To the best of our knowledge this is the first study to have examined the relationship between smoking and TMD in age-specific strata. The key finding was that a history of cigarette smoking was strongly associated with TMD, but only among young adults. Specifically in this case control study, smokers aged 18 to 29 years, had four times the odds of having TMD when compared with 18-29 year old non-smokers. In adults aged 30 to 60 years, TMD case status had no association with smoking status.
The second major contribution of this study is the first reported finding of an association between any history of allergy-related conditions and TMD. We showed the effect of smoking on TMD in young adults was attenuated 20% after adjustment for four allergy-related conditions. The effect was further attenuated 45% to statistical non-significance after additional adjustment for cytokines and psychological profile.
Our finding that age modified the effect of smoking on TMD is in accordance with previous studies of low back pain. Pooled estimates from a meta-analysis showed that the association between current smoking and incident low back pain was stronger in adolescence (OR =1.82, 95% CI =1.12, 2.33) than in adults (OR=1.16; 95% CI= 1.02, 1.32).55
Our results also build on evidence of an association between allergy and chronic pain. In the third US National Health and Nutrition Examination Survey, adults aged 20-39 with any history of asthma, hay fever and other allergies were 50% more likely to report low back pain than 20-39 year olds without allergies.24
Elsewhere a case control study of vulvodynia showed that odds of the condition were elevated between 2.0-fold to 2.5-fold in women with a history of any of seasonal allergies, reactions to insect bites or hives. In that study the self-reported allergy conditions preceded the first report of vulvar pain.21
The authors suggested that an altered immune-inflammatory response to environmentally induced allergic reactions was a possible explanatory mechanism. And in the 51,383 Head-Hunt Study participants, headache was 1.5 times more likely among those with asthma, asthma related symptoms, hay fever and chronic bronchitis.2
Based on their findings from a population-based study, Hurwitz and Morgenstern hypothesized that hypersensitivity reactions evoke dysfunctional reactivity of the hypothalamic–pituitary–adrenal axis to psychological stress with consequences for chronic pain.24
We found that an inflammatory response and allergic conditions had independent effects on odds of TMD in young adult smokers (Model 3, ). In young adults, adjustment for inflammation as indexed by two cytokines, a history of allergy-related conditions, and psychological profile fully accounted for the effect of smoking on TMD.
In line with results from previous clinical studies, 16, 45, 44, 46
we found that levels of the cytokines MCP-1 and IL-1Ra were associated with increased odds of TMD. MCP-1 is a chemotactic cytokine expressed in a variety of cell types, including leukocytes in the periphery 70
and neurons in the central nervous system 67
. IL-1Ra is member of the interleukin-1 cytokine family that is largely expressed in macrophages and epithelial cells 22
as well as in brain. 32
IL-1Ra binds the proinflammatory cytokines interleukin-1α (IL-1α) and interleukin-1β (IL-1β), thus inhibiting their activity. 14
Studies in animal models demonstrate that expression of both MCP-1 and IL-1Ra is strongly upregulated following injury or inflammation. 25, 37, 64, 67
A mechanistic role for MCP-1 in chronic pain is supported by recent studies showing that MCP-1 is able to excite sensory neurons. 67
While a mechanistic role for the anti-inflammatory cytokine IL-1Ra in chronic pain is less clear, its synthesis and release is stimulated by the proinflammatory cytokine IL-1. Kinetic studies have demonstrated that the balance between IL-1Ra and IL-1 production is dependent upon the phase of the inflammatory response. 59
Thus, IL-1Ra may be viewed as a marker of IL-1, which is deemed a prototypical proinflammatory cytokine well known for its ability to activate and sensitize nociceptors 28
as well as drive HPA-related stress responses. 19
Collectively, these results suggest that MCP-1 and IL-1Ra/IL-1 inflammatory pathways contribute to TMD.
One explanation for why the smoking and TMD relationship was found only in young adults is that one or more of the explanatory factors operate differently between young and older individuals. Support of this supposition comes from a study of the Swiss adult population, where odds of being atopic decreased by 21.0% on average with every 10-year increase in age.68
Little is known about exposure to tobacco smoke and IL-1Ra and MCP-1 concentrations in humans. One report of a positive association between smoking and plasma concentration of IL-1Ra in healthy subjects 13
conflicted with the finding of higher IL-1ra concentrations in non-smokers than smokers.39
In the periodontal literature a comparison of gingival crevice fluid IL-1ra concentrations in smokers and non-smokers, found smokers had significantly higher IL-1ra concentrations in healthy periodontal sites than non-smokers. However in subjects with deep bleeding periodontal sites, smokers had significantly lower IL-1ra concentrations than non-smokers.51
A recent experimental study showed that cigarette smoking and nicotine significantly induced MCP-1 expression in pancreatic ductal adenocarcinoma cells.30
In humans, MCP-1 concentration was significantly elevated in healthy smokers compared with healthy former smokers.9
The active ingredients in tobacco smoke that alter pain perception are not fully understood, but it is generally assumed that nicotine is the primary substance that modifies pain perception. The effects of nicotine on pain perception are complex (for a review see Shi et, al., 2010).54
Experimental studies that use brief noxious stimuli following the ingestion of nicotine provide evidence that nicotine has analgesic properties. Chronic exposure to tobacco smoke leads to changes in pain perception such that smokers deprived of nicotine show greater sensitivity to pain evoking stimuli.42, 56
In the postoperative pain setting, the administration of nicotine produces analgesia in nicotine naïve participants and produces little or no analgesic effect in smokers.20, 62
The chronic exposure to nicotine can induce biological states that produce hyperalgesia and dependency similar to that seen with the chronic exposure to opioids when nicotine levels are acutely reduced. We speculate that the diminished effect of smoking at ages older than 30 results from a diminished effect of smoking on the production of proinflammatory substances, which diminishes the likelihood of developing post-nicotine exposure hyperalgesic states.
