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Enhancement of analgesic effect of intrathecal neostigmine and clonidine on bupivacaine spinal anesthesia
Regional Anesthesia and Pain Medicine 23(1): 49-56, 1998
E n h a n c e m e n t of Analgesic Effect of Intrathecal N e o s t i g m i n e and Clonidine on Bupivacaine Spinal A n e s t h e s i a RM. Pan, M.D.,* C.T. Huang, M.RA.,* T.T. Wei, M.D.,* and M.S. Mok, M.D.t
Background and Objectives. Intrathecal administration of neostigmine has been shown to produce analgesia in both animals and humans. The concurrent administration of intrathecal neostigmine and clonidine has been reported to produce no neurotoxicity in sheep. The purpose of the present study was to evaluate the efficacy and safety of the combining intrathecal neostigmine and clonidine for the relief of pain in patients after cesarean delivery. Methods. After giving their consents, 80 parturients who were scheduled for cesarean delivery during spinal anesthesia were enrolled by a doubleblind randomized design into four groups: bupivacaine group (n = 20) received intrathecal (IT) 10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received IT 10 mg bupivacaine + 50 gg neostigmine; bupivacaine + donidine group (n = 20) received IT l0 mg bupivacaine + 150 gg clonidine; and bupivacaine + both (n = 21) received IT 10 mg bupivacaine + 50 p,g neostigmine + 150 gg donidine. The m a x i m u m spread of anesthesia, duration of analgesia and motor block, vital signs, and incidence of adverse effects were recorded for 14 hours postinjection. Fifty milligrams intramuscular meperidine was given as a rescue analgesic whenever patient's pain score was greater than 5/10 by the visual analog scale. Results. The demographic data were similar for all four groups. Bupivacaine + both group had a significantly higher m a x i m u m spread of anesthesia of 23.3 + 2.9 segments than bupivacaine group of 20.5 + 2.9 segment. Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 + 1.5 hours as compared to bupivacaine group of 1.3 + 0.6 hours. The pain score in bupivacaine + both group was significantly lower than that of bupivacaine group during the first 10 hours. The 24-hour meperidine consumption also was lower in bupivacaine + both group than that of bupivacaine group. However, motor b]ock was significantly prolonged from 3.5 _+ 1.1 hours in bupivacaine group to 7.1 + 1.6 hours in bupivacaine + both group. In addition, other side effects such as nausea and vomiting and dizziness were significantly increased in bupivacaine + both group. Conclusion. Our study showed that the combination of 150 gg 1T donidine and 50 gg neostigmine provided longer postsurgical analgesia than with either drug used alone. However, this combination also produced significantly more adverse effects of prolonged motor block and nausea and vomiting. A further study combining the two study drugs but using a lower dose of IT neostigmine (e.g., 25 gg) is recommended. Reg Anesth Pain Med 1998: 23: 49-56. K e y w o r d s : perioperative analgesia, intrathecal neostigmine and donidine, anticholinesterase.
From the *Department of Anesthesia, Mackay Memorial Hospital, Taitung, Taiwan and tDepartment of Anesthesiology, University of Southern Calitornia, Los Angeles, California. This study was done at Mackay Memorial Hospital, Taitung, Taiwan, ROC and was supported by a Mackay Memorial Hospital grant. The abstract ol the study was presented in part at the Annual Meeting of the American Society of Anesthesiologists, October, 1996. Accepted for publication July 30, 1997. Reprinted requests: Peter Mu-His Pan, M.D., Department of Anesthesia, Mackay Memorial Hospital, Taitung, Taiwan, ROC.
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Intrathecal injection of clonidine, an alpha-2 agonist, provides effective relief of pain (1-7). However, the clinical use of intrathecal clonidine is hampered by the side effects of sedation, bradycardia, and hypotension (5-7). Recently, the intrathecal (IT) administration of neostigmine, a cholinesterase inhibitor, has been shown to produce analgesia without neurotoxicity in animals (10,11) and humans, but also produced adverse effects of motor block, dizziness, nausea, or vomiting (8,9). Gordh et al. had shown a relationship between the alpha-adrenergic and the cholinergic systems in the spinal cord to produce analgesia (12). Thus, we hypothesized combining cholinergic and alpha-adrenergic agents will produce improved analgesia by reducing the dose of each individual drug, therefore minimizing their adverse effect. Abram and Winne (13) showed in a rat model that IT neostigmine did indeed potentiate morphine analgesia. Hood et al. (14) had shown in h u m a n volunteers that a neostigmineclonidine combination produced improved analgesia, while side effects were related solely to the dose of the individual drug. The present study evaluated the efficacy and safety of combining a fixed dose IT neostigmine and clonidine in the relief of pain in patients after cesarean delivery.
Methods After approval by the Hospital Research Committee and after obtaining informed consents from all the subjects, we enrolled 80 parturients who were scheduled for cesarean delivery during spinal anesthesia. All patients were ASA II patients without any known cardiopulmonary disease, and all fetuses were at term without signs of fetal distress. None of the patients received premedication. After intravenous infusion of 1000 mL lactated ringer's solution, the patients were turned to right lateral decubitus position and lumbar puncture was performed at L3-L4 interspace with a 25-gauge spinal needle using a midline approach. The patients were divided randomly into four groups and received IT administration of the following drugs: bupivacaine group received 1 mL bupivacaine 0.5% heavy spinal solution (B) (bupivacaine 5 mg/mL with dextrose 80 mg/mL) followed by another 1 ml B 5 minutes later; bupivacaine + neostigmine group received 1 mL B mixed with 50 gg neostigmine followed by another 1 mL B 5 minutes later; bupivacaine + clonidine group received 1 mL B followed by 1 mL B mixed with 150 gg clonidine at 5 minutes; bupivacaine + both group received 1 mL B mixed with 50 gg neostigmine
followed by 1 mL B mixed with 150 gg clonidine 5 minutes later (Bupivacaine 0.5% heavy spinal, Astra Pharmaceutical, Sodertalje, Sweden. Neostigmine methylsulfate 0.5 mg/mL, Santong Pharmaceutical Co. Ltd, Toayuan, Taiwan. Clonidine hydrochloride 150 gg/mL, Boehringer Pharmaceutical, Germany). All the medications were given slowly over 30 seconds by an anesthetist who selected the anesthetic management by blindly picking from a box a piece of paper with the name of study solution. After drug administration, the patient was turned to a supine position. Uterine displacement was performed with the use of a wedge. Blood pressure was monitored every minute for the first 15 minutes and then measured every 3 minutes thereafter throughout the surgery. Patients were monitored with continuous ECG, precordial stethoscope, and pulse oximeter. Supplemental oxygen at 4 L/min was given to all patients by nasal cannula, and intravenous ephedrine at 5 mg increments were given when systolic blood pressure decreased below 100 m m Hg. Dermatomes of the maximal sensory block were assessed by pinprick. In case of inadequate anesthesia, incremental doses of intravenous ketamine were given, but no narcotic analgesics were used intraoperative. The number of patients who had intraoperative ketamine supplementation was recorded. We also measured the duration of absolute analgesia which was defined by Hunt (15) as the time from IT injection to the time when the patient first complained of any pain sensation. Visual analog scale was used to assess amount of pain at rest and with movement (turning from side to side) at 30, 60, 120 minutes, and then every 2 hours for 14 hours. The duration of motor block was recorded from the time of drug injection to the time when the patient could lift her legs. Adverse effects such as nausea, vomiting, dizziness, restlessness, pruritus, and respiratory depression (i.e., a respiratory rate less than 10 breaths/min) were recorded. The severity of nausea and vomiting and pruritus was graded by a 3point scale: 1 = mild, no treatment; 2 = moderate, required one treatment; and 3 = severe, required more than one treatment. In addition, the time of the first dose meperidine administered (effective analgesia) and the total amount meperidine used in the first 24 hours postoperative were also recorded. All the observations were made by an anesthetist who was blinded to the study drugs. Data were expressed as mean + SD. Parametric data were analyzed by one-way ANOVA, and multiple comparison between pairs was done by the Scheffe's test. Between-group differences in the incidences of adverse events were analyzed using
Intrathecal Neostigmine Plus Clonidine
the chi-square test. Fisher's exact test was used when appropriate. A P value less than .05 was considered to be significant.
