Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain.

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

OBJECTIVES: To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). RESULTS: Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CONCLUSIONS: CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.

Components of Patient Satisfaction After Orthognathic Surgery.

The purpose of this study was to compare overall patient satisfaction after orthognathic surgery with the following specific categories: appearance, functional ability, general health, sociability, and patient-clinician communication. A 16-question survey was developed and administered to include patients at either 6 or 12 months after orthognathic surgery between June 2013 and June 2014 at the University of Pennsylvania and Massachusetts General Hospital. The predictor variables included age, sex, type of procedure, medical comorbidities, intra- or postoperative complications, and presence of paresthesia. The outcome variable was patient satisfaction overall and in each category based on a Likert scale (0: not satisfied at all to 5: very satisfied).A total of 37 patients completed the survey and had a high overall rate of satisfaction (100% of responses were 4 or 5 on Likert scale). Overall satisfaction had the highest correlation with appearance (ρ=0.52, P=0.0009) followed by sociability (ρ=0.47, P=0.004), patient-clinician communication (ρ=0.38, P=0.02) functionality (ρ=0.19, P=0.26), and general health (ρ = -0.11, P = 0.51). Patients had high satisfaction scores for orthognathic surgery. Satisfaction with postoperative appearance had the strongest correlation with overall satisfaction.

The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings.

BACKGROUND: The authors evaluated the cardiovascular effects and pharmacokinetics of an intranasal 3 percent tetracaine/0.05 percent oxymetazoline spray developed to provide needle-free anesthesia of maxillary teeth. METHODS: The authors administered to 12 participants a proposed maximum recommended dose (MRD) (18 milligrams tetracaine/0.3 mg oxymetazoline) as three bilateral pairs of 0.1-milliliter nasal sprays. They administered two times this dose (36 mg tetracaine/0.6 mg oxymetazoline) as six bilateral pairs one to three weeks later. The authors recorded the patients' heart rate, blood pressure and oxygen saturation. They drew blood samples at baseline and 15 times during the two hours after drug administration. RESULTS: Physiological measures remained fairly stable throughout the two-hour period, with small but significant decreases (P < .05) in heart rate at 40 and 50 minutes for the two-times MRD (6.1 beats/minute) and MRD (7.5 beats/minute) administrations, respectively, and a significant increase in diastolic blood pressure (5.9 millimeters of mercury) for the two-times-MRD administration at 90 minutes. Mean oxygen saturation remained above 99 percent. Tetracaine plasma levels were undetectable in most participants, whereas concentrations of its major metabolite parabutylaminobenzoic acid from the two-times-MRD administration were approximately twice that from the MRD administration. Oxymetazoline concentrations from the two-times-MRD administration were approximately 50 percent greater than those from the MRD administration, with a half-life of 1.72 to 2.32 hours. CONCLUSIONS: Intranasal tetracaine/oxymetazoline mist generally was well tolerated in study participants. CLINICAL IMPLICATIONS: The safety profile and pharmacokinetics of this intranasal formulation indicate that it appears to be generally well tolerated in patients for achieving anesthesia of the maxilla. Additional safety and efficacy data are required, particularly in patients with cardiovascular disease and other comorbidities.

Double-blind, placebo-controlled, randomized pilot study of cerebral blood flow patterns employing SPECT imaging in dental postsurgical pain patients with and without pain relief.

