Anesthesia for cesarean section: minimizing risk and complications.

Managing cesarean section anesthesia is challenging and fraught with hazards. Each anesthetic option has different maternal and fetal risks. Emphasis on regional anesthesia when possible and utilization of state-of-the-art monitoring such as pulse oximetry and end-tidal capnography will improve the anesthetic outcome.

Elective repeat cesarean section. Effect of anesthesia type on blood loss.

Halothane depresses uterine contractility and may increase cesarean blood loss during the use of general anesthesia. We retrospectively compared the medical records of 399 elective repeat cesarean section patients. We excluded medical and obstetric conditions that may predispose such patients to increased blood loss. Subsequent detailed record analysis included 84 patients receiving epidural anesthesia, 23 receiving halothane-supplemented nitrous oxide for general anesthesia and 14 receiving unsupplemented nitrous oxide for general anesthesia. No patient received a blood transfusion. The incidence of low postoperative hematocrits (less than 32%) following surgery was similar with all the anesthetic methods. Low-dose halothane supplementation of general anesthesia for elective cesarean section did not increase blood loss.

Anesthetic and obstetric outcome in morbidly obese parturients.

BACKGROUND: Large studies reporting anesthetic outcome for morbidly obese parturients are lacking. This study compares the anesthetic and obstetric outcome in morbidly obese parturients and matched control parturients. METHODS: Anesthesia records were prospectively collected for all patients delivering between September 1978 and November 1989 whose weight exceeded 136.4 kg (300 pounds) at the time of delivery. A retrospective control patient group was collected by matching the first patient weighing less than 136.4 kg, delivered in the same month by the same obstertrician, to the corresponding morbidly obese parturient. Anesthetic and obstetric outcome variables were extracted from medical records and analyzed. RESULTS: Sixty-two percent of 117 morbidly obese women underwent cesarean section, while only 24% of control patients delivered abdominally (P < 0.05). Forty-eight percent of all laboring morbidly obese parturients required emergency cesarean section, compared with 9% of control laboring parturients (P < 0.05). Epidural anesthesia was used successfully for labor and cesarean delivery in 74 of 79 morbidly obese women and 66 of 67 control patients. When compared with control patients, initial epidural anesthesia failure was significantly more likely in morbidly obese women, requiring epidural catheter replacement. Difficult tracheal intubation occurred in 6 of 17 morbidly obese women, compared with 0 of 8 control women (P = 0.06). Morbidly obese women had increased incidences of antepartum medical disease, prolonged cesarean section operation times, serious postoperative complications, and increased hospital stays. CONCLUSIONS: The high incidences of antepartum medical disease and emergency cesarean section complicate anesthetic care in the morbidly obese parturients. Epidural anesthesia is feasible; however, the high initial failure rate necessitates early catheter placement, critical block assessment and catheter replacement when indicated, and provision for alternative airway management.

Spinal versus epidural anesthesia for cesarean section in severely preeclamptic patients: a retrospective survey.

BACKGROUND: Selection of spinal anesthesia for severely preeclamptic patients requiring cesarean section is controversial. Significant maternal hypotension is believed to be more likely with spinal compared with epidural anesthesia. The purpose of this study was to assess, in a large retrospective clinical series, the blood pressure effects of spinal and epidural anesthesia in severely preeclamptic patients requiring cesarean section. METHODS: The computerized medical records database was reviewed for all preeclamptic patients having cesarean section between January 1, 1989 and December 31, 1996. All nonlaboring severely preeclamptic patients receiving either spinal or epidural anesthesia for cesarean section were included for analysis. The lowest recorded blood pressures were compared for the 20-min period before induction of regional anesthesia, the period from induction of regional anesthesia to delivery, and the period from delivery to the end of operation. RESULTS: Study groups included 103 women receiving spinal anesthesia and 35 receiving epidural anesthesia. Changes in the lowest mean blood pressure were similar after epidural or spinal anesthesia. Intraoperative ephedrine use was similar for both groups. Intraoperative crystalloid administration was statistically greater for patients receiving spinal versus epidural anesthesia (1780 +/- 838 vs. 1359 +/- 674 ml, respectively). Neonatal Apgar scores and incidence of maternal intensive care unit admission or postoperative pulmonary edema were also similar. CONCLUSION: Although we cannot exclude the possibility that the spinal and epidural anesthesia groups were dissimilar, the magnitudes of maternal blood pressure declines were similar after spinal or epidural anesthesia in this series of severely preeclamptic patients receiving cesarean section. Maternal and fetal outcomes also were similar.

