Antinociceptive effect of low-dose intrathecal neostigmine combined with intrathecal morphine following gynecologic surgery

BACKGROUND: The purpose of this study was to determine whether combination of 1-5 microg intrathecal neostigmine would enhance analgesia from a fixed intrathecal dose of morphine. METHODS: A total of 60 patients undergoing gynecologic surgery were randomized to one of five groups. Patients received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline, 100 microg morphine, or 1-5 microg neostigmine). The control group received spinal saline as the test drug. The morphine group received spinal morphine as test drug. The morphine + 1 microg neostigmine group received spinal morphine and 1 microg neostigmine. The morphine + 2.5 microg neostigmine group received spinal morphine and 2.5 microg neostigmine. Finally, the morphine + 5 microg neostigmine group received spinal morphine and 5 microg neostigmine. RESULTS: The groups were demographically similar. The time to first rescue analgesic (minutes) was longer for all patients who received intrathecal morphine combined with 1-5 microg neostigmine (median, 6 h) compared with the control group (median, 3 h) (P < 0.02). The morphine group (P < 0.05) and the groups that received the combination of 100 microg intrathecal morphine combined with neostigmine (P < 0.005) required less rescue analgesics in 24 h compared with the control group. The incidence of perioperative adverse effects was similar among groups (P > 0.05). CONCLUSIONS: The addition of 1-5 microg spinal neostigmine to 100 microg morphine doubled the duration to first rescue analgesic in the population studied and decreased the analgesic consumption in 24 h, without increasing the incidence of adverse effects. The data suggest that low-dose spinal neostigmine may improve morphine analgesia.     

The effects of intrathecal morphine encapsulated in L- and D-dipalmitoylphosphatidyl choline liposomes on acute nociception in rats

Liposomes can serve as a sustained-release carrier system, permitting the spinal delivery of large opioid doses restricting the dose for acute systemic uptake. We evaluated the antinociceptive effects of morphine encapsulated in liposomes of two isomeric phospholipids, L-dipalmitoylphosphatidyl choline (L-DPPC) and D-dipalmitoylphosphatidyl choline (D-DPPC), in comparison with morphine in saline. Sprague-Dawley rats with chronic lumbar intrathecal catheters were tested for their acute nociceptive response using a hindpaw thermal escape test. Their general behavior, motor function, pinna reflex, and corneal reflex were also examined. The duration of antinociception was longer in both liposomal morphine groups than in the free morphine group. The peak antinociceptive effects were observed within 30 min after intrathecal morphine, L-DPPC or D-DPPC morphine injection. The rank order of the area under the effect-time curve for antinociception was L-DPPC morphine > D-DPPC morphine > morphine. The 50% effective dose was: 2.7 microg (morphine), 4.6 microg (L-DPPC morphine), and 6.4 microg (D-DPPC morphine). D-DPPC morphine had less side effects for a given antinociceptive AUC than morphine. In conclusion, L-DPPC and D-DPPC liposome encapsulation of morphine prolonged the antinociceptive effect on acute thermal stimulation and could decrease side effects, compared with morphine alone. Implications: Two isomers of liposome (L-dipalmitoylphosphatidyl choline and D-dipalmitoylphosphatidyl choline) encapsulation of morphine prolonged the analgesic effect on acute thermal-induced pain when administered intrathecally and could decrease side effects, compared with morphine alone.     

Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: dose response

Background: Intrathecal (IT) neostigmine produces dose-dependent analgesia in adults. However, the dose of spinal neostigmine has not been investigated in infants. The purpose of this study was to assess spinal anesthesia (SA) duration provided by four doses of spinal neostigmine added to bupivacaine for lower abdominal and urogenital procedures in infants.
Methods: Seventy-five infants were randomized into five groups. The control group B received IT plain 0.5% hyperbaric bupivacaine. Groups BN.25, BN.50, BN.75, and BN1.0 received bupivacaine with 0.25, 0.5, 0.75, and 1 μg/kg of neostigmine, respectively. The primary variable was the duration of anesthesia assessed by recovery of hip flexion. Postoperative pain with facial expression, leg activity, arm activity, crying and consolability scale score,and rescue analgesic requirements were the secondary variables measured, and the side effects were noted.
Results: Seventy-three infants completed the study. There was a significant linear increase in SA duration with IT neostigmine to 65.2 (4.3) min with 0.5 μg/kg ( P <0.01), 88.2 (5.1) with 0.75 μg/kg ( P <0.001) and 92 (4.3) with 1 μg/kg ( P <0.001) from 52.4 (4.3) min with bupivacaine alone. SA duration showed no significant difference between plain bupivacaine and BN.25 ( P =0.100) or between groups BN.75 and BN1.0 ( P =0.451). Groups BN.75 and BN1.0 had significantly reduced pain scores, and the median duration before the first dose rescue analgesic was requested prolonged significantly ( P <0.001) compared with the other three groups.
Conclusions: IT neostigmine at a dose of 0.75 μg/kg added to bupivacaine significantly prolonged SA duration with reduced postoperative pain scores and rescue analgesic requirements in infants undergoing lower abdominal and urogenital procedures. No additional benefits were provided on increasing it to 1 μg/kg.     

Antiallodynic effect of intrathecal neostigmine is mediated by spinal nitric oxide in a rat model of diabetic neuropathic pain

BACKGROUND: Intrathecal administration of acetylcholinesterase inhibitors produces antinociception in both animals and humans, but their effect on diabetic neuropathic pain has not been studied. In the current study, we determined the antiallodynic effect of intrathecal injection of an acetylcholinesterase inhibitor, neostigmine, in a rat model of diabetic neuropathic pain. In addition, since acetylcholine can increase release of nitric oxide in the spinal cord, we studied the role of spinal endogenous nitric oxide in the action of intrathecal neostigmine in diabetic neuropathic pain. METHODS: Rats were rendered diabetic with an intraperitoneal 50-mg/kg injection of streptozotocin. Intrathecal catheters were inserted, with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the hind paw. We first determined the dose-dependent effect of intrathecal neostigmine on allodynia. The role of spinal nitric oxide in the action of intrathecal neostigmine was then examined through intrathecal treatments with a neuronal nitric oxide synthase inhibitor (TRIM), a nitric oxide scavenger (PTIO), L-arginine, or D-arginine. RESULTS: The diabetic rats developed a sustained tactile allodynia within 4 weeks after streptozotocin injection. Intrathecal injection of 0.1-0.5 microg neostigmine dose-dependently increased the withdrawal threshold in response to application of von Frey filaments. Intrathecal pretreatment with 30 microg TRIM or 30 microg PTIO abolished the antiallodynic effect of intrathecal neostigmine. Furthermore, the inhibitory effect of TRIM on the action of intrathecal neostigmine was reversed by intrathecal injection of 100 microg L-arginine but not D-arginine. CONCLUSIONS: Intrathecal neostigmine produces a profound analgesic effect in a rat model of diabetic neuropathic pain. Spinal endogenous nitric oxide contributes to the analgesic action of intrathecal neostigmine in this rat model of diabetic neuropathic pain.     

Intrathecal neostigmine and sufentanil for early labor analgesia.