BACKGROUND: Single-photon emission computed tomography (SPECT) has been employed in the study of altered regional cerebral blood flow (CBF) in experimental and chronic pain. CBF patterns have not been evaluated in patients with acute postoperative pain. OBJECTIVE: The purpose of this pilot study was to employ SPECT to measure CBF distribution associated with postoperative dental pain and to compare these CBF patterns to subsequent images in the same patients who were experiencing pain relief versus continued or worsening pain who had received active or placebo analgesic interventions. The primary outcome measure was the percentage change in blood flow in various regions of interest. METHODS: Twenty-two healthy individuals (10 males and 12 females, age range 20-29 years) who underwent the removal of ≥1 partial or full bony impacted mandibular third molars were evaluated for pain intensity as the local anesthesia dissipated, employing a 0 to10 numeric rating scale (0 = no pain; 10 = worst imaginable). When the subjects' pain level reached ≥4/10, they were injected intravenously with 260 MBq of technetium Tc 99m bicisate (ethyl cysteinate dimer). Under double-blind conditions and 10 minutes before being placed in the SPECT scanner, the first 10 subjects were randomized to receive intravenous ketorolac 15 mg or saline while the remaining 12 subjects were randomized to receive by mouth either ibuprofen 400 mg, ibuprofen 200 mg, acetaminophen 1000 mg, or placebo. One hour after drug administration, subjects were reevaluated for pain, injected with 925 MBq of technetium Tc 99m bicisate, given rescue medication if required, and then rescanned. CBF ratios were obtained for regions of interest and by normalizing to average whole brain activity. RESULTS: Subjects generally had a moderate degree (mean [SD], 7.3% [4.0%]) of thalamic asymmetry on initial scans with pain; after treatment, subjects reporting worsening pain regardless of the intervention had higher thalamic asymmetry (8.1% vs 2.8%) than those reporting relief of pain. Subjects who reported reduced pain after the intervention had significantly different (P < 0.05) mean CBF changes compared with those reporting worsening pain in the left prefrontal cortex, left sensorimotor area, right anterior cingulate, and right caudate. CONCLUSIONS: Acute postoperative dental pain was associated with moderate thalamic asymmetry that improved following successful pain management. Sustained or worsening pain was associated with increased CBF in brain regions associated with pain pathways, whereas pain relief was associated with decreased activity in the same areas.

Human bone marrow stromal cells display variable anatomic site-dependent response and recovery from irradiation.

OBJECTIVES: Orofacial bone is commonly affected by osteoradionecrosis (ORN) during head and neck cancer radiotherapy possibly due to interactions of several factors including radiation damage to resident bone marrow stromal cells (BMSCs). Irradiation causes DNA damage, triggers p53-dependent signalling resulting in either cell-cycle arrest or apoptosis. In same individuals, disproportionately higher rapid growth of orofacial BMSCs relative to those of axial/appendicular bones suggests their response to radiation is skeletally site-specific. We hypothesised that survival and osteogenic recovery capacity of irradiated human BMSCs is site-dependent based on anatomic skeletal site of origin. METHODS: Early passage BMSCs from maxilla, mandible and iliac crest of four normal volunteers were exposed to 2.5 to 10 Gy gamma radiation to evaluate clonogenic survival, effects on cell cycle, DNA damage, p53-related response and in vivo osteogenic regenerative capacity. RESULTS: Orofacial bone marrow stromal cells (OF-MSCs) survived higher radiation doses and recovered quicker than iliac crest (IC-MSCs) based on clonogenic survival, proliferation and accumulation in G0G1 phase. Post-irradiation p53 level was relatively unchanged but expression of p21, a downstream effector was moderately increased in OF-MSCs. Re-establishment of in vivo bone regeneration was delayed more in irradiated IC-MSCs relative to OF-MSCs. CONCLUSIONS: Effect of irradiation on human BMSCs was skeletal site-specific with OF-MSCs displaying higher radio-resistance and quicker recovery than IC-MSCs.

The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100,000 and 1:200,000 epinephrine.

OBJECTIVES: The authors conducted a randomized, double-blind, two-way crossover clinical trial to compare the pharmacokinetics and cardiovascular effects of 11.9 milliliters of 4 percent articaine hydrochloride (HCl) plus 1:100,000 epinephrine (A100) with those of 11.9 mL of 4 percent articaine HCl plus 1:200,000 epinephrine (A200). METHODS: During two testing sessions, the authors administered injections of A100 and A200 over a seven-minute period (in one-cartridge doses unless otherwise noted): maxillary right first molar infiltration, maxillary left first molar infiltration, maxillary right first premolar infiltration, maxillary left first premolar infiltration, right inferior alveolar injection, left inferior alveolar injection, right long buccal infiltration (one-half cartridge) and left long buccal infiltration (one-half cartridge). They analyzed venous blood samples for articaine levels. They used noninvasive acoustic tonometry to measure a variety of cardiovascular parameters over a two-hour period. RESULTS: Plasma concentration curves of articaine over time were similar for both solutions, with peak concentrations and times to maximum concentration being 2,037 nanograms per milliliter and 22 minutes for A100 and 2,145 ng/mL and 22 minutes for A200. At the 10-minute point, the mean systolic blood pressure and heart rate were significantly elevated (P < .05) with A100 versus A200. CONCLUSIONS: Maximum dose recommendations for the A100 solution also can be applied to the A200 solution. A200 produces less cardiovascular stimulation than does A100. CLINICAL IMPLICATIONS: A200 is as safe as A100, and may be preferable to A100 in patients with cardiovascular disease and in those taking drugs that reportedly enhance the systemic effects of epinephrine.

