Are Alcohol Containing Mouthwashes Safe?

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Are alcohol containing IN BRIEF • Dentists need to be aware that there is a RESEARCH hypothetical risk for the development of oral cancer from repeated use of alcohol mouthwashes safe? containing mouthwashes. • The existing evidence to support or refute C .W. de A. Werner1 and R. A. Seymour2 such an association has been the subject of two recent conﬂ icting reviews. • This paper critically evaluates the two reviews and further explores the data on the efﬁ cacy of the addition of alcohol to mouthwashes.

Alcohol (ethanol) is a constituent of many proprietary mouthwashes. Some studies have shown that regular use of such mouthwashes can increase the risk of developing oral cancer. Recently, the evidence has been reviewed by two separate authors. The conclusions from these reviews are conﬂ icting. In this paper, we reconsider the epidemiological evidence linking alcohol containing mouthwashes with an increased risk of oral cancer. The evidence is considered in term of sample size, strength of association, confounding variables and data collection. In addition, clinical studies comparing alcohol versus non-alcohol mouthwashes are evaluated. The evidence suggests that the alcohol component of mouthwashes affords little additional beneﬁ t to the other active ingredients in terms of plaque and gingivitis control. In view of this outcome and the hypothetical risk of oral cancer, it would seem prudent that members of the dental team advise their patients accordingly.

INTRODUCTION reviews and the interpretation of the evi- problems: question formulation, verifi ca- Many proprietary mouthwashes contain dence and hopefully provide readers with tion of latest evidence, critical appraisal and alcohol (ethanol) and in some, the concen- an opinion on the safety or otherwise of value assessment of evidence and clinical tration of ethanol can be as high as 26%.1 alcohol containing mouthwashes. indication. Epidemiological studies have Two recent reviews2,3 have considered different weights on the evidence they pro- whether alcohol containing mouthwashes EPIDEMIOLOGICAL EVIDENCE vide. Additional information from in vivo increase the risk of the development of Epidemiological studies are complex and studies, especially those that investigate oral cancer. The conclusions from these aspects such as sample size, strength of the possible mechanism of alcohol toxic- reviews are confl icting, with one stat- association, confounding variables and ity to the oral mucosa, may complement ing ‘there is now sufficient evidence data collection bias can be rightfully chal- the epidemiological evidence and provide to accept the proposition that alcohol lenged. By contrast, arguments can also be possible benefi ts and risks for clinical use containing mouthwashes contribute to made for the exploitation of specifi c aspects of alcohol containing mouthwashes. All the increase of the development of oral of interest (reporting bias). This is obviously of this information is then evaluated to cancer’,2 while the other states that ‘criti- a controversial topic which can lead to dif- ascertain whether the benefi ts of alcohol cal review of the published data revealed ferent courses of clinical action. Dentistry containing mouthwashes outweigh the risk that a link between mouthwash use, spe- often deals with such issues and dentists of damage to the oral mucosa. cifi cally alcohol containing mouthwash have to make ethical decisions on clinical and oral cancers, is not supported by protocols and material based on less than QUESTION FORMULATION epidemiological evidence.’3 ideal types of scientifi c evidence. Do the clinical benefi ts of an alcohol The reviews were published in 2008 and Our aim is to guide the reader through containing mouthwash in the prevention 2009 and for the most part have quoted the a clear pathway which provides relevant of plaque related oral diseases outweigh same evidence to support their conclusion. information for refl ection and leads to the possible safety issues? The signifi cant In this paper we shall look critically at both an informed decision. Scientifi c evidence safety issue is developing oral squamous will be explored in light of the most recent cell carcinoma. This raises the further

1*Clinical Lecturer in Dental Public Health, 2Professor reviews so that we can empower all mem- question, is alcohol containing mouthwash of Restorative Dentistry, School of Dental Sciences, bers of the dental team with the best clini- a justiﬁ able clinical treatment course to Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4BW cal advice on the use of mouthwashes. encourage patients to take? *Correspondence to: Dr Carlos Werner Email: [email protected] Centre for Evidence Based WEIGHTING EPIDEMIOLOGICAL Online article number E19 Dentistry (CEBD) EVIDENCE Refereed Paper - accepted 29 October 2009 DOI: 10.1038/sj.bdj.2009.1014 The CEBD suggests the following step- In an attempt to answer the questions set ©British Dental Journal 2009; 207: E19 wise approach for dealing with clinical out above via an evidence-based approach,