BACKGROUND: Recent efforts to improve the combined spinal epidural (CSE) technique have focused on adding opioids to other classes of analgesics. In this study, the authors used intrathecal neostigmine in combination with intrathecal sufentanil to investigate the usefulness of neostigmine for reducing side effects and prolonging the duration of sufentanil. METHODS: One hundred six healthy pregnant women in labor were enrolled in this study, which was divided into four phases. In all phases, patients received a CSE anesthetic while in the lateral position. In phase I, three groups of six women each received intrathecal neostigmine, 5, 10, or 20 microg, in an open-label, dose-escalating safety assessment. In phase II, 24 women received intrathecal sufentanil alone to establish an ED50 (dose that produces > 60 min of labor analgesia in 50% of patients). In phase III, an ED50 was established for sufentanil combined with a fixed dose of neostigmine (10 microg). In phase IV, 40 women received either twice the ED50 of sufentanil alone or twice the ED50 of sufentanil plus neostigmine, 10 microg. RESULTS: Neostigmine alone had no adverse effects on maternal vital signs, fetal heart rate, or Apgar scores. Neostigmine, 20 microg, produced analgesia in one patient and severe nausea and vomiting in another. The ED50 for intrathecal sufentanil alone was 4.1 +/- 0.31 microg, and the ED50 for intrathecal sufentanil combined with neostigmine, 10 microg, was 3.0 +/- 0.28 microg. The duration of analgesia and side effects from double these ED50s (sufentanil, 9 microg, or sufentanil, 6 microg, plus neostigmine, 10 microg) were similar between groups. CONCLUSIONS: The 10-microg intrathecal neostigmine dose alone produced no analgesia or side effects, but reduced the ED50 of intrathecal sufentanil by approximately 25%. Additionally, doses approximately double these ED50s each produced a similar duration of analgesia and side effects, indicating intrathecal neostigmine shifts the dose-response curve for intrathecal sufentanil to the left.     

Prolonged antinociceptive effect of poly (DL-lactic acid)-fentanyl composites after their intrathecal injection in rats

We synthesized poly (DL-lactic acid)-fentanyl composites and compared the duration of analgesia after the administration of a single intrathecal dose of these agents in rats. The drug was injected with an intrathecal catheter into the intrathecal space. Fentanyl composites or plain fentanyl in doses of 2.5 or 25 micrograms were administered, respectively. Animals were then tested for analgesia using the tail-flick test. The release rate of fentanyl from fentanyl composites in vitro was also evaluated. The antinociceptive effect of fentanyl composites (25 micrograms) was significantly longer than that of plain fentanyl. Administration of poly (DL-lactic acid) alone did not induce the antinociceptive effect. Four of 7 animals given plain fentanyl (25 micrograms) exhibited temporary respiratory depression, but none of the animals given fentanyl composites showed this response. In vitro experiments demonstrated a slow release of fentanyl from the fentanyl composites. We conclude that the antinociceptive effect of fentanyl can be prolonged when administered as a poly (DL-lactic acid)-fentanyl composite in the intrathecal space with decreased systemic side effects compared with the plain formulation.     

Caudal neostigmine with bupivacaine produces a dose-independent analgesic effect in children

PURPOSE: To evaluate the analgesic efficacy and duration of varying doses of caudal neostigmine with plain bupivacaine and its side effects in children undergoing genito-urinary surgery. METHODS: In a randomized double-blind prospective study 80 boys aged two to eight years scheduled for surgical repair of hypospadias were allocated randomly to one of four groups (n = 20 each) and received either only caudal 0.25% plain bupivacaine 0.5 mL.kg(-1) (Group I) or 0.25% plain bupivacaine 0.5 mL.kg(-1) with neostigmine (Groups II-IV) in doses of 2, 3 and 4 microg.kg(-1) respectively. Postoperative pain was assessed for 24 hr using an objective pain score. Blood pressure, heart rate, oxygen saturation, total amount of analgesic consumed and adverse effects were also recorded. RESULTS: The duration of postoperative analgesia in Group I (5.1 +/- 2.3 hr) was significantly shorter than in the other three groups (II -16.6 +/- 4.9 hr; III - 17.2 +/- 5.5 hr; IV - 17.0 +/- 5.8 hr; P < 0.05). Total analgesic (paracetamol) consumption was significantly more in Group I (697.6 +/- 240.7 mg) than in the groups receiving caudal neostigmine (II - 248.0 +/- 178.4; III - 270.2 +/- 180.8 and IV -230.6 +/- 166.9 mg; P < 0.05). Groups II, III and IV were comparable with regards to duration of postoperative analgesia and total analgesic consumption (P > 0.05). Incidence of nausea and vomiting were comparable in all four groups. No significant alteration in vital signs or any other adverse effects were observed. CONCLUSIONS: Caudal neostigmine (2, 3 and 4 microg.kg(-1)) with bupivacaine produces a dose-independent analgesic effect ( approximately 16-17 hr) in children as compared to those receiving caudal bupivacaine alone (approximately five hours) and a reduction in postoperative rescue analgesic consumption without increasing the incidence of adverse effects.     

Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers

BACKGROUND: Intrathecal adjuncts often are used to enhance small-dose spinal bupivacaine for ambulatory anesthesia. Neostigmine is a novel spinal analgesic that could be a useful adjunct, but no data exist to assess the effects of neostigmine on small-dose bupivacaine spinal anesthesia. METHODS: Eighteen volunteers received two bupivacaine spinal anesthetics (7.5 mg) in a randomized, double-blinded, crossover design. Dextrose, 5% (1 ml), was added to one spinal infusion and 6.25, 12.5, or 50 microg neostigmine in dextrose, 5%, was added to the other spinal. Sensory block was assessed with pinprick; by the duration of tolerance to electric stimulation equivalent to surgical incision at the pubis, knee, and ankle; and by the duration of tolerance to thigh tourniquet. Motor block at the quadriceps was assessed with surface electromyography. Side effects (nausea, vomiting, pruritus, and sedation) were noted. Hemodynamic and respiratory parameters were recorded every 5 min. Dose-response relations were assessed with analysis of variance, paired t tests, or Spearman rank correlation. RESULTS: The addition of 50 microg neostigmine significantly increased the duration of sensory and motor block and the time until discharge criteria were achieved. The addition of neostigmine produced dose-dependent nausea (33-67%) and vomiting (17-50%). Neostigmine at these doses had no effect on hemodynamic or respiratory parameters. CONCLUSIONS: The addition of 50 microg neostigmine prolonged the duration of sensory and motor block. However, high incidences of side effects and delayed recovery from anesthesia with the addition of 6.25 to 50 microg neostigmine may limit the clinical use of these doses for outpatient spinal anesthesia.     

The effect of dexamethasone on postoperative pain and emesis after intrathecal neostigmine

We evaluated the effect of a single dose of dexamethasone on the incidence and severity of postoperative nausea and vomiting (PONV) after intrathecal injection of tetracaine plus neostigmine. Sixty ASA physical status I patients scheduled for inguinal herniorrhaphy were studied with a randomized, double-blinded, placebo-controlled protocol. The dexamethasone group (Group D) received 10 mg of dexamethasone IV before performance of spinal anesthesia, whereas the placebo group (Group P) received saline. Spinal anesthesia was performed with intrathecal injection of 15 mg tetracaine plus neostigmine 100 microg in both groups. Pain, PONV, and other side effects were evaluated 24 h after surgery. The duration and severity of analgesia and the incidence of PONV were not significantly different between the two groups. Our results demonstrate that a single dose of dexamethasone (10 mg) did not potentiate the analgesic effect or reduce the incidence of PONV after intrathecal injection of tetracaine and neostigmine. Implications: The results of our evaluation of the effect of IV dexamethasone versus saline control on analgesia and nausea and vomiting after intrathecal neostigmine and tetracaine suggest that IV dexamethasone did not enhance the analgesic effect of neostigmine or reduce the incidence of emesis after intrathecal administration.     

