Efficacy of oral diclofenac with or without codeine for pain control after invasive bilateral third molar extractions.

Postoperative pain and inflammation after oral surgery is mostly managed using non-steroidal anti-inflammatory drugs (NSAIDs). However, opioids combined with NSAIDs may improve pain management in patients, especially after traumatic oral surgery. Few studies have compared NSAIDs with and without opioid use after oral and maxillofacial surgery. This randomized, double-blind, cross-over study compared the clinical efficacy of either diclofenac (50mg) and codeine (50mg) or diclofenac alone (50mg) for the management of postoperative pain after invasive third molar surgery. Volunteers (n=46) who were scheduled to undergo the removal of symmetrically positioned lower third molars in two separate appointments were included. They reported significantly less postoperative pain at various time points within 24h after surgery and also consumed significantly less rescue medication (paracetamol (acetaminophen)) throughout the study when they took diclofenac combined with codeine than when they took only diclofenac. In conclusion, oral diclofenac with codeine was more effective for managing postoperative pain than diclofenac without codeine. It was expected that patients taking two pain medications after surgery would generally have less pain than when taking only one of the two medications. The prospective cross-over design of the present work makes this study distinct from many others.

Efficacy of naproxen with or without esomeprazole for pain and inflammation in patients after bilateral third molar extractions: A double blinded crossover study.

BACKGROUND: Using a double-blinded randomized crossover design, this study aimed to evaluate acute postoperative pain management, swelling and trismus in 46 volunteers undergoing extractions of the two lower third molars, in similar positions, at two different appointments who consumed a tablet of either NE (naproxen 500 mg + esomepraz ole 20 mg) or only naproxen (500 mg) every 12 hours for 4 days. MATERIAL AND METHODS: Parameters were analyzed: self-reported pain intensity using a visual analog scale (VAS) pre- and postoperative mouth opening; incidence, type and severity of adverse reactions; total quantity consumed of rescue medication; and pre- and postoperative swelling. RESULTS: Female volunteers reported significantly more postoperative pain at 1, 1.5, 2, 3 and 4hrs after surgery while also taking their first rescue medication at a time significantly earlier when consuming NE when compared to naproxen (3.7hrs and 6.7hrs). Conversely, no differences were found between each drug group in males. CONCLUSIONS: In conclusion, throughout the entire study, pain was mild after using either drug in both men and women with pain scores on average well below 40mm (VAS), although in women naproxen improved acute postoperative pain management when compared to NE.

Efficacy and Safety of 2% and 4% Articaine for Lower Third Molar Surgery.

This double-blind crossover randomized clinical trial compared the efficacy of 2 concentrations of articaine, 2% (A2) and 4% (A4), with 1:200,000 epinephrine, for lower third molar removal. During 2 separate appointments with either A2 or A4, both similarly positioned lower third molars in 46 volunteers were extracted. The following were evaluated: onset and duration of anesthetic action on soft tissues, intraoperative bleeding, hemodynamic parameters, postoperative analgesia, and mouth opening and wound healing during the 7th postoperative day, along with the incidence, type, and severity of adverse reactions. Nearly identical volumes of both anesthetic solutions were used for each appointment: 3.4 ± 0.9 mL ≈ 68 mg of articaine (A2) and 3.3 ± 0.8 mL ≈ 132 mg of articaine (A4). Statistical analysis indicated no differences in onset or duration of anesthetic action on soft tissues or duration of postoperative analgesia evoked by A2 and A4 anesthetic solutions (P > 0.05). The surgeon's rating of intraoperative bleeding was considered minimal throughout all surgery with both anesthetic solutions. While transient changes in blood pressure, heart rate, and oxygen saturation were observed, these factors were clinically insignificant and were uninfluenced by articaine concentration (P > 0.05). No systemic or local adverse reactions were observed in the preoperative and postoperative periods due to A2 or A4, but 1 case of bilateral paresthesia was observed. There were no significant differences between preoperative and postoperative (7th day) values of mouth opening and wound healing whether volunteers received A2 or A4 (P > 0.05). In conclusion, both A2 and A4, administered in equal volumes, were effective and safe during lower third molar surgery, and no significant differences were found between their efficacy and safety (ClinicalTrials.gov NCT02457325).

Aerobic training prevents dexamethasone-induced peripheral insulin resistance.

