- Journal Details
- Format
- Journal
- eISSN
- 2719-9509
- First Published
- 01 Jan 1992
- Publication timeframe
- 4 times per year
- Languages
- English
The inflammatory response is a highly regulated and critically balanced process involving a wide variety of cell types, cytokines and biochemical mediators with pleiotropic and redundant functions. Too much inflammation may be damaging to tissues, and even fatal in cases such as sepsis; however, an insufficient inflammatory response can lead to delayed healing or failure to resist infection. For this reason, any compound that is active within inflammatory pathways should be comprehensively understood in terms of its intervention potential and unintended consequences of exposure.
Smoking has long been linked to a heightened inflammatory state and has been shown to exacerbate inflammatory conditions such as rheumatoid arthritis and atherosclerosis (1). However, smoking is also negatively associated with some specific inflammatory-based disorders such as ulcerative colitis and primary sclerosing cholangitis (2). Previous studies have shown that nicotine interacts in inflammatory pathways and may have both pro- and anti-inflammatory actions. This finding is more relevant today than ever before as new nicotine-containing products are entering the marketplace, leaving the additional confounding constituents from cigarette smoke behind. Both the pro- and anti-inflammatory pathways of nicotine, which have been proposed through
The mechanisms behind the pro-inflammatory response to nicotine are thought to arise from stimulation of the sympathetic nervous system. Simplistically, nicotine binds to nicotinic acetylcholinergic receptors (nAChRs) on sympathetic nerve cells, leading to increased noradrenaline (9), stimulation of β3 adrenergic receptors, and release of hematopoietic stem and progenitor cells from bone marrow niches (10). These in turn differentiate into monocytes, which infiltrate sites of existing inflammation and recruit further immune cells, perpetuating chronic inflammation.
Anti-inflammatory mechanisms in response to nicotine are thought to arise through the direct interaction of nicotine with nAChRs on the surface of immune regulatory cells. The α7 sub-type of nAChRs is expressed on a variety of immune cells such as B cells, eosinophils, dendritic cells, monocytes, macrophages, T cells and neutrophils, with the inflammatory response specific to each cell type (8). Nicotine binding to the receptor brings about a conformational change to the receptor structure, opening of ion gated channels and the subsequent flux of calcium, potassium and sodium. This leads to reduced inflammatory cytokine release through the JAK/STAT pathway (the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating the immune system), as well as decreased NF-κB signaling and a reduction in TNF-α production (7).
Although the proposed pro- and anti-inflammatory mechanisms have been demonstrated in animal and cell models, the effects of nicotine in humans are less clear. The aim of this study was to carry out a systematic review of publications investigating the inflammatory effects of nicotine in models of human disease.
The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklists were followed during the design and implementation of this study (Supplementary File 1) (11). Meta-analyses were not conducted. The prevalence of studies with small sample size, the heterogeneity of the reported study designs and the range of inflammatory disorders covered precluded the use of meta-analyses. PubMed, Science Direct and the Cochrane Library databases were searched using the strategies outlined in Table 1. Initial searches were carried out on 5th April 2021. No time restrictions were applied with respect to article inclusion. No restrictions were applied with respect to the quality of the articles included in this review. Reference lists of relevant review articles were screened for additional original articles that did not appear in the searches. JTI internal databases were also searched. A subsequent database screen from 5th April 2021 – 19th November 2021 was carried out to make sure the most up-to-date publications were included before submission.
Search strategies employed to identify published articles relevant to nicotine and inflammation in humans.