the epidemiological evidence needs to mouthwashes in the development of oral Table 1 Criteria for quantifying be quantifi ed. The criteria for quantify- cancer. This suggestion is based upon epidemiological evidence ing epidemiological evidence are shown case control studies which examined the Type I A least one good systematic review in Table 1. smoking-alcohol association in general, (including at least one randomised Neither of the review papers can be clas- with no stratifi cation of alcohol contain- clinical trial) sifi ed as systematic reviews as they have ing mouthwash use.4,5 The fi ndings shown Type II At least one good randomised not included a randomised clinical trial in a nation-based alcohol profi le and oral clinical trial (RCT) and do not follow strict reviewing cancer mortality correlation study failed Type III Well designed interventional studies without randomisation protocols. Although this is a criticism, it to indicate that the weight of this associa- should be identifi ed that a RCT to show tion is not as strong as the one from case Type IV Well designed observational studies (case control and cohort studies) an association between oral cancer and control studies.6 Type V Descriptive studies (correlational alcohol containing mouthwash use would The main conclusion of this review studies, cross sectional surveys), be diffi cult to carry out. Oral cancer is a is based upon the evidence provided by case reports, case series, infl uential chronic disease, can take many years to Guha et al.,7 which uses data obtained reports and expert opinion develop and an RCT will require a large from two multi-centred case control stud- follow-up population. ies. Nevertheless, a particularly relevant published in 2001 and a re-analysis of the The possible risk association between fi nding from this study7 curiously was not 1991 data by authors not involved in the alcohol containing mouthwashes and oral mentioned, weakening the review further. original study, followed in 2003.10 cancer is considered from fi ve directly The information related to self reported The 1991 study showed a statistically relevant case control studies (type IV use of more than twice a day mouthwash signifi cant increase in risk of oral cancer evidence). In such studies, subjects were indicated that it increased the chance of associated with regular mouthwash use selected on the basis of whether they do developing oral squamous cell carcinoma and suggested that the risk varied in pro- (cases) or do not have a particular disease by almost six fold (OR 5.86; 95% CI = 2.91, portion to dose, duration and frequency of (controls). Information is then determined 11.77) when compared to those patients mouthwash usage and alcohol concentra- based on the calculated odds ratios (OR). It who reported never having used mouth- tion. The authors concluded that regular is important to differentiate here the fact wash products. use of a mouthwash with high alcohol that risk in another type of study (cohort Lack of more in-depth explanation on content contributes to oral cancer risk. study) is derived from risk ratios (RR), existing evidence of association (or lack The re-analysis of the same data10 divided which are determined by a different math- of association) gives the impression that the cases of oropharyngeal cancers into ematical formulation. The terms OR and the most conclusive epidemiological evi- mucosal (true cases) and non-mucosal RR have been used interchangeably in the dence should be derived solely from the (pseudo cases). The re-analysis concluded literature evaluated and our assumption is most recent published study. The labora- that regular use of a mouthwash was asso- that the calculation appropriate for case tory studies quoted in this review, at best, ciated more strongly with the pseudo cases control studies was carried out, regardless explore the link between alcohol and oral than the true cases in women and there of how it has been reported. cancer as a facilitating factor rather than was a weak dose response relationship Some studies also refer to ‘excess risk’, a causal or risk factor. A more balanced between mouthwash use and oropharyn- which can introduce ambiguity in the ter- view on existing association between geal cancer in pseudo cases. In men, the minology. Excess risk should be defi ned alcohol containing mouthwashes from association between mouthwash use and as the difference between the proportion case control studies would have increased true disease was confi rmed, but considered of subjects in a population with oral can- the credibility of the conclusion from this weak evidence. The re-analysis also com- cer who were exposed to alcohol contain- paper. The review lacked depth of analysis mented that such weak associations might ing mouthwashes and the proportion of on key issues, which brings into question refl ect the use of mouthwashes by ‘smok- subjects with oral cancer who were not the validity of its conclusions. ers’ and ‘drinkers’ to conceal breath odours, exposed. In the context of the literature Review 2: ‘Mouthwash and oral cancer as suggested by previous studies.11–14 One on this subject, ‘excess risk’ seems to refer risk: an update.’3 outcome of the 2003 re-analysis that was to statistically signifi cant risk/odds ratio This second review paper concluded not commented upon was that women beyond 1.0. that alcohol containing mouthwash use classifi ed as ‘true cases’, those who had was not associated with an increased risk started to use mouthwashes before the age LATEST REVIEWS of oral squamous cell cancer. The author of 20 showed a signifi cantly higher risk Two reviews have already been highlighted highlighted the lack of a dose response of oropharyngeal cancer as compared to and these will be considered in further relationship. This review focused on the controls (RR = 2.3). detail. only two papers that specifi cally looked at The 2001 NCI study reported no overall Review 1: ‘The rate of alcohol in oral alcohol containing mouthwashes as a risk increased risk of oral cancer associated carcinogenesis with particular reference to for oral cancer. The studies were conducted with mouthwash use. alcohol containing mouthwashes.’2 by the US National Cancer Institute (NCI) The conclusion of the second review The review initially suggests an and the fi ndings of the fi rst study8 were does not appear to provide a balanced view increased risk from alcohol containing published in 1991. The second study9 was of the analysis of the data. The opposing

Table 2 Comparative studies which have compared alcohol containing and alcohol-free mouthwashes on various oral health parameters

