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Comparison of orofacial pain of patients with different stages of precancer and oral cancer

Orofacial pain impairs a patient's speech, swallowing, eating and interpersonal relations. Thirty-seven patients with a premalignant oral lesion, 124 patients with oral squamous cell carcinoma (OSSC), and 21 patients with a recurrence of OSSC were evaluated for their orofacial pain. The University of California San Francisco Oral Cancer Pain Questionnaire was administered to these patients at their initial visit, before they were prescribed analgesics for pain and before any treatment. Significant differences with respect to orofacial pain between the groups could be evaluatedwere observed. Patients with recurrence had the highest facial pain and patients with precancer had the lowest. Patients with OSSC and recurrence of OSSC reported significant levels of orofacial pain and functional restriction because of pain. Moreover, patients with recurrence of OSSC experienced significantly higher function-related pain, rather than pain qualities. These findings suggest that an important predictor for recurrence of OSSC may be the onset of orofacial pain that is exacerbated during function. The present study examined orofacial pain depending on the disease severity of precancer and oral cancer patients. Earlier recognition of symptoms of OSSC may improve early detection of its recurrence.

orofacial pain in groups of patients with oral precancer, newly diagnosed oral cancer, and recurrence of oral cancer. Here, we demonstrate that patients with oral cancer recurrence experience more intense pain than patients with oral precancer or newly diagnosed oral cancer.

Results
One hundred and eighty-two patients met the eligibility criteria for the study; these patients provided written informed consent and were interviewed. Upon review of the oral biopsy specimens, 124 patients had oral cancer (squamous cell carcinoma), 37 had oral precancer (6 mild dysplasia, 4 moderate dysplasia, 24 severe dysplasia/carcinoma in situ, and 3 proliferative verrucous leukoplakia), and 21 had oral cancer recurrence (squamous cell carcinoma). All recurrence patients had undergone surgery and chemotherapy. The patients with precancer (N = 37) were aged between 31 and 75 years (mean 52.0 ± 10.7 years), the patients with oral cancer (N = 124) were aged between 27 and 78 years (mean 63.6 ± 14.3 years), and the patients with oral cancer recurrence (N = 21) were aged between 36 and 80 years (mean 66.2 ± 12.8 years). A comparison of the mean values of the 3 groups showed that there were a higher number of male patients in all 3 groups (Table 1).

Discussion
Pain control and weight maintenance are especially challenging in patients with oral cancer. Many oral cancer patients experience symptoms that are more severe than those produced by other cancers. They also experience difficulty with eating, drinking, swallowing, and speaking 10,11 . In an attempt to improve management of cancer pain, the World Health Organization and the Agency for Health Care Policy recommends characterizing cancer pain as mild, moderate, or severe, and reevaluating pain levels throughout treatment. Despite this recommendation, there has not been an instrument available to quantify and characterize oral cancer pain. To address the need for such an instrument, in 2004, Connelly  to identify the functions that lead to oral cancer pain 7 . Kolokythas et al. found the UCSF-OCPQ to be an effective tool in quantifying pain from oral cancer 12 .
In our study, oral cancer recurrence patients reported significantly greater functional restriction (P1 = 0.009, P2 = 0.027) and sensitivity to touch (P1 = 0.009, P2 = 0.027) in comparison with both precancer and oral cancer patients. Oral cancer recurrence patients also experienced significantly higher spontaneous sharpness (P2 = 0.000) and functional sharpness (P2 = 0.002) in comparison with oral cancer patients. Thus, we found that patients with oral cancer recurrence reported significant spontaneous and function-related pain at the time of cancer recurrence. These findings suggest that an important predictor of oral cancer recurrence may be the onset of orofacial pain that is exacerbated during function.
In the present study, we found that sharpness and intensity of oral pain in all 3 groups were related to function rather than being spontaneous. Patients with oral cancer report pain during oral functions, including talking, eating, and drinking. In the OSCC groups, there was a significant difference between spontaneous aching (28.33 ± 14.56) and functional aching (33.33 ± 13.54). The functional sharpness (20.87 ± 13.03) pain level was significantly higher than that of spontaneous sharpness (15.60 ± 12.85). Similarly, patients with bone metastases develop acute breakthrough pain with movement of the involved skeleton 13 .
Oral cancer pain is more likely to be a result of the sensitization and/or activation of primary nociceptive afferents by mediators liberated by the cancer and associated cells 14 . The intense, spontaneous, sharp and aching pain reported by oral cancer patients suggests the sensitization and/or activation of both Ad and C fibres in oral cancer pain 15 . Cancer and associated cells in the cancer microenvironment may release a variety of pain mediators, including adenosine triphosphate, bradykinin, cytokines, chemokines, nerve growth factor, prostaglandins, and several vascular factors, including such as endothelin 1 and vascular endothelial growth factor to either excite or sensitize nociceptive primary afferents. Arachidonic acid metabolites, such as prostaglandins, are produced by various cancers, including oral cancer, and are well-known to sensitize nociceptive primary afferents 16 .
In our study, we found that there was no correlation between tumour size and reported pain levels, suggesting that oral cancer pain is not a result of the mass effect of the tumour. This finding is consistent with the clinical observation that small oral carcinomas can be profoundly painful. We did find increased levels of pain in the OSCC patients with lymph node metastasis. The process of tissue infiltration leading to metastasis could be responsible for the increased oral pain reported in these patients. The mechanism of pain in these patients likely involves either perineural infiltration and/or nociceptor hypersensitivity. The mediators responsible for infiltration and metastasis might also be involved with nociceptor hypersensitivity 7 .
There are a number of limitations in our study. The study period included only a few patients with a relapse (recurrence). Despite the low number of recurrence patients included in this study, we were able to establish statistically relevant correlations. Further studies will be performed using a longitudinal design to determine if and how the oral cancer pain of a patient develops during progression of the disease.
In conclusion, earlier recognition of symptoms of OSSC may improve early detection of the recurrence of OSSC. Further investigations into the correlations between pain parameters and the specific biology of OSSC may improve quality of life and survival for OSSC patients.

