|Year : 2016 | Volume
| Issue : 3 | Page : 455-461
Comparison of spinal block after intrathecal clonidine–bupivacaine, buprenorphine–bupivacaine and bupivacaine alone in lower limb surgeries
Major Vishal Arora, Mohammad Zafeer Khan, Major Sanjay Choubey, Mohammad Asim Rasheed, Arindam Sarkar
Department of Anaesthesiology, ERA's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
|Date of Web Publication||27-Sep-2016|
Major Vishal Arora
Wisdom Academy, Urmilapuri, Kamta, Faizabad Road, Lucknow - 226 028, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Various adjuvants are being used with local anesthetics for prolongation of intraoperative and postoperative analgesia. The α2-adrenergic agonist clonidine and potent opioid buprenorphine have the ability to potentiate the effects of local anesthetics.
Aims: The purpose of this prospective, double-blind study was to compare onset, duration of sensory and motor block, effect on hemodynamics, level of sedation, duration of postoperative analgesia, and any adverse effects of clonidine and buprenorphine.
Settings and Design: Seventy-five American Society of Anesthesiologists Class I and II patients undergoing lower limb surgery under spinal anesthesia were randomly allocated into three Groups A, B, and C.
Subjects and Methods: Control Group A received injection bupivacaine 0.5% (heavy) 2.5 ml + saline 0.5 ml whereas Group B received injection bupivacaine 0.5% (heavy) 2.5 ml + injection buprenorphine 50 μg and Group C received injection bupivacaine 0.5% (heavy) 2.5 ml + preservative free injection clonidine 50 μg intrathecally.
Statistical Analysis Used: Unpaired Student's t-test and Z-test were used for comparing data.
Results: Statistically highly significant differences in mean time of sensory regression to L1, mean time to attain the Bromage Score of 1, and mean time of first rescue analgesic request were observed between the three groups. The patients did not suffer any serious side effects.
Conclusion: Administration of buprenorphine and clonidine intrathecally does potentiate the duration of analgesia, sensory and motor block, with buprenorphine having a long-lasting effect.
Keywords: Bupivacaine, buprenorphine, clonidine, intrathecal
|How to cite this article:|
Arora MV, Khan MZ, Choubey MS, Rasheed MA, Sarkar A. Comparison of spinal block after intrathecal clonidine–bupivacaine, buprenorphine–bupivacaine and bupivacaine alone in lower limb surgeries. Anesth Essays Res 2016;10:455-61
|How to cite this URL:|
Arora MV, Khan MZ, Choubey MS, Rasheed MA, Sarkar A. Comparison of spinal block after intrathecal clonidine–bupivacaine, buprenorphine–bupivacaine and bupivacaine alone in lower limb surgeries. Anesth Essays Res [serial online] 2016 [cited 2020 Jan 24];10:455-61. Available from: http://www.aeronline.org/text.asp?2016/10/3/455/177190
| Introduction|| |
Spinal anesthesia was introduced in clinical practice by Karl August Bier in 1898. More than a century has passed and even today, it is one of the most popular techniques for both elective and emergency surgical procedures, particularly cesarean section, lower abdominal surgeries, orthopedic, and urological surgeries, just to name a few.
The prime emphasis of acute pain treatment must be to decrease the pain as much as possible (ideally, to zero). This must be achieved, however, with reasonable cost, safety for the patient, and exclusive of drug- and treatment-related side effects.
This is true even in patients undergoing spinal anesthesia, which is a well-known technique for operations on the lower extremities. Although it is easy to perform and provides fast onset and effective sensory and motor block, it has a limited duration of action.
The need for using additives in local anesthetics was, in former times, due to a desire to prolong the anesthetic action which could allow surgery for several hours. The duration of tetracaine could be prolonged up to 6 h by the addition of adrenaline. Today, bupivacaine is the most commonly used local anesthetic for spinal anesthesia. The duration of bupivacaine spinal anesthesia after a single-shot injection is adequate for hip and knee arthroplasties. Spinal anesthesia can be extended with the use of continuous catheter techniques. Therefore, the purpose of the development of new additives has been related mainly to the prevention and relief of postoperative pain, together with the aim of reducing the dose of local anesthetics and allowing early ambulation after surgery.
α2-adrenoceptors are located on primary afferent terminals (both at peripheral and spinal endings), on neurons in the superficial laminae of the spinal cord, and within several brainstem nuclei implicated in analgesia, supporting the possibility of analgesic action at peripheral, spinal, and brainstem sites. α2-adrenergic agonists also enhance analgesia from intraspinal opioids. This interaction occurs both pre- and post-synaptic to the primary afferent synapse in the spinal cord, and is clearly synergistic when both drugs are administered intrathecally. Elimination from blood is slow, arguing against an action by systemic absorption and redistribution to peripheral or central sites. As expected from these divergent time courses, the correlation between blood clonidine concentration and analgesia within individuals is relatively poor. After spinal administration in volunteers and patients, clonidine is rapidly absorbed, with peak concentrations in arterial blood within 10 min and in venous blood within 30–45 min. Mechanistic studies support a primary spinal site of action of α2-adrenergic agonists for analgesia and a multifactorial mechanism of action in enhancing peripheral or intraspinal blockade from local anesthetics. Pharmacokinetic studies support an EC95 of 130 ng/ml clonidine in cerebrospinal fluid (CSF) for analgesia after intraspinal administration and help to clarify the dose responses observed in clinical studies. In contrast to blood, there is a strong correlation between clonidine concentration in CSF and analgesia after epidural clonidine administration. Clonidine is rapidly and extensively absorbed into the spinal CSF compartment, with concentrations peaking 30–60 min after injection. This coincides closely with an attainment of near-maximal analgesia.