| Search engine | Search strategy | Number of papers returned |
|---|---|---|
| PubMed | nicotine [title] AND inflam* [title/abstract] | 490 |
| Science Direct | nicotine [title] AND inflammation [title/abstract/keywords] | 164 |
| Cochrane Library | Searched ‘nicotine’ and manually screened reported hits for relevant inflammation-related systematic reviews and meta-analyses | 1 |
| References from review articles | Relevant review articles were identified from excluded papers (n = 28). The reference lists of these reviews were screened for any further studies of interest | 10 |
| References from JTI database | Internal JTI databases were searched for additional articles of relevance | 10 |
| Additional articles identified from PubMed alerts | Daily email alerts created for nicotine [title/abstract] and searched for articles which meet the inclusion criteria and which were published between 5th April 2021 and 19th November 2021 | 1 |
Articles were considered for inclusion in this review if they were:
Published in English; Published in peer-reviewed journals; Published as a medical case series detailing the clinical treatment of more than one patient using the same nicotine treatment approach; Studies which reported an effect of nicotine in the treatment of a clinical condition; Experimental studies or clinical trials which investigated an effect of nicotine administration in patients with a clinical condition; or Epidemiological studies which investigated an effect of nicotine administration in patients with a clinical condition.
Articles were excluded from this review if they were:
Published in any language other than English; Including data in the form of journal abstracts, conference posters, conference proceedings, book chapters or patents; Medical case reports; Experimental studies or clinical trials which investigated an effect of nicotine in patients with a clinical condition where nicotine administration was achieved exclusively through smoking of conventional cigarettes, whether or not the experimental study or clinical trial included one or more treatment arm(s) utilizing denicotinized (“nicotine-free”) conventional cigarettes; Review articles containing no original data; or Studies testing drugs acting as nicotinic receptor agonists.
As outlined in Table 1, searches across PubMed and Science Direct returned a total of 844 publications. Duplicates were removed (n = 252), leaving 592 papers to screen for relevance. Studies containing “mouse”/“mice”/“rat” or “
Figure 1
A total of 16 original studies carried out in humans and relating to nicotine and inflammation were identified. After a search of the Cochrane Library, one additional systematic review containing a meta-analysis was added (12), bringing the total to 17 studies to analyze. Twenty-eight relevant review articles were identified from the excluded papers, the references of which were screened for any further studies of interest, returning 10 additional papers. Screening of JTI internal databases added 10 studies. An additional article relating to pulmonary sarcoidosis was identified between 5th April 2021 and 19th November 2021. The final list of 38 studies were categorized into disease areas (digestive diseases, atherosclerosis, skin and healing, pain and infection, pulmonary sarcoidosis, and multiple sclerosis) and detailed below.
The 19 studies reviewed in this section are listed in Supplementary File 3.
Crohn’s disease is one of the two major non-specific inflammatory bowel diseases with the other being ulcerative colitis. Unlike ulcerative colitis, Crohn’s disease can affect any segment of the gastrointestinal tract. Symptoms typically include abdominal pain, diarrhea, fever and weight loss. It is believed to result from a combination of environmental, immune, and bacterial factors in genetically susceptible individuals.
A single open non-randomized clinical study is available on the potential effects of nicotine administration on Crohn’s disease (13). Ten patients with active Crohn’s disease were recruited to participate in the study. The patients comprised seven men and three women and had a mean age of 52 years. Seven were former smokers and three were non-smokers. The patients were given nicotine enemas (containing 6 mg of nicotine) each day for four weeks in an open study in addition to their conventional treatment(s) which continued unchanged throughout the study. At the beginning and end of the trial, a Crohn’s disease activity index (CDAI) score was calculated, sigmoidoscopy was performed, and hematological inflammatory markers were measured. The mean CDAI score decreased from 202 to 153 for the ten patients; the score was reduced in six patients, unchanged in three, and increased in one. Frequency of bowel movements decreased in eight patients and the sigmoidoscopy grade was reduced in seven. The authors concluded that “
In a study investigating chronic inflammatory disease in Swedish construction workers, exclusive use of Swedish moist snuff (snus) was not associated with either an increase or decrease in risk of Crohn’s disease compared to never users of tobacco (relative risk (RR): 1.0; 95 % CI: 0.8–1.4) (14). This suggests that nicotine is not protective against this particular inflammatory disease; however, it is not likely to be responsible for the increased risk observed in smokers either (13). It should be noted that risk of developing disease is not equivalent to treatment of incident disease. Therefore, nicotine may still have pro- or anti-inflammatory properties in a treatment context without protecting against inflammatory disease onset. There were also some important limitations to the study. For example, although the participants were followed-up for a long period (1978–1993) tobacco use was only recorded at one time-point. Therefore, it is impossible to analyze any effect of change in tobacco usage such as quitting after the data was collected.