Phase I safety assessment of intrathecal neostigmine methylsulfate in humans.

BACKGROUND: In dogs, sheep, and rats, spinal neostigmine produces analgesia alone and enhances analgesia from alpha 2-adrenergic agonists. This study assesses side effects and analgesia from intrathecal neostigmine in healthy volunteers. METHODS: After institutional review board approval and informed consent, 28 healthy volunteers were studied. The first 14 volunteers received neostigmine (50-750 micrograms) through a #19.5 spinal needle followed by insertion of a spinal catheter. The remaining 14 volunteers received neostigmine through a #25 or #27 spinal needle without a catheter. Safety measurements included blood pressure, heart rate, oxyhemoglobin saturation, end-tidal carbon dioxide, neurologic evaluation, and computer tests of vigilance and memory. Analgesia in response to ice water immersion was measured. RESULTS: Neostigmine (50 micrograms) through the #19.5 needle did not affect any measured variable. Neostigmine (150 micrograms) caused mild nausea, and 500-750 micrograms caused severe nausea and vomiting. Neostigmine (150-750 micrograms) produced subjective leg weakness, decreased deep tendon reflexes, and sedation. The 750-micrograms dose was associated with anxiety, increased blood pressure and heart rate, and decreased end-tidal carbon dioxide. Neostigmine (100-200 micrograms) in saline, injected through a #25 or #27 needle, caused protracted, severe nausea, and vomiting. This did not occur when dextrose was added to neostigmine. Neostigmine by either method of administration reduced visual analog pain scores to immersion of the foot in ice water. CONCLUSIONS: The incidence and severity of these adverse events from intrathecal neostigmine appears to be affected by dose, method of administration, and baricity of solution. These effects in humans are consistent with studies in animals. Because no unexpected or dangerous side effects occurred, cautious examination of intrathecal neostigmine alone and in combination with other agents for analgesia is warranted.

Maternal and fetal effects of epinephrine in gravid ewes.

Intravenous cannulation by an epidural catheter may complicate epidural anesthesia. Local anesthetic solutions containing epinephrine produce tachycardia and hypertension when given intravenously and may identify intravenous placement. The authors studied the maternal and fetal effects of intravenous epinephrine-containing solutions in ten chronically instrumented gravid ewes. While continuously monitoring maternal and fetal effects, epinephrine 5, 10, or 20 micrograms iv bolus was injected. Solutions of bupivacaine 5 mg and bupivacaine 5 mg combined with epinephrine 10 micrograms given iv were also examined. All epinephrine-containing solutions produced a significant increase (P less than 0.001) in maternal mean arterial pressure, which returned to baseline after 1 min. Maternal heart rates decreased transiently and returned to baseline after 1 min. All epinephrine-containing solutions decreased uterine blood flow (UBF) (P less than 0.001), and, for doses of 10 to 20 micrograms, this decrease lasted more than 3 min. Fetal heart rate and mean arterial blood pressure did not change following any test solution, nor did maternal or fetal arterial blood gas values. The authors conclude that small intravenous boluses of epinephrine decreased UBF in these animals.

Phase I human safety assessment of intrathecal neostigmine containing methyl- and propylparabens.

UNLABELLED: Intrathecal (i.t.) neostigmine produces analgesia in humans with acute experimental, postoperative, and chronic pain. The sole manufacturer of the preservative-free neostigmine solution used in the initial clinical studies no longer markets this preparation. Although solutions containing preservatives are generally avoided for i.t. injection, methyl- and propylparabens have not been demonstrated to be toxic. After preclinical toxicity screening in animals and Food and Drug Administration approval, 12 volunteers received i.t. neostigmine 10, 30, or 100 micrograms, containing these preservatives and glucose. This preparation produced dose-dependent analgesia, nausea, weakness, and sedation similar to the preservative-free preparation. I.t. neostigmine increased acetylcholine but not norepinephrine concentrations in cerebrospinal fluid. Although nitric oxide synthesis has been implicated in analgesia from i.t. neostigmine injection in animals, cerebrospinal fluid concentrations of nitrite as a measure of nitric oxide were not increased by i.t. neostigmine in these volunteers. These data support the investigational application of i.t. neostigmine containing methyl- and propylparabens in the concentrations studied. IMPLICATIONS: Because intrathecal injection of neostigmine may be a useful analgesic, we performed a Phase I tolerability and safety study of the commercially available neostigmine formulation in human volunteers and found no evidence of toxicity. These data are important to the clinical use of this new therapy.

Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers.

UNLABELLED: Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain. Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 microg) before and after the IV or intrathecal injection of clonidine 50 or 150 microg in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 microg of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 microg) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this alpha2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. IMPLICATIONS: To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia.

An isobolographic study of epidural clonidine and fentanyl after cesarean section.

Although the epidural administration of clonidine and fentanyl provides pain relief after surgery, the interaction between the two drugs has not been examined formally. This study used an isobolographic method to determine whether epidurally administered fentanyl and clonidine interact in an additive or synergistic manner. Ninety women with moderate to severe pain after elective cesarean section under epidural anesthesia were studied. Using a randomized, double-blind protocol, we assigned each patient to receive a single epidural injection of one of three doses of fentanyl, clonidine, or a fixed ratio combination. Pain relief, blood pressure (BP), heart rate (HR), and sedation were measured 15 min after injection. Each drug alone and in combination produced analgesia, as measured by pain relief scores, and reduced need for intravenous morphine. Although the effective dose producing analgesia in 50% of patients (ED50) for the mixture was only 52% of that predicted by an additive interaction, this did not differ significantly from additivity, likely due to large variability. Clonidine, alone or in combination with fentanyl, produced a minor reduction in BP, but did not affect HR or cause more sedation than fentanyl. Unlike studies in rodents, this clinical study did not demonstrate synergy between fentanyl and clonidine. This could reflect a true species difference or differences in methodologies used. Nonetheless, a reduced dose of fentanyl and clonidine can be combined for excellent analgesia.

Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and their combination in sheep.

BACKGROUND: Intrathecal neostigmine may produce analgesia by itself and may enhance analgesia from spinal clonidine. Before clinical trials, the spinal cord blood flow effects of these drugs alone and in combination should be examined in animals. METHODS: Conscious, nonpregnant ewes with indwelling vascular and thoracic spinal catheters received intrathecal injection of 0.2 or 2 mg neostigmine, 0.2 mg clonidine, or 2 mg neostigmine plus 0.2 mg clonidine. Mean systemic and pulmonary arterial and central venous pressures, heart rate, and cardiac output were monitored, arterial blood was sampled for blood gas tensions and pH, and spinal cord blood flow was determined by colored microsphere injection before and at 15, 60, and 240 min after spinal study drug injection. RESULTS: Neostigmine alone did not affect cardiorespiratory variables or spinal cord blood flow. Intrathecal clonidine alone decreased systemic arterial and central venous pressures, whereas these effects were not observed with addition of neostigmine. Clonidine or neostigmine alone or the combination of clonidine and neostigmine did not affect spinal cord blood flow. CONCLUSIONS: Intrathecal neostigmine alone or in combination with clonidine does not reduce spinal cord blood flow, an important preclinical toxicity issue. These results provide additional support for initial clinical trials of intrathecal neostigmine for analgesia.

Cerebrospinal fluid norepinephrine and acetylcholine concentrations during acute pain.

Painful stimulation increases spinal cord norepinephrine (NE) in animals, and spinally released NE induces acetylcholine (ACh) release to cause analgesia. The purpose of this study was to determine the relationship between NE and ACh in cerebrospinal fluid (CSF) in sheep and humans during painful stimulation. CSF was sampled in anesthetized sheep before and during electrical nerve stimulation at an intensity sufficient to increase mean arterial pressure 15%-20%. To determine whether spinally released NE caused ACh release by stimulation of alpha(2)-adrenoceptors, seven sheep received intrathecal (IT) idazoxan whereas seven sheep received IT saline before stimulation. To examine the effect of pain on CSF NE and ACh in humans, CSF was sampled in 33 women after at least 4 h of painful labor and in 22 pregnant women without pain. Painful stimulation in sheep increased CSF NE and ACh. IT idazoxan blocked the increase in both NE and ACh. Although mean concentrations of CSF NE and ACh did not differ between parturients with and without pain, there was a significant correlation between NE and ACh concentrations only in those with pain. These data provide evidence in animals for activation of spinal cord noradrenergic-cholinergic systems in response to pain. There is only weak evidence for such activation, however, in women with painful labor.