Results The demographic data were comparable in all groups as shown in Table 1. The maximal sensory block level was significantly higher in bupivacaine + both group with an average of 23.3 segments compared to 20.5 segments in bupivacaine group with a P value of .006 (Table 2). The addition of IT neostigmine, clonidine, or their combination all enhanced per±operative analgesia. Intraoperative, the number of patients needing supplemental analgesics was 35% in bupivacaine group, 10% for either bupivacaine + neostigmine group or bupivacaine + don±dine group and none for bupivacaine + both group. Postoperative, the absolute and effective analgesic times were prolonged for the later three groups. As shown in Figs. 1 and 2, the visual analog scale pain score of bupivacaine + both group was significantly lower than the other three groups up to the 6-hour period. Finally, the dose of meperidine required in the first 24-hour postsurgery was significantly reduced in bupivacaine + both group (Table 2). Hemodynamically, all the study groups showed significantly increased incidence in the use of ephedrine to correct intraoperative blood pressure reduction (below 100 m m Hg) (Table 3). However,
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the change of blood pressure was easily corrected with similar dosage of ephedrine per patient for all four groups. In addition, there was no difference in the mean arterial blood pressure (MAP) and heart rate (HR) among the four groups (Figs. 3 and 4). Neurologically, all three study groups showed prolonged motor block as evidenced by the leglift time with bupivacaine + both group showing the most profound change (Table 2). Incidences of adverse effects were increased in all three study groups, especially nausea and vomiting and dizziness were significantly and similarly higher in bupivacaine + neostigmine group and bupivacaine + both group. Respiratory depression was not observed in any of the patients (Table 3).
Discussion Hood et al. reported that the IT administration of 50-750 gg neostigmine provided analgesia and adverse effects of motor block, and nausea and vomiting in a dose-dependent manner (8). We showed that neostigmine 100 gg added to IT 12 mg hyperbaric tetracaine could provide 12 hours of effective analgesia (9). However, this combination also caused a very prolonged motor block and serious adverse effects of nausea and vomiting. In the present study, we abated to reduce the degree of motor block by replacing tetracaine with bupivacaine (16). Moreover, we also reduced the dose of neostigmine to 50 gg. Realizing that 50 Bg neostigmine might be
T a b l e 1. D e m o g r a p h i c D a t a Group Bupivacaine Bupivacaine + neostigmine Bupivacaine + clonidine Bupivacaine + both
Drugs Added
n
None 50 Bg neostigmine 150 gg clonidine 50 gg neostigmine + 150/.tg clonidine
20 19 20 21
Age (y) 30 29 30 29
_+6 +7 +4 + 5
Height (cm) 156 154 157 157
Weight (kg)
_+ 5 ±6 ± 5 _+ 5
70 68 71 71
Data are m e a n _+ SD.
T a b l e 2. C l i n i c a l C h a r a c t e r i s t i c s
Group No. of patients M a x i m u m spread (segment) Absolute analgesia (h) Effective analgesia (h) Total meperidine used (mg) Insufficient analgesia (%) Leg lift (h)
Bupivacaine (B) 20 20.5 + 2.9 1.3 + 0.6 2.60 + 0.9 i79 + 69 7 (35) 3.6 + 1.1
* P < .05 w h e n B vs BN or BC or BB. P < .05 w h e n BB vs BN or BC.
Bupivacaine + N e o s t i g m i n e (BN) 19 22.0 3.8 8.7 111 + 2* (11) 5.2
+ 3.2 + 2.0"~ + 3,0*t 68*
+ 4.2"f
Bupivacaine + Clonidine (BC) 20 22.2 3.1 6.9 148 + 2* (10) 5.6
+ 2.7 + 1.8"~ + 3.3"t 80t
+ 1.7"*
Bupivacaine + Both (BB) 21 23.3 6.5 11,9 89 + 0* (0) 7.1
+ 2.9* + 1.5" + 4.i* 60*
+ 1.6"
_+ 10 + 15 _+ 11 _+ 12
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6 E
o
~5 g ~ 4 o n buPivacaine(B) ................................. ii bupivacaine+Ne0stigmine(BN) [] Bupivacaine+Clonidine(BC) Q Bup!vacaine+Bgth(BB)...............
W 2
4
6
8
I0
t2
14
Time(horn) Fig. 1. Visual analog scale pain score at rest group comparison: BB vs B P < .002 up to 10 hours; BB vs BC P < .05 up to 8 hours; BB vs BN P < .01 up to 6 hours; BC vs B P < .001 up to 4 hours; and BN vs B P < .001 up to 6 hours.
