Response to intravenous fentanyl infusion predicts subsequent response to transdermal fentanyl.

PURPOSE: Prediction of the response to transdermal fentanyl (FENtd) before its use for chronic pain is desirable. We tested the hypothesis that the response to intravenous fentanyl infusion (FENiv) can predict the response to FENtd, including the analgesic and adverse effects. METHODS: The study subjects were 70 consecutive patients with chronic pain. The response to fentanyl at 0.1 mg diluted in 50 ml of physiological saline and infused over 30 min was tested. This was followed by treatment with FENtd (Durotep MT patch 2.1 mg) at a dose of 12.5 µg/h for 2 weeks. Pain intensity before and after FENiv and 2 weeks after FENtd, and the response to treatment, were assessed by the numerical rating scale (NRS), clinical global impression-improvement scale (CGI-I), satisfaction scale (SS), and adverse effects. RESULTS: The NRS score decreased significantly from 7 (4-9) [median (range)] at baseline to 3 (0-8) after FENiv (p < 0.001), and to 4 (1-8) after FENtd (p < 0.001). The effects of FENiv, as evaluated by ΔNRS, CGI-I, and SS, were significantly greater than those of FENtd (p < 0.001, each), but not by the frequency and the severity of adverse effects, with the exception of dizziness. ΔNRS, and severity of adverse effects (drowsiness, dizziness, nausea, dry mouth, and pruritus) of FENiv correlated significantly with those of FENtd (rs > 0.04, each). CONCLUSIONS: The analgesic and side effects after intravenous fentanyl infusion can be used to predict the response to short-term transdermal treatment with fentanyl.

Pressure-induced endocytic degradation of the Saccharomyces cerevisiae low-affinity tryptophan permease Tat1 is mediated by Rsp5 ubiquitin ligase and functionally redundant PPxY motif proteins.

Cells of Saccharomyces cerevisiae express two tryptophan permeases, Tat1 and Tat2, which have different characteristics in terms of their affinity for tryptophan and intracellular localization. Although the high-affinity permease Tat2 has been well documented in terms of its ubiquitin-dependent degradation, the low-affinity permease Tat1 has not yet been characterized fully. Here we show that a high hydrostatic pressure of 25 MPa triggers a degradation of Tat1 which depends on Rsp5 ubiquitin ligase and the EH domain-containing protein End3. Tat1 was resistant to a 3-h cycloheximide treatment, suggesting that it is highly stable under normal growth conditions. The ubiquitination of Tat1 most likely occurs at N-terminal lysines 29 and 31. Simultaneous substitution of arginine for the two lysines prevented Tat1 degradation, but substitution of either of them alone did not, indicating that the roles of lysines 29 and 31 are redundant. When cells were exposed to high pressure, Tat1-GFP was completely lost from the plasma membrane, while substantial amounts of Tat1(K29R-K31R)-GFP remained. The HPG1-1 (Rsp5(P514T)) and rsp5-ww3 mutations stabilized Tat1 under high pressure, but any one of the rsp5-ww1, rsp5-ww2, and bul1Δ bul2Δ mutations or single deletions of genes encoding arrestin-related trafficking adaptors did not. However, simultaneous loss of 9-arrestins and Bul1/Bul2 prevented Tat1 degradation at 25 MPa. The results suggest that multiple PPxY motif proteins share some essential roles in regulating Tat1 ubiquitination in response to high hydrostatic pressure.

Comparison of cutaneous anesthetic effect of 8% lidocaine spray with lidocaine patch using current perception threshold test.

OBJECTIVE: A lidocaine patch is often used for topical anesthesia prior to venipuncture, but needs to be applied for several hours before the puncture, and the site is fixed. A metered-dose lidocaine pump spray could be used to produce cutaneous topical anesthesia. In this study, we compared the anesthesia between the spray and the patch. DESIGN: Thirteen healthy male volunteers received three treatments of metered-dose 8% lidocaine spray, a lidocaine patch, and no application as control measurement, in a random order separated by at least 2 days. Each treatment was applied topically on the forearm. Sensory nerve fibers (Abeta, Adelta, and C fibers) were evaluated with a series of 5, 250, and 2,000 Hz stimuli using current perception threshold (CPT) before and 30 minutes after each application. RESULTS: Under the control condition, CPTs measured at baseline and at 30 minutes were similar for 2,000 and 250 Hz stimuli, but significantly reduced for 5 Hz stimulation at 30 minutes. Under patch application, CPTs for 2,000 and 250 Hz stimuli at 30 minutes after application were significantly higher than baseline, while CPTs for 5 Hz stimulation at baseline and 30 minutes after application were similar. Under spray application, CPTs for all stimuli at 30 minutes were significantly higher than baseline. CONCLUSIONS: Similar to the lidocaine patch, the lidocaine spray produces cutaneous weak anesthesia at 30 minutes after treatment. The spray seems to produce local anesthesia faster than the patch.

