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Head and neck cancers are largely caused by smoking, alcohol and HPV virus (oral sex).Possible is there a (small) familial factor in this large (altough) retrospective trial, so not conclusive on this familial effect.Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE studyA large study in France confirms thisConclusion:To our knowledge, the ICARE study is the first population-based case–control study in France and one of the largest in the world which investigates the role of risk factors other than tobacco and alcohol consumption in the occurrence of oral cavity cancer. Strengths of this study include large sample size allowing us to perform analyses by subsite, and detailed data about family history of cancer and personal medical history.BackgroundThe aim of this study was to evaluate the role of family history of cancer and personal history of other medical conditions in the aetiology of the oral cavity cancer in FranceMethodsWe used data from 689 cases of cavity squamous cell carcinoma and 3481 controls included in a population-based case–control study, the ICARE study. Odds-ratios (ORs) associated with family history of cancer and personal medical conditions and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression and were adjusted for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking.ResultsPersonal history of oral candidiasis was related to a significantly increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). History of head and neck cancers among the first-degree relatives was associated with an OR of 1.9 (95% CI 1.2-2.8). The risk increased with the number of first-degree relatives with head and neck cancer.ConclusionA family history of head and neck cancer is a marker of an increased risk of oral cavity cancer and should be taken into account to target prevention efforts and screening. Further studies are needed to clarify the association between oral cavity cancer and personal history of candidiasis.Peer Review reportsBackgroundOral cavity cancer (International Classification of Diseases 10th revision (ICD-10) codes C00-C08 [1]) is an important public health burden with an annual worldwide incidence estimated at approximately 263,000 cases, and mortality at 127,000 [2]. Among developed countries, France has the highest age-standardized incidence rate for males (7.6/100,000) and one of the highest for females (1.5/100,000) [3]. As is the case for the other sites of upper aerodigestive tract (UADT), tobacco and alcohol consumption are the main risk factors for oral cavity cancer [4, 5].Besides the role of human papilloma viruses (HPV) 16 and 18 in the aetiology of UADT cancers, few other conditions such as herpetic infection [6–11], candidiasis [6, 10, 11], warts [6, 9–11], and gastro-oesophageal reflux [7] have been investigated. The results of the epidemiological studies on the role of these medical conditions in the occurrence of UADT cancers are contradictory and the underlying mechanisms are not complete elucidated.Other risk factors, such as genetic polymorphism in genes involved in the metabolism of tobacco and alcohol carcinogens and DNA repair seems to play a role in the development of UADT cancers [12–19]. Few epidemiological studies considered the risk of UADT cancers in relatives of subjects with cancer history [20–26]. Familial clustering of UADT cancers may indicate that genetic factors play a role in the process of carcinogenesis, but may also reflect a tendency of relatives to have similar behaviour towards tobacco and alcohol. Limited data are available on the combined effect of family history, and tobacco and alcohol consumption [20, 23, 26]. The literature is contrasted about whether the cancer risk varies according to UADT subsite, gender, type of affected relative (parents, siblings), and their cancer site.The present work aimed to investigate the role of family history of cancer and personal medical history in the aetiology of oral cavity cancer in France using data from a large case–control study, the ICARE study.MethodsICARE studyThe ICARE study (Investigation of occupational and environmental CAuses of REspiratory cancers) is a multicentre population-based case–control study on lung and upper aerodigestive tract cancers carried out from 2001 to 2007 in 10 French administrative areas (“départements”) covered by a general cancer registry. This study was set up to explore the role of lifestyle, environmental and occupational risk factors in lung and UADT cancers. The study design has been described in details elsewhere [27].Briefly, all newly diagnosed primary oral cavity, pharynx, larynx, sinusal cavities, trachea and lung cancers were selected. Only histologically confirmed cases aged 75 or younger at interview, identified between 2001 and 2007, and residing in one of the 10 départements, were eligible. Clinical and anatomo-pathology reports were reviewed to determine topography and histological type of the tumours according to the International Classification of Diseases for Oncology [28]. All histological types were included.Controls were selected from the general population by random digit dialling [29]. The controls were frequency-matched to the cases by age, gender and area of residence (“département”). Additional stratification ensured that controls were representative of the population of the “département” in terms of socio-economic status based on the last job held.Present analysisThe present analysis included all ICARE controls and only the cases with oral cavity cancer (ICD-10 codes C01-C06).Among the 1316 oral cavity cancer cases identified as eligible, 196 could not be reached, 81 were deceased and 71 were too sick to be interviewed. Of the 968 cases who were contacted, 176 refused to participate and 792 (81.8%) answered the questionnaire. We focused only on the cases with squamous cell carcinoma (772 subjects, 97.5% of all cases with oral cavity cancer).Of 4673 eligible controls, 4411 were contacted, and 3555 (80.6%) agreed to participate.Data collectionTrained interviewers administered a detailed standardised questionnaire during face-to-face interviews. If the subject was too sick to be interviewed, a shortened version of the questionnaire was used to interview him or a next-of-kin. Among the 772 subjects with squamous cell carcinoma of the oral cavity, 689 (89.2%) filled a complete questionnaire and 83 (10.8%) a shortened questionnaire. Among controls, 3481 (97.9%) filled a complete questionnaire and 74 a shortened questionnaire (2.1%). As the shortened version of the questionnaire did not contain information about family history of cancer and medical conditions, the present analysis was based on 689 cases with squamous cell carcinoma and 3481 controls, all with a complete questionnaire.The complete questionnaire consisted of the following items: socio-demographic characteristics (age, gender, birth country, education level, marital status), residential history, personal medical history, family history of cancer, detailed tobacco and alcohol consumption (quantity, duration, type of product, age at starting, time since cessation), non-alcoholic beverage consumption (coffee, tea), anthropometric variables (height, weight at interview, two years before and at age 30), detailed lifelong job history and occupational exposures.To ascertain personal medical history, study participants were asked if, throughout their lives, they had ever had (“yes, no, or don’t know”) any of the following diseases: tuberculosis, chronic bronchitis, asthma, recurrent rhinitis, nasal polyps, recurrent nose bleeds, recurrent sinusitis, gastro-oesophageal reflux (heartburn or regurgitation), herpes, candidiasis, and warts. If the answer was “yes”, the subjects were asked to specify the age at first occurrence, the treatment and if the diagnosis was made by a doctor. Subjects reporting having ever had herpes, candidiasis or warts were asked to specify the location: lip and genitals for herpes, oral cavity and genitals for candidiasis, and hands, feet and head and neck for warts.To ascertain the family history of cancer, subjects were first asked to give the year of birth of their biological mother and father, and of their full brothers or sisters (“brother or sister having the same mother and the same father than you”). Then, they were asked for each of these relatives if she/he had ever had a cancer (“yes, no or don’t know”). If the answer was “yes”, the subjects were asked to specify the age at cancer diagnosis and if possible the type of cancer. No verification of the cancer diagnosis in the relatives was performed.Statistical analysisWe used unconditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (95% CI). All p-values were derived from two-sided statistical tests.All logistic regression models controlled for age (≤ 50, 51–59, 60–69, ≥ 70 years), gender, area of residence, education level (primary or less, vocational secondary, general secondary and university), BMI two years before the interview (categorical, according to the classification of the World Health Organization [30]: < 18.5, 18.5-24.9, 25.0-29.9, ≥ 30 kg/m2). Previous analyses of our data showed that the variables that best characterize the association between tobacco and alcohol consumption and oral cancer risk were smoking status, smoking duration, daily quantity of tobacco smoked and daily quantity of alcohol drinking [31]. To control for smoking, we used smoking status (never, current, former), average daily quantity of tobacco smoked (1–19, 20–39, ≥ 40 grams), and duration of smoking (1–30, 31–40, > 40 years) [32]. Average daily quantity of alcohol drinking in quartiles (never, < 0.6, 0.6-2.0, 2.1-4.5, > 4.5 standard glasses) was included in the models to adjust for alcohol drinking. The quantity of pure alcohol contained in a standard glass (15 cl of wine, 30 cl of beer, 5 cl of spirits, 10 cl of aperitif, and 30 cl of cider) is the same for each type of alcoholic beverage.We analysed the risk of oral cavity cancer related to the personal medical history using two variables: all medical conditions self-reported by the subjects and medical conditions reportedly diagnosed by a doctor. The date of interview was used as the date of reference for both cases and controls. This date was close to the date of diagnosis of the cases since cases were interviewed on average within three months of diagnosis.The family history of cancer was evaluated separately for mothers, fathers, brothers and sisters, and then among all first-degree relatives taken together. We analysed the risk of oral cavity cancer related to the cancer site among relatives: all sites together, head and neck (including oral cavity, pharynx, larynx, nasal cavity and sinuses) and non-head and neck cancers. Because a high number of cancers in family members were reported non-specifically as “cancer of the head and neck”, we chose to group the locations of head and neck cancers to reduce potential inaccurate reporting of cancer subsites. We nevertheless performed some analyses for family history of specific head and neck cancer sites among all first-degree relatives.We also conducted analyses stratified by tobacco and alcohol consumption. We also performed the same analyses using a more restricted definition of the oral cavity excluding base of tongue (C01), lingual tonsils (C02.4), soft palate (C05.1) and uvula (C05.2), since these subsites are often included in the oropharynx. In addition, seven subsites (base of the tongue, mobile tongue, floor of the mouth, gums, soft palate, hard palate, and other parts of the oral cavity) were compared for family history of cancer and personal history of other medical conditions using unconditional polytomous logistic regression.Statistical analyses were conducted using STATA software version 10.0 (StataCorp, Texas, USA).ResultsAmong the 689 cases, the most common tumour location was floor of the mouth (188 cases, 27.3%), followed by mobile tongue (162 cases, 23.5%) and base of the tongue (130 cases, 18.9%). Less frequent tumour locations were: other parts of the oral cavity (81 cases, 11.7%), soft palate (74 cases, 10.7%), gums (37 cases, 5.4%), and hard palate (17 cases, 2.5%). The analysis using the restricted definition of oral cavity involved 485 cases.The main characteristics of cases and controls are presented in Table 1.Table 1 Main characteristics of cases and controlsFull size tableMen represented more than two-thirds of subjects in both cases and controls. Cases were younger (mean age around 57 years) than controls (mean age around 59 years) (p < 0.001).Compared with controls, cases had a lower education level (p < 0.001), a higher consumption of tobacco (p < 0.001) and alcohol (p < 0.001), and a lower BMI two years before the interview (p < 0.001).Personal medical conditionsStatistical analysis showed significant positive associations between the risk of oral cavity cancer (C01-C06) and chronic bronchitis (OR 1.7, 95% CI 1.2-2.4) (Table 2). Histories of tuberculosis and candidiasis overall were associated with an increased risk of oral cavity cancer (ORs 1.6), but the results did not reach statistical significance. Among candidiasis locations, oral candidiasis was associated with an increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). Significant inverse relations were observed between the risk of oral cavity cancer and recurrent rhinitis (OR 0.6, 95% CI 0.4-0.9), nasal polyps (OR 0.3, 95% CI 0.1-0.9), and gastro-oesophageal reflux (OR 0.5, 95% CI 0.4-0.7). Herpetic lesions were not related to the risk of oral cavity cancer, regardless of the location of the herpes. The risks associated with a history of skin warts were reduced, but the results did not reach statistical significanceTable 2 Risks of oral cavity cancer associated with personal medical conditionsFull size tableBecause high prevalence of oropharyngeal candidiasis has been described in subjects with head and neck cancer undergoing radio/chemotherapy [33, 34], we also conducted analysis after excluding subjects declaring candidiasis at the time of interview or at the time of diagnosis of another cancer; the association between oral cavity cancer risk and oral candidiasis remained practically unchanged (OR 6.0, 95% CI 2.2-16.4). Oral candidiasis may also constitute an early manifestation of the cancerous disease. When we excluded all subjects reporting a history of oral candidiasis near the current cancer (up to two years before the cancer diagnosis), the association between oral cavity cancer and oral candidiasis remained significant (OR 3.7, CI 95% 1.3-10.1).We calculated the ORs for oral candidiasis in strata of tobacco and alcohol consumption. The OR was slightly higher in ever smokers (OR 5.6, 95% CI 2.0-15.2) than in never smokers (OR 4.3, 95% CI 0.5-41.7), but the interaction between tobacco smoking and oral candidiasis was not significant (p-value for interaction = 0.14). Oral candidiasis was associated with an elevated risk of oral cavity cancer in drinkers of more than 2 glasses/day (OR 3.9, 95% CI 1.0-14.8) but not in drinkers of 2 glasses/day or less (OR 1.1, 95% CI 0.2-23.8), although the ORs were not statistically different (p-value for interaction = 0.50).When the analysis was restricted to medical conditions that the subjects reported as diagnosed by a doctor, similar results were observed, except for the association between bronchitis and oral cavity cancer which became weaker and non-significant (OR 1.2, 95% CI 0.9-1.6) (data not shown).Family history of cancerThe associations between family history of cancer and risk of oral cavity cancer are presented in Table 3.Table 3 Risks of oral cavity cancer associated with family history of cancer among first-degree relativesFull size tableHistory of cancer in general, and of head and neck cancer in particular, among fathers, were associated with a slightly elevated risk of oral cavity cancer, but the results were not statistically significant (OR 1.3, 95% CI 0.9-1.6, and 1.5, 95% CI 0.9-2.4, respectively).History of head and neck cancer among mothers was significantly associated with an elevated risk of oral cavity cancer (OR 5.2, 95% CI 1.2-23.9). This OR was higher than that observed for fathers. When cancer history among siblings was analysed, after adjustment for the number of sisters and brothers, we observed a significant association between the risk of oral cavity cancer and history of cancer of any type (OR 1.4, 95% CI 1.1-1.9). History of head and neck cancer among siblings was associated with an increased risk of oral cavity cancer (OR 2.3, 95% CI 1.2-4.2). Analysis by type of sibling showed a significantly increased risk only among subjects having brothers with a history of head and neck cancer (OR 2.6, 95% CI 1.2-5.8); history of head and neck cancer among sisters was not significantly associated with an increased risk of oral cavity cancer (OR 1.7, 95% CI 0.6-4.2).When we analysed the relationship between cancer history among all first-degree relatives and oral cavity cancer risk, we observed significant association for history of head and neck cancer (OR 1.9, 95% CI 1.2-2.8). A family history of any type of cancer slightly increased the risk of oral cavity cancer, but the results were not statistically significant (OR 1.2, 95% CI 0.9-1.5). The risk associated with first-degree relatives’ history of cancer (any type and head and neck) increased with the number of affected relatives.Analysis by type of head and neck cancer in first-degree relatives showed significantly increased risks of oral cavity cancer in subjects with family history of oral cavity cancer (OR 3.5, 95% CI 1.1-11.2) and of “head and neck cancer” (not specified) (OR 1.8, 95% CI 1.1-2.9). A family history of pharyngeal, laryngeal, and sinonasal cancer was associated with non-significantly elevated risks of oral cavity cancer (OR 4.6, 95% CI 0.5-44.8 for history of pharyngeal cancer; 1.6, 95% CI 0.6-4.4 for history of laryngeal cancer; and 1.7, 95% CI 0.3-8.8 for history of sinonasal cancer). However, few subjects reported a specific location of head and neck cancer in first degree relatives (26 oral cavity, 5 pharynx, 35 larynx, and 11 nasal cavity/sinuses cancer).Analysis stratified by gender of first-degree relatives showed that history of head and neck cancer among female relatives (mothers and sisters) was not significantly associated with the risk of oral cavity cancer (OR 2.3, 95% CI 0.9-5.4), although the result was borderline significant. Conversely, history of head and neck cancer in male relatives (fathers and brothers) was significantly associated with the risk of oral cavity cancer (OR 1.9, 95% CI 1.2-3.3). However, these ORs did not differ significantly (p-value of test of comparison of ORs = 0.91).We found a stronger association between the risk of oral cavity cancer and family history of head and neck cancer in subjects aged 45 or more (OR 2.3, 95% CI 1.5-3.4) compared to subjects aged less than 45 (OR 1.3, 95% CI 0.3-6.7), although the ORs were not statistically different (p-value for interaction = 0.46).Analysis by cancer site among first-degree relatives (Table 4) showed elevated ORs among subjects having a family history of lung, oesophagus, cervix and corpus uteri, brain and nervous system cancer, but the results were not statistically significant (OR 1.4, 95% CI 0.9-1.9; 1.5, 95% CI 0.7-3.3; 1.7, 95% CI 0.9-3.1; 2.0, 95% CI 0.9-4.8 respectively).Table 4 Odds ratios for oral cavity cancer risk related to family history of selected cancers in first-degree relativesFull size tableWhen we stratified by tobacco smoking and/or alcohol drinking (Table 5), significantly increased risks of oral cavity cancer related to family history of any type of cancer were observed only in smokers and/or moderate to heavy drinkers. Significantly elevated risks of oral cavity cancer associated with family history of head and neck cancer were seen for both never and ever smokers and for light and moderate to heavy drinkers. However, the increase in risk was small and not significant for never smokers who were also light drinkers.Table 5 Risks of oral cavity cancer related to family history of cancer in first-degree relatives stratified by tobacco smoking and alcohol drinkingFull size tableAnalyses restricted to intraoral cavityWhen the analyses were limited to intraoral cavity (C02.0-C02.3, C02.8, C02.9, C03, C04, C05.0, C05.8, C05.9, C06), the results were similar to that observed for oral cavity globally (C01-C06). Thus, family history of UADT cancer among first-degree relatives was associated with an OR of 1.7 (95% CI 1.1-2.7), personal history of oral candidiasis with an OR of 4.9 (95% CI 1.8-13.3), gastro-oesophageal reflux with an OR of 0.6 (95% CI 0.4-0.8), recurrent rhinitis with an OR of 0.6 (95% CI 0.4-0.9), and nasal polyps with an OR of 0.3 (95% CI 0.1-0.9).Analyses by subsiteWe assessed the risk of oral cavity cancer by anatomical site of the oral cavity (base of tongue, mobile tongue, gum, floor of mouth, hard and soft palate, and other parts of oral cavity) for personal medical conditions and for family history of cancer using a polytomous regression. We did not find any difference between subsites for any variable of interest (tests of comparison of odds ratios non-significant) (data not shown).DiscussionTo our knowledge, the ICARE study is the first population-based case–control study in France and one of the largest in the world which investigates the role of risk factors other than tobacco and alcohol consumption in the occurrence of oral cavity cancer. Strengths of this study include large sample size allowing us to perform analyses by subsite, and detailed data about family history of cancer and personal medical history.The ICARE study was conducted in collaboration with the cancer registries, allowing us to recruit cancer cases in all healthcare establishments in the selected areas. The control group was population-based and common for both pathologies (lung and UADT cancers), which explains the significantly different distribution of age and area of residence between oral cavity cancer cases and controls. However, the large number of subjects in each category allowed for satisfactory adjustment for these variables.The results of the epidemiological studies are contrasted concerning the role of candidiasis in the occurrence of oral cavity cancer, Thus, history of oral candidiasis was associated with an increased risk of oral cavity and oropharyngeal cancer in one study [11], with a reduced risk of oral cavity cancer in another study [7], whereas other authors found no association [6]. Our results have shown that personal history of oral candidiasis was associated with an elevated risk of oral cavity cancer. The increase in cancer risk with oral candidiasis may be explained by the production of endogenous nitrosamines by Candida albicans[35]. These nitrosamines act on the normal epithelium leading to oral dysplasia and further development of oral carcinoma. Nevertheless, some authors suggested that Candida albicans have only an indirect role and that the possibility of their involvement exist in conjunction with other etiological factors such as tobacco smoking [36]. In our study, the risk of oral cavity cancer associated with history of candidiasis was slightly higher in smokers than in never smokers, but the ORs were not significantly different. Other studies showed that Candida albicans may metabolize ethanol into its carcinogenic metabolite, acetaldehyde and, accordingly, candidiasis may be associated with elevated acetaldehyde levels in the oral cavity [37, 38]. Consistent with this mechanism, we found a significantly elevated risk of oral cavity cancer associated with history of candidiasis in moderate to heavy drinkers but not in light drinkers. However, the interaction of oral candidiasis with alcohol drinking was not statistically significant. Also, chronic infections, specifically chronic hyperplastic candidiasis, may trigger cell proliferation, inhibit apoptosis, interfere with cellular signalling mechanisms and up-regulate tumour promoters [39, 40]. In our study only 14 cases and 80 controls reported prior candidiasis and the results should be confirmed by other studies, especially with medical conditions validated by a doctor.In agreement with previous studies [7, 8, 11], we did not find a significant association between the risk of oral cavity cancer and history of herpetic infection. Conversely, only one case–control study [10] found an increased risk of oral cavity and oropharynx cancer associated with this infection and two case–control studies [6, 9] found a decreased risk.Cutaneous warts are caused by different types of HPV, notably 2, 4, 7 and 57, whereas genital warts are caused mostly by HPV types 6 and 11 [41]. Three studies [6, 8, 11], like ours, did not find any association between history of warts (any location) and the risk of oral cavity cancer, whereas one study found a reduced risk of UADT cancer associated with feet, genital and head and neck warts [7].We found an inverse association between the oral cavity cancer risk and history of rhinitis and nasal polyps. These pathologies often have an allergic origin, and several studies found a decreased risk of head and neck cancer associated with a history of allergies [42–45]. The inverse association between allergies and cancer may be explained by an overactive immune function in allergic subjects that effectively detects and eradicates malignant cells, toxins or pathogens from the body [46, 47]. However, we did not find any association with the history of asthma, another allergies-related condition.We found also an inverse association between oral cavity cancer risk and history of gastro-oesophageal reflux but we cannot point to any specific mechanism. The possibility that this result is due to the chance may not be ruled out. Unlike our results, a recent case–control study [7] did not find any association between oral cavity cancer risk and gastro-oesophageal reflux.After controlling