i n s u f f i c i e n t i n its analgesic activity, 150 btg c l o n i d i n e was a d d e d to the IT m i x t u r e . W h i l e o u r s t u d y was n e a r c o m p l e t i o n , Lauretti et al. (17) r e p o r t e d t h a t IT 25 gg n e o s t i g m i n e w o u l d give sufficient analgesia i n p a t i e n t s following v a g i n a l h y s t e r e c t o m y . H o o d et al. (18) h a v e f o u n d t h a t e v e n a dose as l o w as IT 10 gg n e o s t i g m i n e p r o d u c e d sufficient analgesic effect w i t h o u t c a u s i n g m o r e side effects i n c e s a r e a n delivery patients. Recently, Lauretti et al. (19) h a v e
s h o w n a c o m b i n a t i o n of IT 50 gg n e o s t i g m i n e a n d 50 gg m o r p h i n e p r o d u c e d excellent p r o l o n g e d a n a l gesia w i t h m i n i m a l side effects i n p a t i e n t s u n d e r g o ing vaginoplasty. I n o u r study, 50 gg n e o s t i g m i n e or 150 gg clonid i n e u s e d a l o n e did n o t e n h a n c e t h e level of sensory b l o c k of IT b u p i v a c a i n e , b u t t h e c o m b i n a t i o n of b o t h a g e n t s did p r o d u c e a h i g h e r s e g m e n t a l block. I n t h e b u p i v a c a i n e group, m o r e t h a n 5 0 % of
i0 9 8 E
7
8
6 g o~ <
] >
5
m bupivacaine(B) Iiibupivacaine+Neosdgmine(BN) Bupivacaine+Clonidine(BC)
4 3 2 1 0
8 i0 ~2 14 Time (hour) Fig. 2. Visual analog scale pain score during m o v e m e n t group comparison: BB vs B P < .05 up to 10 hours; BB vs BC P < .05 up to 6 hours; BB vs BN P < .05 up to 6 hours; BC vs B P < .05 up to 6 hours; and BN vs B P < .05 up to 4 hours. 2
4
6
Intrathecal Neostigmine Plus Clonidine
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Pan et al.
53
1i0 ~105 i0C 95 90 85 ImBupivacaine ' i Bupivacair~e+n Bupivacainc+c Supivaca!ae+b
:g 75 N 70 65 60 55 5O 45 4O Time:(rain)
Fig. 3. Changes in mean arterial blood pressure (MAP) in four groups. Results are expressed in m m Hg. Statistics were performed on raw data. No significant differences in MAP were found among the groups. t h e patients e x p e r i e n c e d i n t r a o p e r a t i v e p a i n especially w h e n the p e r i t o n e u m w a s being p u l l e d at a n d 3 5 % of the patients in this g r o u p r e q u i r e d k e t a m i n e . We realized t h a t using k e t a m i n e to c o n trol i n t r a o p e r a t i v e p a i n m i g h t bias o u r p o s t o p e r a tive analgesic m e a s u r e m e n t (20), b u t w e f o u n d t h a t i n h a l a t i o n a l a g e n t at l o w c o n c e n t r a t i o n pro-
v i d e d i n a d e q u a t e analgesia w i t h t h e potential a d d e d risk of aspiration, w h e r e a s the use of opioid w o u l d bias o u r p o s t o p e r a t i v e p a i n m e a s u r e m e n t e v e n m o r e . The t h r e e s t u d y g r o u p s s h o w e d a m u c h l o w e r i n c i d e n c e in patients n e e d i n g k e t a m i n e . Hence, the a d d i t i o n of either clonidine or neostigm i n e , especially the c o m b i n e d use of both, deft-
t40
t20
I00 ! Bupivacaine i Bupivacaine+n ;F'IBupivacaine+c N1Bup)vacaine+b
80 eo
60
40
20
0 ¢s
o
Time(rain) Fig. 4. Changes in heart rate (HR) in four groups. Results are expressed in beats/min. Statistics were performed on raw data. No significant differences in EIR were found among the groups.
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Regional Anesthesia and Pain Medicine Vol. 23 No. 1 January-February 1998
Table 3. Adverse Effects Group Nausea or vomiting Mild Moderate Severe Dizziness Restlessness Hypotension Ephedrine use (rag) Respiratory depression
Bupivacaine (B) 2/20(10%) 1 1 0 0/20(0%) 0/20(0%) 8/20(40%) 31 ± 11 0/20(0%)
Bupivacaine + Neostigmine (BN) 15/19(79%)* 6 6 2 4/19(21%)* 1/18(5.5%) 10/19(53%)t 24± 12 0/19(0%)
Bupivacaine + Clonidine (BC) 6/20(30%)*+ 0 5 1 1/19(5.3%)t 0/19(0%) 14/20(70%)* 29 ± 12 0/20(0%)
Bupivacaine + Both (BB) 18/21(86%)* 1 8 9 9/21(42%)* 2/20(10.0%) 18/21(86%)* 35 ± 13 0/21(0%)
* P < .05 when B vs BN or BC or BB. t p < .05 w h e n BB vs BN or BC.
nitely enhanced the anesthetic effect of bupivacaine spinal anesthesia. Our findings are in agreement with results from other studies, which demonstrated a similar enhancement either by neostigmine (12,18) or clonidine alone (1-3). We also found that clonidine (1,2) or neostigmine (9) produced more than twofold prolongation of spinal anesthesia as evident by the prolongation of absolute analgesia which is in accordance with other reports in the literature. Furthermore, combination of these two drugs produced an effective analgesia with an average of 11.9 hours which is significantly longer than that of either drug alone. In our study, the addition of 150 ~g clonidine provided effective analgesia for 6.9 hours which is in agreement with that reported by Filos et al. (7). Finally, the postoperative analgesic effect is further documented by the reduced dose of meperidine used for pain relief in the first 24-hour period in neostigmine-added groups but not in clonidine group. This finding is also in agreement with other studies probably because of the relatively short action of clonidine (3) as compared with neostigmine (9,18,19). Klimscha et al. (5) and Niemi (6) have shown that IT 2-3 gg/kg clonidine produced postoperative decreases in HR and MAP. In our study, we did not observe significant HR or MAP changes postoperative. However, we did observe significantly more patients with a decrease of HR and MAP in the two clonidine-added groups intraoperatively, which necessitated the use of ephedrine. Perhaps suffident time lapsed to allow resolution of the hemodynamic changes in the patients intraoperative, therefore bradycardia and hypotension were not observed postoperative. Intraoperafive, the lack of HR and MAP changes could result from the "masking" hemodynamic effects of IT bupivacaine (21,22) and the use of ephedrine given to correct blood pressure under 100 mm Hg. Postoperative, the change of HR and MAP in the bupivacaine both group might be