Ulcerative colitis (UC) has been defined as “
In their study of Swedish construction workers (also included in other sections of this review), C
After positive results from a pilot study using nicotine patches in 10 UC patients in conjunction with mesalazine (17), another trial comparing the efficacy of nicotine with prednisone treatment was carried out (18). Fifteen participants were randomly assigned to receive nicotine or prednisone whilst continuing with mesalazine therapy. Results demonstrated that even though short-term use of corticosteroids seemed to be more effective than nicotine therapy, a lower incidence of relapse was observed in those patients who received transdermal nicotine patches compared to those patients who received corticosteroid treatment. The authors suggested that nicotine therapy may be a suitable alternative in patients who cannot tolerate corticosteroids (18).
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An oral formulation known as ‘Nicolon’ was designed to deliver sustained levels of nicotine directly to the ileum and colon over a six-hour period as an alternative to nicotine enemas, nicotine chewing gum or transdermal nicotine patches (21). An initial investigation into its safety and tolerance in patients with inflammatory bowel diseases reported it to be a safe potential treatment but also noted that there was considerable variation in tolerance between patients (22). Although more participants were asymptomatic at the end of the study, compared to baseline, no conclusions regarding the efficacy of nicotine for the treatment of inflammatory bowel disease can be drawn from this preliminary study as no placebo control participants were included. The researchers stated that “
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There are two meta-analyses currently available which have attempted to assess the efficacy of nicotine for achieving remission in UC patients.
The first meta-analysis, published as a Cochrane Review, investigated the efficacy of transdermal nicotine administration for induction of remission in UC (24). The authors only included randomized, controlled clinical studies in which patients with active mild to moderate UC were randomly allocated to receive transdermal nicotine patches (between 15 and 25 mg per day total dose), placebo or another pharmaceutical treatment (corticosteroids or mesalamine). The authors of the Cochrane Review identified nine studies, five of which met their inclusion criteria (18, 25,26,27,28) and four of which were excluded due to use of nicotine chewing gum (29), nicotine enemas (30, 31) or as a result of the fact that they investigated maintenance of remission rather than induction of remission (32). Four of these nine studies were excluded from this current systematic review as they did not meet the inclusion criteria (26, 28, 30, 31). A meta-analysis of two trials (25, 27) in which 71 patients were randomized to receive nicotine and 70 to receive placebo showed a statistically significant benefit for nicotine treatment. After four to six weeks of treatment, 19 of 71 patients treated with transdermal nicotine were in clinical remission compared to 9 of 70 treated with placebo (odds ratio of 2.56; 95% CI of 1.02 to 6.45). A further 29 of the 71 patients assigned to receive nicotine showed signs of improvement or remission compared to 14 of the 70 patients assigned to receive placebo (odds ratio of 2.72; 95% CI of 1.28 to 5.81). For patients with left sided colitis the odds ratio for improvement or remission was 2.31 (95% CI of 1.05 to 5.10). A meta-analysis of the three other trials where transdermal nicotine was compared to standard medical therapy (18, 26, 28) found no significant benefit for nicotine. After four to six weeks of standard therapy (oral prednisone or mesalamine), 34 of 63 patients were in clinical or sigmoidoscopic remission compared to 33 of 66 patients treated with transdermal nicotine (odds ratio of 0.77; 95% CI of 0.37 to 1.60). A meta-analysis of all five studies which included 137 patients treated with transdermal nicotine and 133 patients treated with a placebo or standard therapy demonstrated no statistically significant benefit of nicotine therapy (odds ratio of 1.23; 95% CI of 0.71 to 2.14). Patients treated with transdermal nicotine were significantly more likely to withdraw due to adverse events (odds ratio of 5.82; 95% CI of 1.66 to 20.47) and were significantly more likely to suffer from an adverse event (odds ratio of 3.54; 95% CI of 2.07 to 6.08), than patients treated with placebo or standard medical therapy. The authors of the Cochrane Review concluded that overall “
The excluded study by T
In the excluded study by L
The excluded study by S
