The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model.

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.

Oral findings in 58 adults with tuberous sclerosis complex.

BACKGROUND: Gingival fibromas and dental pitting are among the diagnostic criteria for tuberous sclerosis complex (TSC). OBJECTIVE: Our goal was to document the oral findings in 58 adult patients with TSC. RESULTS: Forty patients (69%) had oral fibromas, appearing mostly on the attached or interdental gingiva. Other oral mucosal sites with fibromas included buccal and labial mucosa, the superior labial frenulum, palate, and tongue. In all, 56 patients (97%) had multiple dental enamel pits. LIMITATIONS: This case series comprised predominantly adult women with TSC and lymphangioleiomyomatosis. CONCLUSIONS: Oral fibromas in TSC are mostly, but not exclusively, gingival. Dental pits are present in nearly all patients. The multiple oral papules in TSC may appear similar to those observed in Cowden syndrome, Birt-Hogg-Dubé syndrome, and rarely in multiple endocrine neoplasia type 1.

A novel case of bisphosphonate-related osteonecrosis of the torus palatinus in a patient with metastatic breast cancer.

Bisphosphonates administered orally and intravenously are used for a variety of endocrine and oncologic indications. Long-term intravenous use of bisphosphonates has been shown to cause osteonecrosis of the jaw. We report a case in which a 58-year-old woman with metastatic breast cancer received 18 doses of 4 mg intravenous zoledronic acid over a period of 16 months and developed a region of osteonecrosis on the posterior edge of a large, lobular torus palatinus. Torus palatinus, a type of maxillary exostosis, is common among postmenopausal women, and is vulnerable to blunt trauma that could predispose to osteonecrosis. Sequestrum of dead bone was removed and the site healed within 4 weeks. This case demonstrates that patients with a torus palatinus may be at high risk for osteonecrosis, and reinforces the need for good oral hygiene and frequent dental examination while receiving bisphosphonate therapy.

Dental implants in children.

Some children and adolescents have anodontia, partial anodontia, congenitally missing teeth, and lost teeth as a result of trauma, and they may benefit from early placement of dental implants. Clinicians should have an understanding of the potential risks involved in placing implants in jaws that are still growing and developing and consider the effect that implants have on craniofacial growth. Implants may act as ankylotic teeth and fail to move together with the surrounding structures, which produces an infraocclusion that leads to difficulties with prosthetics. Young patients may require general anesthesia for the procedure and there may be limited cooperation in maintaining good oral hygiene.

In vivo selectivity of a selective cyclooxygenase 2 inhibitor in the oral surgery model.

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.

Peripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue injury model.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) analgesia is generally attributed to peripheral suppression of cyclooxygenase (COX) enzymes, leading to decreased products of the arachidonic acid cascade. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after systemic or local NSAID administration in a clinical model of tissue injury. METHODS: Subjects in two replicate clinical trials had one or two mandibular third molars removed and a microdialysis probe implanted at the surgical site for measurement of immunoreactive prostaglandin E(2) (PGE(2)) or immunoreactive thromboxane B(2) (TxB(2)) and pain measured concurrently. In the first study, ketorolac tromethamine (INN, ketorolac) was administered at pain onset in a 30-mg intramuscular dose, a 1-mg intramuscular dose, or a 1-mg submucosal dose at the extraction site in comparison with placebo. In the second study, subjects received either ketorolac tromethamine 30 mg by the intravenous route or placebo at pain onset. RESULTS: PGE(2) was detectable in the first postoperative sample, decreased over the next hour, and then increased significantly coincident with the onset of postoperative pain. Administration of 30 mg ketorolac tromethamine produced parallel decreases in pain, PGE(2) levels, and TxB(2) levels at the surgical site. Administration of 1 mg ketorolac tromethamine intramuscularly or directly at the surgical site was analgesic but without measurable effects on PGE(2) levels. CONCLUSION: The temporal profile of PGE(2) and TxB(2) in the immediate postoperative period is consistent with constitutive COX-1 initially, followed by an increase in PGE(2) resulting from expression of COX-2. The temporal association between NSAID analgesia and decreased prostanoids at the site of injury is consistent with a dual COX-1/COX-2 peripheral site of action. The analgesic effects of 1 mg ketorolac tromethamine without a reduction in PGE(2) at the site of injury suggests an additional central site for NSAID analgesia.

Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model.

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.

Comparison of experimental and acute clinical pain responses in humans as pain phenotypes.

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.

Endometrial carcinoma metastatic to the retromolar pad.