for main confounding factors, we observed a higher risk of oral cavity cancer among subjects having first-degree relatives with head and neck cancer history, compared to subjects without such a family history. The risk increased with the number of affected relatives. On the other hand we did not find a significant relationship between the risk of oral cavity cancer and family history of non-head and neck cancers. Several studies [20, 22, 23, 26] reported similar results.Early age of onset may be a feature of hereditary forms of cancer. Higher family risks for many cancers were found when the cancer subjects were diagnosed at an early age [48, 49]. Concerning the association between the risk of oral cancer and family history of head and neck cancer, no clear pattern emerges from epidemiological studies: some of them found a stronger association in younger subjects compared to older subjects [20, 21, 23], others found a contrary result [22, 26], but the differences in risk with age of onset were never significant. Similarly, in our study the interaction of family history of head and neck cancer with age was not significant, although the OR was somewhat higher in older subjects.Familial clustering of cancer cases could be explained by genetic polymorphism in genes involved in the metabolism of tobacco and alcohol carcinogens and DNA repair [12–19], but may also reflect a tendency of relatives to have similar behaviour concerning alcohol and tobacco.In our study, associations between oral cavity cancer risk and family history of cancer were observed among smokers and/or drinkers of >2 glasses/day only. Conversely, an increased risk of oral cavity cancer associated with a family history of head and neck cancer was also observed in non-smokers and light drinkers, but the risk increased with the exposure. Our results are similar to those of other studies on oral/pharyngeal or head and neck cancer [20, 23, 26].The differential ability of subjects to metabolize carcinogens when exposure to tobacco and/or alcohol occurs may explain the higher risk of oral cavity cancer observed in our study among smokers and drinkers having a family history of UADT cancer. Nevertheless, we did not observe an increased risk of oral cavity cancer in subjects having a family history of other cancers related to smoking and/or alcohol drinking (e.g. lung, oesophagus, liver, pancreas), suggesting that other genetic factors might explain these findings.When the analyses were limited to intraoral cavity (C02.0-C02.3, C02.8, C02.9, C03, C04, C05.0, C05.8, C05.9, C06), excluding the sites usually attached to oropharynx (C01, C02.4, C05.1, C05.2), the results were similar to that observed for oral cavity C01-C06. We did not find any difference between subsites base of the tongue, mobile tongue, gums, floor of the mouth, soft palate, hard palate, and other parts of the mouth for any variable of interest.Some limitations of our study can be discussed. The subjects self-reported their own medical history and family history of cancer. Thereby, recall bias could not be ruled out and it is possible that the cases had a higher motivation to recall their personal and family medical history than the controls. Nevertheless, two studies have shown that subjects in case–control studies are able to report accurately family history of common types of cancer among first-degree relatives, with little observable recall bias [50, 51]. In addition, family history of cancer sites other than head and neck was not associated with an increased risk of oral cavity cancer in this study, suggesting that no major recall bias concerning cancer in general has affected our results.With regards to oral candidiasis, a possible explanation would be that cases with oral cancer are more prone to recall previous oral lesions than controls. However, no association was found with labial herpes, another oral condition, suggesting that differential recall between cases and controls is unlikely to explain our results. Moreover, when we limited the medical conditions to those reportedly diagnosed by a doctor, the results were similar. Medical treatments were also collected and those reported for candidiasis were consistent with this pathology. So, we think that misclassification of candidiasis is unlikely to explain our results.Information about other known risk factors for oral cavity cancer such as diet, human papilloma virus (HPV) or dental health was not collected, and residual confounding cannot be excluded. Nevertheless, no association between diet, HPV infection or dental health and family history of cancer has ever been shown in the literature. Also, the possibility of residual confounding for the main risk factors may not be ruled out.We have no way to assess whether cases included in our study differed according to past medical conditions and family history of cancer from cases that could not be included. Nevertheless, the distribution of included cases by age, gender and cancer subsite was very similar to that of all oral cancer cases diagnosed in France [52], suggesting that no major selection bias occurred. We excluded from analysis all subjects with shortened questionnaires because information on medical conditions and family history of cancer was not available. However, these subjects were comparable in age, gender, and tobacco and alcohol consumption to subjects with complete questionnaires.ConclusionThis study showed that family history of head and neck cancer is related to an increased risk of oral cavity cancer, and suggested an association with personal history of oral candidiasis. From a public health point of view, these factors should be taken into account to target prevention efforts and screening.References1.World Health Organization: International Classification of Diseases 10th Revision. 2007, Geneva: World Health OrganizationGoogle Scholar2.Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. 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Oral Oncol. 2011, 47: 302-307. 10.1016/j.oraloncology.2011.02.013.ArticlePubMedGoogle ScholarPre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/560/prepubDownload referencesAcknowledgementsICARE study was supported by the French National Research Agency (ANR), the French Agency for Food, Environmental and Occupational Health and Safety (ANSES), the French Institute for Public Health Surveillance (InVS), the Foundation for Medical Research (FRM), the Foundation of France, the Agency for Research on Cancer (ARC), the French Ministry of Work, Solidarity and Public Function (Direction Générale du Travail), and the Ministry of Health (Direction Générale de la Santé). L. Radoï was supported by the French National Cancer Institute (InCA), grant n° 2009–349 for this work.Author informationAffiliationsCentre for Research in Epidemiology and Population Health (CESP), Inserm U1018, Epidemiology of Occupational and Social Determinants of Health Team, F-94807, Villejuif, FranceLoredana Radoï, Sophie Paget-Bailly, Diane Cyr, Gwenn Menvielle, Annie Schmaus, Matthieu Carton & Danièle LuceUniversity Versailles St-Quentin, F-78035, Versailles, FranceLoredana Radoï, Sophie Paget-Bailly, Diane Cyr, Gwenn Menvielle, Annie Schmaus, Matthieu Carton & Danièle LuceCentre for research in Epidemiology and Population Health (CESP), Inserm U1018, Environmental Epidemiology of Cancer Team, F-94807, Villejuif, FranceFlorence Guida, Sylvie Cénée, Marie Sanchez & Isabelle StückerUniversity Paris-Sud, UMRS 1018, F-94807, Villejuif, FranceFlorence Guida, Sylvie Cénée, Marie Sanchez & Isabelle StückerCalvados Cancer Registry, F-1400, Caen, FranceAnne-Valérie GuizardHérault Cancer Registry, F-34298, Montpellier, FranceBrigitte TrétarreInserm U1085, Irset, Faculté de Médecine, Campus de Fouillole, BP 145, 97154, Pointe-à-Pitre, Guadeloupe French West IndiesDanièle LuceCorresponding authorCorrespondence to Danièle Luce.Additional informationCompeting interestThe authors declare that they have no conflict of interest.Authors’ contributionsDL and LR conceived and designed the current study and drafted the manuscript; LR and DC analyzed the data; DL and IS are the principal investigators of ICARE, conceived the study, designed the questionnaire, and coordinated the original collection of the data. AS, DC, SC, MS, AVG and BT contributed to data collection and quality control; SPB, FG, GM, MC contributed to the statistical analysis. All authors participated to data interpretation and critical revision of the manuscript. All authors read and approved the final manuscript.Rights and permissionsReprints and PermissionsAbout this articleCite this articleRadoï, L., Paget-Bailly, S., Guida, F. et al. Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE study. BMC Cancer 13, 560 (2013). Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE studyDownload citationReceived18 January 2013Accepted03 November 2013Published28 November 2013http://DOIhttps://doi.org/10.1186/1471-2407-13-560Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkKeywordsFamily historyMedical conditionsOral cavity cancerRisk factorsCase–control studyDownload PDFBMC CancerISSN: 1471-2407Contact usSubmission enquiries: Access here and click Contact UsGeneral enquiries: [email protected] more on our blogsReceive BMC newslettersManage article alertsLanguage editing for authorsScientific editing for authorsPoliciesAccessibilityPress centerSupport and ContactLeave feedbackCareersFollow BMCBMC Twitter pageBMC Facebook pageBMC Weibo pageBy using this website, you agree to our Terms and Conditions, Privacy statement and Cookies policy. 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Health dysgenics is a major issue facing the modern word since natural selection has been eliminated.Health dysgenics: a very brief reviewWoodley reminded me of the dysgenics for health outcomes by linking me to a study about the increasing rates of cancer. I had first reached this conclusion back in 2005 when I realized what it means for evolution that we essentially keep almost everyone alive despite their genetic defects. The problem is quite simple: mutations accumulate and mutations have net negative impact on the functioning of the body. Most of the genome appears not to be relevant for anything (‘junk’ / non-coding), so mutations in these areas don’t do anything. Of mutations that hit other areas, many of them are synonymous, and thus usually have no effect. Mutations in areas that matter generally have negative effects. Why? The human body is an intricate machine and it’s easier to fuck it up when you make random changes to the blueprint/recipe than improving upon it. So, basically, one has to get rid of the harmful mutations that happen and this is done via death and mate choice (preference for healthy partners), collectively: purifying selection. Humans still have mate choice and some natural selection, but the natural selection has been starkly reduced in strength since before medicine that actually works (i.e. not bloodletting etc.), and thus, by mutation-selection balance, the rates of genetic disorders and genetic dispositions for disease should increase. In other words, mutation load for disease in general should increase. Does it?It’s not quite so simple to answer because of various confounders. The most important ones are improved diagnosing (we have better equipment to spot disorders now) and population aging (older people are more sick). Population aging can be avoided by compared same-aged samples measured in different times. Diagnosis changes are much harder to deal with, and one has to look for data where the diagnostic criteria either did not change for the period in question or changed in a way we can adjust for.There’s also another issue. For a number of decades, we have been using a clever form of selection: prenatal screening (and preconception screening in some groups), which obviously selects against mutational load for the screened diseases. However, most of this testing is for aneuplodies (mostly Down’s) which usually results in sterile offspring and is thus irrelevant for mutational load for disease (because it is not contributed to the gene pool). However, some of the testing is for specific diseases, usually ones that happen to be quite prevalent in some racial group: Tay-Sachs etc. in Ashkenazis, Charlevoix-Saguenay etc. in Quebecians, Aspartylglucosaminuria etc. in Finns etc. One obviously cannot look for evidence of dysgenics for these diseases as the selection against them distorts the picture.The studiesI didn’t do a thorough search. In fact, these were the first two studies I found plus the one Michael found. The point of this review is to bring the idea to your mind, not prove it conclusively with an exhaustive review.CancerCancer incidence increasing globally: The role of relaxed natural selectionCancer incidence increase has multiple aetiologies. Mutant alleles accumulation in populations may be one of them due to strong heritability of many cancers. The opportunity for the operation of natural selection has decreased in the past ~150 years because of reduction of mortality and fertility. Mutation-selection balance may have been disturbed in this process and genes providing background for some cancers may have been accumulating in human gene pools. Worldwide, based on the WHO statistics for 173 countries the index of the opportunity for selection is strongly inversely correlated with cancer incidence in peoples aged 0-49 and in people of all ages. This relationship remains significant when GDP, life expectancy of older people (e50), obesity, physical inactivity, smoking and urbanization are kept statistically constant for fifteen (15) out of twenty-seven (27) individual cancers incidence rates. Twelve (12) cancers which are not correlated to relaxed natural selection after considering the six potential confounders are largely attributable to external causes like viruses and toxins. Ratios of the average cancer incidence rates of the 10 countries with highest opportunities for selection to the average cancer incidence rates of the 10 countries with lowest opportunities for selection are 2.3 (all cancers at all ages), 2.4 (all cancers in 0-49 years age group), 5.7 (average ratios of strongly genetically based cancers) and 2.1 (average ratios of cancers with less genetic background).Coeliac diseaseIncreasing prevalence of coeliac disease over timeBackground  The number of coeliac disease diagnoses has increased in the recent past and according to screening studies, the total prevalence of the disorder is around 1%.Aim  To establish whether the increased number of coeliac disease cases reflects a true rise in disease frequency.Methods  The total prevalence of coeliac disease was determined in two population-based samples representing the Finnish adult population in 1978–80 and 2000–01 and comprising 8000 and 8028 individuals, respectively. Both clinically–diagnosed coeliac disease patients and previously unrecognized cases identified by serum endomysial antibodies were taken into account.Results  Only two (clinical prevalence of 0.03%) patients had been diagnosed on clinical grounds in 1978–80, in contrast to 32 (0.52%) in 2000–01. The prevalence of earlier unrecognized cases increased statistically significantly from 1.03% to 1.47% during the same period. This yields a total prevalence of coeliac disease of 1.05% in 1978–80 and 1.99% in 2000–01.Conclusions  The total prevalence of coeliac disease seems to have doubled in Finland during the last two decades, and the increase cannot be attributed to the better detection rate. The environmental factors responsible for the increasing prevalence of the disorder are issues for further studies.Arthritis and other rheumatic conditionsEstimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part IIObjectiveTo provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions.MethodsThe National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition.ResultsWe estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self-reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4–10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months.ConclusionEstimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.Does it matter?Yes. Treating diseases, especially rare diseases, is extremely expensive. As such, for countries with public health-care, there’s a very strong economic argument in favor of health eugenics via editing or embryo/gamete selection.Socio-economic burden of rare diseases: A systematic review of cost of illness evidenceCost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project (“Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe”) we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n=29) and Haemophilia (n=22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect.Economic burden of common variable immunodeficiency: annual cost of diseaseObjectives: In the context of the unknown economic burden imposed by primary immunodeficiency diseases, in this study, we sought to calculate the costs associated with the most prevalent symptomatic disease, common variable immunodeficiency (CVID). Methods: Direct, indirect and intangible costs were recorded for diagnosed CVID patients. Hidden Markov model was used to evaluate different disease-related factors and Monte Carlo method for estimation of uncertainty intervals. Results: The total estimated cost of diagnosed CVID is US$274,200/patient annually and early diagnosis of the disease can save US$6500. Hospital admission cost (US$25,000/patient) accounts for the most important expenditure parameter before diagnosis, but medication cost (US$40,600/patients) was the main factor after diagnosis primarily due to monthly administration of immunoglobulin. Conclusion: The greatest cost-determining factor in our study was the cost of treatment, spent mostly on immunoglobulin replacement therapy of the patients. It was also observed that CVID patients’ costs are reduced after diagnosis due to appropriate management.There’s also lots of these kinds of studies, the second paper summarizes a number of them for this cluster of diseases:A Spanish study reported that mean annual treatment costs for children and adult PID patients were e 6520 and 17,427, respectively. Total treatment costs spent on IVIg therapy proce- dures in Spain were approximately e 91.8 million annually, of which 94% consisted of drug cost [27] . Another study conducted in Belgium estimated the annual costs for IVIg therapy on an average to be e 12,550 [28].Galli et al . [29] assessed the economic impact associated with method of treatment of PID patients in Italy. Regarding the monthly treatment costs associated with the treatment of a typ- ical 20 kg child, the study reported antibiotic therapy to cost of e 58,000, Ig cost of e 468,000 and patients ’ hospitalizations cost of e 300,000 for IVIg method.Haddad et al . [26] conducted a cost analysis study in the French setting and reported the total monthly treatment cost for a patient using hospital-based 20 g IVIg to be e 1192.19, in which approximately 57% of the total treatment cost was spent on Ig preparation and 39% on hospital admission charges. Another investigation on French PID patients demonstrated the yearly cost of hospital-based IVIg to be e 26,880 per patient [30] .Other cost analysis studies comparing the direct cost impacts of Ig replacement methods reported annual per patient costs for hospital-based IVIg were US$14,124 in Sweden [31] , e 31,027 and e 17,329 for adults and children in Germany, respectively [32] , and e 18,600 in UK [33] . On the basis of one Canadian study, we found that total annual base case expenditure for hospital-based IVIg therapy of children and adults were $14,721 and $23,037 (in Canadian dollars), respectively. The annual per patient cost of Ig was 75%, the cost of physician and nurse care and hospital admission was 16% and the cost of time lost because of treatment was 8% [34]The Genomic Health Of Ancient Hominins?Davide Piffer reminded me that there is study of ancient genomes’ health, which finds that:The genomes of ancient humans, Neandertals, and Denisovans contain many alleles that influence disease risks. Using genotypes at 3180 disease-associated loci, we estimated the disease burden of 147 ancient genomes. After correcting for missing data, genetic risk scores were generated for nine disease categories and the set of all combined diseases. These genetic risk scores were used to examine the effects of different types of subsistence, geography, and sample age on the number of risk alleles in each ancient genome. On a broad scale, hereditary disease risks are similar for ancient hominins and modern-day humans, and the GRS percentiles of ancient individuals span the full range of what is observed in present day individuals. In addition, there is evidence that ancient pastoralists may have had healthier genomes than hunter-gatherers and agriculturalists. We also observed a temporal trend whereby genomes from the recent past are more likely to be healthier than genomes from the deep past. This calls into question the idea that modern lifestyles have caused genetic load to increase over time. Focusing on individual genomes, we find that the overall genomic health of the Altai Neandertal is worse than 97% of present day humans and that Otzi the Tyrolean Iceman had a genetic predisposition to gastrointestinal and cardiovascular diseases. As demonstrated by this work, ancient genomes afford us new opportunities to diagnose past human health, which has previously been limited by the quality and completeness of remains.The authors themselves note the connection to the proposed recent dysgenic selection:The genomic health of ancient individuals appears to have improved over time (Figure 3B). This calls into question the idea that genetic load has been increasing in human populations (Lynch 2016). However, there exists a perplexing pattern: ancient individuals who lived within the last few thousand years have healthier genomes, on average, than present day humans. This deviation from the observed temporal trend of improved genomic health opens up the possibility that deleterious mutations have accumulated in human genomes in the recent past. The data presented here do not provide adequate information to address this hypothesis, which we leave for future follow-up studies.In other words, we expect the recent pattern to look something like this:Mutations occasionally pop up in any population. Since the vast majority are adverse, stable fertility for an entire population still means deterioration. The maintenance of the quality of the population requires not just a stable population at all levels but the active weeding out of the unfit. The results of the slacking of selection in our modern world is apparent in disease. Today, almost 1% of children born have a mutation for a common genetic disorder. Due to carriers of bad genes surviving and new mutations, it’s estimated that the rates of hemophilia, cystic fibrosis and phenylketonuria are increasing every generation by 26%, 120%, and 300% respectively. Humanity requires that we save children that can be saved but breeding for those with diseased genes needs to be restricted. Lynn hints that better genetic screening and selective abortion can offset some of the consequences of modern medicine.

ABSTRACT:Objective:To study and understand the side effects, efficiency and outcomes of Gabapentin, Intravenous Lidocaine and their combination for the reduction of postoperative pain after the total knee replacement.Study design:After understanding the objective, a case-control study was done and all the side effects, as well as benefits, were observed after ensuring the safety of all the patients.Place and Duration of study:The study was performed in Tertiary Care Hospital and the duration for the study was six months.Methodology:Sixty-six patients were included in the study. Group A, B and C were given Gabapentin, lidocaine and their combination respectively. For the data analysis procedure, Statistical Package for Social Science Software of version 22 was used. Chi-square test was used to collect categorical data and p-value less than 0.05 was considered significant.Results:Age, weight, gender and duration of surgery were some factors that did not differ significantly in all groups. Relief of pain was observed in all three groups within 24 hours. Blurred vision, uncontrolled eye movement and dizziness were observed in patients of group B. Whereas in Group A, vomiting and change of body temperature were observed.Conclusion:To reduce the postoperative pain by analgesic effect, intravenous lidocaine as well as Gabapentin, both are effective, safe and significant but have some side effects too. Also, their combination reduces the pain, but the side effects are decreased by its use. For overcoming postoperative nausea and vomiting, Gabapentin is the most suitable drug.Keywords: anaesthesia, Gabapentin, intravenous lidocaine, postoperative pain, surgerytotal knee replacementINTRODUCTION:End-stage Osteoarthritis, rheumatic arthritis, trauma, and other joint disorders can cause severe pain, restrict mobility and physical inactiveness. These joint destructive disorders are usually common in older and mid-aged adults. Inflammation of the synovial membrane and damage to knee cartilage are some of the consequences of these disorders. To have a pain-free life and increased mobility, total knee replacement, also known as total knee arthroplasty is recommended in these severe conditions (1)(2).In the United States, osteoarthritis is the major cause of total knee replacement. The damaged cartilage and the bone are removed from that point where femur and tibia meet on the knee joint. Then these damaged parts of the knee joint are replaced by metal and plastic artificial parts in the surgery so that, you can move and bend your knee without any pain. Postoperative pain is usually associated with this procedure. 