The second meta-analysis investigated the efficacy and tolerability of nicotine preparations in inducing remission of UC (35). The authors included three placebo-controlled trials representing 233 patients with UC and two randomized controlled trials that compared nicotine to corticosteroids (prednisolone/prednisone) in 81 patients with UC (18, 25, 26, 27, 31). Two of these studies were excluded from this current systematic review as they did not meet the inclusion criteria (26, 31). The RR for clinical remission after nicotine administration compared to placebo was 1.40 (95% CI of 0.63 to 3.12; p > 0.05). The RR for experiencing an adverse event after nicotine administration compared to placebo was 1.95 (95% CI of 1.38 to 2.78; p < 0.001) and the RR for withdrawal from a study after nicotine administration compared to placebo was 3.44 (95% CI of 0.71 to 16.71; p > 0.05). The RR for clinical remission after nicotine administration compared to corticosteroid administration was 0.74 (95% CI of 0.50 to 1.09; p > 0.05) and the RR for withdrawal from a study after nicotine administration compared to corticosteroid administration was 2.28 (95% CI of 0.76 to 6.83; p > 0.05). The authors of the meta-analysis concluded that “
Twelve patients with Primary Sclerosing Cholangitis (PSC) were recruited into a randomized, double-blind, placebo-controlled study (36). Of the 12 patients, 11 were male and had a median age of 37 years. Six suffered from UC which was reported to have been in remission in all cases. All patients had been treated with ursodeoxycholic acid (UDCA; one of the key treatments currently prescribed for PSC) for at least six months without normalization of alkaline phosphatase, aspartate aminotransferase or alanine aminotransferase levels. The patients were randomized to receive either a transdermal nicotine patch (Nicorette®) or an identical placebo patch for eight weeks. After a wash-out period of four weeks, the patients were switched to the opposite treatment for a further eight weeks. The initial nicotine dose was 5 mg per day which was increased by 5 mg every three days until a maintenance dose of 15 mg was achieved. The patches were applied each day from 7am until 11pm. One patient developed
Post-operative ileus is an inflammatory response triggered by the manipulation of the intestines during abdominal surgery. A double-blind randomized control trial was carried out to assess the safety and efficacy of nicotine chewing gum in patients undergoing colorectal surgery, compared to chewing gum without nicotine. Forty patients were recruited, with 20 receiving the nicotine-containing gum and 20 receiving the non-nicotine-containing gum two hours preoperatively and three times per day postoperatively. The primary outcome was the post-operative time to first passage of feces and tolerance of solid food for at least 24 hours. Serum IL-6, C-reactive protein (CRP) and white blood cells count were also measured. No significant differences were observed in the recovery of the two groups. The authors suggest that this may be due to the low concentration of nicotine gum used in the study (2-mg Nicorette®), or that the patients were non-compliant, as they self-administered the gum during their hospital stay. No biochemical measurements were assessed to check patient participation (38).
The six studies reviewed in this section are listed in Supplementary File 3.
The acute effects of nicotine on vascular function have been extensively investigated, whereby the mechanisms predominantly manifest through stimulation of the sympathetic nervous system and activation of the hypophysis adrenal axis leading to increased plasma levels of adrenocorticotropic hormone (ACH), cortisol and adrenaline (39). The development of atherosclerosis, however, is a chronic process. Although definitive pathways relating nicotine to atherosclerosis have not been established, one proposed mechanism is through the recruitment of inflammatory cells via release of adhesion molecules (6). Evidence for this mechanism has been extensively provided though
M
In another study in 23 young, healthy smokers, 24 h smoking abstinence with nicotine replacement therapy (NRT) did not result in a change to markers of inflammation such as C-reactive protein, monocyte chemo-attractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) or myeloperoxidase (MPO), or changes in flow mediated dilation (FMD). Co-administration of nicotine replacement therapy and γ-tocopherol-rich mixture of tocopherols (antioxidants) resulted in a significant decrease in FMD, suggesting that the mechanism was driven by oxidative stress, rather than inflammation in this study. The authors suggest that smokers who quit using NRT may limit any improvement of vascular endothelial function (42).