Evaluation of an oral mandibular advancement titration appliance.

OBJECTIVES: To determine whether a manually adjustable oral mandibular advancement titration appliance (EMA-T) predicts successful long-term treatment with an oral mandibular advancement appliance (MAA). STUDY DESIGN: At an academic medical center, 21 adults with obstructive sleep apnea (AHI > 10 events/hr) performed baseline, titration, and MAA (Klearway) polysomnograms. During the titration polysomnogram with EMA-T, the mandible was advanced until apneas and hypopneas were eliminated or maximum tolerable advancement was reached. Participants then used the MAA at home and, once the mandible was advanced to the amount determined during the titration polysomnogram, a polysomnogram with MAA was performed. RESULTS: Mean AHI at baseline was 33.5 +/- 18.3 (SD) events/hr. During the titration polysomnogram, 9 subjects achieved an AHI < 10 and at least a 50% reduction in AHI. None of the subjects met these criteria on the MAA polysomnogram. CONCLUSIONS: EMA-T lowered the AHI to efficacious levels in 43% of patients but this acute response did not predict the efficacy of long-term MAA treatment.

Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain.

BACKGROUND: ProSorb diclofenac potassium (K) is a novel, liquid-filled rapid-dispersion formulation of the nonsteroidal anti-inflammatory drug diclofenac, placed into soft gelatin capsules. Its time to maximal plasma drug concentration has been shown to be approximately half, and its maximal plasma drug concentration nearly twice, that of immediate-release diclofenac K tablets. OBJECTIVE: This study compared the analgesic dose-response relationship and tolerability of 3 doses of ProSorb diclofenac K and placebo in the treatment of pain after dental impaction surgery. METHODS: This randomized, double-blind, double-dummy, placebo-controlled parallel-group study was conducted at 6 centers across the United States. Patients aged 18 to 65 years with moderate or severe pain after the removal of > or =1 impacted mandibular third molar were randomly assigned to receive a single dose of ProSorb diclofenac K 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed up to 6 hours after dosing. Rescue treatment was allowed after 1 hour. Efficacy end points included the summed pain intensity difference over 3 and 6 hours (SPID3 and 6); total pain relief at 3 and 6 hours (TOTPAR3 and 6); median times to onset of perceptible and meaningful relief (analgesic onset) and rescue medication use (analgesic duration); and cumulative percentage of patients using rescue medication. Tolerability was assessed using vital sign measurements and spontaneous reporting of adverse events. RESULTS: A total of 265 patients (154 women, 111 men; mean age, 23.3 years) were enrolled. All 3 ProSorb diclofenac K groups showed higher SPID6 and TOTPAR6 scores and longer median times to rescue medication use than the placebo group (all, P < 0.001). For these end points, a dose-response relationship was evident between the 100-mg dose and the 25- and 50-mg doses (P < or = 0.05); the 25- and 50-mg doses were similar. In the diclofenac groups, median onset times for first perceptible (< or =22.5 min) and meaningful (< or =53.0 min) relief were significantly more rapid than placebo (P < or = 0.01). Proportions of patients requiring rescue analgesic were < or =50.8% with diclofenac compared with 79.4% with placebo. Proportions of patients assigning a global evaluation of good or better was > or =68% with diclofenac compared with 21% for placebo. Tolerability was similar across all treatment groups. CONCLUSION: In this study of patients treated for pain following dental impaction surgery, single doses of ProSorb diclofenac K 25, 50, and 100 mg were more efficacious than placebo with respect to reduction of pain. All 3 doses provided a rapid analgesic onset and were well tolerated.