Computer-controlled epidural infusion to targeted cerebrospinal fluid concentrations in humans. Clonidine.

BACKGROUND: Pharmacokinetically designed infusions have been demonstrated to achieve rapidly and maintain desired concentrations of drug in plasma after intravenous administration. In this study we tested whether a similar approach, targeting concentrations in cerebrospinal fluid (CSF), could be used with epidural administration of the alpha 2-adrenergic analgesic clonidine. METHODS: After institutional review board approval and informed consent had been obtained, seven healthy volunteers received a clonidine infusion through a lower lumbar epidural catheter. Infusion of clonidine (10 micrograms/ml) was controlled by the STANPUMP program for sequential 75-min periods to targeted CSF clonidine concentrations of 25, 50, 75, and 150 ng/ml. Before reprogramming to the next higher targeted concentration, mean arterial blood pressure and heart rate were measured; blood was obtained for clonidine and catecholamine assays; and visual analog score for sedation and pain to immersion of foot and hand in ice water were obtained. CSF was collected during infusion with an indwelling lumbar intrathecal catheter and was analyzed for clonidine, catecholamines, and acetylcholine. RESULTS: CSF clonidine concentrations rapidly increased and were maintained at steady values with the stepped infusion, although observed concentrations were consistently greater than targeted. The relation between CSF clonidine concentration and analgesia in the foot was similar to that previously observed after epidural bolus administration. Clonidine also was associated with concentration-dependent sedation; decreased mean arterial blood pressure, heart rate, and CSF norepinephrine concentration; and increased CSF acetylcholine concentration. CONCLUSIONS: This study suggests that pharmacokinetically designed infusions of drugs in the epidural space in humans can maintain steady concentrations of drug in CSF. In addition to providing a useful tool for investigation of mechanisms of action and drug interactions, this technique may improve analgesia and diminish side effects from epidurally administered analgesics.

Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition.

Intravenous opioids cause analgesia and increase release of ACh in spinal cord dorsal horn in animals, and these effects are enhanced by intrathecal neostigmine injection. The purpose of the current study was to test whether intrathecal neostigmine enhanced analgesia and increased cerebrospinal fluid concentrations of ACh over those induced by i.v. alfentanil in volunteers, and also to test whether neostigmine enhanced alfentanil-induced side effects. After human studies committee approval, 40 healthy volunteers received an intrathecal injection of saline or neostigmine (50, 100 or 200 microg) followed in 60 min by a computer-controlled, stepped i.v. infusion of alfentanil to escalating targeted plasma concentrations. Pain report to hand and foot immersion in ice water, sedation, nausea, weakness, vital signs, end-tidal CO2 and oxyhemoglobin saturation were measured 60 min after spinal injection and at the end of each 20-min alfentanil infusion. Cerebrospinal fluid was sampled once after drug administration. Intrathecal neostigmine alone caused analgesia in the foot but not in the hand, and was accompanied by leg weakness, whereas IV alfentanil alone caused equivalent analgesia in both the hand and the foot and was accompanied by nausea, sedation, increased end-tidal CO2 and decreased oxyhemoglobin saturation. Neostigmine enhanced analgesia but not respiratory effects induced by i.v. alfentanil; it also enhanced nausea and sedation. Intravenous alfentanil increased cerebrospinal fluid ACh concentration, and neostigmine enhanced this change. These data in humans are consistent with a spinal cholinergic mechanism of i.v. opioid analgesia. Because neostigmine enhances both analgesia and side effects induced by i.v. alfentanil, the clinical utility of their use in combination will depend on the relative strength of these interactions.

Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans.