Contrary to this finding, serum levels of the inflammatory markers sICAM-1 and interleukin (IL)-1β decreased after three months when healthy male smokers transitioned to nicotine patches. Improvements were found in arterial stiffness; however, no change was observed in endothelial function. The authors concluded “
A randomized, double-blinded, crossover trial in 17 healthy occasional users of tobacco products was carried out to investigate acute vascular and pulmonary effects of nicotine-containing e-liquids. After 30 puffs of an e-cigarette containing either nicotine or no nicotine, no difference was found in the exhaled marker of pulmonary inflammation, fractional exhaled nitric oxide. Although acute vascular response was measured, markers of vascular inflammation were not (44). These results repeated a finding from a previous study from the same group, where there was no difference in fractional exhaled nitric oxide or serum inflammatory-associated micro-vesicles found after 10 puffs of an e-cigarette containing nicotine. In this previous clinical trial, the authors did find a significant increase in endothelial progenitor cells (EPC) circulating after e-cigarette exposure; however, it is unclear if this increase related to an inflammatory response (45). In fact, the premise that increased circulating EPC levels indicated a pathological response was challenged by a letter to the editor pointing out that a reduction in circulating EPCs is usually associated with chronic diseases such as hyperlipidemia, hypertension, obesity and diabetes. Longer term interventions such as exercise and green tea consumption have also been shown to increase circulating EPCs (46). Overall, the relationship between EPC release into the bloodstream and inflammation or atherosclerosis is far from clear, especially considering the differences in acute and chronic responses (47).
The five studies reviewed in this section are summarized in Supplementary File 3.
In a small study of ten participants, nicotine patches were applied before the skin was exposed to different irritants. The authors found that nicotine suppressed the inflammatory response to topical sodium lauryl sulphate and UV-B irradiation. No difference in cutaneous blood flow was observed (48). The authors point out that despite the therapeutic potential of transdermal nicotine in the context of inflammatory skin conditions, application in non-smokers could be limited due to the adverse events typically experienced in those not desensitized to nicotine.
A Japanese medical team demonstrated that transdermal nicotine patches were effective in the treatment of eosinophilic pustular folliculitis. Of the eight patients recruited, six showed significant clinical improvement; two were unchanged (49).
A systematic review highlighted six studies where smokers were randomized either to receive transdermal nicotine patches or complete nicotine abstinence post wound infliction (either surgical or as a controlled procedure). Different wound healing mechanisms seemed to be affected both positively and negatively in the studies, making overall interpretation difficult. The authors concluded that “
Behçet’s disease is a rare and poorly understood systemic vasculitis that results in inflammation of the blood vessels and tissues. The disease is characterized by periods of remission and exacerbation with symptoms including genital and oral aphthae.
Two non-smoking patients with Behçet’s disease (among a larger group of ten patients) were given either a transdermal nicotine patch (14 mg per 24 h) or nicotine chewing gum (2 mg) (51). Use of a nicotine transdermal nicotine patch or the nicotine chewing gum resulted in complete resolution of oral lesions within a three-week period. It is not reported which patients were administered which product. In the first patient, who initially exhibited three oral lesions, a further three oral lesions developed once nicotine administration was stopped. No information is provided for the second patient. In a second study, five former smokers with active mucocutaneous lesions which were not responsive to standard pharmacological treatments, were treated with transdermal nicotine patches (52). The patients were administered 14 mg transdermal nicotine patches on a daily basis for six months. Four out of the five patients experienced complete resolution of mucocutaneous lesions within the six-month treatment period. Symptoms returned once nicotine administration was stopped in these individuals. One patient experienced no benefit from nicotine administration; she re-started smoking through her own choice after the six-month treatment period had ended and experienced complete resolution of oral aphthae and partial resolution of genital ulcers. The authors concluded that “
The four studies reviewed in this section are listed in Supplementary File 3.
