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.

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.

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.

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.

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.

Epinephrine suppresses stress-induced increases in plasma immunoreactive beta-endorphin in humans.

The present study evaluated the hypothesis that increased plasma levels of epinephrine (EPI) stimulate immunoreactive beta-endorphin (i beta END) secretion in humans experiencing a mild stress. The stressor consisted of intraoral injections of a local anesthetic solution (with or without EPI) just before the surgical extraction of impacted third molars in 26 awake unsedated patients. The EPI group experienced a 30-fold increase in plasma EPI levels by 2 min after injection; these concentrations were physiologically active, as evidenced by increased pulse rate and systolic blood pressure. However, compared to a no EPI control group the EPI group had a significantly reduced i beta END response to the stressor, as evaluated by comparison of plasma levels at individual time points, maximal increases in plasma i beta END levels, and areas under the time-response curve. Whereas there was no association between plasma levels of EPI and i beta END in the EPI group (r = 0.119; P = NS), EPI and i beta END levels were strongly related in the no EPI group (r = 0.82; P less than 0.001). These results do not support the hypothesis of a stimulatory effect for EPI on i beta END release and, instead, suggest that an inhibitory relationship may exist in humans experiencing stress. The association between EPI and i beta END responses observed in the control group during this form of stress appears to be due to activation of a common central neural element.

Enhanced analgesia and suppression of plasma beta-endorphin by the S(+)-isomer of ibuprofen.

BACKGROUND: Peripheral nociceptive barrage after tissue injury results in acute pain and a variety of physiologic responses, including pituitary secretion of beta-endorphin. This study evaluated whether administration of the pharmacologically active S(+)-isomer of ibuprofen suppresses acute pain and plasma beta-endorphin levels in the oral surgery model of acute pain. METHODS: Subjects in a single-dose, double-blind, parallel-group study received either 200 mg S(+)-ibuprofen, 400 mg S(+)-ibuprofen, 400 mg racemic ibuprofen, or placebo. Both doses of S(+)-ibuprofen resulted in significantly greater analgesia over the first 60 minutes in comparison to racemic ibuprofen and placebo; the 400 mg dose of S(+)-ibuprofen also produced greater analgesia at 2 and 3 hours. Plasma levels of immunoreactive beta-endorphin decreased over time coincident with the onset of analgesia in all groups but were significantly less than placebo after both doses of S(+)-ibuprofen from 30 to 120 minutes. CONCLUSIONS: These findings show that, compared with racemic ibuprofen, administration of the S(+)-isomer of ibuprofen results in faster analgesic onset, greater peak analgesia, similar duration of action, and a low incidence of adverse effects, while suppressing nociceptive activation of the pituitary-adrenal axis.

Ibuprofen elevates immunoreactive beta-endorphin levels in humans during surgical stress.

Release of beta-endorphin is modulated by physiologic stress and a variety of hormonal and pharmacologic factors. Prostaglandin E2 inhibits release of beta-endorphin and corticotropin from pituitary corticotroph cells, suggesting that suppression of prostaglandin levels should increase beta-endorphin release. This hypothesis was tested by administration of 600 mg ibuprofen before surgical stress in humans in comparison to placebo and methylprednisolone. Plasma samples were analyzed for immunoreactive beta-endorphin with concurrent measurement of pain and apprehension. Levels of immunoreactive beta-endorphin increased during surgery in the placebo group but were significantly greater in the group of patients pretreated with ibuprofen. Methylprednisolone suppressed intraoperative immunoreactive beta-endorphin, compared with both placebo and ibuprofen. Parallel in vivo and in vitro studies indicate that nonsteroidal anti-inflammatory drug potentiation of endorphin release is mediated at the level of the pituitary corticotroph cell. These results show that ibuprofen enhances pituitary release of beta-endorphin by corticotroph cells in response to stress.

Naloxone, fentanyl, and diazepam modify plasma beta-endorphin levels during surgery.