The risk of chronic TMD in young former or current smokers was more than four times as high compared with older adults who had never smoked. Simultaneous adjustment for psychological profile, cytokines and allergy conditions approximately halved this effect and rendered the effect of smoking in young adults statistically non-significant showing these to be explanatory factors for excess risk. Nonetheless in the fully adjusted model, allergy conditions, interleukin-1 receptor antagonist and trait anxiety score remained significantly associated with TMD in young adults showing these to be independent risk indicators beyond the effects of tobacco. These findings highlight noteworthy age-related differences. For instance, ever smokers were twice as likely as life-time non-smokers to perceive high psychological distress but this effect was evident only in young adults. In addition, ever-smokers were twice as likely as non-smokers to have a history of allergy conditions and to use antihistamines, and again these effects were more pronounced in young versus older adults. Furthermore ever smokers had four times the odds of chronic TMD than lifetime non-smokers, but only among young adults. This consistency of evidence suggests that the relationships between smoking, psychological stress, allergy and TMD risk differ on the basis of age; indeed these case control results formally confirmed that age significantly modified the smoking and TMD relationship. Of these risk indicators in young adults, smoking may be the most easily modified and smoking cessation may have long-term benefits for inflammatory function, psychological health and conditions such as allergic rhinitis 33
However it is not known whether smoking cessation might negate any analgesic effects of nicotine on TMD pain.
Strengths of this study were use of the well-validated Research Diagnostic Criteria for determining TMD case status and the diverse dataset that included psychological instruments and cytokines. Another major strength was that we were able to reproduce our findings in two large national surveys with representative samples of female adults. The self-reported nature of TMD symptoms in these national surveys inevitably results in over-estimation or under-estimation of TMD prevalence. Despite this misclassification, the relationship was sufficiently strong to replicate our case control findings, which strengthened this study’s external validity.
Nonetheless, several possible limitations should be considered when interpreting our study findings. This case-control study design and the cross-sectional design of the national survey did not establish a temporal sequence between smoking and onset of TMD. It is plausible that some people might have begun to smoke as a consequence of developing TMD symptoms. Moreover anxiety and psychological stress may make smoking cessation efforts more difficult, as smokers with TMD may rely on tobacco to elevate mood and relieve comorbid depressive symptoms. This “reverse causation” might account for some of the observed association between smoking and TMD. However, the evidence from prospective cohort studies of other chronic pain conditions suggests that the predominant effect is in the expected causal direction.55
The degree to which TMD cases and controls were misclassified during examination is unrelated to the exposures of interest in this study (tobacco use, psychological profile, cytokines, allergy conditions). Therefore any misclassification of case status would produce non-differential bias, which does not pose a concern to the strength or direction of associations reported in this study. The only adverse impact of misclassification is increased variance (i.e. widened 95%CIs) around our estimates. A related concern with case-control studies is whether controls are selected from the same source population that gives rise to the cases.47
Yet, most controls heard about the study through the same methods reported by nearly all cases, suggesting that the majority of cases and controls came from the community at large.
Due to the relatively small number of current smokers, we limited the analysis of effect modification to a binary exposure measure. Hence, the risk of TMD associated with smoking cannot be attributed solely to elevated concentrations of nicotine or other substances inhaled in cigarette smoke because there is no such elevation in former smokers. Yet, the bivariate findings in show that the odds ratio for TMD is greater in current smokers than in former-smokers. This suggests that exposure to tobacco itself confers an additional risk for TMD, in addition to behavioral characteristics or other antecedents of smoking behavior. The small number of current smokers in this study reduces precision of estimates making interpretation of the strength of the smoking and TMD relationship more difficult.
Finally, our measures of allergy-related conditions were taken by convenience from the medical history questionnaire and were not planned in advance. However in future analyses we will examine IgE levels in stored blood. We used history of antidepressant medication as a marker of psychological profile. This may introduce misclassification as chronic pain sufferers are sometimes prescribed antidepressants for pain control as well as fatigue, or sleep disturbances.
This study has shed light on a complex interplay of allergy, cytokines, and smoking in a case control study of chronic TMD. Understanding the mechanisms underlying these relationships can best be addressed in large prospective studies of chronic TMD pain.