Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways.

PURPOSE: Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson's. The symptoms in Parkinson's including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT). PATIENTS AND METHODS: Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19-21, D21), completion (days 38-42, D42), and four weeks post-EBRT (days 68-72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach. RESULTS: Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p<0.001) and ELISA (p<0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r=0.55, p<0.05) and plasma α-synuclein concentrations on D42 of EBRT (r=0.54, p=0.04). CONCLUSION: Fatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.

COX inhibitors downregulate PDE4D expression in a clinical model of inflammatory pain.

Tumor necrosis factor-alpha (TNF-alpha) has a central role in inflammation and is modulated by prostaglandin E(2) (PGE(2)) and cyclic adenosine monophosphate (cAMP). Using microarray, quantitative real-time polymerase chain reaction (qRT-PCR), and protein detection techniques, we showed that ketorolac and rofecoxib had no significant effect on TNF-alpha gene expression in oral mucosal biopsies 3 h after surgery. They both, however, downregulated the gene and protein expression of phosphodiesterase type 4 (PDE4D), which might represent a novel mechanism contributing to their analgesic and anti-inflammatory effects.

Evidence of safety for individualized dosing of enteral sedation.

Fear of dentistry is a pervasive and persistent phenomenon that contributes to avoidance of dental care and results in a substantial public health problem. While the use of incremental enteral sedation has increased, there is a paucity of published evidence to evaluate its safety. This study sought to assess the safety of individualized dosing of enteral sedation for adults in the dental outpatient setting. The authors sent a mail survey to members of the Dental Organization for Conscious Sedation (DOCS) concerning their practice and practitioner characteristics. Anonymous treatment forms with monitoring records were collected from respondents and analyzed for pre-specified adverse event criteria. The majority of respondents reported practicing incremental enteral sedation for two to five years, accounting for less than 10% of their practice. Incremental enteral sedation, either alone or in combination with nitrous oxide and oxygen, was used most frequently. Monitoring with both pulse oximetry and automated blood pressure (BP) were prevalent. Triazolam was the drug used most commonly for enteral sedation. Of the 7740 cases submitted, 1686 (21.8%) met event criteria; the most frequent event was a decrease of more than 25% in diastolic BP from pre-drug baseline. Neither provider training nor the percentage of practices engaged in incremental enteral sedation were associated with any event; however, practicing incremental enteral sedation for less than 12 months was a significant predictor of any event (p = 0.001). Risk of having an event was not related to practice factors (that is, the time spent practicing incremental enteral sedation, the percentage of the practice devoted to practicing incremental enteral sedation, the number of cases performed, or the type of monitoring) or training factors. This survey represents the largest number of subjects reported in the literature concerning enteral sedation. These observations provide evidence for the safety of enteral sedation when these drugs and combinations are administered by properly-trained dentists who monitor patients with pulse oximetry, BP measurement, and direct observation.

Development and interim results of a clinical research training fellowship.

While the ability to base clinical training and patient care on scientific evidence is highly dependent on the results of translational and clinical research, a shortage of trained clinical investigators delays advances upon which to base evidence-based therapeutics. In response to this perceived shortage, a clinical research training program was developed in the Division of Intramural Research at the National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH) as a prototype for training health professionals in clinical research methodologies and their application to oral-craniofacial problems. All but one of the trainees initiated at least one clinical trial leading to a scientific publication. Of eleven fellows, ten completed the program with diverse outcomes: four trainees have entry-level academic or equivalent research positions; three trainees continued on to Ph.D. programs; one is completing a postdoctoral fellowship combined with clinical specialty training; one is completing a clinical residency; and two are in clinical practice. Six of the trainees received NIH funding, or the equivalent, in the NIH Intramural Research Program. These outcomes suggest that a program focused on translational and clinical research training is a successful strategy for improving the future supply of clinical researchers to support evidence-based practices and therapeutic innovation.

Genetic predictors for acute experimental cold and heat pain sensitivity in humans.

BACKGROUND: The genetic contribution to pain sensitivity underlies a complex composite of parallel pain pathways, multiple mechanisms, and diverse inter-individual pain experiences and expectations. METHODS: Variations for genes encoding receptors related to cold and heat sensation, such as transient receptor potential A subtype 1 (TRPA1), M subtype 8 (TRPM8), V subtype 1 (TRPV1), delta opioid receptor subtype 1 (OPRD1), catechol O-methyltransferase (COMT), and fatty acid amide hydrolyase (FAAH), were investigated in four major ethnic populations. RESULTS: We defined 13 haplotype blocks in European Americans, seven blocks in African Americans, seven blocks in Hispanic subjects, and 11 blocks in Asian Americans. Further study in European American subjects found significant associations between short duration cold pain sensitivity and variations in TRPA1, COMT, and FAAH in a gender dependent manner. Our observations demonstrate that genetic variations in TRPA1, COMT, and FAAH contribute gender specifically to individual variations in short duration cold pain sensitivity in a European American cohort. CONCLUSIONS: The effects of TRPA1 variations on experimental short duration heat pain sensitivity may contribute to inter-individual variation in pain sensitivity in humans.

