Co-crystal of Tramadol-Celecoxib in Patients with Moderate to Severe Acute Post-surgical Oral Pain: A Dose-Finding, Randomised, Double-Blind, Placebo- and Active-Controlled, Multicentre, Phase II Trial.

BACKGROUND: Co-crystal of tramadol-celecoxib (CTC), containing equimolar quantities of the active pharmaceutical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg rac-tramadol hydrochloride and 56 mg celecoxib), is a novel API-API co-crystal for the treatment of pain. We aimed to establish the effective dose of CTC for treating acute pain following oral surgery. METHODS: A dose-finding, double-blind, randomised, placebo- and active-controlled, multicentre (nine Spanish hospitals), phase II study (EudraCT number: 2011-002778-21) was performed in male and female patients aged ≥ 18 years experiencing moderate to severe pain following extraction of two or more impacted third molars requiring bone removal. Eligible patients were randomised via a computer-generated list to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 8 h assessed in the per-protocol population. RESULTS: Between 10 February 2012 and 13 February 2013, 334 patients were randomised and received study treatment: 50 mg (n = 55), 100 mg (n = 53), 150 mg (n = 57), or 200 mg (n = 57) of CTC, 100 mg tramadol (n = 58), or placebo (n = 54). CTC 100, 150, and 200 mg showed significantly higher efficacy compared with placebo and/or tramadol in all measures: SPID (0-8 h) (mean [standard deviation]): - 90 (234), - 139 (227), - 173 (224), 71 (213), and 22 (228), respectively. The proportion of patients experiencing treatment-emergent adverse events was lower in the 50 (12.7% [n = 7]), 100 (11.3% [n = 6]), and 150 (15.8% [n = 9]) mg CTC groups, and similar in the 200 mg (29.8% [n = 17]) CTC group, compared with the tramadol group (29.3% [n = 17]), with nausea, dizziness, and vomiting the most frequent events. CONCLUSION: Significant improvement in the benefit-risk ratio was observed for CTC (doses ≥ 100 mg) over tramadol and placebo in the treatment of acute pain following oral surgery. FUNDING: Laboratorios del Dr. Esteve, S.A.U.

The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis.

Incidence rates of oral and oropharyngeal cancers (oral cancer) in Spain are among the highest in Europe. Spain has a population heavily exposed to various types of tobacco and alcoholic beverages but the role and impact of tobacco type and beverage type in oral carcinogenesis remain controversial. To estimate the independent and joint effects of tobacco smoking and alcohol drinking habits on the risk of developing oral cancer, we carried out a multicenter, hospital-based, case-control study in Spain. Data from 375 patients newly diagnosed with cancer of the oral cavity or oropharynx and 375 matched control subjects were analyzed using multivariate logistic regression procedures. All exposure characteristics of amount, duration and cessation of both tobacco smoking and alcohol drinking were strongly associated with cancer risk following a dose-dependent relationship. At equal intake or duration levels, black-tobacco smoking and drinking of spirits were both associated with a 2- to 4-fold increase in cancer risk compared to blond tobacco smoking or drinking of wine or beer, respectively. While ever exposure to smoking only or drinking only was associated with a moderate and nonsignificant increase in cancer risk, a history of simultaneous exposure to both habits was associated with a 13-fold increase that was compatible with a synergistic effect model (p-value for interaction: 0.008). Exposure to black tobacco smoking and/or drinking of spirits may account for up to 77% of oral cancer occurrence in Spain. Both black tobacco smoking and drinking of spirits place individuals at a very high risk of developing oral cancer. Simultaneous exposure to tobacco and alcohol consumption increases oral cancer risk in a synergistic fashion, even when consumption levels are moderate. These results underline the importance of type of tobacco and alcohol concentration in oral carcinogenesis.