Nitric oxide is negatively correlated to pain during acute inflammation.

BACKGROUND: The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. RESULTS: Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo group but not in the ketorolac group. CONCLUSION: We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression.

Kinin B1 receptors contributes to acute pain following minor surgery in humans.

BACKGROUND: Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. RESULTS: Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor. CONCLUSIONS: These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the early phase of inflammation and inflammatory pain. The up-regulation of B1 receptors may contribute to acute inflammatory pain through TRPV1 activation.

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.

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.

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.