Metastatic carcinoma from the female genitalia to the oral mucosa is exceptionally rare, with only 11 such cases having been previously reported in the English-language literature. We describe a new case in a 65-year-old woman with a history of endometrial carcinoma who presented with swelling of the retromolar pad. Radiographic examination showed slight opacities and irregular trabecular bone in the left posterior mandible. Following an incisional biopsy, histologic examination and immunohistochemical studies revealed glandular adenocarcinoma with positivity for progesterone receptor, estrogen receptor, and cytokeratin 7. The patient was referred to her primary care physician for comprehensive treatment. This case illustrates the value of considering cancer metastasis in the differential diagnosis of an oral swelling, particularly in a patient with a history of cancer.

Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation.

Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.

Transcriptional events in a clinical model of oral mucosal tissue injury and repair.

Tissue injury in the oral mucosa activates a cascade of transcriptional events important during the healing process that are not yet clearly defined. To characterize these events and identify potential gene targets for future studies, we used cDNA expression arrays in a clinical model of tissue injury. Mucosal biopsies were taken before third molar extraction, 2-4 hours postoperatively, or at 48 hours. Hybridization patterns were analyzed and validated using real-time polymerase chain reaction. Prior to extraction, the biopsied mucosal tissues were characterized by a panoply of genes that were constitutively expressed. After injury, analysis revealed differential expression of genes involved in transcription, inflammation, and remodeling. At 2-4 hours after injury, genes such as Fos, Jun, and early growth response protein were up-regulated, while genes responsible for intercellular adhesion were down-regulated. At 48 hours after injury, the gene profile had shifted toward tissue remodeling. Here we identify genes constitutively expressed in normal oral mucosa and transcriptional events following mucosal tissue injury, which may be useful in identifying new therapeutic targets.

Dexamethasone suppresses peripheral prostanoid levels without analgesia in a clinical model of acute inflammation.

PURPOSE: The therapeutic effects of glucocorticoids are generally attributed to suppression of multiple signaling pathways involved in the inflammatory response leading to decreased levels of inflammatory mediators at the site of injury. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after dexamethasone administration in a clinical model of tissue injury. METHODS: Subjects were administered dexamethasone 4 mg or placebo 12 hours and 1 hour before the removal of 2 mandibular third molars. A microdialysis probe was implanted at each surgical site for measurement of immunoreactive prostaglandin E2 (PGE(2)) or immunoreactive thromboxane B(2) (TxB(2)), and pain was measured concurrently. Subjects received either ketorolac 30 mg intravenously or placebo at pain onset. RESULTS: PGE(2) was detectable in the first postoperative sample, decreased over the next hour and then increased coincident with the onset of postoperative pain. Administration of dexamethasone suppressed PGE(2) levels in samples collected at pain onset in comparison to placebo and significantly suppressed TxB(2) at the surgical site but without any effect on pain report. Subsequent administration of ketorolac significantly reduced pain while decreasing both PGE(2) and TxB(2) levels at the surgical site. CONCLUSION: The lack of an analgesic effect for dexamethasone while reducing both PGE(2) and TxB(2) at the site of injury in comparison to ketorolac analgesia accompanied by greater reductions in levels of these prostanoids suggests that glucocorticoids at this dose do not suppress PGE(2) release sufficiently to attenuate peripheral sensitization of nociceptors after tissue injury.

Prospective clinical trial of dental implants in persons with ectodermal dysplasia.

STATEMENT OF PROBLEMS: Ectodermal dysplasia is a hereditary condition in which hypodontia is the second most frequently occurring sign. Hypodontia is associated with lack of development of the alveolar ridge and results in less volume of bone for support of conventional prostheses. Minimal development of the alveolar ridge can affect the bone volume available for the placement of dental implants. PURPOSE: This clinical trial evaluated the survival of implants placed in individuals with a form of ectodermal dysplasia and severe hypodontia. MATERIAL AND METHODS: Two hundred sixty-four titanium endosteal dental implants were placed in 51 subjects: 37 males and 14 females between the ages of 8 and 68 (mean age 20.5 years, median age 16.5 years). Two hundred forty-three implants were placed in the anterior mandible, and 21 were placed in the anterior maxilla with a 2-stage surgical protocol. Either fixed-detachable dentures or bar-clip overdentures were provided. Subjects were followed up for 0 to 78 months after second-stage surgery. Kaplan-Meier survival rates and curves were produced to describe the survival of the implants for the different age groups and implant locations. Repeated-measures Cox regression models were used to evaluate the hazard ratios for age and location, with alpha=.05 as the criteria for significance. RESULTS: Of the 243 implants placed in the anterior mandible, 221 (91%) survived. Of the 21 implants placed in the anterior maxilla, 16 (76%) survived. Fourteen of the 51 (27%) subjects had a failed implant. All but 2 failures occurred before or at second-stage surgery. Implant-supported prostheses were provided for all patients. CONCLUSION: Within the limitations of this study, the results support the continued use of endosteal dental implants in this patient population with appropriate precautions in the maxilla.