Analgesic effects of intrathecal neostigmine in perianal surgery

BACKGROUND AND OBJECTIVE: In recent human and animal studies, intrathecal administration of various doses of neostigmine produces analgesia without neurotoxicity. The aim was to examine the effects of intrathecal neostigmine and bupivacaine in patients undergoing perianal surgery under spinal anaesthesia. METHODS: The patients were randomly allocated into three groups of 15: Group 1 (controls) received hyperbaric bupivacaine 10 mg + dextrose 5%, 1 mL, to a total volume of 3 mL; Group 2 received hyperbaric bupivacaine 10 mg + neostigmine 25 microg in dextrose 5%, 1 mL, to a total volume of 3 mL; and Group 3 received hyperbaric bupivacaine 10 mg + neostigmine 50 microg in dextrose 5%, 1 mL, to a total volume of 3 mL. RESULTS: The onset of sensory block was significantly earlier for Group 2 and 3 patients compared with Group 1 patients (P < 0.05). The full time to recovery of motor block and sensory block was significantly longer in Group 3 compared with Group 1 (P < 0.05). In Group 3, the average time until the first dose of tramadol was longer than Group 1 (P < 0.05). The incidence rate of nausea and vomiting was significantly higher in Groups 2 and 3 than in Group 1 (P < 0.05). CONCLUSIONS: The use of intrathecal neostigmine as an analgesic drug in perianal surgery is unsatisfactory because of prolonged motor blockade and nausea.     

Analgesic and anticonvulsive effect of midazolam via intrathecal administration in the rat

We have studied analgesic and anticonvulsive effect of midazolam by means of tail-flick test and electroshock respectively. The drug was administered via cervical and lumbar intrathecally in chronically implanted rats. Total doses were 50, 125, and 250 microg. Control animals received 0.3125, 0.625, 1.25 and 2.5 mg intraperitoneally. Degree of sedation was also measured with a motor activity scale with the purpose of correlating sedation with analgesic and anticonvulsive effect. Tail-flick test was carried out 5 and 30 minutes after the administration of midazolam. Results showed that lumbar intrathecal midazolam has analgesic effect in tail-flick test whereas cervical intrathecal or intraperitoneal midazolam has no analgesic effect and shows a non significant hyperalgesic trend. Cervical intrathecal and intraperitoneal midazolam has anticonvulsive effect. As sedative effect of the administered doses increases, there was also a not significant trend to shorten latency period of tail-flick test and to increase anticonvulsive effect.     

Transdermal nitroglycerine enhances spinal neostigmine postoperative analgesia following gynecological surgery

BACKGROUND: Intrathecal neostigmine causes analgesia by inhibiting the breakdown of acetylcholine. Experimental data suggest that the production of endogenous nitric oxide is necessary for tonic cholinergic inhibition of spinal pain transmission. The purpose of this study was to determine whether association of transdermal nitroglycerine would enhance analgesia from a low dose of intrathecal neostigmine in patients undergoing gynecologic surgery during spinal anesthesia. METHODS: Forty-eight patients were randomized to one of four groups. Patients were premedicated with use of 0.05-0.1 mg/kg intravenous midazolam and received 15 mg bupivacaine plus 1 ml test drug intrathecally (saline or neostigmine, 5 microgram). Twenty to 30 min after the spinal puncture, a transdermal patch of either 5 mg nitroglycerin or placebo was applied. The control (Con) group received spinal saline and transdermal placebo. The neostigmine group received spinal neostigmine and transdermal placebo. The nitroglycerin group received spinal saline and a transdermal nitroglycerine patch. Finally, the neostigmine-nitroglycerin group received spinal neostigmine and transdermal nitroglycerine. Pain and adverse effects were evaluated using a 10-cm visual analog scale. RESULTS: Patients in the groups were similar regarding age, weight, height, and American Society of Anesthesiologists status. Sensory level to pin prick at 10 min, surgical duration, anesthetic duration, and visual analog scale score for pain at the time of administration of first rescue medication were statistically the same for all groups. The time to administration of first rescue analgesic (min) was longer in the neostigmine-nitroglycerin group (550 min; range, 458-1,440 min; median, 25-75th percentile) compared with the other groups (P < 0.001). The neostigmine-nitroglycerin group required fewer rescue analgesics in 24 h than did the control group (P < 0.0005), whereas the neostigmine group required less analgesics compared with the control group (P < 0.02). The incidence of perioperative adverse effects (nausea, vomiting, headache, back pain) was similar among groups (P > 0.05). CONCLUSION: Although neither intrathecal 5 microgram neostigmine alone nor transdermal nitroglycerine alone (5 mg/day) delayed the time to administration of first rescue analgesics, the combination of both provided an average of 14 h of effective postoperative analgesia after vaginoplasty, suggesting that transdermal nitroglycerin and the central cholinergic agent neostigmine may enhance each other's antinociceptive effects at the dose studied.     