attenuated by the IT neostigmine (14); but the reason for the lack of change in the clonidine group is not apparent. We speculated that because most of our patients were in labor and in a relatively hyperdynamic hemodynamic state they are more resistant to the hypotensive and bradycardic effects of IT donidine. Shnider (23) reported that laboring cesarean delivery patients did have a lower incidence of hypotension than nonlaboring elective cesarean parturients. Filos (7) did not find any change in HR but did find change in MAP in his study on nonlaboring elective cesarean delivery patients. Different observations on the hemodynamic change with IT clonidine have been reported in the literature: Racle (1), Bonnet (2), Fogarty (3), and Eisenach (4) did not find any change, whereas Klimsche (5) and Niemi (6) reported significant changes. These discrepancies appear to be due to different patient populations studied (23) and different dose of local anesthetics employed (22). Intrathecal neostigmine has a direct action on the motorneuron outflow and can cause motor weakness (8). Intrathecal clonidine also has been shown to have a direct inhibition of impulse conduction in motor nerve fibers (24). The motor block effect of these two agents was observed in our three study groups with delayed leg lifting, and, as might be expected, the combination of the two drugs produced the most prolonged motor block. The most troublesome side effect of IT neostigmine is nausea and vomiting. Intrathecal don±dine, on the other hand, has been used to treat nausea and vomiting in patients with gastroparesis (25). We hypothesized that combining IT clonidine with neostigmine would reduce the incidence of nausea and vomiting induced by neostigmine. Unfortunately, our data did not support this hypothesis. We actually found an increased incidence of nausea and vomiting with IT clonidine in our bupivacaine clonidine group. Hood et al. (14)
Intrathecal Neostigmine Plus Clonidine
f o u n d that in h u m a n volunteers given a combination of IT neostigmine and epidural clonidine, each drug seemed to p r o d u c e i n d e p e n d e n t adverse effects. A pharmacologic study had s h o w n that b o t h IT clonidine and IT neostigmine cause an a c c u m u l a t i o n of acetylcholine in the cerebrospinal fluid (CSF) (26). Due to its high polarity and hydrophilicity in the CSF (I3), IT neostigmine m a y migrate cephalad to the brainstem (8), while IT clonidine can also reach the brainstem by cephalad migration in CSF or by systemic circulation (27). Once at the brainstem, b o t h drugs could cause an a c c u m u l a t i o n of acetylcholine to act on the c h e m o r e c e p t o r trigger zone. In conclusion, our study s h o w e d that combining IT clonidine (150 gg) and neostigmine (50 gg) e n h a n c e d bupivacaine spinal anesthesia and produced prolonged postoperative analgesia compared with adding either drug alone to bupivacaine. However, this combination also p r o d u c e d significantly m o r e adverse effects. The neostigmine 50 gg dose could still be too large, and a m o r e favorable effect and adverse effect profile might be achieved with a smaller dose such as 25 gg, as suggested by others (17,18).
8.
9.
10.
11.
12.
13.
14.
References 1. Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg 1987: 66: 442-446. 2. Bonnet E Brun-Buisson V, Saada M. Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg 1989: 68: 619-622. 3. Fogarty DJ, Carine UA, Milligan KR. Comparison of analgesic effects of intrathecal clonidine and intrathecal morphine alter spinal anaesthesia in patients undergoing total hip replacement. Br J Anaesth 1993: 71: 661-664. 4. Eisenach JC, Tong C. Site of hemodynamic effects of intrathecal alpha-adrenergic agonists. Anesthesiology 1991: 74: 766-771. 5. Klimscha W, Chiari A, Krafft E Plattner O, Taslimi R, Mayer N, Weinstabl C, Schneider B, Zimpfer M. Hemodynamic and analgesic effect of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg 1995: 80: 322-327. 6. Niemi L. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand 1994: 38: 724-728. 7. Filos KS, Goudas LC, Patroni O, Polyzou V. Hemodynamic and analgesia profile after intrathecal cloni-
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dine in humans: a dose-response study. Anesthesiology 1994: 81: 591-601. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995: 82: 331-343. Pan PM, Mok MS. Efficacy of intrathecal neostigmine for the relief of post caesarean pain (Abstract). Anesthesiology 1995:83 (Suppl): 786. Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995: 82: 412-427. Hood DD, Eisenach JC, Tong CY, Tommasi E, Yaksh TL. Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and their combination in sheep. Anesthesiology 1995: 82: 428-435. Gordh T, Jansson P, Gillberg PG, Post C. Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing. Acta Anaesthesiol Scand 1989: 33: 39-47. Abrams SE, Winne RP. Intrathecal acetylcholinesterase inhibitors produce analgesia that is synergistic with morphine and clonidine in rats. Anesth Analg 1995: 81: 501-507. Hood DD, Eisenach JC, Mallak K. The analgesic interaction between intrathecal neostigmine and epidural clonidine in humans. Anesthesiology 1996: 85: 315-325. Hunt CO, Naulty JS, Bader AM, Hauch MA, Vartikar JV, Datta S, Hertwig LM, Ostheimer GW. Perioperative analgesia with subarachnoid fentanyl-bupivacaine for cesarean delivery. Anesthesiology 1989: 71: 535-540. Skretting P, Vaagenes P, Sundnes KO, Edstrom HH, Lind B. Subarachnoid anaesthesia: comparison of hyperbaric solutions of bupivacaine and amethocaine. Br J Anaesth 1984: 56: 155-159. Lauretti GR, Eisenach JC, Hood DD, Pfeifer BL. Intrathecal neostigmine for postoperative analgesia: dose response (abstract). Reg Anesth 1996: 21 (Suppl): 7.4. Hood DD, Krukowski MD, Eisenach JC, Mallak KA. Intrathecal neostigmine for cesarean section analgesia: dose response (abstract). Reg Anesth 1996: 21 (Suppl): 78. Lauretti GR, Reis MP, Prado WA. Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in the patients undergoing anterior or ]posterior vaginoplasty. Anesth Analg 1996: 82: 1182-1187. Lauretti GR, Azevedo VM. Intravenous ketamine or fentanyl prolongs postoperative analgesia after intrathecal neostigmine. Anesth Analg 1996: 83: 766-770. Lauretti GR, Reis MR Subarachnoid neostigmine does not affect blood pressure or heart rate during
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bupivacaine spinal anesthesia. Reg Anesth 1996: 21: 586-591. 22. Eisenach JC, De Kock M, Klimscha W. Alpha-2adrenergic agonists for regional anesthesia: a clinical review of clonidine (1984-1995). Anesthesiology 1996: 85: 655-674. 23. Shnider SM, Levinson G. Anesthesia for obstetrics. 2nd ed. Baltimore, Williams & Wilkins, 1987: 162. 24. Butterworth JF, Strichartz GR. The alpha-2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block in conduction in rat sciatic nerve fibers. Anesth Analg 1993: 76: 295-301.
25. Rosa e Silva L, Troncon LE, Oliveira RB, Iazigi H, Gallo L, Foss MC. Treatment of diabetic gastroparesis with oral clonidine. Aliment Pharmacol Ther 1995: 9: 179-183. 26. Detweiler D J, Eisenach JC, Tong C, Jackson C. A cholinergic interaction in alpha-2-adrenoceptormediated antinociception in sheep. J Pharmacol Exp Ther 1993: 265: 536-542. 27. DeKock M, Eisenach JC, Tong C, Schmite AL, Scholtes JL. Analgesic doses of intrathecal but not intravenous clonidine increase acetylcholine in cerebrospinal fluid in humans. Anesth Analg 1997: 84: 800-803.