Twenty healthy non-smokers were randomized and blinded to receive either a nicotine patch or a placebo patch during their recovery from third molar tooth removal. During the post-operative period, the participants who had received the nicotine patches were administered significantly fewer analgesic tablets compared to the placebo control group (mean 2.35
Infection with gram negative bacteria, such as
A Cochrane Review investigated the effect of transdermal or intranasal nicotine administration on post-operative pain, opioid analgesic use and opioid-related adverse events (12). The meta-analysis identified nine randomized, placebo-controlled studies including a total of 666 patients. Nicotine was estimated to reduce post-operative pain scores at 24 h post-surgery by a small, but statistically significant, amount compared with placebo (mean difference of 0.88 on a 0 to 10 scale; 95% CI of −1.58 to −0.18; eight studies). Statistical heterogeneity was substantial and not adequately explained by stratification of studies according to type of surgical procedure, smoking status of the patient, method of nicotine administration or timing of nicotine administration. Nicotine increased the risk of post-operative nausea to a statistically significant extent (relative risk of 1.24; 95% CI of 1.03 to 1.50; seven studies). However, it did not increase the risk of vomiting (risk difference of 0.03; 95% CI of 0.04 to 0.09; seven studies). The authors of the meta-analysis concluded that “
The three studies reviewed in this section are listed in Supplementary File 3.
Pulmonary sarcoidosis is a systemic granulomatous disease of unknown cause which affects young to middle-aged adults. It is characterized by the development of non-necrotizing granulomatous inflammation in the absence of identifiable infectious, autoimmune or environmental causes (56). The disease typically involves the lungs, frequently leading to impaired exercise tolerance and associated shortness of breath. The majority of patients with active pulmonary sarcoidosis complain of overwhelming fatigue which often persists despite immune-modulating drugs typically used to treat sarcoidosis (56).
A pilot study noted that treatment of symptomatic pulmonary sarcoidosis patients (n = 7) with transdermal nicotine patches over a twelve-week period, in addition to their existing medications, resulted in an immunological phenotype which was highly comparable to that of asymptomatic patients (57). The daily nicotine dose was increased from 7 mg to 14 mg to 21 mg at one-week intervals from the start of the study. The authors concluded that their results “
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A study protocol for a randomized, double-blind, placebo-controlled clinical trial investigating the effect of transdermal nicotine patch administration as a treatment approach for pulmonary sarcoidosis has been published (56). The primary objective outcome of the study was reported as being an improvement in forced vital capacity at study week 26 from baseline measurements. Results from this clinical trial have recently been published and indicated that treatment with transdermal nicotine patches (21 mg daily) over a 26-week period was associated with a clinically significant, approximate 2.1% (70 mL) improvement in forced vital capacity (FVC) from baseline to 26 weeks (58). FVC decreased by a similar amount (2.2%) in the placebo group with a net increase of 140 mL (95% confidence intervals of 10 mL to 260 mL) when comparing nicotine and placebo treatment groups at 26 weeks. No improvements were observed in lung texture scores, fatigue assessment scores, St George’s Respiratory Questionnaire Score or the Sarcoidosis Assessment Tool. The study was, however, underpowered to show the expected treatment effect for nicotine treatment, and despite randomization there were large baseline differences in FVC.
The three studies reviewed in this section are listed in Supplementary File 3.
In their 2009 study, H
In contrast to this finding, a study investigating chronic inflammatory disease in Swedish construction workers, reported that exclusive use of Swedish snus was associated with a marginally increased risk of MS compared to never tobacco users (relative risk of 1.8; 95 % CI of 1.1 to 2.9) (14). The authors could not offer an explanation for their findings, although they did point out that they had limited information about other risk factors for disease in their participants and the result was of “
UC dominated the literature related to digestive diseases, contributing 14 studies out of the 19 studies analyzed in this section. Each of the studies varied greatly in terms of participant number, study design and study endpoints. Two meta-analyses were carried out. M
Studies investigating nicotine in relation to clinical improvements in patients with UC seem to more consistently suggest a beneficial role of nicotine, especially when used in conjunction with traditional therapies such as mesalazine and corticosteroids (17, 18, 34). As L
In contrast to the relatively large body of evidence surrounding the use of nicotine as a treatment in patients with UC, very few studies have been published in relation to other digestive diseases. I
Two studies investigated the use of nicotine as a treatment for primary sclerosing cholangitis, one using transdermal treatment (36) and the other oral treatment (37). V
Finally, in this section a single study assessed whether nicotine could reduce the inflammatory response in the gut post-surgery. Nicotine gum was used as the mode of delivery; however, no overall benefit was seen in the 40 participants who took part.