BACKGROUND: Intradermal injection of capsaicin produces brief pain followed by hyperalgesia and allodynia in humans, and the latter effects are mediated by spinal N-methyl-D-aspartate mechanisms. Amitriptyline recently was shown to antagonize N-methyl-D-aspartate receptors, and in this study, the authors sought to determine the effect of amitriptyline alone and with the opioid alfentanil on hyperalgesia and allodynia produced by intradermal injection of capsaicin. METHODS: Forty-six healthy volunteers in the general clinical research center received repeated intradermal injections of capsaicin (100 microg) alone or before and after systemic injection of 4 mg midazolam, 25 mg amitriptyline, alfentanil by computer-controlled infusion, or amitriptyline plus alfentanil. Acute pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. Blood was obtained for alfentanil and amitriptyline assay. RESULTS: Capsaicin injection produced acute pain followed by hyperalgesia and allodynia. Alfentanil reduced these pain responses in a plasma-concentration-dependent manner, and reduction in hyperalgesia and allodynia correlated with reduction in acute pain. Amitriptyline alone had no effect and did not potentiate alfentanil. Alfentanil produced concentration-dependent nausea, an effect diminished by amitriptyline. DISCUSSION: These data correspond with previous studies in volunteers demonstrating reduction in hyperalgesia and allodynia after intradermal injection of capsaicin by systemically administered opioids, and they suggest that this reduction may be secondary to reduced nociceptive input by acute analgesia. These data do not support the use of acute systemic administration of amitriptyline for acute pain, hyperalgesia, and allodynia, although the roles of chronic treatment and spinal administration are being investigated.

Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans.

BACKGROUND: This study defines the cerebrospinal fluid (CSF) pharmacokinetics of neostigmine after intrathecal injection in humans and its effect on CSF acetylcholine, and it correlates physiologic effects with neostigmine dose and CSF acetylcholine concentrations. METHODS: The CSF was sampled via an indwelling spinal catheter in 12 volunteers receiving intrathecal neostigmine (50-750 microg) and analyzed for neostigmine and acetylcholine. Pharmacokinetic and pharmacodynamic analyses were performed with NONMEM. Effect-site models linked the time course of the neostigmine concentration with the time course of analgesia. RESULTS: Acetylcholine concentrations increased from <20 pmol/ml at baseline to >100 pmol/ml within 15 min of neostigmine injection. The pharmacokinetics of intrathecal neostigmine were best described by a triexponential function with an absorption phase. Individual predicted concentrations varied 100-fold. Post hoc Bayesian estimates described the observed neostigmine concentrations with a median error of 22% and did not show systematic model misspecification. Individual estimates of effect site concentration producing a 50% maximal effect for foot visual analog scale analgesia correlated with the magnitude of individual CSF neostigmine concentrations. CONCLUSIONS: Intrathecal neostigmine concentrations can be well described by a triexponential disposition function, but the intersubject variability is large. The correlation between intersubject variability in concentration and intersubject variability in 50% maximal effect for foot analgesia suggests that both are offset by a common scalar, possibly the distance from the site of injection to the sampling and effect sites. These data provide the basis for the hypothesis of "observation at a distance" to describe the pharmacodynamics of intrathecally administered drugs.

Sex differences in cholinergic analgesia I: a supplemental nicotinic mechanism in normal females.

BACKGROUND: Cholinergic agents produce analgesia after systemic and intrathecal administration. A retrospective review showed that intrathecal neostigmine was more potent in women than in men, suggesting a sex difference in this response. The purpose of this study was to determine whether such a sex difference exists in normal rats and to examine the pharmacologic mechanisms that underlie this difference. METHODS: Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), or RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), or phentolamine alpha-adrenergic antagonist) with antinociception determined to a noxious heat stimulus to the hind paw. Time versus subcutaneous paw temperature relationships were defined for males and females. RESULTS: Neostigmine produced dose-dependent antinociception with five times greater potency in female than in male rats. Neostigmine-induced antinociception was reversed in male rats by atropine and unaffected by mecamylamine, whereas it was partially reduced by each antagonist alone in females and completely reversed after injection of both. RJR-2403 was more potent in females than in males, whereas there was no sex difference to bethanechol. Phentolamine partially reversed antinociception from RJR-2403 in females. Paw temperature increased more rapidly in females than in males for the same lamp intensity. CONCLUSIONS: These data demonstrate a large sex difference in antinociception to intrathecal neostigmine that is primarily the result of a nicotinic component in females. Phentolamine reversal suggests that part of this nicotinic component may rely on spinal norepinephrine release. A better understanding of this sex difference could lead to development of novel pain therapy for women.