Efficacy of a metered-dose 8% lidocaine pump spray for patients with post-herpetic neuralgia.

OBJECTIVE: Topical lidocaine patch is effective in the treatment of post-herpetic neuralgia (PHN), but not suited for paroxysmal pain because of the long latency of analgesia. Here, we examined the efficacy of 8% lidocaine pump spray (Xylocaine pump spray, XPS) for PHN. DESIGN: Twenty-four patients with PHN were recruited into a randomized, double-blind, placebo-controlled, crossover study (study 1), and 100 patients with PHN were recruited into an open-labeled study (study 2). In study 1, patients were randomized to receive either XPS or saline placebo pump spray (PPS) applied to the painful skin areas. Following a 7-day period, patients were crossed over to receive the alternative treatment. In study 2, XPS was prescribed for patients who were advised to use the spray anytime, with a 2-hour gap between applications, for 2 weeks. The pain was assessed with a visual analogue scale (VAS). Details of use were noted in the diary. RESULTS: In study 1, greater decreases in VAS of persistent pain followed application of XPS (baseline: 6.1 +/- 1.7 cm, 15-minute post-spray: 2.3 +/- 2.5 cm, mean +/- SD) than with PPS (6.1 +/- 1.7 cm, 5.7 +/- 1.6 cm, [P < 0.01]). The effect persisted for a median of 4.5 hours (range, 2 to 24 hours) after application. In study 2, 13 of 100 patients discontinued the treatment because of mild local side effects or insufficient effect. In the remaining 87 patients, XPS maintained significant pain relief relative to baseline throughout the 2-week period. Satisfaction with the therapy was reported by 79% of patients. CONCLUSIONS: In both studies, XPS provided a significant improvement in PHN due to its prompt analgesia, lack of systemic side effects, and convenience of use.

8% Lidocaine pump spray relieves pain associated with peripheral blood flow disorders.

OBJECTIVES: It is often difficult to reduce pain associated with peripheral blood flow disorders (PBFD) using standard analgesics. We assessed the analgesic effects of a metered-dose 8% lidocaine in patients with PBFD. METHODS: Twenty-four patients with PBFD-related pain were enrolled in this double-blind placebo-controlled crossover study. Patients were randomized to receive either 8% lidocaine or saline on the painful site with a metered-dose spray. After a 3-day period, patients were crossed over to receive the alternative treatment. Pain was assessed with a visual analog scale (VAS) before and 15 minutes after the treatment. Patients were also asked to record the time at which pain appeared again. The blood concentration of lidocaine was measured at 15, 30, and 60 minutes after lidocaine application. RESULTS: There were no significant differences in VAS before treatment between the placebo and lidocaine treatments. However, lidocaine significantly decreased VAS at rest from 5.5+/-3.1 cm (mean+/-SD) to 0.6+/-0.9 cm and on movement from 8.4+/-2.0 cm to 1.7+/-1.7 cm, resulting in a significant difference between the 2 sprays. The median time to recurrence of pain was 3 hours. The blood concentration of lidocaine was less than 0.3 microg/mL in all patients. DISCUSSION: A metered-dose 8% lidocaine pump spray produced prompt analgesia in patients with PBFD-related pain without severe side effects.

Regression of sensory and motor blockade, and analgesia during continuous epidural infusion of ropivacaine and fentanyl in comparison with other local anesthetics.

OBJECTIVE: To compare the regression of sensory and motor blockade, and the analgesia during continuous epidural infusion between ropivacaine and other local anesthetics. DESIGN: Two studies were conducted. Study 1: Eighty patients were scheduled for orthopedic procedures of the lower extremity under lumbar epidural anesthesia. Following the operation, continuous infusion of a randomized solution (0.2% ropivacaine, 0.125% bupivacaine, 0.5% lidocaine, or 0.2% ropivacaine with 2.5 microg/mL fentanyl) was commenced at a rate of 6 mL/h. The regression of sensory and motor blockade were compared among the groups. Study 2: After gynecologic abdominal surgery, 39 patients were randomized to one of the three epidural infusion groups: 0.2% ropivacaine, 0.125% bupivacaine, or 0.2% ropivacaine with 2.5 microg/mL fentanyl at a rate of 6 mL/h with an additional bolus injection of 3 mL, which can be used when patients have pain. Visual analog scale (VAS) was compared among the groups. RESULTS: Study 1: The level of sensory blockade in all the groups appeared to decrease progressively. However, the regression of sensory blockade was significantly prolonged in patients treated with ropivacaine. The addition of fentanyl to ropivacaine augmented this prolonged analgesic effect. Study 2: VAS after the bolus in the ropivacaine and the ropivacaine + fentanyl groups were significantly lower than that in the bupivacaine group. Patients in the ropivacaine + fentanyl group required significantly fewer supplemental bolus injections. CONCLUSIONS: Continuous epidural infusion of ropivacaine may induce a slower regression of sensory blockade compared with bupivacaine and lidocaine. The addition of fentanyl to ropivacaine can enhance this prolonged analgesic effect with little effect on motor blockade. Epidural infusion of ropivacaine with fentanyl provides effective pain relief, possibly because of the maintenance of sensory blockade by ropivacaine and fentanyl.