This study investigated how proteins of the insulin signaling cascade could modulate insulin resistance after dexamethasone (Dexa) treatment and aerobic training. Rats were distributed into 4 groups: sedentary control (SC), sedentary+Dexa (SD), trained control (TC), and trained+Dexa (TD), and underwent aerobic training for 70 days or remained sedentary. Dexa was administered during the last 10 days (1 mg · kg(-1) per day i. p.). After 70 days, an intraperitoneal glucose tolerance test (ipGTT) was performed. Protein levels of IRS-1, AKT, and PKC-α in the tibialis anterior (TA) muscle were identified using Western blots. Dexa treatment increased blood glucose and the area under the curve (AUC) of ipGTT. Training attenuated the hyperglycemia and the AUC induced by Dexa. Dexa reduced IRS-1 (- 16%) and AKT (- 43%) protein level with no changes in PKC-α levels. Moreover, these effects on IRS-1 and AKT protein level were prevented in trained animals. These results show for the first time that aerobic exercise prevented reductions of IRS-1 and AKT level induced by Dexa in the TA muscle, suggesting that aerobic exercise is a good strategy to prevent Dexa-induced peripheral insulin resistance.

Comparison of oral versus sublingual piroxicam during postoperative pain management after lower third molar extraction.

In this study, 53 patients received piroxicam, administered orally or sublingually, after undergoing removal of symmetrically positioned lower third molars, during two separate appointments. This study used a randomized, blind, cross-over protocol. Objective and subjective parameters were recorded for comparison of postoperative results for 7 days after surgery. Patients treated with oral or sublingual piroxicam reported low postoperative pain scores. The patients who received piroxicam orally took a similar average amount of analgesic rescue medication compared with patients who received piroxicam sublingually (p>0.05). Patients exhibited similar values for mouth opening measured just before surgery and immediately following suture removal 7 days later (p>0.05), and showed no significant differences between routes of piroxicam administration for swelling control during the second or seventh postoperative days (p>0.05). In summary, pain, trismus and swelling after lower third molar extraction, independent of surgical difficulty, could be controlled by piroxicam 20mg administered orally or sublingually and no significant differences were observed between the route of delivery used in this study.

Differential endocannabinoid regulation of baroreflex-evoked sympathoinhibition in normotensive versus hypertensive rats.

Previously, we found that endocannabinoids acting at cannabinoid 1 receptors in the nucleus tractus solitarius prolonged baroreflex inhibition of renal sympathetic nerve activity in normotensive Sprague Dawley rats. The current study investigated whether endocannabinoid signaling was altered in spontaneously hypertensive rats, a model marked by elevated sympathetic activity and depressed baroreflex responses. The effects of endocannabinoids in the nucleus tractus solitarius on baroreflex control of renal sympathetic nerve activity evoked by systemic pressor changes or by direct stimulation of nucleus tractus solitarius neurons, which produced depressor and sympathoinhibitory responses, were studied in Sprague Dawley rats, Wistar Kyoto rats, and spontaneously hypertensive rats. Evoked responses were compared before and after microinjection of AM404, which prolonged actions of endogenous endocannabinoids, or microinjection of an endocannabinoid, anandamide, into the baroreceptive region of the nucleus tractus solitarius. AM404 microinjections significantly prolonged evoked sympathoinhibition in Sprague Dawley and Wistar Kyoto rats, but had little effect in spontaneously hypertensive rats. Microinjections of anandamide prolonged sympathoinhibition in Sprague Dawley rats, with lesser effects in Wistar Kyoto rats and no effects in spontaneously hypertensive rats. Parallel studies found that density of binding sites of endocannabinoids in the nucleus tractus solitarius was significantly reduced in spontaneously hypertensive rats versus the normotensive rats. Results indicate that attenuated function of the endocannabinoid system in the nucleus tractus solitarius of spontaneously hypertensive rats resulted in less modulation of baroreflex-evoked sympathoinhibition and that reduced cannabinoid 1 receptor density could contribute to blunted baroreflex-induced sympathoinhibition and elevated sympathetic tone characteristic of spontaneously hypertensive rats.

Postnatal developmental changes in CO2 sensitivity in rats.