The role of COX-2 in acute pain and the use of selective COX-2 inhibitors for acute pain relief.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain. Cyclooxygenase (COX) enzyme is of particular interest because it is the major target of NSAIDs. Although NSAIDs are remarkably effective in the management of pain and inflammation, their use is limited by several adverse effects including gastrointestinal bleeding and ulceration, impaired renal function, and inhibition of platelet aggregation. Discovery of a second cyclooxygenase, COX-2, led to the hypothesis that NSAID side effects could be decreased, as the inhibition of COX-2 is more directly implicated in ameliorating inflammation while the inhibition of COX-1 is related to adverse effects in the GI tract. This stimulated the development of selective COX-2 inhibitors (coxibs) that are better tolerated than nonselective NSAIDs but comparable in analgesic efficacy. This article provides an overview on the therapeutic use of selective COX-2 inhibitors for relief of acute pain, largely based on clinical trials in patients undergoing the surgical removal of impacted third molars, with focus on analgesic efficacy and the potential safety associated with their use compared to dual COX-1/COX-2 inhibitors.

Immunohistochemical localization of mu-opioid receptors in human dental pulp.

Studies in both animal and clinical models suggest that opioids exert their analgesic effects not only through activation of receptors in the CNS but also through interaction with peripheral opioid receptors. This study evaluated the presence and distribution of mu-opioid receptors in human dental pulp. Human third molars indicated for extraction were removed, fixed in 4% paraformaldehyde and 0.2% picric acid, and decalcified in 10% EDTA and 7.5% polyvinylpyrrolidone. The teeth were cut using a cryostat, and the avidin-biotin peroxidase immunohistochemistry technique was used. Immunostaining for mu-opioid receptors was detected along the nerve bundle of the radicular as well as coronal dental pulp. Positive immunostaining was also observed in the individual nerve fibers in the coronal region. This demonstration of opiate receptors on pulpal nerve fibers suggests a peripheral site in the dental pulp where endogenous or exogenous opioids can interact with mu-opioid receptors.

Analgesia and COX-2 inhibition.

While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia.

Therapeutic uses of non-steroidal anti-inflammatory drugs in dentistry.

The non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of drugs for the management of acute and chronic pain in dentistry. Their therapeutic efficacy and toxicity are well-documented and provide evidence that NSAIDs generally provide an acceptable therapeutic ratio of pain relief with fewer adverse effects than the opioid-mild analgesic combination drugs that they have largely replaced for most dental applications. The great many studies done with the oral surgery model of acute pain indicate that a single dose of an NSAID is more effective than combinations of aspirin or acetaminophen plus an opioid, with fewer side-effects, thus making it preferable for ambulatory patients. The combination of an NSAID with an opioid generally results in marginal analgesic activity but with an increased incidence of side-effects, which limits its use to patients in whom the NSAID alone results in inadequate analgesia. The selective COX-2 inhibitors hold promise for clinical efficacy with less toxicity from chronic administration and may prove advantageous for the relief of chronic orofacial pain. The use of repeated doses of NSAIDs for chronic orofacial pain should be re-evaluated in light of a lack of documented efficacy and the potential for serious gastrointestinal and renal toxicity with repeated dosing.

Comparing efficacy and safety of four intravenous sedation regimens in dental outpatients.

BACKGROUND: Management of patients' fear and anxiety during dental treatment is a primary concern of dental practitioners. Pharmacological strategies used in outpatient dental settings must be both safe and effective. Regimens of intravenously administered sedative drugs were evaluated in a collaborative, multicenter study of outpatients undergoing removal of impacted third molars. METHODS: A total of 997 patients randomly received one of five treatments: placebo; midazolam administered to a clinical endpoint of conscious sedation (mean dose, 8.6 milligrams); midazolam plus additional midazolam as needed during the procedure (mean total dose, 12.2 mg); fentanyl (1.4 micrograms/kilogram) plus midazolam to achieve the same endpoint of conscious sedation (mean dose, 5.7 mg); or fentanyl (1.4 (micrograms/kg), midazolam (mean dose, 5.8 mg) and methohexital as needed during the procedure (mean dose, 61.0 mg). RESULTS: Each drug regimen reduced anxiety during surgery in comparison with placebo, with the combination of midazolam, fentanyl and methohexital resulting in significantly less anxiety in comparison with the other treatment groups. Pain reports by patients during surgery also were reduced significantly by the combination of fentanyl, midazolam and methohexital. Patients' global evaluations of the efficacy of sedation ranked midazolam with supplemental midazolam and the combination of fentanyl, midazolam and methohexital as significantly more efficacious than the other two drug regiments. The authors noted transient respiratory depression in patients in the two opioid-treated groups, but no other physiological changes were detected. CONCLUSIONS: These data provide evidence that the drugs and doses evaluated resulted in therapeutic benefit to dental outpatients, with minimal incidence of potentially serious adverse effects. CLINICAL IMPLICATIONS: The results of this large-scale study provide assurance to both the public and the dental profession of the safety of parenteral sedation with these drugs and combinations of these drugs when titrated slowly in the recommended doses by appropriately trained dentists.

Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation.

A series of double-blind, placebo-controlled clinical trials demonstrated that low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a dose-related naloxone-reversible analgesia. This analgesic effect is mediated by a local mechanism in the inflamed tissue, because subcutaneous administration of a 1.2 mg dose of morphine failed to elicit an analgesic response. In contrast, submucosal administration of 1.2 mg morphine or 50 microg fentanyl to the site of extraction of an impacted third molar after the onset of acute pain failed to elicit an analgesic response despite demonstration of a sensitive bioassay. These data indicate that peripheral opioid analgesia can be evoked in a model of chronic, but not acute, inflammatory pain, suggesting a temporal dependent mechanism needed for the expression of peripheral opiate analgesia during inflammation in humans.

Pharmacologic advances in orofacial pain: from molecules to medicine.

The management of chronic orofacial pain often follows a pattern of claims of efficacy based on clinical observations superseded by equivocal findings of effectiveness or belated recognition of toxicity. While therapeutic innovation spurred by genomics and proteomics is likely to result in new drugs for pain, inflammation, and neuropathic pain, the process of drug development and approval takes five to ten years and is often unsuccessful. Therapeutic strategies for improving treatment for chronic orofacial pain are proposed, but recognition of impediments to changing clinical practices suggest the need for interim measures. Greater understanding of the molecular and genetic events that contribute to pain chronicity and interindividual variations in pain responsiveness may eventually result in individualized molecular pain medicine to prevent and treat chronic orofacial pain.

Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain.

BACKGROUND: Previous studies suggest that 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA)/kainate antagonists reduce experimentally induced pain. There have been no studies of AMPA/kainate antagonists in clinical pain. METHODS: Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 30 mg) and placebo in a randomized, double-blind, parallel-group study after oral surgery (n = 70). Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. RESULTS: High-dose LY293558 and ketorolac tromethamine were superior to placebo (P < .05) for pain evoked by mouth opening and one of several measures of spontaneous pain: SPID240 +/- SEM for pain evoked by mouth opening was highest for ketorolac tromethamine (151 +/- 58), intermediate for high-dose LY293558 (-45 +/- 35), and least for low-dose LY293558 (-151 +/- 39) and placebo (-162 +/- 50). High-dose LY293558 was superior to placebo at individual time points (45 to 240 minutes) for pain evoked by mouth opening but not for spontaneous pain. The spontaneous summed pain intensity difference over 240 minutes (SPID240 +/- SEM) was highest for ketorolac tromethamine (303 +/- 84), intermediate for high-dose LY293558 (-51 +/- 40) and low-dose LY293558 (-96 +/- 45), and least for placebo (-180 +/- 24). LY293558 was well tolerated, with dose-dependent and reversible side effects including hazy vision in 20% of patients and sedation in 15%. CONCLUSIONS: This is the first evidence that an AMPA/kainate antagonist reduces clinical pain. Tests of evoked pain may be more sensitive to certain analgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful compounds otherwise missed if only spontaneous pain is evaluated.

SYM-2081 a kainate receptor antagonist reduces allodynia and hyperalgesia in a freeze injury model of neuropathic pain.

Cold-freeze injury at -4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)-4-methylglutamic acid (SYM-2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague-Dawley rats were evaluated for frequency of withdrawal from von Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to -4 degrees C for 15 min (n=24). For control rats (n=24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post-operative day, SYM-2081 (150 or 100 mg/kg), fentanyl citrate (0. 04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p<0.05). SYM-2081 and fentanyl significantly reduced these responses (p<0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.

Antidepressants for chronic orofacial pain.

The management of chronic orofacial pain has a history of therapeutic misadventures, charismatic-based treatment philosophies, controversies over the correct nomenclature, and a lack of scientific documentation. The dental profession has struggled to develop a systematic approach to nomenclature, treatment, and clinical research through numerous conferences, workshops, and consensus attempts. Despite these efforts, there is no generally accepted agreement on the etiology of chronic orofacial pain, its natural history, the role of occlusion, the need for aggressive treatment, or the effectiveness, safety, and indications for most current practices. These professional differences are often fostered by a lack of appreciation for the difference between clinical observations, which may form the basis for therapeutic innovation, and the need to verify the safety and efficacy of treatments in studies that control for factors that can mimic clinical success. This article describes the use of antidepressants as an example for the treatment of chronic orofacial pain. The treatment arose from the clinical observations of astute clinicians, but was subjected to scientific validation in well-controlled clinical trials.