Six papers were analyzed in relation to the potential effects of nicotine on atherosclerosis via inflammatory pathways. All the studies recruited current smokers and therefore the results are heavily confounded. Three of the studies investigated acute cardiovascular responses after use of electronic cigarettes as their mode of nicotine delivery, measuring markers of endothelial function such as endothelial progenitor cells and extracellular vesicles (41, 44, 45). Unfortunately, the full characteristics of the measured biomarkers are not known, so it is impossible to conclude whether the effects observed are pro- or anti-inflammatory in nature.
Two studies found no effect of nicotine replacement therapies on inflammatory markers associated with atherosclerotic formation (40, 42). One study found a beneficial effect of nicotine replacement therapies on markers of vascular inflammation compared to continued smoking. This is not necessarily surprising, given the relationship between smoking and cardiovascular disease (61); however, as there was no comparator group of never smokers, it is impossible to state that the decrease in inflammatory markers observed was as a result of nicotine administration or as a result of the removal of other pro-inflammatory agents found in cigarette smoke (43).
Overall, the data surrounding the relationship between nicotine and atherosclerosis is inconclusive. Mechanisms have been proposed via
Five studies addressed the effect of nicotine on inflammatory conditions of the skin, although these were spread across a range of conditions. Two very small studies in participants with Behçet’s disease both described positive clinical outcomes when nicotine was administered via transdermal patch or gum (51, 52). In two other studies that used transdermal patch administration, an anti-inflammatory effect of nicotine was shown in response to dermal irritation and to symptoms of eosinophilic pustular folliculitis (48, 49). A systematic review of the effect of nicotine on wound healing, however, showed mixed results. Analysis of six studies suggested that nicotine may have an anti-inflammatory effect on the wound healing process, whilst maintaining other proliferative and angiogenic mechanisms. Overall, no beneficial or detrimental effect was recognized (50).
Although there was an anti-inflammatory effect of nicotine observed in all five of the studies included in this section, the small study sizes and confounding smoking histories of the participants mean that the evidence is insufficient to support an anti-inflammatory effect of nicotine on human skin conditions or healing.
Three small studies (maximum participant number = 20) were reviewed in relation to pain and infection. One study related to post-operative pain management and reported positive outcomes of nicotine administration on both pain and oedema. Two studies used a LPS administration as a model of systemic inflammation; the first showed no effect of nicotine patch application on relieving any of the associated symptoms; the other showed a faster resolution of inflammation in the participants who received nicotine patch treatment. A fourth study reviewed in this section was a Cochrane systematic review and meta-analysis, which analyzed nine studies with a total of 666 participants and concluded that there was a small but positive effect of nicotine on post-operative pain. Although these results support an anti-inflammatory role for nicotine in the resolution of pain and infection, it should be noted that adverse effects of nicotine were repeatedly cited. Nicotine administration in never smokers can lead to symptoms of mild nicotine adverse effects, such as nausea, vomiting and increased heart rate, which unless managed with careful dosing, is likely to nullify the positive effects of nicotine over the use of other established analgesics.
Three studies regarding pulmonary sarcoidosis were identified. Two addressed treatment of active symptoms with transdermal nicotine patches (57, 58) and the other investigated the risk of developing pulmonary sarcoidosis in users of nicotine-containing products (14). As in the studies that suggested improvement of inflammatory skin conditions with nicotine application, significant clinical improvement was observed in the small group of patients treated with nicotine for their pulmonary sarcoidosis. No effect on the risk of developing pulmonary sarcoidosis was seen in the 37,459 cohort participants who exclusively used snus. The results of these three separate studies cannot be compared as the risk of developing disease is a distinct process from treatment of symptoms when disease has already manifested.