E n h a n c e m e n t of Analgesic Effect of Intrathecal N e o s t i g m i n e and Clonidine on Bupivacaine Spinal A n e s t h e s i a RM. Pan, M.D.,* C.T. Huang, M.RA.,* T.T. Wei, M.D.,* and M.S. Mok, M.D.t
Background and Objectives. Intrathecal administration of neostigmine has been shown to produce analgesia in both animals and humans. The concurrent administration of intrathecal neostigmine and clonidine has been reported to produce no neurotoxicity in sheep. The purpose of the present study was to evaluate the efficacy and safety of the combining intrathecal neostigmine and clonidine for the relief of pain in patients after cesarean delivery. Methods. After giving their consents, 80 parturients who were scheduled for cesarean delivery during spinal anesthesia were enrolled by a doubleblind randomized design into four groups: bupivacaine group (n = 20) received intrathecal (IT) 10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received IT 10 mg bupivacaine + 50 gg neostigmine; bupivacaine + donidine group (n = 20) received IT l0 mg bupivacaine + 150 gg clonidine; and bupivacaine + both (n = 21) received IT 10 mg bupivacaine + 50 p,g neostigmine + 150 gg donidine. The m a x i m u m spread of anesthesia, duration of analgesia and motor block, vital signs, and incidence of adverse effects were recorded for 14 hours postinjection. Fifty milligrams intramuscular meperidine was given as a rescue analgesic whenever patient's pain score was greater than 5/10 by the visual analog scale. Results. The demographic data were similar for all four groups. Bupivacaine + both group had a significantly higher m a x i m u m spread of anesthesia of 23.3 + 2.9 segments than bupivacaine group of 20.5 + 2.9 segment. Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 + 1.5 hours as compared to bupivacaine group of 1.3 + 0.6 hours. The pain score in bupivacaine + both group was significantly lower than that of bupivacaine group during the first 10 hours. The 24-hour meperidine consumption also was lower in bupivacaine + both group than that of bupivacaine group. However, motor b]ock was significantly prolonged from 3.5 _+ 1.1 hours in bupivacaine group to 7.1 + 1.6 hours in bupivacaine + both group. In addition, other side effects such as nausea and vomiting and dizziness were significantly increased in bupivacaine + both group. Conclusion. Our study showed that the combination of 150 gg 1T donidine and 50 gg neostigmine provided longer postsurgical analgesia than with either drug used alone. However, this combination also produced significantly more adverse effects of prolonged motor block and nausea and vomiting. A further study combining the two study drugs but using a lower dose of IT neostigmine (e.g., 25 gg) is recommended. Reg Anesth Pain Med 1998: 23: 49-56. K e y w o r d s : perioperative analgesia, intrathecal neostigmine and donidine, anticholinesterase.
From the *Department of Anesthesia, Mackay Memorial Hospital, Taitung, Taiwan and tDepartment of Anesthesiology, University of Southern Calitornia, Los Angeles, California. This study was done at Mackay Memorial Hospital, Taitung, Taiwan, ROC and was supported by a Mackay Memorial Hospital grant. The abstract ol the study was presented in part at the Annual Meeting of the American Society of Anesthesiologists, October, 1996. Accepted for publication July 30, 1997. Reprinted requests: Peter Mu-His Pan, M.D., Department of Anesthesia, Mackay Memorial Hospital, Taitung, Taiwan, ROC.
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Regional Anesthesia and Pain Medicine Vol. 23 No. 1 January-February 1998
Intrathecal injection of clonidine, an alpha-2 agonist, provides effective relief of pain (1-7). However, the clinical use of intrathecal clonidine is hampered by the side effects of sedation, bradycardia, and hypotension (5-7). Recently, the intrathecal (IT) administration of neostigmine, a cholinesterase inhibitor, has been shown to produce analgesia without neurotoxicity in animals (10,11) and humans, but also produced adverse effects of motor block, dizziness, nausea, or vomiting (8,9). Gordh et al. had shown a relationship between the alpha-adrenergic and the cholinergic systems in the spinal cord to produce analgesia (12). Thus, we hypothesized combining cholinergic and alpha-adrenergic agents will produce improved analgesia by reducing the dose of each individual drug, therefore minimizing their adverse effect. Abram and Winne (13) showed in a rat model that IT neostigmine did indeed potentiate morphine analgesia. Hood et al. (14) had shown in h u m a n volunteers that a neostigmineclonidine combination produced improved analgesia, while side effects were related solely to the dose of the individual drug. The present study evaluated the efficacy and safety of combining a fixed dose IT neostigmine and clonidine in the relief of pain in patients after cesarean delivery.
Methods After approval by the Hospital Research Committee and after obtaining informed consents from all the subjects, we enrolled 80 parturients who were scheduled for cesarean delivery during spinal anesthesia. All patients were ASA II patients without any known cardiopulmonary disease, and all fetuses were at term without signs of fetal distress. None of the patients received premedication. After intravenous infusion of 1000 mL lactated ringer's solution, the patients were turned to right lateral decubitus position and lumbar puncture was performed at L3-L4 interspace with a 25-gauge spinal needle using a midline approach. The patients were divided randomly into four groups and received IT administration of the following drugs: bupivacaine group received 1 mL bupivacaine 0.5% heavy spinal solution (B) (bupivacaine 5 mg/mL with dextrose 80 mg/mL) followed by another 1 ml B 5 minutes later; bupivacaine + neostigmine group received 1 mL B mixed with 50 gg neostigmine followed by another 1 mL B 5 minutes later; bupivacaine + clonidine group received 1 mL B followed by 1 mL B mixed with 150 gg clonidine at 5 minutes; bupivacaine + both group received 1 mL B mixed with 50 gg neostigmine
followed by 1 mL B mixed with 150 gg clonidine 5 minutes later (Bupivacaine 0.5% heavy spinal, Astra Pharmaceutical, Sodertalje, Sweden. Neostigmine methylsulfate 0.5 mg/mL, Santong Pharmaceutical Co. Ltd, Toayuan, Taiwan. Clonidine hydrochloride 150 gg/mL, Boehringer Pharmaceutical, Germany). All the medications were given slowly over 30 seconds by an anesthetist who selected the anesthetic management by blindly picking from a box a piece of paper with the name of study solution. After drug administration, the patient was turned to a supine position. Uterine displacement was performed with the use of a wedge. Blood pressure was monitored every minute for the first 15 minutes and then measured every 3 minutes thereafter throughout the surgery. Patients were monitored with continuous ECG, precordial stethoscope, and pulse oximeter. Supplemental oxygen at 4 L/min was given to all patients by nasal cannula, and intravenous ephedrine at 5 mg increments were given when systolic blood pressure decreased below 100 m m Hg. Dermatomes of the maximal sensory block were assessed by pinprick. In case of inadequate anesthesia, incremental doses of intravenous ketamine were given, but no narcotic analgesics were used intraoperative. The number of patients who had intraoperative ketamine supplementation was recorded. We also measured the duration of absolute analgesia which was defined by Hunt (15) as the time from IT injection to the time when the patient first complained of any pain sensation. Visual analog scale was used to assess amount of pain at rest and with movement (turning from side to side) at 30, 60, 120 minutes, and then every 2 hours for 14 hours. The duration of motor block was recorded from the time of drug injection to the time when the patient could lift her legs. Adverse effects such as nausea, vomiting, dizziness, restlessness, pruritus, and respiratory depression (i.e., a respiratory rate less than 10 breaths/min) were recorded. The severity of nausea and vomiting and pruritus was graded by a 3point scale: 1 = mild, no treatment; 2 = moderate, required one treatment; and 3 = severe, required more than one treatment. In addition, the time of the first dose meperidine administered (effective analgesia) and the total amount meperidine used in the first 24 hours postoperative were also recorded. All the observations were made by an anesthetist who was blinded to the study drugs. Data were expressed as mean + SD. Parametric data were analyzed by one-way ANOVA, and multiple comparison between pairs was done by the Scheffe's test. Between-group differences in the incidences of adverse events were analyzed using
Intrathecal Neostigmine Plus Clonidine
the chi-square test. Fisher's exact test was used when appropriate. A P value less than .05 was considered to be significant.
