efforts to improve combined spinal - epidural ( cse ) technique have focused on adding opioids to other classes of analgesics , exemplifying multimodal analgesia . opioids are considered excellent analgesics , but their clinical effectiveness is frequently limited by adverse effects . by contrast , nonnarcotic agents may represent the ideal approach for outpatients undergoing minor orthopedic procedures , and there are encouraging trials of nonopioid drugs in cse technique . among nonnarcotics , neostigmine was suggested to be more efficacious for somatic then for visceral pain , making it attractive for orthopedic procedures . on the other hand , epidural dexamethasone has been extensively evaluated for visceral and neuropathic types of pain , but not for the somatic pain , such as orthopedic procedures , to our knowledge . because steroids such as dexamethasone are known to share certain mechanisms of action with nonsteroidal antiinflammatory drugs ( nsaid ) , and since the co - administration of neostigmine with nsaid resulted in a synergistic interaction in mice , the purpose of this study was to determine whether the combination of either low - dose intrathecal neostigmine or epidural dexamethasone , or both , enhances analgesia from spinal bupivacaine in minor orthopedic surgery , an example of somatic pain , once in spite of evaluation in animals , this association has not been evaluated in patients to date . the local ethical committee of the teaching hospital of the school of medicine of ribeiro preto from the university of so paulo , brazil , approved this protocol ( governmental clinical trial hc-7189 - 2008 ) . after gaining the subjects approval and written informed consent , 60 american society of anesthesiology ( asa ) status i and ii patients , 18 - 60 year old , undergoing minor orthopedic surgery were computer randomized to one of four groups ( n = 15 ) and prospectively evaluated using a placebo - controlled double - blind design to examine both analgesia and perioperative adverse effects . the concept of a visual analog scale ( vas ) , which consisted of a 10 cm line with 0 equaling  no nausea ( vas n ) or  no pain at all  and 10 equaling  worst possible nausea  or  the worst possible pain  was introduced to the subjects before surgery . exclusion criteria included diabetes , glaucoma , patient 's refusal or allergy for any of the study drugs . the patients were premedicated with 0.05 - 0.1 g / kg intravenous ( iv ) midazolam immediately before going to the operating room . hydration consisted of a rapid infusion of 10 ml / kg lactate solution before surgery and 10 ml / kg / h after intrathecal anesthesia . cse anesthesia was performed in theater at the l2-l3 ( epidural ) and l3-l4 ( spinal ) interspaces in the sitting position . one anesthesiologist prepared the test drugs , while a different one performed the spinal / epidural punctures . the epidural test drug was either saline or 10 mg dexamethasone diluted in saline ( for a final volume of 10 ml ) injected as a bolus . just after epidural drugs administration , spinal drugs were injected at 1 ml per 7 s through a 25-gauge intrathecal needle . all patients received 15 mg bupivacaine plus 1 ml of saline or 1 g neostigmine [ table 1 ] . patients from the control group ( cg ) received spinal saline and epidural saline as the test drugs . patients from the dexamethasone group ( dg ) received spinal saline and epidural dexamethasone , and patients from the neostigmine - dexamethasone group ( ndg ) received spinal neostigmine and epidural dexamethasone . the quality of sensation of the anaesthetized areas as described by the patient during the blockade installation was recorded as either : 
 heaviness;increase in temperature;numbness orpricking . intraoperative sensory loss assessment included the pinprick test at 5 and 10 min after the spinal anesthesia . intraoperative sensory loss assessment included the pinprick test at 5 and 10 min after the spinal anesthesia . blood pressure was monitored noninvasively every 5 min throughout surgery , and heart rate and oxyhemoglobin saturation ( spo2 ) were continuously monitored throughout surgery . a decrease in mean arterial pressure > 15% below preanesthetic baseline decreases in heart rate below 50 bpm were treated with atropine , 0.25 mg iv , according to the anesthesiologist 's judgment . intraoperative nausea was scored by the patient using the 10 