Forty-eight patients received either naloxone (10 mg), fentanyl (0.1 mg), diazepam (0.3 mg/kg), or saline solution placebo, and then underwent surgical removal of impacted third molars under local anesthesia. Placebo resulted in significantly elevated levels of immunoreactive beta-endorphin (i beta-END), norepinephrine, and anxiety during surgery. Patients receiving naloxone had significantly greater intraoperative i beta-END and pain as compared with those receiving placebo. The naloxone effect on intraoperative pain was a result of a difference in perceived unpleasantness. Both the fentanyl and diazepam groups had significantly lower intraoperative i beta-END and anxiety levels as compared with the placebo group. Norepinephrine levels increased significantly in response to surgical stress in all groups except the diazepam group. Postoperative circulating levels of i beta-END and norepinephrine and pain increased significantly from the 1 to 3-hour postoperative period for all groups, with the exception of stable norepinephrine levels observed in patients receiving diazepam. Results indicate that opiate antagonists stimulate and agonists suppress the release of i beta-END, possibly by affecting the patient's perceived level of pain and anxiety. In addition, the association of intraoperative hyperalgesia with naloxone predosing suggests that endogenous opioid peptides inhibit the perception of intraoperative pain even in the presence of concurrent local anesthesia.

Dexamethasone alters plasma levels of beta-endorphin and postoperative pain.

Secretion of pituitary immunoreactive beta-endorphin is hypothesized to modulate the perception of pain. The present study examined this question by evaluating the effects of intravenous placebo or dexamethasone (0.1, 0.32, or 1.0 mg) on suppression of immunoreactive beta-endorphin secretion and development of postoperative pain after the surgical removal of impacted third molars in 48 patients. Compared with placebo, all doses of dexamethasone suppressed the postoperative increase in circulating levels of immunoreactive beta-endorphin. Patients administered 0.1 mg dexamethasone reported greater levels of pain, compared with those given placebo, from 60 through 120 minutes after surgery. Postoperative pain for the 0.32 and 1.0 mg doses did not differ from that for the placebo group. The increased pain after suppression of beta-endorphin release by the low dose of dexamethasone suggests that pituitary secretion of immunoreactive beta-endorphin alleviates postoperative pain under these conditions.

Proglumide potentiates morphine analgesia for acute postsurgical pain.

Proglumide, an antagonist of cholecystokinin, has been shown to potentiate morphine analgesia in animal and human experimental pain models. This study was undertaken to determine whether proglumide enhances morphine analgesia for patients experiencing postoperative pain. At onset of pain after the removal of impacted third molars, patients (n = 60) received intravenously either 4 mg morphine, 8 mg morphine, or 4 mg morphine plus proglumide (0.05, 0.5, or 5 mg). The administration of 8 mg morphine significantly reduced pain, in comparison with baseline and 4 mg morphine, for the first 30 minutes. The addition of 0.05 mg proglumide resulted in a significant increase in the magnitude and duration of the analgesic activity of 4 mg morphine; 0.5 and 5.0 mg proglumide did not produce this effect. No difference was seen in respiratory rate or in the frequency of side effects among the various forms of treatment. These data indicate that a low dose of proglumide potentiates both the magnitude and the duration of morphine analgesia in a clinical model of acute pain, without any detectable increase in side effects.

Bradykinin is increased during acute and chronic inflammation: therapeutic implications.

Bradykinin is a potent pain-producing substance, yet little is known about its role in inflammation. The present study measured circulating levels of immunoreactive bradykinin in a clinical model of acute inflammation (oral surgery) and chronic inflammation (rheumatoid arthritis) and in the rat carrageenan model of inflammation. The effects of a kallikrein inhibitor (soybean trypsin inhibitor) on blocking bradykinin synthesis in vitro and its analgesic actions in the rat model were also evaluated. Levels of immunoreactive bradykinin increased threefold to fourfold during oral surgery. Levels were twofold to threefold greater in patients with rheumatoid arthritis compared with control subjects. Levels of immunoreactive bradykinin increased twofold in rats during carrageenan inflammation. Soybean trypsin inhibitor blocked synthesis of bradykinin in vitro and possessed analgesic activity in rats. The results indicate that the bradykinin system is activated during inflammation. Kallikrein inhibitors may represent a new class of analgesic/antiinflammatory drugs.