Additive analgesic effects of oxycodone and ibuprofen in the oral surgery model.

PURPOSE: A traditional approach to achieve greater analgesic efficacy is to combine an efficacious dose of a nonopioid with a dose of an opioid sufficient to produce additive analgesia without a substantial increase in the incidence of adverse effects. This study evaluated the additive analagesic effects of the combination of ibuprofen and oxycodone. PATIENTS AND METHODS: A dose of 400 mg ibuprofen was compared with 400 mg ibuprofen with oxycodone in doses of 2.5, 5, or 10 mg in the oral surgery model of acute pain. Analgesic efficacy was measured with category and visual analog scales at 15, 30, 45, and 60 minutes and hourly up to 6 hours. RESULTS: Ibuprofen plus 10 mg oxycodone produced significantly greater analgesia compared with the other three groups, as measured by the visual analog scale from 15 minutes after drug administration up to the 2-hour observation. All four treatments were similar from 3 to 6 hours, with the area under the pain intensity difference curve being similar across groups. Neither the 2.5-mg nor the 5-mg oxycodone dose provided any additive analgesia over ibuprofen at any points. Addition of oxycodone resulted in a dose-related increase in the number of patients reporting adverse effects, with significantly greater drowsiness and vomiting at the 10-mg dose. CONCLUSIONS: These results indicate that additive analgesia can be achieved for the combination of a nonsteroidal anti-inflammatory drug and an orally effective opioid, with faster onset of relief for the combination of 400 mg ibuprofen and 10 mg oxycodone over the first 2 hours after administration, but at the expense of an increased incidence of adverse events.

Analgesic efficacy and pharmacokinetics of ketoprofen administered into a surgical site.

A series of three clinical trials in the oral surgery model evaluated the analgesic efficacy and pharmacokinetics of ketoprofen administered locally as a strategy for decreasing systemic exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). A gel formulation was administered directly into extraction sites 1 hour following oral surgery, and pain intensity was evaluated for 6 hours. Significantly less pain was seen following peripheral administration of both 10 and 30 mg ketoprofen in comparison to the placebo. In a second study, peripheral administration of the 1 mg dose resulted in greater analgesia than oral administration of the same dose formulation or the placebo. The third study demonstrated lower plasma drug levels following the peripheral route of administration in comparison to oral administration of the same dose or ingestion of a 25 mg oral capsule. These data indicate that administration of an NSAID to a peripheral site of tissue injury results in greater analgesia than oral administration and suggests the potential for less drug toxicity through lower circulating drug levels.

Antihyperalgesic effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan in the oral surgery model.

Peripheral neuronal barrage from tissue injury produces central nervous system hyperexcitability through the activation of N-methyl-D-aspartate (NMDA) receptor sites by excitatory amino acids and neuropeptides. This study evaluated if attenuation of NMDA receptor activation with dextromethorphan (DM) suppresses the postoperative development of hyperalgesia. Seventy-five patients undergoing oral surgery in a parallel-group, double-blind study randomly received either a placebo or the maximally tolerated dose of DM administered orally prior to and continuing for 48 hours following surgery. Pain as measured by category, visual analog, and verbal descriptor scales was not significantly different between groups during the first 6 hours following surgery. However, pain at 48 hours was decreased in the DM group as measured by scales for pain intensity and unpleasantness. Subjects in the DM group also self-administered fewer acetaminophen tablets for unrelieved pain over 24 to 48 hours postoperatively. The results suggest that DM at maximally tolerated doses does not produce an analgesic effect in the immediate postoperative period but reduces pain at 48 hours. This may be related to antagonism of NMDA receptors necessary for the expression of hyperalgesia associated with noxious afferent input postoperatively.

The substance P receptor antagonist CP-99,994 reduces acute postoperative pain.

BACKGROUND: Animal studies suggest that substance P, a peptide that preferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammation. METHODS: The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surgery: 750 microg/kg CP-99,994 infused intravenously over 5 hours on a tapering regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects were randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset. RESULTS: In the first study, ibuprofen significantly reduced pain, as measured by visual analog scale, from 90 to 240 minutes postoperatively compared with placebo. CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 60, 90, and 120 minutes (P < 0.05). The incidence of side effects was similar across groups. CONCLUSIONS: This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis that substance P contributes to the generation of pain in humans. The reduction in postoperative pain at doses not producing side effects suggests that NK1 antagonists may be clinically useful.