Ventilatory sensitivity to CO(2) in awake adult Brown Norway (BN) rats is 50-75% lower than in adult Sprague-Dawley (SD) and salt-sensitive Dahl S (SS) rats. The purpose of the present study was to test the hypothesis that this difference would be apparent during the development of CO(2) sensitivity. Four litters of each strain were divided into four groups such that rats were exposed to 7% inspired CO(2) for 5 min in a plethysmograph every third day from postnatal day (P) 0 to P21 and again on P29 and P30. From P0 to P14, CO(2) exposure increased pulmonary ventilation (Ve) by 25-50% in the BN and SD strains and between 25 to over 200% in the SS strain. In all strains beginning around P15, the response to CO(2) increased progressively reaching a peak at P19-21 when Ve during hypercapnia was 175-225% above eucapnia. There were minimal changes in CO(2) sensitivity between P21 and P30, and at both ages there were minimal between-strain differences. At P30, the response to CO(2) in the SS and SD strains was near the adult response, but the response in the BN rats was 100% greater at P30 than in adults. We conclude that 1) CO(2)-sensing mechanisms, and/or mechanisms downstream from the chemoreceptors, change dramatically at the age in rats when other physiological systems are also maturing ( approximately P15), and 2) there is a high degree of age-dependent plasticity in CO(2) sensitivity in rats, which differs between strains.

Effects on breathing in awake and sleeping goats of focal acidosis in the medullary raphe.

Our aim was to determine the effects of focal acidification in the raphe obscurus (RO) and raphe pallidus (RP) on ventilation and other physiological variables in both the awake and sleep states in adult goats. Through chronically implanted microtubules, 1) a focal acidosis was created by microdialysis of mock cerebrospinal fluid (mCSF), equilibrated with various levels of CO2, and 2) medullary extracellular fluid (ECF) pH was measured by using a custom-made pH electrode. Focal acidosis in the RO or RP, by dialyzing either 25 or 80% CO2 (mCSF pH approximately 6.8 or 6.3), increased (P < 0.05) inspiratory flow by 8 and 12%, respectively, while the animals were awake during the day, but not at night while they were awake or in non-rapid eye movement sleep. While the animals were awake during the day, there were also increases in heart rate and blood pressure (P < 0.05) but no significant change in metabolic rate or arterial Pco2. Dialysis with mCSF equilibrated with 25 or 80% CO2 reduced ECF pH by the same amount (25%) or three times more (80%) than when inspired CO2 was increased to 7%. During CO2 inhalation, the reduction in ECF pH was only 50% of the reduction in arterial pH. Finally, dialysis in vivo only decreased ECF pH by 19.1% of the change during dialysis in an in vitro system. We conclude that 1) the physiological responses to focal acidosis in the RO and RP are consistent with the existence of chemoreceptors in these nuclei, and 2) local pH buffering mechanisms act to minimize changes in brain pH during systemic induced acidosis and microdialysis focal acidosis and that these mechanisms could be as or more important to pH regulation than the small changes in inspiratory flow during a focal acidosis.

Do genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to regulation of breathing?

As part of a large scale, high through-put physiologic genomics study, we sought to determine whether genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to phenotypic differences in the control of breathing between two inbred rat strains (SS/Mcw and BN/Mcw). Through a chromosomal substitution breeding strategy, we created 5 consomic rat strains (SS.BN9, SS.BN13, SS.BN16, SS.BN18, and SS.BN20), which were BN/Mcw homozygous at only one chromosome and SS/Mcw homozygous at all other chromosomes. Standard plethsmography was used to assess eupneic breathing and ventilatory responses to CO(2) (FI(CO(2))=0.07) and hypoxia (FI(CO(2))=0.12), and Pa(CO(2)) during treadmill exercises provided the index of the exercise hyperpnea. There were no robust differences in eupneic breathing between any strains. The ventilatory response to CO(2) was 150% greater (P<0.001) in the SS/Mcw rats than in the BN/Mcw rats and all consomic strains had the SS/Mcw phenotype. Hyperventilation during hypoxia did not differ between the parental and the consomic strains, but ventilation during hypoxia was greater (P<0.001) in the SS/Mcw than in the BN/Mcw, and the SS.BN9, and SS.BN18 appeared to acquire this BN/Mcw phenotype. The hyperventilation during treadmill walking was greater (P<0.006) in the BN/Mcw and the SS.BN18 rats than in the SS/Mcw rats. Finally, the duration of the apnea following an augmented breath (post sigh apnea, PSA) was greater (P<0.001) in the BN/Mcw and the SS.BN9 rats than all other strains. We conclude that the robust difference between the parental strains in ventilatory CO(2) sensitivity is not due to genotypic differences on the 5 chromosomes studied to date, but genotypic differences on chromosomes 9 and 18 contribute to differences in ventilatory responses to hypoxia, exercise, and/or to the differences in the PSA.

Serotonin and serotonin receptor expression in the aorta of carotid intact and denervated newborns.