Antinociceptive Effect of Low-Dose Intrathecal Neostigmine Combined with Intrathecal Morphine following Gynecologic Surgery

Background: The purpose of this study was to determine whether combination of 1-5 [mu]g intrathecal neostigmine would enhance analgesia from a fixed intrathecal dose of morphine.

Methods: A total of 60 patients undergoing gynecologic surgery were randomized to one of five groups. Patients received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline, 100 [mu]g morphine, or 1-5 [mu]g neostigmine). The control group received spinal saline as the test drug. The morphine group received spinal morphine as test drug. The morphine + 1 [mu]g neostigmine group received spinal morphine and 1 [mu]g neostigmine. The morphine + 2.5 [mu]g neostigmine group received spinal morphine and 2.5 [mu]g neostigmine. Finally, the morphine + 5 [mu]g neostigmine group received spinal morphine and 5 [mu]g neostigmine.

Results: The groups were demographically similar. The time to first rescue analgesic (minutes) was longer for all patients who received intrathecal morphine combined with 1-5 [mu]g neostigmine (median, 6 h) compared with the control group (median, 3 h) (P < 0.02). The morphine group (P < 0.05) and the groups that received the combination of 100 [mu]g intrathecal morphine combined with neostigmine (P < 0.005) required less rescue analgesics in 24 h compared with the control group. The incidence of perioperative adverse effects was similar among groups (P > 0.05).     

Intrathecal bupivacaine with morphine or neostigmine for postoperative analgesia after total knee replacement surgery

PURPOSE: To compare the postoperative analgesic efficacy and safety of intrathecal (IT) neostigmine and IT morphine in patients undergoing total knee replacement under spinal anesthesia. METHODS: Sixty patients scheduled for elective total knee replacement under spinal anesthesia were randomly divided into three equal groups which received IT 0.5% hyperbaric bupivacaine 15 mg with either normal saline 0.5 mL, neostigmine 50 microg, or morphine 300 microg. The maximal level of sensory block, duration of analgesia, time to use of rescue analgesics, the overall 24-hr and four-hour interval visual analogue scale (VAS) pain score, and the incidence of adverse effects were recorded for 24 hr after administration. RESULTS: There was no significant difference in maximal level of sensory block among the three groups. The morphine group had a later onset of postsurgical pain and longer time to first rescue analgesics than the neostigmine group (P <0.05). Overall 24-hr VAS pain scores were significantly higher in the saline group vs the morphine and neostigmine groups (P <0.05). Motor block lasted significantly longer in the neostigmine group than in the morphine and saline groups (P <0.05). The incidence of adverse effects was similar in the neostigmine and morphine groups except for pruritus (70%) occurring more frequently in the morphine group than in the neostigmine and saline groups (0%; P <0.05). Overall satisfaction rates were better in the neostigmine group than in the morphine and saline groups (P <0.05). CONCLUSIONS: IT neostigmine 50 microg produced postoperative analgesia lasting about seven hours with fewer side effects and better satisfaction ratings than IT morphine 300 microg.     

Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test

BACKGROUND: Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. RESULTS: Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). CONCLUSIONS: Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.     