60% of the patients experience chronic pain whereas 30% face moderate pain. Not all the patients have the courage to have this surgery, because of the fear of postoperative pain. Moreover, thromboembolism risk and early ambulation are consequences of postoperative pain. So, the need for the management of postoperative pain after the knee replacement is obvious (3)(4).Opioid analgesics are mostly used to reduce the postoperative pain, but they are also associated with high morbidity rate and hospital costs. Not only this, but it also comes with some severe side effects including development of tolerance, constipation, pruritus and respiratory depression. Several analgesics and anaesthetic medications are used to overcome the pain. But, every medicine, along with its benefits, has some side effects (5). In this research, we will discuss two medicines, Gabapentin and Intravenous Lidocaine, their efficiency and side effects as a treatment for the postoperative pain.Gabapentin (1-aminomethyl cyclohexane acetic acid) is an anticonvulsant drug that is usually used to treat migraine and other several neuropathic pain syndromes (6)(7). It is associated with alpha 2-delta subunit of voltage-gated calcium channels. Some of the recent studies have proved that Gabapentin can be used as an analgesic agent for postoperative pain after the total knee replacement. It is not an analgesic drug, but the opioid requirement can be decreased by its use as well as it can improve analgesia. This non-epileptic drug has central and peripheral antalgic activity (6). Some research has shown that Gabapentin shows its effect within 24 hours of the surgery and also preoperative anxiety, postoperative nausea, vomiting, and pruritus can be treated by its use. Fatigue, dizziness, uncoordinated movement, tiredness, blurred vision, uncontrolled or repetitive eye movements and tremor can be some of the side effects of Gabapentin (8) (7). Another side effect on the drug is sleepiness but this side effect can be considered beneficial because it can soothe the patient and provide them with some rest after the surgery. This route of administration for this medication is oral.Lidocaine is an anaesthetic drug, also known as lignocaine, that is used to numb a specific area of the body to reduce the pain (9)(10). The chemical formula of the drug is 2-(Diethylamino)-N-(2,6-dimethyl phenyl) acetamide. In 1943, the medication was first used for pain as a result of a burn. peripheral nociceptors sensitization and central hyperexcitability, both the activities are supported by lidocaine. It can also play a role as an anti-inflammatory and anti-hyper analgesic drug. Intravenous lidocaine has some benefits that the other local anaesthetics lack including the perioperative infusion. It has been observed that postoperative pain is reduced after the introduction of lidocaine in the dorsum of the foot. The half-life of the drug is increased by more than 5.5 times after it is introduced. Other benefits include a lesser opioid requirement, first flatus in a very short time, reduce hospital stay and decrease nausea. Whereas the common side effects are dizziness, vomiting, feeling hot or cold, confusion, ringing in your ears and blurred vision. Apart from the separate use of these two drugs, some studies have analysed that the combination of both the drugs can give the best results and reduce the pain after the surgery. (11)(12).The time duration during which the Gabapentin's peak plasma level is obtained is 2-3 hours after its intake. Metabolism does not occur and it is removed from the body in some form, from the urine. Multiple types of research have been done and the results showed that dose of Gabapentin, surgery nature and administration, all factors are not the same for every patient. Ho et al. performed a study in which the dose of Gabapentin used was 1200 mg before the surgery. This was done to make sure that the consumption of opioid should be minimized after the surgery (13). Sedation was an expected side effect of this procedure but the patients did not have to face the side effects of opioid consumption. (14) Pandey et al. made a review in which he kept on rising the dose from 600mg to 1200mg. The increased dosage did not lessen the postoperative pain hence, 600 mg was considered as the ideal dosage (15). Another study performed to reduce the postoperative pain after total knee replacement showed that 300mg of Gabapentin given 90 hours before the surgery to the patients will show significant results. Farag et al. had a study in which IV lidocaine was given to the patients having spin surgery. The postoperative pain was reduced (P < 0.001. almost, 25% of the opioid consumption was also reduced in the study so, we can correlate this one with the present study (16).In some other researches, it has shown that intravenous lidocaine is not significant in treating postoperative pain. Also, the opioid consumption was not reduced in any kind of surgery by its use. Martin et al. performed a surgery that included the patients having total hip arthroplasty. The lidocaine bolus was given to the patients and no significant effect was noticed about pain score or opioid consumption(17)(18).Another study performed by De Oliveira and co-authors showed that if the patients of two groups, one has given IV lidocaine and other have given saline, no effect was noticed regarding pain as well as morphine consumption(17)(18).In addition to the above-discussed studies, this ineffective result of intravenous lidocaine was also observed in some other research. The mismatch between the results of the current study and these previous studies is due to the varying amount of dosage and different nature of surgeries. Also, we can say that the difference is due to the unique pain thresholds of a particular individual. So, each of them has a different response to each drug(19).So, according to the above-discussed literature, both the methods have some better results as well as bad side effects. We will study the significant effect of oral Gabapentin and intravenous lidocaine in patients undergoing total knee replacement. So, the side effects and results of both the drugs and their combined effects are observed in the study to understand the best way to overcome the postoperative pain after total knee replacement.METHODOLOGY:It was a case-control study performed at Tertiary Care Hospital and the duration of the study was 6 months. 66 patients that were suffering from any kind of arthritis or knee joint disorder were selected for the study. Ethical statement of the patient was the priority and written consent was also taken from every patient as a record. The whole procedure was explained to all patients and the choice of with-drawl at any time was provided as well. The inclusion criteria for the study included patients of age more than 18 years, both male and female gender, patients undergoing surgery with general anaesthesia and mainly the patients that were suffering from any kind of arthritis or knee joint disorder. Whereas the exclusion criteria included patients with neoplastic aetiology, infection, traumatic fracture, metal sensitivity, obstructive sleep apnea, revision surgery, mental diseases, and use of the local anaesthetic technique or a nerve block. Three groups were made and named as A, B and C. Patients were divided equally so that each group consists of 22 patients.Before the study, the whole procedure will be explained to the patients. All the steps will be performed after taking consent from them in a written form. Every minor detail including the delicacies, benefits, risks and complaints of the procedure will be made clear. No one will be forced to take part in the study. The Hospital ethical committee should also have approved the study.The patients of A group were given placebo capsules 1 hour before the surgery. Then, just before giving anaesthesia, IV bolus injection of 1.0 mg/kg lidocaine (Xylocaine 2%; AstraZeneca, 600 Capability Green, Luton, LU1 3LU, UK) was introduced to the patients. The solution was diluted by normal saline to a 10 ml volume. Then, it was infused continuously, until the skin was closed. A syringe was pumped at the rate of 2 mg/kg/h during surgery. In group B, 1 hour before the surgery, patients were given 600 mg gabapentin capsules (Neurontin; Pfizer, Cairo, Egypt). They were allowed to ingest the capsule. Then, before giving anaesthesia the patients were given 10 ml of the saline bolus. After that saline infusion was done intraoperatively (the same volume as lidocaine infusion in group A). The same syringe pump was used for the procedure until the closure of skin. Whereas in group c, patients were allowed to ingest 600 mg gabapentin