cm vas n. the numbers of patients with nausea ( of any degree ) or vomiting at any time intraoperatively were noted . nausea > 2/10 at any time or vomiting during the study was treated with 8 mg iv ondansetron , if necessary . for patients with > 1 episode of nausea , postoperative assessment included pain scores , adverse effects and the duration of motor block , measured from spinal anesthesia until time to reach a bromage 2 score . the second rescue analgesic drug was the nonsteroidal dipyrone ( 1 g ) , administered intravenously , 1-h after the ketoprofen , if necessary , at 6-h - intervals . pain was assessed at the time of the first rescue analgesic and 24-h after the spinal puncture by the anesthesiologist who was blind to the treatment . nausea and occurrence of vomiting were assessed intraoperatively and 24-h after the spinal puncture by the same anesthesiologist , blind to the treatment . the duration of efficacious analgesia was measured as the time from the spinal anesthesia to the patient 's first request for analgesics either in the recovery room or infirmary , recorded in min . the vas at the time of the first rescue analgesic was measured using the 10 cm vas . the 24-h vas pain score and vas n reflected the patient 's overall impression of the 24-h following spinal injection . we hypothesized that 10 mg of epidural dexamethasone would increase the time to first rescue analgesic by 100% compared to the cg in the population studied , and expected that the addition of intrathecal neostigmine would further increase the time to first rescue analgesic by 20% compared to the dg . if a standard deviation was estimated , an 80% and an alpha value of 0.05 , these assumptions would require 12 patients in each group . groups were compared for demographic data ( i.e. , age , weight and height ) and duration of surgery by one - way anova . incidence of adverse events , gender , asa status and adjuvant drug use were compared among groups by chi - square corrected for multiple comparisons . p < 0.0125 was considered as significant ( i.e. , 0.05 divided by the number of groups ) . blood pressure , heart rate , level of anesthesia ( by pinprick test ) and vas scores were compared among groups by two - way anova for repeated measures . tukey analysis was applied to decrease the probability of type i error . the time to first rescue analgesics and the analgesic consumption ( mg ) in 24-h we hypothesized that 10 mg of epidural dexamethasone would increase the time to first rescue analgesic by 100% compared to the cg in the population studied , and expected that the addition of intrathecal neostigmine would further increase the time to first rescue analgesic by 20% compared to the dg . if a standard deviation was estimated , an 80% and an alpha value of 0.05 , these assumptions would require 12 patients in each group . groups were compared for demographic data ( i.e. , age , weight and height ) and duration of surgery by one - way anova . incidence of adverse events , gender , asa status and adjuvant drug use were compared among groups by chi - square corrected for multiple comparisons . p < 0.0125 was considered as significant ( i.e. , 0.05 divided by the number of groups ) . blood pressure , heart rate , level of anesthesia ( by pinprick test ) and vas scores were compared among groups by two - way anova for repeated measures . tukey analysis was applied to decrease the probability of type i error . the time to first rescue analgesics and the analgesic consumption ( mg ) in 24-h 1 patient from the ng was excluded from the study due to incomplete data collection , while 2 patients from the cg declined to participate . 6 patients in the cg , ng and ndg ; and 7 patients in the dg underwent knee arthroscopy / meniscus repair , while the others underwent knee ligamental reconstruction ( p > 0.05 ) . the four groups showed no differences regarding asa status , gender , age , weight or height [ p > 0.05 , table 2 ] . the numbers of patients in each group reporting either : flow diagram of progress through the phases enrolment , allocation , follow - up and analysis 
 heaviness;increase in temperature;numbness ora prickly sensation , as the main sensation in the anaesthetized area during the blockade installation are described in table 3 ( p > 0.05 ) . table 3quality of sensation described by the patient during the spinal / epidural blockade installation 