Results The demographic data were comparable in all groups as shown in Table 1. The maximal sensory block level was significantly higher in bupivacaine + both group with an average of 23.3 segments compared to 20.5 segments in bupivacaine group with a P value of .006 (Table 2). The addition of IT neostigmine, clonidine, or their combination all enhanced per±operative analgesia. Intraoperative, the number of patients needing supplemental analgesics was 35% in bupivacaine group, 10% for either bupivacaine + neostigmine group or bupivacaine + don±dine group and none for bupivacaine + both group. Postoperative, the absolute and effective analgesic times were prolonged for the later three groups. As shown in Figs. 1 and 2, the visual analog scale pain score of bupivacaine + both group was significantly lower than the other three groups up to the 6-hour period. Finally, the dose of meperidine required in the first 24-hour postsurgery was significantly reduced in bupivacaine + both group (Table 2). Hemodynamically, all the study groups showed significantly increased incidence in the use of ephedrine to correct intraoperative blood pressure reduction (below 100 m m Hg) (Table 3). However,
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Pan et al.
51
the change of blood pressure was easily corrected with similar dosage of ephedrine per patient for all four groups. In addition, there was no difference in the mean arterial blood pressure (MAP) and heart rate (HR) among the four groups (Figs. 3 and 4). Neurologically, all three study groups showed prolonged motor block as evidenced by the leglift time with bupivacaine + both group showing the most profound change (Table 2). Incidences of adverse effects were increased in all three study groups, especially nausea and vomiting and dizziness were significantly and similarly higher in bupivacaine + neostigmine group and bupivacaine + both group. Respiratory depression was not observed in any of the patients (Table 3).
Discussion Hood et al. reported that the IT administration of 50-750 gg neostigmine provided analgesia and adverse effects of motor block, and nausea and vomiting in a dose-dependent manner (8). We showed that neostigmine 100 gg added to IT 12 mg hyperbaric tetracaine could provide 12 hours of effective analgesia (9). However, this combination also caused a very prolonged motor block and serious adverse effects of nausea and vomiting. In the present study, we abated to reduce the degree of motor block by replacing tetracaine with bupivacaine (16). Moreover, we also reduced the dose of neostigmine to 50 gg. Realizing that 50 Bg neostigmine might be
T a b l e 1. D e m o g r a p h i c D a t a Group Bupivacaine Bupivacaine + neostigmine Bupivacaine + clonidine Bupivacaine + both
Drugs Added
n
None 50 Bg neostigmine 150 gg clonidine 50 gg neostigmine + 150/.tg clonidine
20 19 20 21
Age (y) 30 29 30 29
_+6 +7 +4 + 5
Height (cm) 156 154 157 157
Weight (kg)
_+ 5 ±6 ± 5 _+ 5
70 68 71 71
Data are m e a n _+ SD.
T a b l e 2. C l i n i c a l C h a r a c t e r i s t i c s
Group No. of patients M a x i m u m spread (segment) Absolute analgesia (h) Effective analgesia (h) Total meperidine used (mg) Insufficient analgesia (%) Leg lift (h)
Bupivacaine (B) 20 20.5 + 2.9 1.3 + 0.6 2.60 + 0.9 i79 + 69 7 (35) 3.6 + 1.1
* P < .05 w h e n B vs BN or BC or BB. P < .05 w h e n BB vs BN or BC.
Bupivacaine + N e o s t i g m i n e (BN) 19 22.0 3.8 8.7 111 + 2* (11) 5.2
+ 3.2 + 2.0"~ + 3,0*t 68*
+ 4.2"f
Bupivacaine + Clonidine (BC) 20 22.2 3.1 6.9 148 + 2* (10) 5.6
+ 2.7 + 1.8"~ + 3.3"t 80t
+ 1.7"*
Bupivacaine + Both (BB) 21 23.3 6.5 11,9 89 + 0* (0) 7.1
+ 2.9* + 1.5" + 4.i* 60*
+ 1.6"
_+ 10 + 15 _+ 11 _+ 12
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6 E
o
~5 g ~ 4 o n buPivacaine(B) ................................. ii bupivacaine+Ne0stigmine(BN) [] Bupivacaine+Clonidine(BC) Q Bup!vacaine+Bgth(BB)...............
W 2
4
6
8
I0
t2
14
Time(horn) Fig. 1. Visual analog scale pain score at rest group comparison: BB vs B P < .002 up to 10 hours; BB vs BC P < .05 up to 8 hours; BB vs BN P < .01 up to 6 hours; BC vs B P < .001 up to 4 hours; and BN vs B P < .001 up to 6 hours.