Analgesic effect of low-dose intrathecal morphine after spinal fusion in children

BACKGROUND: This study was designed to assess the postoperative analgesic effect of low-dose intrathecal morphine after scoliosis surgery in children. METHODS: Thirty children, 9-19 yr of age, scheduled for spinal fusion, were randomly allocated into three groups to receive a single dose of 0 (saline injection), 2, or 5 microg/kg intrathecal morphine. After surgery, a patient-controlled analgesia device (PCA) provided free access to additional intravenous morphine. Children were monitored for 24 h in the postanesthesia care unit. RESULTS: The three groups were similar for age, weight, duration of surgery, and time to extubation. The time to first PCA demand was dose-dependently delayed by intrathecal morphine. The first 24 h of PCA morphine consumption was 49 +/- 17, 19 +/- 10, and 12 +/- 12 mg (mean +/- SD) in the saline, 2 microg/kg morphine, and 5 microg/kg morphine groups, respectively. Pain scores at rest were significantly lower over the whole study period after 2 and 5 microg/kg intrathecal morphine than after saline, but there was no difference between intrathecal doses. Pain scores while coughing and the incidence of side effects were similar in the three groups. CONCLUSIONS: These data demonstrate that low-dose intrathecal morphine supplemented by PCA morphine provides better analgesia than PCA morphine alone after spinal fusion in children. The doses of 2 and 5 microg/kg seem to have similar effectiveness and side-effect profiles, whereas a reduction of intraoperative bleeding was observed in patients who received 5 microg/kg but not 2 microg/kg intrathecal morphine.     

Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl

BACKGROUND: Combining bupivacaine with fentanyl for intrathecal analgesia in labor is well recognized, but dosages commonly used are arbitrarily chosen and may be excessive. This study aimed to determine the median effective dose (ED50) of intrathecal bupivacaine, defined as the minimum local analgesic dose (MLAD), and then use this to assess the effect of different doses of fentanyl. METHODS: In this double-blind, randomized, prospective study, 124 parturients receiving combined spinal epidural analgesia at 2-6-cm cervical dilatation were allocated to one of four groups to receive bupivacaine alone or with 5, 15, or 25 microg fentanyl, using the technique of up-down sequential allocation. Analgesic effectiveness was assessed using 100-mm visual analog pain scores, with less than or equal to 10 mm within 15 min defined as effective. MLAD was calculated using the formula of Dixon and Massey. Pruritus and duration of spinal analgesia were also recorded. RESULTS: Minimum local analgesic dose of intrathecal bupivacaine was 1.99 mg (95% confidence interval, 1.71, 2.27). There were similar significant reductions in MLAD (P < 0.001) for all bupivacaine-fentanyl groups compared with bupivacaine control. There was a dose-dependent increase in both pruritus and duration of spinal analgesia with increasing fentanyl (P < 0.0001). CONCLUSION: Under the conditions of this study, the addition of intrathecal fentanyl 5 microg offers a similar significant bupivacaine dose-sparing effect as 15 and 25 microg. Analgesia in the first stage of labor can be achieved using lower doses of fentanyl, resulting in less pruritus but with a shortening of duration of action.     

Antihyperalgesic and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain

BACKGROUND: Although intrathecal clonidine produces pronounced analgesia, antinociceptive doses of intrathecal clonidine produce several side effects, including hypotension, bradycardia, and sedation. Intrathecal tizanidine, another alpha(2)-adrenergic agonist, has provided antinociception without producing pronounced hemodynamic changes in animal studies. However, it has been unclear whether antihyperalgesic doses of intrathecal clonidine and tizanidine produce hypotension and bradycardia in a neuropathic pain state. This study was designed to evaluate the antihyperalgesic effects and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain. METHODS: Male Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters, and the sciatic nerve was loosely ligated. After 21-28 days after surgery, the rats received intrathecal clonidine (0.3, 1.0, and 3.0 microg) and tizanidine (1.0, 2.0, and 5.0 microg), and the antihyperalgesic effects of thermal and mechanical stimuli were examined. In addition, the changes in blood pressure and heart rate, sedation level, and other side effects after intrathecal administration of drugs were recorded. RESULTS: The administration of 3.0 microg intrathecal clonidine or 5.0 microg tizanidine significantly reversed both thermal and mechanical hyperalgesia. The administration of 3.0 microg intrathecal clonidine, but not 5.0 microg tizanidine, significantly decreased mean blood pressure and heart rate and produced urinary voiding. A greater sedative effect was produced by 3.0 microg intrathecal clonidine than by 5.0 microg tizanidine. CONCLUSION: The antihyperalgesic dose of intrathecal clonidine and the antinociceptive doses produced several side effects. Intrathecal tizanidine at the dose that reversed hyperalgesia would be preferable for neuropathic pain management because of absence of hypotension and bradycardia and lower incidence of sedation.     

