Effect of intra-articular versus systemic anti-inflammatory drugs in a rabbit model of temporomandibular joint inflammation.

PURPOSE: In an attempt to better understand the time course of inflammatory mediator production or release in inflammatory joint disease, a rabbit model of acute temporomandibular joint (TMJ) inflammation was established. This model was used to evaluate the effects of specific anti-inflammatory agents administered either systemically (intraperitoneal, IP) or locally (intra-articular, IA) on the modulation of in vivo tissue levels of two prototypic inflammatory mediators, prostaglandin E2 (PGE2) and bradykinin (BK). MATERIALS AND METHODS: An experimental model of inflammation was created by administering carrageenan (carra) into one joint and an equivalent volume of saline (control) into the contralateral joint of 42 male New Zealand White rabbits. The development of hyperthermia was assessed by placement of a microthermister probe into the joint space. The inflammatory mediators, immunoreactive PGE2 (iPGE2) and BK (iBK), were recovered with microdialysis probes, and samples were assayed in conjunction with specific pharmacologic interventions. In the first part of the study, the time course for the release or production of iBK and iPGE2 was determined. In the second part, the effects of IP versus IA administration of dexamethasone and a nonsteroidal anti-inflammatory drug, ketorolac tromethamine, were compared. Dexamethasone and ketorolac were administered at 3 hours and 1 hour, respectively, before the peak release of the inflammatory mediators. RESULTS: The onset of IA hyperthermia, an index of inflammation, was evident by 90 minutes post-carra and reached a maximum of 1.2 degrees C above core temperature by 150 minutes post-carra. Intra-articular levels of iPGE2 and iBK peaked at 240 minutes (3.35+/-1.9 nmol/L) and 270 minutes (0.45+/-0.29 nmol/L), respectively, after the induction of inflammation in the superior joint space. iBK levels within the superior joint space were significantly decreased by dexamethasone and ketorolac. Ketorolac (50 microg) decreased iBK and iPGE2 levels when given IA or IP. With dexamethasone (3 mg), the levels of iBK were significantly reduced, and iPGE2 levels were not changed. CONCLUSIONS: This study shows that the rabbit model of TMJ inflammation, with concurrent collection of iBK and iPGE2 via microdialysis, is a reproducible and reliable method to investigate the time course of inflammatory mediator release and their modulation by either the local or systemic administration of anti-inflammatory medications.

The use of opioid drugs in management of chronic orofacial pain.

The use of opioid analgesics for the management of patients with chronic pain is controversial. However, randomized and double-blind clinical trials have shown that in select groups of patients with chronic pain, the daily administration of oral opioids decreases pain levels and improves quality of life. This article provides a review of the most recent basic and clinical research supporting the rationale for the use of opioids in a select group of patients with chronic orofacial pain. Critical to the employment of this technique are proper patient evaluation and use of comprehensive management strategies. This management scheme should be reserved for patients with chronic pain that is refractory to most nonopioid therapy. The primary reason for the clinician's reluctance to initiate long-term opioid therapy for their patients with chronic pain is the potential risk of developing opioid tolerance, dependence, or addiction. In contrast to these beliefs, studies have shown a nonexistent to low risk of opioid dependence or addiction behavior with administration of scheduled oral opioids in chronic pain patients. It is essential that potential patients for this type of therapy have been carefully screened and have not had a history of drug addiction. The criteria to be evaluated when considering opioid therapy for chronic orofacial pain control include 1) inadequate pain diminution from prior nonopioid therapy, 2) negative history of substance abuse, 3) definitive determination that the pain being treated is of physiologic rather than psychologic origin, 4) a willingness to adhere to an "opioid contract" between the doctor and patient, 5) compliance with a scheduled, rather than "as needed" or "breakthrough," administration of an oral opioid, and 6) close clinical follow-up to evaluate pain relief, return to daily activities, and titration of drug levels. If these criteria are followed, administration of oral opioids may be a successful means of decreasing the patient's debilitating chronic pain to tolerable levels, enabling an improvement in the quality of life and return to function.

Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery.

The aim of this study was to measure tissue levels of immunoreactive prostaglandin E2 (iPGE2), immunoreactive leukotriene B4 (iLTB4), and pain after periodontal surgery and to evaluate the effect of the non-steroidal anti-inflammatory drug (NSAID), ibuprofen, on these levels. Two contralateral quadrants in each of nine patients were selected to undergo separate surgical procedures, one with ibuprofen (800 mg 1 hour presurgery and 400 mg postsurgery) and one with a placebo. Intra-operatively, a custom-made microdialysis probe, with a 3,000 dalton molecular weight cut-off, was inserted beneath the soft tissue flap and a dialysate collected every 20 minutes for 4 hours after surgery. Pain perception was measured at the same time intervals using two pain scales. Dialysate samples were assayed using two enzyme immunoassays. Mean tissue levels of iPGE2 in the placebo group increased from 74 nM at 40 minutes to a peak of 261 nM at 200 minutes. Mean tissue levels of iLTB4 in the placebo group fluctuated between 0.2 and 0.6 nM. Pain levels in this group increased continuously with time, peaking at 4 hours. Mean tissue levels of iPGE2 in the ibuprofen group were significantly suppressed, exhibiting more than a 95% reduction. This was accompanied by a significant reduction in pain. Ibuprofen had no detectable effect on tissue levels of iLTB4. These data indicate that iPGE2 and iLTB4 are present at relatively high concentrations in the periodontal tissues after surgery. Since these concentrations exceed the Kd values for binding to their respective receptors, PGE2 and LTB4 may be associated with the development of postsurgical pain and inflammation. These data also indicate that ibuprofen can successfully inhibit iPGE2 production in the periodontal tissues and in this way may help reduce postoperative pain and inflammation.