i n s u f f i c i e n t i n its analgesic activity, 150 btg c l o n i d i n e was a d d e d to the IT m i x t u r e . W h i l e o u r s t u d y was n e a r c o m p l e t i o n , Lauretti et al. (17) r e p o r t e d t h a t IT 25 gg n e o s t i g m i n e w o u l d give sufficient analgesia i n p a t i e n t s following v a g i n a l h y s t e r e c t o m y . H o o d et al. (18) h a v e f o u n d t h a t e v e n a dose as l o w as IT 10 gg n e o s t i g m i n e p r o d u c e d sufficient analgesic effect w i t h o u t c a u s i n g m o r e side effects i n c e s a r e a n delivery patients. Recently, Lauretti et al. (19) h a v e
s h o w n a c o m b i n a t i o n of IT 50 gg n e o s t i g m i n e a n d 50 gg m o r p h i n e p r o d u c e d excellent p r o l o n g e d a n a l gesia w i t h m i n i m a l side effects i n p a t i e n t s u n d e r g o ing vaginoplasty. I n o u r study, 50 gg n e o s t i g m i n e or 150 gg clonid i n e u s e d a l o n e did n o t e n h a n c e t h e level of sensory b l o c k of IT b u p i v a c a i n e , b u t t h e c o m b i n a t i o n of b o t h a g e n t s did p r o d u c e a h i g h e r s e g m e n t a l block. I n t h e b u p i v a c a i n e group, m o r e t h a n 5 0 % of
i0 9 8 E
7
8
6 g o~ <
] >
5
m bupivacaine(B) Iiibupivacaine+Neosdgmine(BN) Bupivacaine+Clonidine(BC)
4 3 2 1 0
8 i0 ~2 14 Time (hour) Fig. 2. Visual analog scale pain score during m o v e m e n t group comparison: BB vs B P < .05 up to 10 hours; BB vs BC P < .05 up to 6 hours; BB vs BN P < .05 up to 6 hours; BC vs B P < .05 up to 6 hours; and BN vs B P < .05 up to 4 hours. 2
4
6
Intrathecal Neostigmine Plus Clonidine
•
Pan et al.
53
1i0 ~105 i0C 95 90 85 ImBupivacaine ' i Bupivacair~e+n Bupivacainc+c Supivaca!ae+b
:g 75 N 70 65 60 55 5O 45 4O Time:(rain)
Fig. 3. Changes in mean arterial blood pressure (MAP) in four groups. Results are expressed in m m Hg. Statistics were performed on raw data. No significant differences in MAP were found among the groups. t h e patients e x p e r i e n c e d i n t r a o p e r a t i v e p a i n especially w h e n the p e r i t o n e u m w a s being p u l l e d at a n d 3 5 % of the patients in this g r o u p r e q u i r e d k e t a m i n e . We realized t h a t using k e t a m i n e to c o n trol i n t r a o p e r a t i v e p a i n m i g h t bias o u r p o s t o p e r a tive analgesic m e a s u r e m e n t (20), b u t w e f o u n d t h a t i n h a l a t i o n a l a g e n t at l o w c o n c e n t r a t i o n pro-
v i d e d i n a d e q u a t e analgesia w i t h t h e potential a d d e d risk of aspiration, w h e r e a s the use of opioid w o u l d bias o u r p o s t o p e r a t i v e p a i n m e a s u r e m e n t e v e n m o r e . The t h r e e s t u d y g r o u p s s h o w e d a m u c h l o w e r i n c i d e n c e in patients n e e d i n g k e t a m i n e . Hence, the a d d i t i o n of either clonidine or neostigm i n e , especially the c o m b i n e d use of both, deft-
t40
t20
I00 ! Bupivacaine i Bupivacaine+n ;F'IBupivacaine+c N1Bup)vacaine+b
80 eo
60
40
20
0 ¢s
o
Time(rain) Fig. 4. Changes in heart rate (HR) in four groups. Results are expressed in beats/min. Statistics were performed on raw data. No significant differences in EIR were found among the groups.
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Regional Anesthesia and Pain Medicine Vol. 23 No. 1 January-February 1998
Table 3. Adverse Effects Group Nausea or vomiting Mild Moderate Severe Dizziness Restlessness Hypotension Ephedrine use (rag) Respiratory depression
Bupivacaine (B) 2/20(10%) 1 1 0 0/20(0%) 0/20(0%) 8/20(40%) 31 ± 11 0/20(0%)
Bupivacaine + Neostigmine (BN) 15/19(79%)* 6 6 2 4/19(21%)* 1/18(5.5%) 10/19(53%)t 24± 12 0/19(0%)
Bupivacaine + Clonidine (BC) 6/20(30%)*+ 0 5 1 1/19(5.3%)t 0/19(0%) 14/20(70%)* 29 ± 12 0/20(0%)
Bupivacaine + Both (BB) 18/21(86%)* 1 8 9 9/21(42%)* 2/20(10.0%) 18/21(86%)* 35 ± 13 0/21(0%)
* P < .05 when B vs BN or BC or BB. t p < .05 w h e n BB vs BN or BC.
nitely enhanced the anesthetic effect of bupivacaine spinal anesthesia. Our findings are in agreement with results from other studies, which demonstrated a similar enhancement either by neostigmine (12,18) or clonidine alone (1-3). We also found that clonidine (1,2) or neostigmine (9) produced more than twofold prolongation of spinal anesthesia as evident by the prolongation of absolute analgesia which is in accordance with other reports in the literature. Furthermore, combination of these two drugs produced an effective analgesia with an average of 11.9 hours which is significantly longer than that of either drug alone. In our study, the addition of 150 ~g clonidine provided effective analgesia for 6.9 hours which is in agreement with that reported by Filos et al. (7). Finally, the postoperative analgesic effect is further documented by the reduced dose of meperidine used for pain relief in the first 24-hour period in neostigmine-added groups but not in clonidine group. This finding is also in agreement with other studies probably because of the relatively short action of clonidine (3) as compared with neostigmine (9,18,19). Klimscha et al. (5) and Niemi (6) have shown that IT 2-3 gg/kg clonidine produced postoperative decreases in HR and MAP. In our study, we did not observe significant HR or MAP changes postoperative. However, we did observe significantly more patients with a decrease of HR and MAP in the two clonidine-added groups intraoperatively, which necessitated the use of ephedrine. Perhaps suffident time lapsed to allow resolution of the hemodynamic changes in the patients intraoperative, therefore bradycardia and hypotension were not observed postoperative. Intraoperafive, the lack of HR and MAP changes could result from the "masking" hemodynamic effects of IT bupivacaine (21,22) and the use of ephedrine given to correct blood pressure under 100 mm Hg. Postoperative, the change of HR and MAP in the bupivacaine both group might be
