events;

10. Withdrawal due to adverse events;

11. Psychotropic adverse events (including mental health effects such as psychosis and schizophrenia); and

12. Cannabis dependence and withdrawal effects (as defined and measured by primary studies).

Search methods for identification of studies

Electronic searches

We will search the following databases from inception to date:

1. MEDLINE (Ovid);

2. Embase (Ovid);

3. WHO ICTRP;

4. The Cochrane IBD Group Specialized Register; and

5. The Cochrane Library (CENTRAL).

Conference proceedings will also be searched to identify additional studies.

Searching other resources

We will search conference proceedings to identify studies only published in abstract form. We will search ClinicalTrials.gov and EU Clinical Trials Register to identify ongoing studies. We will also search the references sections of applicable studies and systematic reviews to identify additional studies that may meet the inclusion criteria.

Data collection and analysis

Selection of studies

We will review studies and abstracts identified by the literature search. Two authors (TK and NC) will independently screen the search results to identify potentially relevant studies for full text evaluation. The studies selected for full text review will be independently assessed by two authors (TK and NC) and consensus for study inclusion and exclusion will be reached through discussion. Any conflicts regarding inclusion or exclusion will be resolved by consultation with a third author (JKM). Studies published in abstract form will only be included if the authors can be reached for further information.

Data extraction and management

Two authors (TK and NC) will independently extract the outcome data of interest from each study. Any conflicts will be resolved by discussion and consensus or by consultation with a third author (JKM) as necessary. If data are missing or unclear, the study authors will be contacted for clarification.

Other information extracted from the studies will include:

a. Study characteristics and design;

b. Characteristics of patients;

c. Inclusion and exclusion criteria;

d. Interventions (if available, we will extract specific information per the Herbal CONSORT statement) (Gagnier 2006); and

e. Outcomes scoring methods.

Assessment of risk of bias in included studies

Two authors (TK and NC) will independently assess methodological quality using the Cochrane risk of bias tool (Higgins 2011). Any conflicts will be resolved by discussion and consensus or by consultation with a third author (JKM) as required. Items to be assessed will include:

1. Random sequence generation;

2. Allocation sequence concealment;

3. Blinding of participants, personnel and outcome assessors;

4. Incomplete outcome data;

5. Selective outcome reporting; and

6. Other potential sources of bias.

Each category will be evaluated as low, high or unclear risk of bias and justification for judgement will be provided in the characteristics of included studies section of the review.

GRADE Analysis

The overall quality of the evidence supporting the primary outcome and selected secondary outcomes will be evaluated using the GRADE criteria (Guyatt 2008; Schünemann 2011). Using this approach outcome data will be rated as high, moderate, low or very low quality. Outcome data from randomized controlled trials begins as high quality, but can be downgraded based on several criteria. These criteria include:

1. Risk of bias from the studies;

2. Indirect evidence (by comparison, population, setting);

3. Inconsistency (i.e. unexplained heterogeneity);

4. Imprecision (i.e. few events and wide confidence intervals); and

5. Likelihood of publication bias.

Measures of treatment effect

For dichotomous outcomes, we will calculate the risk ratio (RR) and corresponding 95% confidence interval (CI). For continuous outcomes, we will calculate the mean difference (MD) and corresponding 95% CI.

Unit of analysis issues

For multi‐arm trials (e.g. with two or more dose groups) with a single placebo group, we will split the placebo group across the treatment groups to avoid a unit of analysis error (Higgins 2011b). In order to avoid potential carry‐over effects, we will only include the first part of the study (i.e. before the cross‐over) for any cross‐over studies (Higgins 2011b). For studies where events may re‐occur we will include the first event. When there are repeated observations on participants, we will use the primary endpoint defined by the study. It is unlikely that we will find study designs applicable to cannabis in ulcerative colitis where multiple treatment attempts are used. We do not anticipate encountering any available cluster‐randomized studies.

Dealing with missing data

Data will be analysed on an intention‐to‐treat basis, whereby missing data with no explanations will be assumed to be treatment failures. We will count treatment failures as a relapse for maintenance studies and as a failure to enter remission for induction studies. We will conduct a sensitivity analysis to assess the impact of this assumption on the effect estimate. If possible, we will impute missing standard deviations. We will conduct an available case analysis for missing continuous outcomes.

Assessment of heterogeneity

We will use the Chi2 test and the I2 statistic to assess heterogeneity. For the Chi2 test, we will consider a P value of 0.10 to be statistically significant. We will use the I2 statistic to quantify the proportion of variation that is due to heterogeneity rather than to chance. An I2 value of 25% will indicate low heterogeneity, >50% will indicate moderate heterogeneity and >75% will indicate high heterogeneity. We will visually inspect the forest plots to identify any outliers. If outliers are identified, a sensitivity analysis will be conducted to explore potential explanations for the heterogeneity.

Assessment of reporting biases

Reporting bias will be assessed by comparing the outcomes pre‐specified in study protocols to the outcomes reported in the study manuscripts. However, if the protocols are not available, we will assess reporting bias by comparing the outcomes specified in the methods section of the manuscript to those reported in the results section. If a sufficient number of studies are included in the pooled analysis (i.e. > 10), we will construct a funnel plot to assess the potential for publication bias (Egger 1997).

Data synthesis

We will pool data from individual studies for meta‐analysis when the outcomes, patient groups and interventions are similar enough to justify pooling (to be determine by consensus). A fixed‐effect model will be used to calculate the pooled RR and 95% CI for dichotomous outcomes. For continuous outcomes we will calculate the pooled MD and corresponding 95% CI. However, if the continuous outcomes utilize different scales to measure the same underlying construct (e.g. for quality of life), we will calculate the standardized mean difference (SMD) and corresponding 95% CI. If significant heterogeneity is identified, a random‐effects model will be used to pool data. We will not pool data for meta‐analysis if a high degree of heterogeneity is detected (e.g. I2 > 75%).

Subgroup analysis and investigation of heterogeneity

Subgroup analysis based on dose of cannabis or cannabinoid will be performed if the data allow for such comparisons. Other subgroup analyses of interest may include the form of cannabis consumed, UC disease location, cigarette smoking status, history of prior biologic therapy and failure of biologic therapy.

Sensitivity analysis

We will attempt to perform a sensitivity analysis of study quality by excluding studies with a high risk of bias to see if there is an impact on the effect estimate.