  increase in temperature ; a prickly sensation , as the main sensation in the anaesthetized area during the blockade installation are described in table 3 ( p > 0.05 ) . table 3quality of sensation described by the patient during the spinal / epidural blockade installation 
  quality of sensation described by the patient during the spinal / epidural blockade installation the sensory level to pinprick at 5 and 10 min after the spinal puncture , surgical and anesthetic time , and intraoperative ephedrine consumption were similar among the groups [ table 4 ] . the intraoperative hemodynamic data in different time intervals in four groups was similar ( p > 0.05 , data not shown ) . the intraoperative midazolam administration was also similar among the groups ( 2 - 4 mg , p > 0.05 ) . the pain vas score at the time of the first rescue analgesic medication was similar among the four groups ( p > 0.05 ) . the cg was similar to the ng related in time to first rescue analgesic , iv ketoprofen consumption and overall vas the time to first rescue analgesic was longer for the dg compared to both the cg and ng ( p < 0.0002 ) , and the dg had less ketoprofen consumption and lower overall vas - pain sores compared to both cg and ng ( p < 0.0005 ) . the addition of 1 g neostigmine ( ndg ) resulted in a longer time to rescue analgesic ( p < 0.02 ) and lower ketoprofen consumption ( p < 0.05 ) compared to the dg . 5 patients in the dg and 9 patients in the ndg did not request any analgesic during the 24-h evaluation . all other patients requested a rescue analgesic at least once ; however , no patients needed dipyrone . postoperative analgesia data there were no differences in the incidence of perioperative adverse effects ( p > 0.05 ) . intraoperatively , only 1 patient from the ng complained of transient intraoperative nausea ( vas 3 cm ) ; however , and no pharmacological treatment was necessary ( p > 0.05 ) . postoperatively , 1 patient from the ng had vomited once after dinner ; however , no pharmacological treatment was necessary . 1 patient from the dg complained of nausea ( vas 5 cm ) followed by transient headache . two patients from the ndg needed vesical catheterization at 6 and 7-h after the spinal puncture . here , we report a significant enhancement of the analgesic effect of spinal bupivacaine plus epidural dexamethasone by a combination with an intrathecal injection of 1 g of neostigmine in patients that underwent minor orthopedic procedures . this is the third double - blind clinical evaluation demonstrating enhancement of opioid analgesia after such a low - dose of neostigmine , and the first clinical trial to demonstrate enrichment from the combination of spinal neostigmine and epidural dexamethasone . epidural steroid injections have been used in acute pain under different circumstances , that is , in patients suffering from spinal stenosis , in which exacerbations of a chronic pain state occurs ; or for acute postoperative pain , in which epidural 5 mg of dexamethasone , before or after surgery reduces pain and analgesic requirement after radical subtotal gastrectomy . the use of dexamethasone at a dose of 10 mg instead of 5 mg was based on a pilot study , in which 5 mg of epidural dexamethasone produced little analgesic effect in a similar population . in this study , the addition of 10 mg of epidural dexamethasone to spinal bupivacaine resulted in a longer time to first rescue analgesic and less rescue analgesic consumption over 24-h . moreover , 30% of patients in the dg did not request any rescue analgesic , which was further optimized to 60% by the addition of 1 g of neostigmine . epidural dexamethasone may be acting at spinal sites by inducing the synthesis of the phospholipase - a2 inhibitory protein lipocortin , and thus , reducing prostaglandin and leukotriene synthesis and suppressing hyperalgesia associated with acute nociception during surgery . in addition , high levels of glucocorticoid receptor and mineralocorticoid receptor are colocalized in the substantia gelatinosa , suggesting that the pain pathways are strongly regulated by these receptors . dexamethasone was also shown to down - regulate cyclooxygenase-2 mrna , an important step for its antiinflammatory action . epidural dexamethasone could also cross through the spinal hole from the epidural into the spinal canal and inhibit the induction of excitatory amino acids , important neurotransmitters in central