Effectiveness of prostaglandin E1 for the treatment of patients with neuropathic pain following herpes zoster.

OBJECTIVE: Postherpetic neuralgia (PHN) is one of the most painful neuropathic conditions, the mechanism of which remains unclear. There is no universally accepted treatment. The pain in PHN is often relieved by bathing, heating, or sympathetic blockade, suggesting a circulation-dependent property of the pain. Therefore, we examined the effectiveness of prostaglandin E(1) (PGE(1)), which has an analgesic effect via improvement of peripheral blood circulation, for patients with PHN. DESIGN: A total of 27 patients with PHN underwent intravenous administration of 60 microg of PGE(1) dissolved in 100 mL of physiological saline and 5 mL of 8.4% sodium bicarbonate solution at an infusion rate of 0.02 microg/kg/min. Oral administration of PGE(1), limaprost alfadex, was followed at doses of 30 microg/day for 2 weeks. Pain at rest and tactile allodynia before and after the treatment was evaluated with visual analog scale (VAS). RESULTS: Intravenous PGE(1) significantly decreased VAS in rest pain and tactile allodynia without severe adverse effects. The analgesic effect of PGE(1) continued during the 2 weeks of oral administration of PGE(1). Oral PGE(1) caused nausea in seven cases, diarrhea in three, and abdominal distention in one subject. All subjects, except for two cases of nausea, continued the treatment until the end of the study, although some required a decrease in the dose to 15 microg/day. During the 2-week oral administration, the VAS did not change remarkably in the three patients whose VAS were not decreased by at least 80% during the initial infusion. CONCLUSIONS: The results of the present study indicate that oral PGE(1) following the intravenous administration produces prompt and continuous analgesia in patients with PHN. Moreover, the intravenous treatment using PGE(1) appears useful for predicting the analgesic effect of PGE(1) in the patients.

Sumatriptan alleviates pain in patients with trigeminal neuralgia.

OBJECTIVES: Arterial compression of the trigeminal root may lead to trigeminal neuralgia. 5-HT1B/1D receptor agonists may inhibit vasodilation and inflammation near the irritated trigeminal root. A recent study showed attenuation of mechanical allodynia by a 5-HT1A receptor agonist in a rat model of trigeminal neuralgia. The present study examined the effectiveness of a 5-HT1A/1B/1D receptor agonist, sumatriptan, on pain relief in patients with trigeminal neuralgia. METHODS: The study was conducted in 15 patients with idiopathic trigeminal neuralgia. The patients had been suffering from painful paroxysms for at least 1 month. Each patient was injected with 1 mL of saline subcutaneously (placebo), followed 15 minutes later with subcutaneous sumatriptan (3 mg in 1 mL saline). This was followed the next day by oral sumatriptan (50 mg twice daily) for 1 week. RESULTS: The visual analog scale did not change after saline, but significantly decreased after subcutaneous sumatriptan. Both 1 week after oral sumatriptan and 1 week after discontinuation of the drug, visual analog scale scores resulted in a significant decrease from the baseline. Adverse events after subcutaneous sumatriptan occurred in 4 patients: fatigue in 4 and nausea in 2. Side effects from the oral medication appeared in 4 patients: fatigue in 2, nausea in 1 and chest discomfort in 1. These side effects subsided soon after discontinuation of sumatriptan. CONCLUSIONS: Our results indicate that subcutaneous injection followed by oral administration of sumatriptan produces prompt and continuous analgesia in patients with trigeminal neuralgia.

Rapid injection of epidural mepivacaine speeds the onset of nerve blockade.