Wound infiltration with liposomal bupivacaine prolongs analgesia in rats

Background: Wound infiltration with local anesthetics does not reliably produce satisfactory postoperative analgesia, and the dose of local anesthetic which may be safely administered is limited by the potential for systemic toxicity. This study evaluated the efficacy of a slow-release liposomal bupivacaine formulation on duration of wound analgesia.
Methods: Multilammelar liposomes containing bupivacaine were assessed using a rat paw wound model. Twenty-four hours after surgical incision, paw wounds determined to be hyperalgesic to graded force testing with von Frey hairs were infiltrated with 0.3 ml of 2% liposomal bupivacaine, 0.5% plain bupivacaine, saline, or 'empty' (normal saline) liposomes (n=6/group). The duration of analgesia was measured. The 0.5% plain concentration was chosen because, in preliminary experiments, larger doses were often fatal. Analgesia duration was compared using Mann-Whitney U test at P < 0.05. In other rats, plasma bupivacaine levels after wound infiltration with either 2% liposomal formulation or 0.5% plain formulation were assessed (n=8/group).
Results: The mean duration of analgesia was 23+/-3 (SD) min for plain bupivacaine and 180+/-30 min for liposomal bupivacaine. No wound analgesia was detected in animals given normal saline or 'empty' liposomes. Plasma bupivacaine levels tended to be lower after liposomal than plain bupivacaine.
Conclusions: The 8-fold increase in duration of wound analgesia and the lower plasma levels seen with the liposomal formulation are explained by gradual drug release from the liposomal depot. These results may have important implications for achieving safe and effective analgesia with wound infiltration techniques in humans.     

Efficacy of intrathecal neostigmine for the relief of postinguinal hemiorrhaphy pain

BACKGROUND: Intrathecal administration of various doses of neostigmine has been reported to produce analgesia without neurotoxicity in both animal and human studies. The present study was undertaken to evaluate the efficacy and safety of intrathecal neostigmine for the relief of pain for patients having undergone inguinal herniorrhaphy surgery. METHODS: Sixty men scheduled for elective inguinal herniorrhaphy with spinal anaesthesia were randomly allocated to three groups: group I (n=20) received intrathecal (IT) tetracaine 15 mg, group II (n=20) received IT tetracaine 15 mg+ neostigmine 50 microg, and group III (n=20) received IT tetracaine 15 mg+neostigmine 100 microg. The onset of anaesthesia, duration of analgesia, time to use of first rescue analgesics, the overall 24 h VAS pain scores and the incidence of adverse effects were recorded for 24 h postdrug administration. RESULTS: Onset of anaesthesia (time to T6 sensory block) was significantly faster for group II and III patients compared with group I patients. Motor block (time to lift leg) was greatly prolonged for group III patients, with an average of 6.4 h, compared with 4.1 h for group II patients. Group III patients also showed a later onset of postsurgical pain, lower overall 24-h VAS pain score and prolonged time to first rescue analgesics than did group II patients. There was a significantly greater incidence of adverse effects associated with IT neostigmine, especially nausea and vomiting. CONCLUSION: Our study showed that intrathecal neostigmine at 50 pg or 100 microg enhanced the onset of tetracaine anaesthesia and provided analgesia lasting for 6-9 h, although increased incidences of prolonged motor blockade and nausea or vomiting were noted.