Three studies were analyzed in relation to nicotine use and risk of developing MS, all of which were carried out in Swedish cohorts and all investigated snus as the mode of nicotine delivery (14, 59, 60). Despite the similarities in the studies, conflicting results were found. H
The role of nicotine in the development of MS remains unclear. No studies exist in humans where nicotine is administered as a potential treatment of MS symptoms, and therefore its role in the inflammatory pathways of this disease remains unknown.
Although multiple databases were searched, there is the possibility that some studies, especially those only included on clinical trial databases, may have been missed from the analysis. This review was not pre-registered and a protocol was not prepared. Many of the studies included in this systematic review were small, pilot trials carried out in a convenience sample of participants with no placebo controls. For this reason, most are considered of low quality and are open to a high chance of recruitment bias. Therefore, significant caution should be used in their interpretation. Studies such as these can only be regarded as preliminary evidence as the improvement in the reported clinical condition may be due to a pharmaceutical or environmental variable not reported by the patient(s) to the authors rather than being a direct result of nicotine administration. In addition, there is a possibility that publication bias may be present in the reported studies. Furthermore, since inflammation is an orchestrated dynamic process with various phases involving a wide variety of cell types, cytokines, and biochemical mediators with pleiotropic and redundant functions it is possible that nicotine may differentially modulate these mechanisms leading to variable apical effects on different types of inflammatory processes. For instance, one potential effect is that nicotine increased corticosteroids release which decreased the severity of the inflammatory conditions. In addition, the action of the α7 nicotinic acetylcholine receptor involved in the “cholinergic anti-inflammatory pathway” may also contribute. On the other hand, proinflammatory effects mediated through other nicotinic receptors in cells involved in inflammation may counteract those anti-inflammatory mechanisms.
Randomized, double-blind, placebo-controlled clinical studies are required for each of these disease states to determine whether or not nicotine administration does have a pro- or anti-inflammatory effect allowing statistically significant differences between treatment arms to be determined.
The role of nicotine and inflammation in the progression of COVID-19 in humans was eventually considered. Unfortunately, we found the publications list returned from our search essentially not complying with our manuscript inclusion and exclusion criteria, and thus have not addressed any additional content regarding issues related to animal models of COVID-19 human disease, as this subject falls beyond the scope of the paper.
This literature review analyzes detailed clinical scientific articles which have investigated whether controlled administration of nicotine can result in a pro- or anti-inflammatory effect in individuals with inflammatory-based diseases or conditions. There was weak evidence for an anti-inflammatory effect of nicotine when used to treat some dermatological conditions. However, the studies included were not able to offer strong enough data to draw a definitive conclusion. For other diseases, no consistent evidence of a pro- or anti-inflammatory effect of nicotine was observed in patients with atherosclerosis, ulcerative colitis, Crohn’s disease, primary sclerosing cholangitis, postoperative ileus, pain, infection, Behçet’s disease or other dermatological conditions, pulmonary sarcoidosis or multiple sclerosis.
Figure 1
Search strategies employed to identify published articles relevant to nicotine and inflammation in humans.
| Search engine | Search strategy | Number of papers returned |
|---|---|---|
| PubMed | nicotine [title] AND inflam* [title/abstract] |
490 |
| Science Direct | nicotine [title] AND inflammation [title/abstract/keywords] | 164 |
| Cochrane Library | Searched ‘nicotine’ and manually screened reported hits for relevant inflammation-related systematic reviews and meta-analyses | 1 |
| References from review articles | Relevant review articles were identified from excluded papers (n = 28). The reference lists of these reviews were screened for any further studies of interest | 10 |
| References from JTI database | Internal JTI databases were searched for additional articles of relevance | 10 |
| Additional articles identified from PubMed alerts | Daily email alerts created for nicotine [title/abstract] and searched for articles which meet the inclusion criteria and which were published between 5th April 2021 and 19th November 2021 | 1 |