RESUMO
BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates.
Assuntos
Anestésicos Locais/efeitos adversos , Bupivacaína/efeitos adversos , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/metabolismo , Lidocaína/efeitos adversos , Mucosa Bucal/efeitos dos fármacos , Procedimentos Cirúrgicos Bucais , Dor Pós-Operatória/induzido quimicamente , Acetaminofen/uso terapêutico , Adolescente , Adulto , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Codeína/uso terapêutico , Ciclo-Oxigenase 1/biossíntese , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Método Duplo-Cego , Indução Enzimática/efeitos dos fármacos , Feminino , Humanos , Lactonas/uso terapêutico , Masculino , Dente Serotino/cirurgia , Mucosa Bucal/enzimologia , Mucosa Bucal/metabolismo , Medição da Dor , Dor Pós-Operatória/enzimologia , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/prevenção & controle , Sulfonas/uso terapêutico , Fatores de Tempo , Dente Impactado/cirurgiaRESUMO
OBJECTIVE: Prostanoids formed by cyclooxygenase play an important role in pain and the induction of inflammation. It is generally believed that COX-1 is constitutively expressed, whereas COX-2 is primarily inducible during inflammation. This study examined the in vivo selectivity of celecoxib, a COX-2 inhibitor, and evaluated whether estimates of selectivity that are based on in vitro and ex vivo analyses are reliable indicators of in vivo selectivity. METHODS: Subjects (103 outpatients undergoing surgical removal of two impacted mandibular third molars) received either 200 mg celecoxib, 600 mg ibuprofen, or placebo 8 hours before surgery and a second dose 1 hour before surgery. After surgery, microdialysis probes were placed in the surgical sites for collection of inflammatory transudate. Samples were collected every 20 minutes and pain intensity was estimated concurrently with a visual analog scale and a categorical rating scale for up to 4 hours after surgery. RESULTS: A significant analgesic effect (P <.01, compared with placebo) was shown for both drugs, with the efficacy of celecoxib being intermediate between ibuprofen and placebo. A similar relationship was observed for the suppression of prostaglandin E(2) (a product of both isoforms) at time points consistent with COX-2 expression (P <.001). Ibuprofen consistently suppressed thromboxane B(2) (a product of COX-1) levels at all time points (P <.05), whereas the effect of celecoxib did not differ from that of placebo. CONCLUSIONS: The suppression of products of COX-2 coincident with pain suppression and the absence of COX-1 inhibition suggest that celecoxib is a relatively selective COX-2 inhibitor in vivo.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Isoenzimas/metabolismo , Procedimentos Cirúrgicos Bucais , Dor Pós-Operatória/tratamento farmacológico , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulfonamidas/uso terapêutico , Adulto , Celecoxib , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Ibuprofeno/uso terapêutico , Masculino , Proteínas de Membrana , Microdiálise , Dente Serotino , Medição da Dor/efeitos dos fármacos , Pirazóis , Especificidade por Substrato , Tromboxano B2/metabolismo , Extração DentáriaRESUMO
Nonsteroidal anti-inflammatory drugs produce their analgesic and adverse effects through interaction with cyclooxygenase in a variety of tissues. The authors evaluated the therapeutic potential of administering a sustained-release formulation of flurbiprofen into a surgical wound following oral surgery to produce analgesia at the site of injury while minimizing exposure to potential targets for toxicity. Subjects (N = 98) received 1 of 8 treatments: flurbiprofen in a microparticle formulation in doses of 3.125 mg, 6.25 mg, 12.5 mg, 25 mg, or 50 mg; PO flurbiprofen 25 mg or 50 mg; or placebo. The flurbiprofen microparticle formulation or matching placebo was placed into the extraction sites at the end of surgery (removal of 2 lower impacted third molars). The sum of the pain visual analog scale over the 6-hour observation period demonstrated significantly less pain (P < .05) for flurbiprofen microparticle in comparison with placebo. Fewer subjects remedicated in the flurbiprofen microparticle drug groups, primarily for the 12.5-mg and higher doses. The incidence of adverse effects and local complications did not differ across groups. These data suggest that direct administration of flurbiprofen in a microparticle formulation at a site of tissue injury delays the onset and lowers the intensity of postoperative pain at lower doses than usually administered orally.
Assuntos
Administração Tópica , Analgesia/métodos , Preparações de Ação Retardada/uso terapêutico , Flurbiprofeno/uso terapêutico , Modelos Dentários , Cirurgia Bucal , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Química Farmacêutica/classificação , Química Farmacêutica/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Relação Dose-Resposta a Droga , Flurbiprofeno/sangue , Flurbiprofeno/farmacologia , Humanos , Medição da Dor/métodos , Dor Pós-Operatória/classificação , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Tamanho da Partícula , Periodonto/efeitos dos fármacos , Periodonto/lesões , Periodonto/cirurgia , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Resultado do TratamentoRESUMO
UNLABELLED: This study evaluates the sensitivity of normal subjects (N = 617; 369 women, 248 men) to experimentally induced pain including thermal stimuli and the cold pressor test to delineate individual response patterns and pain phenotypes. A subset of subjects (n = 157; 99 women and 58 men) also underwent standardized oral surgery, and the responses to clinically induced acute inflammatory pain were evaluated. A wide range of pain responses was found in both the experimental and clinical situations. The latency for withdrawal in the cold pressor test exhibited a dichotomous distribution of short and long times. Women exhibited higher responses to cold (P < .001) and thermal stimuli (P < .05) than men. Ethnicity affected pain responses to thermal stimuli ranging from 43 degrees C to 47 degrees C (P < .05) and cold stimuli (P < .001). However, neither gender nor ethnicity affected pain responses to clinically induced acute inflammatory stimuli. Cross-modality comparisons of responses within experimental pain showed strong correlations (P < .01) but weaker relationships with clinical inflammatory pain. These data suggest that the background factors and characteristics of experimental pain responses differ from those of clinical pain; therefore, experimental pain ratings alone are not sufficient to predict responses to clinically induced acute pain. PERSPECTIVE: The findings of the present study suggest that investigations of pain phenotypes should take into consideration the subjects' gender and ethnicity and the pain-inducing stimuli. The predictive value of experimental pain for clinically induced pain is weak and not reliable.