Study Agents Number of Model/Design Duration Outcome subjects

Quirynen et al. *CHX 0.2% + alcohol 16 Randomised, double-blind 11 days with 3 week CHX 0.2% + alcohol, CHX 0.12% + alcohol 200121 CHX 0.12% + alcohol four way crossover study of washout period and CHX 0.12% + CPC were equi-effective CHX 0.12% + sodium experimental gingivitis model between treatments anti-plaque and anti-infl ammatory agents fl uoride No mechanical plaque con- over the 11 day observation period **CPC 0.05% trol for 11 days All three products were signifi cantly superior Plaque scored after 7 and to CHX 0.12% + sodium fl uoride 11 days of treatment

Leyes Borrajo CHX 0.12% + alcohol 96 Parallel, double-blind study 28 days with Both CHX rinses resulted in signiﬁ cant differ- et al. 200222 (11%) to evaluate mouthwashes evaluation at 14 and ences in plaque, gingivitis and papilla bleed- CHX 0.12% no alco- with respect to plaque and 28 days ing index when compared to placebo hol placebo gingival bleeding No differences between the two CHX rinses

Van Strydonck CHX 0.2% + alcohol 40 Single-blind randomised two 3 days No signiﬁ cant differences between treatment et al. 200523 CHX 0.12% no alco- group parallel design using groups with respect to plaque accumulation hol + 0.05% CPC the 3 day plaque develop- Subjects preferred the taste of the non- ment model alcoholic CHX + 0.05% CPC solution

Almerich et al. Hydroalcoholic tri- 30 Double-blind crossover 21 days with a The development of both gingivitis and 200524 closan 0.15% + zinc design using the 21 day 14 day washout plaque indices showed no signiﬁ cant differ- chloride experimental gingivitis model period ences between treatment groups Aqueous triclosan The alcohol containing mouthwash produced 0.15% + zinc chloride a larger number of unwanted oral effects

Arweiler et al.25 CHX 0.2% + alcohol 21 Crossover design x 3 with 4 days The CHX 0.2% with alcohol showed superior- CHX 0.2% with a 0-day washout period ity in the inhibition of plaque regrowth and anti-discolouration between treatment reducing bacterial vitality when compared system, no alcohol to the CHX solution without alcohol, but Placebo containing an anti-discolouration additive

Lorenz et al. CHX 0.2% no alcohol 90 Investigator blind, ran- 21 days with No difference in efﬁ cacy between the three 200626 CHX 0.2% no alco- domised study of parallel examinations at 0, 7, CHX preparations with respect to plaque hol + NaF 0.055% design 14 and 21 days inhibition and gingival inﬂ ammation CHX 0.2% with alcohol

*Chlorhexidine **Cetylpyridinium arguments were not considered. Results The prime metabolite of alcohol is the active mouthwash ingredient incorpo- from previous case control studies12,14,15 acetaldehyde, which is mutagenic and rated into an alcohol-free preparation with were not mentioned and epidemiologi- animal studies have shown this substance alcohol mouthwash, but a full systematic cal evidence from case control studies to be carcinogenic.18 While the bulk of review has yet to be carried out. However, showing no association between alcohol the metabolism of alcohol is carried out relevant studies obtained via a Medline containing mouthwashes and oral cancer in the liver, there is evidence that alcohol search are listed in Table 2 and show that were scant. metabolism could occur in the oral cav- alcohol containing mouthwashes afford ity and that various bacteria in plaque little or no advantage in terms of effi cacy SAFETY AND EFFICACY OF ALCO- can metabolise alcohol to acetaldehyde. over the alcohol-free competitors. HOL CONTAINING MOUTHWASHES This may support the only theory for why The incorporation of ethanol into mouth- patients with poor oral hygiene are at an CONCLUSION washes serves several purposes: it is a increased risk of oral cancer. Two review papers2,3 have reviewed the solvent for other active ingredients, has In addition to the possible risk of evidence suggesting alcohol containing antiseptic properties and acts as a pre- oral cancer, alcohol containing mouth- mouthwashes as a risk for the develop- servative. Ethanol is easy to produce and washes are also reported to have other ment of oral cancer and also cancer of relatively cheap. adverse effects on oral structures and the mucosal surfaces of the upper aero- In vitro studies have demonstrated functions. These include burning mouth, digestive tract. The conclusion from these that alcohol enhances the mucosal pen- drying of the oral mucosa, softening two reviews is confl icting. Both papers etration of the various carcinogens found effects on composite fi lling materials and have been selective in the studies that in tobacco.16 Alcohol on its own does mucosal pain.19,20 they have reviewed on this topic and cause damage to the oral mucosa and The concern over the alcohol content their interpretation of the data. There is includes epithelial atrophy and decease of mouthwashes has led to the develop- evidence to show an association between in basal cell size atrophy with associated ment of alcohol-free preparations. Various use of an alcohol containing mouthwash hyper-regeneration.17 studies have been completed comparing and oral cancer. However, this evidence

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