A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy.

BACKGROUND: Intrathecal neostigmine injection produces analgesia in volunteers and reduces hypotension from intrathecal bupivacaine in animals. Initial clinical trials with neostigmine studied doses of more than 100 microg, but animal studies suggest that smaller doses may be effective. In addition, all controlled clinical trials of neostigmine have come from one Brazilian university. This multicenter, placebo-controlled trial investigated the effects of 25-75 microg intrathecal neostigmine on analgesia and blood pressure in women undergoing vaginal hysterectomy. METHODS: After institutional review board approval was obtained at the three university centers, and after patients gave informed consent, 92 women scheduled for vaginal hysterectomy were randomized to receive an intrathecal injection of 2 ml bupivacaine, 0.75%, in dextrose plus either 1 ml saline or 25, 50, or 75 microg neostigmine. Blood pressure, heart rate, pain and nausea (both assessed by visual analog scale), and intravenous morphine use were recorded during surgery and at specified intervals afterward. RESULTS: Morphine use was reduced similarly by all doses of neostigmine. Only the 75-microg dose of neostigmine increased the nausea score in the recovery room. The incidence of treatment for nausea was greater in patients receiving neostigmine (61%) than in those receiving saline placebo (29%) and was unaffected by neostigmine dose. Neostigmine did not reduce the incidence of hypotension from bupivacaine. CONCLUSION: These data in patients after vaginal hysterectomy suggest that analgesia from intrathecal neostigmine may occur at doses less than 50 microg. In these doses, neostigmine does not reduce spinal bupivacaine-induced hypotension but may increase the need for treatment of nausea.

Interaction between intrathecal neostigmine and epidural clonidine in human volunteers.

BACKGROUND: alpha 2-Adrenergic agonists are thought to produce analgesia, in part, by activating spinal acetylcholine release. The purpose of the current study was to examine the interaction between intrathecal neostigmine and epidural clonidine for analgesia and side effects in humans. METHODS: A total of 58 volunteers received an intrathecal injection of 5% dextrose in normal saline (D5NS) or neostigmine (50, 100, or 200 micrograms in D5NS), followed in 1 h by epidural saline or clonidine (computer-controlled infusion targeted to 50, 100, 200, or 400 ng/ml in cerebrospinal fluid) using an isobolographic design. Visual analog scale pain to a noxious cold stimulus, nausea, weakness, sedation, and other safety variables was measured before and at specified intervals after drug administration. RESULTS: The first 21 volunteers randomized to receive intrathecal hyperbaric neostigmine rather than D5NS received the drug while in the sitting position, and had none-to-minimal analgesia 1 h later. The remaining volunteers received the drug while in the lateral position, and demonstrated dose-dependent analgesia in the foot 1 h later. Epidural clonidine also caused dose-dependent analgesia. The combination of neostigmine and clonidine resulted in an additive enhancement for analgesia, but no enhancement of each drug's side effects, and a reduction in clonidine-induced hypotension. Neostigmine injected into subjects in the lateral position diminished clonidine-induced reductions in blood pressure and plasma norepinephrine. CONCLUSION: These results support enhancement of alpha 2-adrenergic analgesia by intrathecal neostigmine, but do not demonstrate synergy, as observed in animals. Lack of enhancement of side effects suggests this combination may be clinically useful.

Intravenous opioids stimulate norepinephrine and acetylcholine release in spinal cord dorsal horn. Systematic studies in sheep and an observation in a human.

BACKGROUND: Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways. METHODS: The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan. RESULTS: Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose-dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphine's effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphine's effect on dorsal horn norepinephrine. CONCLUSIONS: These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone-sensitive mechanism. Idazoxan blockade of morphine's effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha 2-adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine-induced activation of bulbospinal pathways.