sensitization . spinal dexamethasone was demonstrated to modulate the development of morphine tolerance and the expression of glutamate transporters in rats . in this study , 1 g of spinal neostigmine did not enhance the analgesic effect of spinal bupivacaine , but potentiated the analgesic effect of epidural dexamethasone . one g spinal neostigmine has been previously demonstrated to enhance intrathecal morphine analgesia following orthopedic surgery combined to intrathecal morphine and to intrathecal fentanyl . the analgesic effect of spinal neostigmine was suggested to result from an increase in the concentration of the neurotransmitter acetylcholine , and its consequent action at muscarinic m1 and m3 and presynaptic nicotinic receptors , present in the cholinergic interneurons at the laminae ii and v of the dorsal horn . the inhibitory action at muscarinic receptors of dorsal horn neurons was suggested to be mediated in part by spinal gamma amino butyric acid - b receptors . intrathecal neostigmine also induced nitric oxide release in the spinal cord , suppressed fos expression and facilitated the activation of spinal m(2 ) receptors , ultimately leading to the release of adrenal catecholamines . these mediators which contributed to the antiinflammatory effect observed at the site of tissue inflammation . in addition to the apparent synergistic interaction between spinal neostigmine / bupivacaine and epidural dexamethasone observed in the present study , an interaction between ketoprofen , used as first line rescue analgesic , and spinal neostigmine in mice has been described . however , an interaction between ketoprofen and the study drugs can be ruled out , because neither group showed enhanced postoperative analgesia after ketoprofen administration . one explanation for the lack of synergy effect between ketoprofen and neostigmine could be the low - dose used ( 1 g ) in the ng . unfortunately , neither intraoperative nor postoperative sedation was evaluated , as epidural dexamethasone could have interfered with it . spinal 1 g neostigmine further enhanced analgesia from spinal bupivacaine combined with epidural dexamethasone , without increasing the incidence of adverse effects in the population studied , suggesting a role for a multimodal approach , including these drugs in the management of postoperative analgesia following minor orthopedic surgery . fsv - data collection , performing anesthesia , randomization . at - data collection , performing anesthesia .
background : opioids are considered mainstream for combined spinal - epidural anesthesia , but frequently limited by adverse effects . the aim of this study was to examine whether low - dose spinal neostigmine , epidural dexamethasone or their combination enhances analgesia from spinal bupivacaine without adverse effects.materials and methods : a total of 60 patients undergoing orthopedic surgery were randomized to one of four groups and evaluated for 24-h after surgery for analgesia ( time to first rescue analgesic ) and rescue analgesic consumption . 
 patients received 15 mg bupivacaine plus the test drug intrathecally ( saline or 1 microgram ( g ) neostigmine ) . 
 the epidural test drug was either saline or 10 mg dexamethasone . 
 the control group ( cg ) received spinal and epidural saline . 
 the neostigmine group ( ng ) , spinal neostigmine and epidural saline ; the dexamethasone group ( dg ) , spinal saline and epidural dexamethasone ; and the neostigmine - dexamethasone group ( ndg ) , spinal neostigmine and epidural dexamethasone.results:the cg ( 282  163 min ) and ng ( 524  142 min ) were similar in their times to first rescue analgesic and analgesic consumption . 
 the time to first rescue analgesic was longer for the dg ( 966  397 min ) compared with cg and ng ( p < 0.0002 ) , and the dg had less ketoprofen consumption and lower overall visual analogue scale - pain sores compared with cg and ng ( p < 0.0005 ) . 
 addition of 1 mg - neostigmine ( ndg ) resulted in longer time to rescue analgesic ( 1205  303 min ; p < 0.02 ) and lower ketoprofen consumption ( p < 0.05 ) compared to dg . 
 sporadic cases of vesical catheterization and emesis were observed , however adverse effects were similar among groups.conclusion:spinal 1 microgram ( g ) neostigmine further enhanced analgesia from spinal bupivacaine combined with epidural dexamethasone , without increasing the incidence of adverse effects .