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.

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.

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.

Blockade of peripheral neuronal barrage reduces postoperative pain.

Peripheral afferent neuronal barrage from tissue injury produces central nervous system hyperexcitability which may contribute to increased postoperative pain. Blockade of afferent neuronal barrage has been reported to reduce pain following some, but not all, types of surgery. This study evaluated whether blockade of sensory input with a long-acting local anesthetic reduces postoperative pain after the anesthetic effects have dissipated. Forty-eight patients underwent oral surgery with general anesthesia in a parallel group, double-blind, placebo-controlled study. Subjects randomly received either 0.5% bupivacaine or saline intraoral injections, general anesthesia was induced with propofol, a non-opioid anesthetic, and 2-4 third molars extracted. Subjects were assessed at 24 and 48 h for postoperative pain and analgesic intake. Blood samples were collected at baseline, intraoperatively and at 1-h intervals postoperatively for measurement of beta-endorphin as an index of CNS response to nociceptor input. Plasma beta-endorphin levels increased significantly from baseline to the end of surgery in the saline group in comparison to the bupivacaine group (P < 0.05), indicating effective blockade of nociceptor input into the CNS by the local anesthetic. Pain intensity was not significantly different between groups at 24 h. Pain at 48 h was decreased in the bupivacaine group as measured by category scale and graphic rating scales for pain and unpleasantness (P < 0.05). Additionally, subjects in the bupivacaine group self-administered fewer codeine tablets for unrelieved pain over 24-48 h postoperatively (P < 0.05). These data support previous animal studies demonstrating that blockade of peripheral nociceptive barrage during and immediately after tissue injury results in decreased pain at later time points. The results suggest that blockade of nociceptive input by administration of a long-acting local anesthetic decreases the development of central hyperexcitability, resulting in less pain and analgesic intake.

Suppression of dental pain by the preoperative administration of flurbiprofen.

In a series of three studies involving dental outpatients undergoing removal of impacted third molars, preoperative and postoperative administration of flurbiprofen (Ansaid, Upjohn) led to superior pain relief when compared with acetaminophen alone or in combination with oxycodone. Patient preference and global evaluations clearly favored flurbiprofen. Side effects were mild and generally more common in patients receiving the opiate/mild analgesic combination. In two additional studies, flurbiprofen and etidocaine, a long-acting local anesthetic, also resulted in significantly less postoperative pain than a combination of acetaminophen/oxycodone and lidocaine; 67 percent of patients in the flurbiprofen plus etidocaine group reported no or only slight pain during the entire observation period. The greater analgesic efficacy of flurbiprofen appears to represent a genuine therapeutic advantage, since it is not achieved at the expense of greater side effects.

Clinical evaluation of H1-receptor and H2-receptor antagonists for acute postoperative pain.

The acute analgesic activity of an H1-histamine antagonist, terfenadine 60 mg, and an H2-histamine antagonist, ranitidine 150 mg, were compared with ibuprofen 600 mg and placebo in a double-blind, placebo-controlled, parallel-group study. Treatments were administered to a total of 127 patients 1 hour before oral surgery. Analgesia was assessed every 30 minutes for 240 minutes after surgery. Analgesic efficacy was compared using the following standard pain intensity scales: visual analog scale, category, graphic rating, and global evaluation. Ibuprofen was significantly better than all other treatments for all measures of analgesic activity. The effects of terfenadine and ranitidine were similar to placebo. These data indicate that pretreatments with a single dose of a histamine receptor antagonist specific for either the H1- or H2-receptor does not produce analgesia in an oral surgery model of acute pain with overall assay sensitivity, suggesting that antihistamines that act primarily at peripheral sites are devoid of analgesic activity. These data contrast with other studies that have demonstrated analgesia using centrally acting antihistamines such as hydroxyzine, phenyltoloxamine, or orphenadrine.

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.