Methods
Ethics statement. This study complied with the guidelines of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital, Zhengzhou University (Zhengzhou, China). Since this study involved retrospective review of existing data, a waiver of written informed consent was obtained from the Institutional Review Board. All primary data was collected according to procedures outlined in epidemiology guidelines that strengthen the reporting of observational studies. Patient information was anonymized and de-identified prior to analysis.

Study inclusion criteria and protocol.
Only patients with an oral premalignant lesion (leukoplakia, erythroplakia, lichen planus), oral cancer, or and aoral cancer recurrence were included in this study. Potential patients would have beenPatients were excluded from the study because of foreseeable missing opportunity ofif they were unable to attend a follow-up examination, were pregnant or nursing, had undergone recent surgery, or had heart, infectious, circulation, systemic, malignant, or immune system diseases, blood coagulation disorders, or allergic reactions to pharmaceuticals and antibiotics. In addition, patients diagnosed with a psychiatric condition, or had an addiction to pain medications or recreational drugs, or had taken pain medications in the previous 6 months were also excluded. Demographic information was also collected for each patient, which included age, sex, racial/ethnic identity, current smoking and high-risk drinking status, oral lesion location, and tumour size.

UCSF Oral Cancer Pain Questionnaire. The University of California San Francisco Oral Cancer Pain
Questionnaire (UCSF-OCPQ) was used to assess patients' pain and to identify the functions that lead to oral cancer pain. The questionnaire was designed to differentiate function-related and spontaneous pain, as well as to determine the nature and quality of pain. The questionnaire is specifically designed for patients with oral cancer and was used because it has been shown to be better for demonstrating changes in pain that occur because of illness.
The UCSF-OCPQ was administered to patients meeting the inclusion criteria at their initial visit, and before they were prescribed analgesics for any orofacial pain or received any treatment. This questionnaire, consisting of 8 questions on a visual analogue scale of 0-100 mm, has been validated previously 12 . Briefly, the 8 questions differentiate spontaneous and function-related pain, and determine the quality of pain. Questions 1 through 6 examine the intensity, sharpness, and aching nature of orofacial pain. Question 7 focuses on the degree of sensitivity to touch. Question 8 determines the level of functional restriction as a result of orofacial pain. Patients were instructed to place a vertical line along the scale to approximate their orofacial pain level (if any).
Statistical analysis. Statistical analysis was conducted using SPSS for Windows version 20.0 (SPSS Inc., Chicago, IL, USA). The sociodemographic data and results of the UCSF-OCPQ were analysed using descriptive statistics. The data were tested for normal distribution with the Kolmogorov-Smirnov test, which revealed that the data do not significantly differ from normal distribution. Since the data were normally distributed, a t-test was used to compare the means of 2 interval-scaled independent samples. For categorical variables, the χ2 test was used for comparison. For all tests, P values of less than 0.05 were considered statistically significant.