attenuated by the IT neostigmine (14); but the reason for the lack of change in the clonidine group is not apparent. We speculated that because most of our patients were in labor and in a relatively hyperdynamic hemodynamic state they are more resistant to the hypotensive and bradycardic effects of IT donidine. Shnider (23) reported that laboring cesarean delivery patients did have a lower incidence of hypotension than nonlaboring elective cesarean parturients. Filos (7) did not find any change in HR but did find change in MAP in his study on nonlaboring elective cesarean delivery patients. Different observations on the hemodynamic change with IT clonidine have been reported in the literature: Racle (1), Bonnet (2), Fogarty (3), and Eisenach (4) did not find any change, whereas Klimsche (5) and Niemi (6) reported significant changes. These discrepancies appear to be due to different patient populations studied (23) and different dose of local anesthetics employed (22). Intrathecal neostigmine has a direct action on the motorneuron outflow and can cause motor weakness (8). Intrathecal clonidine also has been shown to have a direct inhibition of impulse conduction in motor nerve fibers (24). The motor block effect of these two agents was observed in our three study groups with delayed leg lifting, and, as might be expected, the combination of the two drugs produced the most prolonged motor block. The most troublesome side effect of IT neostigmine is nausea and vomiting. Intrathecal don±dine, on the other hand, has been used to treat nausea and vomiting in patients with gastroparesis (25). We hypothesized that combining IT clonidine with neostigmine would reduce the incidence of nausea and vomiting induced by neostigmine. Unfortunately, our data did not support this hypothesis. We actually found an increased incidence of nausea and vomiting with IT clonidine in our bupivacaine clonidine group. Hood et al. (14)
Intrathecal Neostigmine Plus Clonidine
f o u n d that in h u m a n volunteers given a combination of IT neostigmine and epidural clonidine, each drug seemed to p r o d u c e i n d e p e n d e n t adverse effects. A pharmacologic study had s h o w n that b o t h IT clonidine and IT neostigmine cause an a c c u m u l a t i o n of acetylcholine in the cerebrospinal fluid (CSF) (26). Due to its high polarity and hydrophilicity in the CSF (I3), IT neostigmine m a y migrate cephalad to the brainstem (8), while IT clonidine can also reach the brainstem by cephalad migration in CSF or by systemic circulation (27). Once at the brainstem, b o t h drugs could cause an a c c u m u l a t i o n of acetylcholine to act on the c h e m o r e c e p t o r trigger zone. In conclusion, our study s h o w e d that combining IT clonidine (150 gg) and neostigmine (50 gg) e n h a n c e d bupivacaine spinal anesthesia and produced prolonged postoperative analgesia compared with adding either drug alone to bupivacaine. However, this combination also p r o d u c e d significantly m o r e adverse effects. The neostigmine 50 gg dose could still be too large, and a m o r e favorable effect and adverse effect profile might be achieved with a smaller dose such as 25 gg, as suggested by others (17,18).
8.
9.
10.
11.
12.
13.
14.
References 1. Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg 1987: 66: 442-446. 2. Bonnet E Brun-Buisson V, Saada M. Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg 1989: 68: 619-622. 3. Fogarty DJ, Carine UA, Milligan KR. Comparison of analgesic effects of intrathecal clonidine and intrathecal morphine alter spinal anaesthesia in patients undergoing total hip replacement. Br J Anaesth 1993: 71: 661-664. 4. Eisenach JC, Tong C. Site of hemodynamic effects of intrathecal alpha-adrenergic agonists. Anesthesiology 1991: 74: 766-771. 5. Klimscha W, Chiari A, Krafft E Plattner O, Taslimi R, Mayer N, Weinstabl C, Schneider B, Zimpfer M. Hemodynamic and analgesic effect of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg 1995: 80: 322-327. 6. Niemi L. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand 1994: 38: 724-728. 7. Filos KS, Goudas LC, Patroni O, Polyzou V. Hemodynamic and analgesia profile after intrathecal cloni-
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21.
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dine in humans: a dose-response study. Anesthesiology 1994: 81: 591-601. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995: 82: 331-343. Pan PM, Mok MS. Efficacy of intrathecal neostigmine for the relief of post caesarean pain (Abstract). Anesthesiology 1995:83 (Suppl): 786. Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995: 82: 412-427. Hood DD, Eisenach JC, Tong CY, Tommasi E, Yaksh TL. Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and their combination in sheep. Anesthesiology 1995: 82: 428-435. Gordh T, Jansson P, Gillberg PG, Post C. Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing. Acta Anaesthesiol Scand 1989: 33: 39-47. Abrams SE, Winne RP. Intrathecal acetylcholinesterase inhibitors produce analgesia that is synergistic with morphine and clonidine in rats. Anesth Analg 1995: 81: 501-507. Hood DD, Eisenach JC, Mallak K. The analgesic interaction between intrathecal neostigmine and epidural clonidine in humans. Anesthesiology 1996: 85: 315-325. Hunt CO, Naulty JS, Bader AM, Hauch MA, Vartikar JV, Datta S, Hertwig LM, Ostheimer GW. Perioperative analgesia with subarachnoid fentanyl-bupivacaine for cesarean delivery. Anesthesiology 1989: 71: 535-540. Skretting P, Vaagenes P, Sundnes KO, Edstrom HH, Lind B. Subarachnoid anaesthesia: comparison of hyperbaric solutions of bupivacaine and amethocaine. Br J Anaesth 1984: 56: 155-159. Lauretti GR, Eisenach JC, Hood DD, Pfeifer BL. Intrathecal neostigmine for postoperative analgesia: dose response (abstract). Reg Anesth 1996: 21 (Suppl): 7.4. Hood DD, Krukowski MD, Eisenach JC, Mallak KA. Intrathecal neostigmine for cesarean section analgesia: dose response (abstract). Reg Anesth 1996: 21 (Suppl): 78. Lauretti GR, Reis MP, Prado WA. Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in the patients undergoing anterior or ]posterior vaginoplasty. Anesth Analg 1996: 82: 1182-1187. Lauretti GR, Azevedo VM. Intravenous ketamine or fentanyl prolongs postoperative analgesia after intrathecal neostigmine. Anesth Analg 1996: 83: 766-770. Lauretti GR, Reis MR Subarachnoid neostigmine does not affect blood pressure or heart rate during
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bupivacaine spinal anesthesia. Reg Anesth 1996: 21: 586-591. 22. Eisenach JC, De Kock M, Klimscha W. Alpha-2adrenergic agonists for regional anesthesia: a clinical review of clonidine (1984-1995). Anesthesiology 1996: 85: 655-674. 23. Shnider SM, Levinson G. Anesthesia for obstetrics. 2nd ed. Baltimore, Williams & Wilkins, 1987: 162. 24. Butterworth JF, Strichartz GR. The alpha-2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block in conduction in rat sciatic nerve fibers. Anesth Analg 1993: 76: 295-301.
25. Rosa e Silva L, Troncon LE, Oliveira RB, Iazigi H, Gallo L, Foss MC. Treatment of diabetic gastroparesis with oral clonidine. Aliment Pharmacol Ther 1995: 9: 179-183. 26. Detweiler D J, Eisenach JC, Tong C, Jackson C. A cholinergic interaction in alpha-2-adrenoceptormediated antinociception in sheep. J Pharmacol Exp Ther 1993: 265: 536-542. 27. DeKock M, Eisenach JC, Tong C, Schmite AL, Scholtes JL. Analgesic doses of intrathecal but not intravenous clonidine increase acetylcholine in cerebrospinal fluid in humans. Anesth Analg 1997: 84: 800-803.