capsules. Similar to group A and B, it was done 1 hour before surgery. Then, just before having anaesthesia, they received IV bolus of 1.0 mg/kg lidocaine. After that, the same syringe pump was used in this procedure for intraoperative lidocaine infusion. Before the closure of skin, the process was done at the rate of 2 mg/kg/h. there was no specific dose for the administration of IV drug. The amount to be given was calculated according to the weight of the patient. All the persons involved in the research including the surgeons, patients as well as anaesthesiologists did not know the allocation of the groups. So, they could deduce the result without any doubts. Preoperative condition of the patients including their assessment was done 24 hours before the surgery. The patients were explained how to express the intensity of pain ranging from 10-10 by using the visual analogue score (VAS; 0 = no pain and 10 = worst pain imaginable) (20).DATA ANALYSIS:For data analysis procedure, SPSS software (Statistical Package for the Social Science; SPSS Inc, Chicago, IL, USA) was used with version 22. In statistical analysis, data were explained as mean ± standard deviation (±SD), or frequencies (number of cases) and percentages when appropriate. All of the three groups were evaluated and the results were compared by one-way analysis of variance (ANOVA) test. Mann Whitney U test was used to evaluate the independent samples. Also, Bonferroni correction was used for several evaluations in every group for comparison. Categorical data were compared by using the Chi-square (χ2) test was used to collect categorical data. If the frequency was less than 5, Exact test was used. P-values less than 0.05 was considered significant (21)(22).RESULTS:The study was completed by sixty-six patients that were undergoing total knee replacement surgery by using general anaesthesia. 22 patients were present in each group (n=22 in group A, B and C). Age, weight, gender and duration of surgery were some factors that did not differ significantly in all groups. Relief of pain was observed in all three groups within 24 hours. Blurred vision, uncontrolled eye movement and dizziness were observed in patients of group B. Whereas in Group A, vomiting and change of body temperature were observed. Intra-operative heart rate, postoperative side-effects, and mean arterial pressure changes were also recorded as results.TABLE Ⅰ: Intra-operative heart rate.Time(A) Group(n=22)(B) Group(n=22)(C) Group(n=22)Before induction95.4 ± 12.294.8 ± 12.492.5 ± 11.9After induction99.2 ± 10.898.6 ± 11.696.9 ± 12.6After 15 min94.6 ± 9.893.7 ± 10.292.4 ± 10.3After 30 min95.4 ± 10.994.8 ± 10.793.8 ± 11.7After 45 min93.7 ± 10.294.7 ± 10.692.4 ± 10.2After 60 min92.6 ± 11.893.9 ± 11.792.6 ± 12.1After 75 min93.5 ± 10.593.5 ± 11.491.5 ± 11.6After 90 min92.5 ± 10.193.4 ± 9.692.4 ± 9.2At the end of surgery93.2 ± 10.894.6 ± 12.293.8 ± 12.8TABLE Ⅱ: Changes in mean arterial pressureTime(A) Group(n=22)(B) Group(n=22)(C) Group(n=22)Before induction86.4 ± 16.585.8 ± 16.782.2 ± 15.6After induction90.2 ± 7.890.6 ± 6.789.4 ± 9.5After 15 min87.6 ± 7.886.7 ± 6.986.5 ± 7.1After 30 min87.7 ± 7.988.4 ± 8.287.9 ± 8.4After 45 min86.5 ± 8.287.7 ± 8.485.8 ± 8.8After 60 min86.7 ± 7.489.6 ± 8.285.9 ± 7.9After 75 min91.4 ± 7.890.1 ± 7.990.2 ± 7.8After 90 min88.6 ± 8.287.3 ± 8.489.4 ± 8.6At the end of surgery90.7 ± 8.991.4 ± 8.489.4 ± 8.2TABLE Ⅲ: Post-operative side effectsPostoperative side effects(A) Group(n=22)(B) Group(n=22)(C) Group(n=22)Nausea5 (22.7%)2 (9%)2 (9%)Vomiting4 (18.1%)2 (9%)1 (4.5%)Dizziness4 (18%)6 (27%)7 (31%)Headache4 (18.1%)3 (13.6%)4 (18.1%)Dry mouth4 (18.1%)6 (27.2%)6 (27.2%)TABLE Ⅳ: Demographic Data of PatientsVariables(A) Group(n=22)(B) Group(n=22)(C) Group(n=22)Age (years)46.9 ± 7.745.4 ± 6.747.8 ± 8.2Male/female (n)6/165/177/15ASA class 1 / 2 (n)8/146/168/14Weight (kg)89 ± 8.790.2 ± 8.288.7 ± 8.6Duration of surgery (min)130 ± 28134 ± 29132 ± 28Intraoperative fentanyl227 ± 39.8220 ± 34.2180 ± 30.4Extubation time (min)10.4 ± 1.49.8 ± 1.710.6 ± 1.2DISCUSSION:Pre-operative anxiety is usually a serious issue, but postoperative pain is more a centre of attention here. Both of them are somehow connected as the anxiety leads to decreased pain thresholds as a result of which severe pain is suffered by the patients that have undergone knee surgery. Also, the pain and anxiety have a significant effect on wound healing time as well as the immune system. So, to overcome the pain, analgesics are sued. In this study, we used oral Gabapentin, intravenous lidocaine and their combination.Total knee replacement is major surgery with severe postoperative pain as a complication. To avoid a long-hospital stay, it is mandatory to manage postoperative pain. A method that has been used for 25 years to control the postoperative pain is a multimodal analgesic pathway which decreases the severity of pain. Gabapentin used to overcome this pain has varying effects on the patients. 6 out of 7 studies have reported that opioid use does not play role in releasing the pain in between the 24 hours of the surgery.The result of the present study shows that group C having a combination of Gabapentin and lidocaine shows fewer postoperative complications and side effects than the other two groups. Also, the other two groups A and B, Intravenous Lidocaine and Gabapentin respectively. The intravenous lidocaine was considered significant for improving the postoperative pain at the initial stage. Less pain was detected in the patients on each movement that were given the dose of lidocaine. In addition to it, the requirement of morphine was reduced in this case. Gabapentin was considered to decrease the postoperative pain in the first 24 hours of the surgery. If compared these three groups with placebo, then lidocaine group had no difference in the case of nausea and vomiting. In contrast, the gabapentin group and combined group were more significant than these two. (23)The postoperative sedation was found in all the three groups in the study. The level of sedation was different in the cases if compared to previous studies. In previous studies, the sedation level was higher in the gabapentin group just because of higher or repeated dosages. Other factors of Gabapentin that was compared to other groups were headache and dizziness. So, some research has shown that if the ideal amount of Gabapentin is used, i.e., 600-800mg is consumed, then all the postoperative effects can be overcome. (24)Kaba et al. performed a study in which patients who had laparoscopic colectomy were included. Intravenous lidocaine was given to these patients for the reduction of postoperative pain. His research showed significant results and postoperative pain, along with the need for opioid use was decreased. IV magnesium infusion and placebo infusion were compared to IV lidocaine in another study. The pain was reduced both by lidocaine and magnesium than placebo. The result of these studies supports the results of our research that IV lidocaine can manage postoperative pain (25).Now, there were some limitations to the study. A limitation was that the plasma lidocaine concentration was not measured. Also, the amount of lidocaine given to the patients in a short time was lesser as compared to other studies. These additional studies showed no side effects, and their toxic level was not found. Another limitation of the study is a smaller sample size which has limited the better exposure to the side effects of any group. Either it is gabapentin or IV lidocaine, both were significant in lowering the postoperative pain. Also, they were safe and inexpensive and a better solution as compared to opioid. Not only in knee surgery but different surgeries should also be studied profoundly, and the safe, optimum and effective dosage should be detected for them to reduce the postoperative pain.CONCLUSION:To reduce the postoperative pain by analgesic effect, intravenous lidocaine as well as Gabapentin, both are effective, safe and significant but have some side effects too including nausea, vomiting, headache, dizziness and dry mouth. Also, their combination reduces the pain, but the main point is that its use also decreases the side effects. Whereas, for overcoming postoperative nausea and vomiting, among all three methods, oral Gabapentin is the most suitable drug.REFERENCES:1. M.-L. W, Y.-J. F, C.-J. T, P.-J. Y, Y.-L. L, C.-C. J. Successful management of 73 patients for total knee arthroplasty using a combination of ultrasound-guided nerve block and targeted sedation. Anesth Analg. 2018;2. Skou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Simonsen O, et al. 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