Pharmacological blocking of serotonin (5-HT) 5A receptors abolishes aortic ventilatory chemosensitivity of carotid body denervated (CBD) piglets [J. Appl. Physiol. 92 (2002) 893]. Accordingly, the purpose of the present study was to determine whether 5-HT and 5-HT receptors exist at aortic sites that are chemosensitive after CBD. Aortas from CBD and sham CBD rats and piglets and from aortic denervated (AOD) and combined AOD+CBD piglets were harvested, sectioned and then studied using immunohistochemistry and western blot techniques. 5-HT immunoreactivity in piglets and rats was concentrated in the endothelium and sub-endothelial areas in several aortic regions studied, and in some areas also in the adventitia. At the aortic chemosensitive site (descending aorta in CBD piglets and the ascending aorta in CBD rats), the immunoreactivity was greater (P < 0.05) than in other aortic regions and greater than in other groups studied. The 5-HT(5a) receptor was expressed only at the chemosensitive sites and only in aortic innervated piglets. We conclude that the data from this and a previous study [J. Appl. Physiol. 92 (2002) 893] suggest that a serotonergic mechanism contributes to the aortic ventilatory chemoreflex after CBD.

Effects of carotid and aortic chemoreceptor denervation in newborn piglets.

The objective of the present study was to test the hypothesis that in neonatal piglets there would be no hypoventilation after sham denervation or aortic denervation (AOD) alone, but there would be transient hypoventilation after carotid body denervation (CBD) and the hypoventilation would be greatest after combined carotid and aortic denervation (CBD+AOD). There was a significant (P < 0.05) hypoventilation in CBD and CBD+AOD piglets denervated at 5, 15, and 25 days of age. The hypoventilation in CBD+AOD piglets denervated at 5 days of age was greater (P < 0.05) than that of all other groups. Conversely, sham-denervated and AOD piglets did not hypoventilate after denervation. Injections of sodium cyanide showed that aortic chemoreceptors were a site of recovery of peripheral chemosensitivity after CBD. This aortic sodium cyanide response was abolished by prior injection of a serotonin 5a receptor blocker. Residual peripheral chemosensitivity after CBD+AOD was localized to the left ventricle. We conclude that 1) aortic chemoreceptors contribute to eupneic breathing in piglets that were carotid denervated at 5 days of age and 2) there are multiple sites of residual peripheral chemosensitivity after CBD.

Mortality after carotid body denervation in rats.

Carotid body denervation (CBD) in neonatal goats and piglets results in minimal irregular breathing and no fatalities. Redundancy and/or plasticity of peripheral chemosensitivity and a relatively mature ventilatory control system at birth may contribute to the paucity of CBD effects in these species. In the present study, we tested the hypothesis that CBD mortality would be greater in neonates of a less mature species such as the rat. We found that the mortality in rats denervated at 2-3 and 7-8 days of age was significantly higher (P < 0.05) than in sham-CBD rats. In all surviving rats, pulmonary ventilation during hypoxia was lower in CBD than in sham operated rats 2 days after denervation. In surviving rats denervated during the 7th and 8th postnatal days, there was also reduced weight gain and pulmonary ventilation during eupnea, including apneas up to 20 s in duration. However, the effects of CBD were compensated within 3 wk after denervation. Local injections of NaCN indicated that aortic chemoreceptors might have been one of the sites of recovery of peripheral chemosensitivity. We concluded that CBD has higher mortality in newborn rats than in other mammals, possibly because of the relative immaturity of these animals at birth. Nonetheless, in survivors there was enough redundancy and plasticity in the control of breathing to eventually compensate for the consequences of CBD.

Anti-somatostatin antisera, but neither a somatostatin agonist (octreotide) nor antagonist (CYCAM), attenuates hyperalgesia in the rat.

Somatostatin has been reported to have both nociceptive and antinociceptive roles in sensory transmission in the spinal cord. In this study, antisera against SOM (alpha-SOM), a somatostatin antagonist (CYCAM) and a somatostatin agonist (octreotide), were evaluated for their role in thermal and mechanical hyperalgesia in a model of carrageenan-induced inflammatory pain in the rat. Intrathecal administration of alpha-SOM prior to hindpaw inflammation dose-dependently attenuated thermal and mechanical hyperalgesia and the increase in paw size for up to 4 h following injury. Administration of alpha-SOM 3 h following injury had no effect. Intrathecal administration of octreotide or CYCAM prior to or following injection of carrageenan had no effect on any measure. It is suggested that the lack of effect of octreotide and CYCAM resulted from low affinity for the SOM receptor subtypes in the rat spinal cord. The attenuation of hyperalgesia and paw size produced by alpha-SOM may have resulted from attenuation of somatostatin's role in producing a dorsal root reflex that modulates the increase in paw size following injury.