Systematic Review and Meta-Analysis of the Efficacy and Tolerability of Nicotine Preparations in Active Ulcerative Colitis

doi:10.1016/j.clinthera.2011.01.004

Clinical Therapeutics

Volume 32, Issue 14, December 2010, Pages 2304-2315

https://doi.org/10.1016/j.clinthera.2011.01.004 Get rights and content

Abstract

Background

Findings from clinical studies of the efficacy and tolerability of nicotine preparations in maintaining remission of ulcerative colitis (UC) have been inconsistent.

Objectives

This systematic review and meta-analysis aimed to assess the efficacy and tolerability of nicotine preparations in inducing remission in UC.

Methods

A literature search (1966August 2010) of Scopus (EMBASE), PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted for clinical trials that investigated the efficacy and/or tolerability (any adverse events [AEs] and withdrawals due to AEs) of any nicotine preparation for the induction of remission in UC.

Results

The electronic searches yielded 788 items. Of these, 3 placebo-controlled trials representing 233 patients with UC and 2 randomized controlled trials that compared nicotine to corticosteroids in 81 patients with UC were included in meta-analysis. The summary relative risks (RRs) (95% CI) in comparing nicotine to placebo were 1.40 (0.63–3.12) (P = NS) for clinical remission, 1.95 (1.38–2.78) (P < 0.001) for AEs, and 3.44 (0.71–16.71) (P = NS) for withdrawal due to AEs. The summary RRs in comparing nicotine to corticosteroids (prednisolone/prednisone) were 0.74 (0.5–1.09) (P = NS) for clinical remission in 2 trials and 2.28 (0.76–6.83) (P = NS) for withdrawal due to AEs.

Conclusion

The findings from this meta-analysis do not support the efficacy or tolerability of nicotine preparations in inducing remission in UC.

Introduction

Ulcerative colitis (UC) is a nontransmural inflammatory disease of the colon with episodic flares and remissions.¹ The etiology and pathogenesis of inflammatory bowel disease (IBD) are unclear. It is believed that a constellation of factors are involved in the pathogenesis of UC, including immune dysregulation (caused by genetic or environmental factors); abnormal gastrointestinal (GI) tract luminal factors, such as microorganisms constituting the GI tract flora, oxidative stress, and tumor necrosis factor (TNF-α); and defects in the GI mucosal barrier that allow luminal factors to penetrate into the mucosa.2, 3, 4, 5

Although aminosalicylates and corticosteroids are the standard first-line therapies for UC,6, 7 several other agents (eg, anti–TNF-α,⁸ antibiotics⁹) have been reported to be effective in the remission of active disease in previously published meta-analyses.

There is evidence of amelioration of disease in smokers with UC.10, 11, 12 Because the pathogenesis of IBD is not yet completely understood, any discussion on the possible mechanisms of smoking and nicotine is speculative. Several mechanisms have been suggested for the effects of nicotine in UC, such as decreasing expression of proinflammatory cytokines (eg, interleukin [IL]-1β, IL-8, transforming growth factor–β),13, 14 increasing antiinflammatory cytokines (eg, IL-4, IL-10),¹⁵ and the antiinflammatory effects and modulation of innate immune response through a Toll-like receptor-4–dependent pathway.¹⁶ In studies that have reported beneficial effects of nicotine,17, 18, 19, 20 no exact mechanism for nicotine has been described, but effects on the immune system, synthesis of proinflammatory molecules, alteration of gut motility and permeability, and alterations in the microcirculation have been proposed.²¹

Some clinical trials have investigated the efficacy of nicotine preparations, including patches, enemas, and chewing gum, in the remission of UC and concluded that nicotine preparations were effective.17, 18, 19, 20 Contrarily, some studies reported no efficacy of nicotine in the remission of UC.22, 23 This review and meta-analysis was conducted to determine the efficacy and tolerability of nicotine in maintaining remission of UC using data from available clinical trials.

Section snippets

Materials and Methods

Scopus (EMBASE), PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies that investigated the efficacy and/or tolerability of 4- to 6-week treatment with nicotine in maintaining remission of UC. Data from 1966–August 2010 were collected. The search terms were ulcerative colitis and nicotine. For PubMed, all relevant MeSH terms were used. For Web of Science and the Cochrane Central Register of Controlled Trials, the same entry terms including

Results

The electronic searches yielded 788 items (542 from Scopus [EMBASE], 153 from PubMed, 67 from Web of Science, and 26 from Cochrane Central) (Figure 1). Of those, 8 trials were scrutinized in full text and 1 in abstract form. Three reports were considered ineligible. Three trials had a Jadad score ≥3 and represented 233 patients with UC who were randomly assigned to receive a nicotine preparation or placebo (Table II, Table III).19, 20, 22 In 2 randomized controlled trials (n = 81), patients

Discussion

This meta-analysis found that patients with UC undergoing nicotine treatment for 4 to 6 weeks were 1.4-fold more likely to experience clinical remission compared with those who received placebo. However, these data did not carry statistical significance or considerable clinical effect. The occurrence of AEs in the nicotine group was significantly greater than in the placebo group (P < 0.001). Patients with UC who received nicotine were 3.44-fold more likely to be withdrawn due to AEs compared

Conclusion

The findings from this meta-analysis do not support the efficacy or tolerability of nicotine preparations for induction of remission in UC.