Pharmacology of peripheral neuropeptide and inflammatory mediator release.

Research conducted in the last 10 years has increased our knowledge on pain mechanisms substantially. Although many local tissue mediators, including neuropeptides, are known to exert pro-inflammatory effects, comparatively little is known about the actual tissue levels of these inflammatory mediators and their pharmacologic regulation. This article describes two new methods, clinical microdialysis and superfusion of dental pulp, which provide data on the pharmacology of peripheral neuropeptide and inflammatory mediator release. Collectively, these methods provide a biochemically based approach toward determining the mechanisms and management of orofacial pain.

Effect of flurbiprofen on tissue levels of immunoreactive bradykinin and acute postoperative pain.

This study evaluates whether preoperative administration of flurbiprofen alters the levels of immunoreactive bradykinin (iBK) peripherally released into inflamed tissue. Thirty-six patients were randomly treated on a double-blind basis with either flurbiprofen (100 mg) or placebo before the surgical extraction of impacted third molars. Microdialysis probes were implanted into the surgical site and dialysates, and subjective pain reports were collected every 15 minutes for 4 hours after surgery. Tissue levels of iBK were measured using a radioimmunoassay. Preoperative administration of flurbiprofen significantly reduced patients' reports of pain from 120 to 240 minutes after surgery and blocked the peak increase in tissue levels of iBK (135 to 150 minutes after surgery). Although these results indicate that flurbiprofen has an "antibradykinin" effect, the analgesia both preceded and persisted beyond the inhibition of iBK levels. Accordingly, an antibradykinin effect may only partly contribute to flurbiprofen analgesia. The data are consistent with the hypothesis that prostaglandins contribute to the peak release of iBK owing to the potent inhibition of prostaglandin synthesis by flurbiprofen, but other yet unidentified mediators are also required for the sustained release of this inflammatory mediator into the surgical field.

Bradykinin and inflammatory pain.

The pro-inflammatory pharmacology of bradykinin has been well established. However, knowledge of the actual tissue concentrations and pharmacological manipulation of immunoreactive bradykinin in clinical and animal models of inflammation remain relatively sparse. We have developed a microdialysis method to implant probes into the inflamed tissue compartment in order to collect dialysate continuously in patients following the surgical removal of impacted third molars. Dialysate samples can be analyzed for levels of inflammatory mediators (eg., bradykinin, prostaglandins, etc) and drugs in order to determine the time-response curves for local release of substances in inflamed tissue.

Extracranial and mandibular augmentation with hydroxyapatite-collagen in induced diabetic and nondiabetic rats.

This study evaluated three hydroxyapatite (HA) preparations placed subperiosteally in rats given streptozotocin (70 mg/kg) to induce diabetes (ID) (n = 24) and in nondiabetic (ND) rats (n = 24) used as controls. Implants of 1) nonporous HA granules (HAG), 2) HA granules hand-mixed with bovine collagen (HACM), and 3) HA granules and purified fibrillar collagen in a preprocessed block (PFC-HA) were randomly placed in subperiosteal pockets created on the cranium and adjacent to the left/right mandibles of each rat. Six rats from each group were killed at 3, 6, 12, and 24 weeks postimplantation. Animals killed after 3 weeks showed sporadic bone proliferation and bone resorption, whereas those killed after 6, 12, and 24 weeks showed formation of new bone at the implant/bone interface. Contact of the implant with bone was a requirement for osteogenesis, but bone formed only into the basilar layers of the implants. The ID group showed the greatest inflammatory response as well as the greatest degree of osteogenesis at all intervals of time. The addition of collagen to HA appeared to reduce the inflammatory response. Specimens implanted with HACM showed the least inflammation of the three implanted materials in both ID and ND groups.

Subcutaneous implantation of hydroxylapatite/collagen in induced diabetic and non-diabetic rats.

To evaluate tissue reaction to hydroxylapatite (HA) and HA/collagen mixtures in rats with uncontrolled induced diabetes, 48 males were divided: 24 with induced diabetes (ID) from Streptozotocin (70 mg/kg) and 24 non-diabetic (ND) controls. Three subcutaneous sites in each chest were randomly implanted with non-porous HA, or non-porous HA and bovine collagen, or non-porous HA and purified fibrillar collagen. Subgroups of 6 ID and 6 ND rats were killed at 4, 6, 12, and 24 weeks post-implantation. Histologic specimens showed that all materials elicited greater inflammatory response in ID than in ND at all intervals. Each specimen had HA particles encapsulated by host fibrous tissue. Compared to ND, ID specimens had markedly reduced ingrowth and maturity of collagen at each time interval. There was no osteogenesis, but there was dystrophic mineralization within the implant sites in both ID and ND. Mixed HA/collagen exceeded HA alone in maintaining implant contour. In soft tissue, no materials were osteoinductive. Adding collagen did not increase or decrease inflammatory reaction nor improve density and maturity of tissue synthesized around implants.