PURPOSE: When used intraoperatively, mepivacaine can produce a satisfactory sensory block. However, insufficient information is available concerning the factors that affect the speed of nerve blockade with epidural analgesia. The optimal rate of injection of mepivacaine has not been determined. We examined whether the speed of epidural infusion of mepivacaine affects the speed of nerve blockade. METHODS: Forty patients, physical status ASA I-II, scheduled for gynecological abdominal surgery, were enrolled in this double blind randomized trial. A catheter was inserted 4 cm in the epidural space in the midline at L1-L2. Three minutes after a test dose of 2 mL plain 1% mepivacaine over four seconds, 8 mL were injected epidurally at a rate of 1 mL.sec(-1) (fast group) or 0.05 mL.sec(-1) (slow group). Sensory and motor blockade, blood pressure, and heart rate were assessed at five, ten, and 15 min after the epidural injection. RESULTS: There was a significant difference in the spread of sensory blockade at five minutes after the epidural injection between the two groups, but not at ten and 15 min. Blood pressure decreased at five and ten minutes, recovered at 15 min in the fast group, and remained stable in the slow group. CONCLUSION: Rapid injection of mepivacaine in the epidural space produced a more rapid onset of epidural block than slow injection, but there was no difference in the final extent of the block.

[Effectiveness of ropivacaine and fentanyl for postoperative epidural analgesia following thoracic surgery].

BACKGROUND: Epidural ropivacaine is now a common drug used for postoperative analgesia. However, little information is available concerning regression of sensory blockade and analgesia following prolonged epidural infusion of ropivacaine. We investigated the efficacy of ropivacaine and fentanyl for postoperative analgesia after thoracic surgery. METHODS: Thirty patients undergoing thoracic surgery were enrolled. After surgery with general and thoracic epidural anesthesia, continuous epidural infusion of 0.2% ropivacaine+fentanyl (1.67 microg x ml(-1)) was started at a rate of 6 ml x h(-1) for patients whose height was more than 155 cm and 4 ml x h(-1) for those below 155 cm with possibility of an additional bolus injection of 3 ml at least every 60 min. RESULTS: An additional epidural injection of 3 ml produced a decrease in VAS without significant changes of vital signs. The greatest VAS was 10+/-25 mm in the incision site and 36+/-38 mm in the ipsilateral shoulder. Sensory blockade was sustained until the morning after the day of surgery. Also blood pressure and heart rate were stable throughout the observation period. There were no adverse effects except for slight nausea in three patients. CONCLUSIONS: A bolus of 3 ml with continuous 4-6 ml x h(-1) epidural injection of ropivacaine plus a small dose of fentanyl would decrease postoperative pain with stable vital signs in patients after thoracic surgery.

[Advantage of ropivacaine for postoperative epidural analgesia following leg orthopedic surgery].

BACKGROUND: Epidural administration of local anesthetics may lead to effective pain relief. However, tachyphylaxis or other problems following prolonged epidural anesthesia may develop and in many cases difficulties exist in the maintenance of the similar degree of sensory blockade. The present study was therefore performed to investigate the analgesic effect of continuous postoperative epidural infusion of ropivacaine with fentanyl in comparison with that of bupivacaine or ropivacaine alone. METHODS: After leg orthopedic surgery with lumbar combined spinal-epidural anesthesia, thirty-six patients were randomized to one of the three postoperative epidural infusion groups: bupivacaine 0.125%, ropivacaine 0.2%, or ropivacaine 0.2% with 2.2 microg x ml(-1) (400 microg x 180 ml(-1)) of fentanyl. Continuous epidural infusion was started at a rate of 6 ml x h(-1) with possibility of an additional bolus injection of 3 ml at least every 60 min. Pain was assessed using a 10-cm visual analog scale (VAS) just before and 15 min after epidural bolus injections, and 15-20 h after the start of continuous epidural infusion as the severe at pain through the observation. The spread of analgesia (loss of sharpness in pinprick perception) and motor block (Bromage scale) were evaluated bilaterally. Systolic and diastolic blood pressure and heart rate were also measured. RESULTS: The epidural bolus infusion was associated with a significant decrease of VAS (P < 0.001) and stable blood pressure and heart rate in all groups. The maximal VAS in patients receiving 0.2% ropivacaine+fentanyl was significantly less compared to that in the other two groups. The regression of sensory blockade was significantly prolonged in patients treated with ropivacaine+fentanyl. There was no significant difference in the spread of sensory analgesia between 20 min and 15-20 h after the continuous epidural anesthesia in this group. None of the patients developed adverse effects such as respiratory depression, nausea, and pruritus. CONCLUSIONS: Epidural injection of ropivacaine with fentanyl decreased postoperative pain with stable vital signs in patients undergoing leg orthopedic surgery, as compared to bupivacaine or ropivacaine alone, possibly because of the maintenance of sensory blockade by ropivacaine and enhancement of this sensory blockade by fentanyl.