Acknowledgments

Dr. Nikfar reviewed all of the data, conducted the meta-analysis, prepared the figures, and completed the Methods, Results, and Discussion sections of the manuscript. Ms. Ehteshami-Ashar compiled the reference list, collected data, prepared the tables, and drafted the Introduction and Discussion sections of the manuscript. Dr. Rahimi reviewed data and completed the drafting of the manuscript. Prof. Abdollahi conceived the study, supervised and reviewed the entire study, and edited the

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Citation Excerpt :
The study on autism and ADHD showed a trend to improvement (n = 1) or improvement (n = 1). In ulcerative colitis, studies and metanalyses reported no benefits compared to standard treatment [47]. In other diseases, the efficacy is poor of absent and results heterogeneous (Excel file in additional material section).
Recent data show an interaction between COVID-19 and nicotine and indicate the need for an assessment of transdermal nicotine use in non-smokers. Assessments have been conducted into the short-term cognitive effects of nicotine and into diseases such as Parkinson's, Tourette syndrome, ADHD or ulcerative colitis.
Analyses of nicotine administration protocols and safety were conducted after reviewing Medline and Science Direct databases performing a search using the words [transdermal nicotine] AND [non-smoker] AND selected diseases.
Among 298 articles identified, there were 35 reviewed publications reporting on 33 studies of non-smokers receiving transdermal nicotine for > 48 hours. In the 16 randomized trials, 7 crossover, 1 case/control and 9 open studies patients received an initial nicotine dose of between 2.5 mg and 15 mg/day. In 22 studies, daily doses increased by 2 to 7 steps in 3 to 96 days until the dose was between 5 mg and 105 mg/day. The target nicotine dose was 19.06 ± 20.89 mg/day. The 987 non-smokers (534 never-smokers, 326 ex-smokers and 127 classified as “non-smokers”) received or did not receive nicotine. The most common side-effects were nausea and skin itching. Forty-three (7.1%) non-smokers stopped treatment because of an adverse event of nicotine. No hospitalization related to nicotine side-effects were reported.
Despite a relatively safe tolerance profile, transdermal nicotine therapy in non-smokers can only be used in clinical trials. There is a lack of formal assessment of the potential risk of developing a tobacco addiction. This review offers baseline data to set a transdermal nicotine protocol for non-smokers with a new purpose.
Common contributing factors to COVID-19 and inflammatory bowel disease
2021, Toxicology Reports
The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual’s dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19.
We have previously identified many contributing factors (CFs) (representing toxic exposure, lifestyle factors and psychosocial stressors) common to myriad chronic diseases. We hypothesized significant overlap between CFs associated with COVID-19 and inflammatory bowel disease (IBD), because of the strong role immune dysfunction plays in each disease.
A streamlined dot-product approach was used to identify potential CFs to COVID-19 and IBD. Of the fifty CFs to COVID-19 that were validated for demonstration purposes, approximately half had direct impact on COVID-19 (the CF and COVID-19 were mentioned in the same record; i.e., CF---→COVID-19), and the other half had indirect impact. The nascent character of the COVID-19 core literature (∼ one year old) did not allow sufficient time for the direct impacts of many CFs on COVID-19 to be identified. Therefore, an immune system dysfunction (ID) literature directly related to the COVID-19 core literature was used to augment the COVID-19 core literature and provide the remaining CFs that impacted COVID-19 indirectly (i.e., CF---→immune system dysfunction---→COVID-19).
Approximately 13000 potential CFs for myriad diseases (obtained from government and university toxic substance lists) served as the starting point for the dot-product identification process. These phrases were intersected (dot-product) with phrases extracted from a PubMed-derived IBD core literature, a nascent COVID-19 core literature, and the COVID-19-related immune system dysfunction (ID) core literature to identify common ID/COVID-19 and IBD CFs. Approximately 3000 potential CFs common to both ID and IBD, almost 2300 potential CFs common to ID and COVID-19, and over 1900 potential CFs common to IBD and COVID-19 were identified. As proof of concept, we validated fifty of these ∼3000 overlapping ID/IBD candidate CFs with biologic plausibility. We further validated 24 of the fifty as common CFs in the IBD and nascent COVID-19 core literatures. This significant finding demonstrated that the CFs indirectly related to COVID-19 -- identified with use of the immune system dysfunction literature -- are strong candidates to emerge eventually as CFs directly related to COVID-19. As discussed in the main text, many more CFs common to all these core literatures could be identified and validated.
ID and IBD share many common risk/contributing factors, including behaviors and toxic exposures that impair immune function. A key component to immune system health is removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.
Smoke and Autoimmunity: The Fire Behind the Disease
2019, Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases
The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune diseases as it may trigger the development of autoantibodies and act on pathogenic mechanisms possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases.
The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation
2017, Gastroenterology
Citation Excerpt :
The final evidence that activation of the vagal anti-inflammatory pathway is a breakthrough for the clinical management of immune-mediated inflammatory diseases will ultimately have to come from clinical trials evaluating specific nicotinic agonists or electrical, pharmacological, or nutritional activation of the CAIP. The effect of nicotine (rectal enemas or transdermal application) has been extensively evaluated in patients with ulcerative colitis, albeit with controversial results.132 Side effects due to interaction with several nAChR subtypes and toxicity issues most likely prevent effective dosing with nicotine.
Although the gastrointestinal tract contains intrinsic neural plexuses that allow a significant degree of independent control over gastrointestinal functions, the central nervous system provides extrinsic neural inputs that modulate, regulate, and integrate these functions. In particular, the vagus nerve provides the parasympathetic innervation to the gastrointestinal tract, coordinating the complex interactions between central and peripheral neural control mechanisms. This review discusses the physiological roles of the afferent (sensory) and motor (efferent) vagus in regulation of appetite, mood, and the immune system, as well as the pathophysiological outcomes of vagus nerve dysfunction resulting in obesity, mood disorders, and inflammation. The therapeutic potential of vagus nerve modulation to attenuate or reverse these pathophysiological outcomes and restore autonomic homeostasis is also discussed.
Smoke and autoimmunity: The fire behind the disease
2016, Autoimmunity Reviews
Citation Excerpt :
Interestingly, no difference was detected in disease onset between female ex-smokers and non-smokers [137,138]. Nicotine has demonstrated variable efficacy in the induction of remission in UC when compared to placebo and conventional therapy, including oral corticosteroids or mesalazine [139–141]. Different application methods have been used, including transdermal nicotine patches, nicotine chewing gum, and a nicotine-based enema [139–141].
The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases.
Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: The Toronto consensus
2015, Gastroenterology
Citation Excerpt :
The negative results of the meta-analysis153 for Escherichia coli Nissle were confirmed in another recent RCT, which found lower rates of clinical remission with adjunctive E coli Nissle compared with placebo.155 Similarly, there are currently insufficient data to support the routine use of nicotine,156 tacrolimus,157 cyclosporine,158,159 phosphatidylcholine,160–162 Trichuris suis,163 or tofacitinib164 in an ambulatory population. Studies on these agents are generally small and characterized by heterogeneity, indirectness, and imprecision, and the quality of evidence was assessed as very low.
The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC.
A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists.
The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti–tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes.
Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

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PharmacotherapyReview articleSystematic Review and Meta-Analysis of the Efficacy and Tolerability of Nicotine Preparations in Active Ulcerative Colitis

Abstract

Background

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Materials and Methods

Results

Discussion

Conclusion

Acknowledgments

Mayo Clin Proc

Best Pract Res Clin Gastroenterol

Int J Immunopharmacol

Clin Gastroenterol Hepatol

Respir Med

The diagnosis and treatment of Crohn's disease and ulcerative colitis

Dtsch Arztebl Int

Recent understanding of IBD pathogenesis: Implications for future therapies

Inflamm Bowel Dis

Study on the correlations among disease activity index and salivary transforming growth factor-beta 1 and nitric oxide in ulcerative colitis patients

Ann N Y Acad Sci

Oxidative stress and pathogenesis of inflammatory bowel disease: An epiphenomenon or the cause?

Dig Dis Sci

Alterations in antioxidant power and levels of epidermal growth factor and nitric oxide in saliva of patients with inflammatory bowel diseases

Dig Dis Sci

Review article: The management of mild to severe acute ulcerative colitis

Aliment Pharmacol Ther

A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis

Dig Dis Sci

Meta-analysis technique confirms the effectiveness of anti-TNF-alpha in the management of active ulcerative colitis when administered in combination with corticosteroids

Med Sci Monit

A meta-analysis of antibiotic therapy for active ulcerative colitis

Dig Dis Sci

Smoking and ulcerative colitis

Br Med J (Clin Res Ed)

Effects of active and passive smoking on disease course of Crohn's disease and ulcerative colitis

Inflamm Bowel Dis

Does nicotine influence cytokine profile and subsequent cell cycling/apoptotic responses in inflammatory bowel disease?

Inflamm Bowel Dis

Pharmacotherapy
Review article
Systematic Review and Meta-Analysis of the Efficacy and Tolerability of Nicotine Preparations in Active Ulcerative Colitis