The adrenergic agonist clonidine has a variety of different actions, including the ability to potentiate the effects of local anesthetics. Clonidine α2-adrenergic agonist, has central brain stem action and peripheral action. Hypothalamic α2-adrenoceptors are inhibitory and causes decrease in outflow from the vasomotor centers and sympathetic centers. This explains resultant decrease in peripheral vascular resistance heart rate (HR), blood pressure (BP), and cardiac output. Action by transdermal application is better, gives consistent blood levels and less side effects. Extradural analgesic action is because of postsynaptic activation of descending inhibitory pathway that synapse into dorsal horn of spinal cord. However, unlike spinal opioids, clonidine does not produce pruritus or respiratory depression. It also prolongs the sensory blockade.,, It also reduces the amount or concentration of local anesthetic required to produce postoperative analgesia. It has been used as a sole agent as well as admixed with opioids and local anesthetics in labor analgesia and orthopedic surgery.
Mechanistic studies support a primary spinal site of action of α2-adrenergic agonists for analgesia and a multifactorial mechanism of action in enhancing peripheral or intraspinal blockade from local anesthetics. Pharmacokinetic studies support an EC95 of 130 ng/ml clonidine in CSF for analgesia after intraspinal administration and help to clarify the dose responses observed in clinical studies buprenorphine partial antagonist receptor when added to bupivacaine is known to increase the duration of analgesia at least by 12–15 h and it is not associated with any significant fall in BP or pulse rate. It is a thebaine derivative (naturally occurring opium alkaloid) with powerful agonist action at µ opioids receptors and partial antagonist action and does not cause addiction or physical dependence. Intrathecal doses are smaller and have prolonged and profound analgesia because of its highly lipophilic nature. It remains attached to spinal opioid receptors for long duration and spreads into CSF to higher centers causing late respiratory depression, which is associated with morphine and is much less likely with buprenorphine. Adverse effects associated with buprenorphine such as nausea and vomiting and constipation are less as compared with fully agonist morphine.
Buprenorphine displays a bell-shaped or inverted U-shaped curve in dose–effect relationship curve [Figure 1]. When buprenorphine is used intrathecally in combination with bupivacaine, it improves the quality and duration of postoperative analgesia compared to bupivacaine alone.
This study is a comparative evaluation of spinal block characteristics after intrathecal clonidine–bupivacaine, buprenorphine–bupivacaine, and bupivacaine alone in lower limb surgeries. Spinal block characteristics to be observed are in terms of onset of spinal block, duration of sensory and motor block, effect on HR and BP, duration of postoperative analgesia, and any adverse effects encountered.
| Subjects and Methods|| |
This study was conducted on 75 American Society of Anesthesiologists (ASA) I and II patients posted for routine lower limb surgeries who were divided into three groups.
Inclusion criteria were ASA grades I and II patients, aged 20–60 years, undergoing lower limb orthopedic surgery emergency or elective scheduled to last <180 min, and willing to participate in study.
Exclusion criteria were patient refusal, patients using α-adrenergic receptor antagonist for any reason, hypertension, hypotension, patients receiving angiotensin-converting enzyme inhibitors/β blockers, dysrhythmias on electrocardiography (ECG), morbidly obese patients, contraindication to subarachnoid block, and general or epidural anesthesia given in addition to subarachnoid block.
All the patients underwent preanesthetic evaluation as per the protocol in preanesthetic clinic. The anesthetic and surgical plan was explained to the patients in a simple language and informed consent was obtained. The patients were divided into two groups of 25 each using chit in a box technique. On the day of surgery, inside the operation theater, basal pulse rate and BP were obtained. A wide bore intravenous (i.v.) line was established and the patients were connected to monitors such as ECG, SpO2, and a noninvasive BP recording device. The patients received Ringer's lactate infusion 10 ml/kg, prior to intrathecal anesthesia. All the patients received injection ondansetron 4 mg i.v. The patients were positioned sitting for spinal puncture. Under strict aseptic precautions, lumbar puncture was done at L3–L4 interspace using 26-gauge Quincke Spinal Needle by midline approach. After ensuring a free flow of CSF, Group A received injection bupivacaine 0.5% (heavy) 2.5 ml + saline 0.5 ml.
Group B received injection bupivacaine 0.5% (heavy) 2.5 ml + 50 µg buprenorphine (in 0.5 ml of normal saline [NS]).
Group C received injection bupivacaine 0.5% (heavy) 2.5 ml + preservative free injection clonidine 50 µg (in 0.5 ml of NS). The observer was blinded to the drug administered intrathecally.
Time of onset of block, i.e., from completion of spinal injection to achieving T10 block (in minutes) was recorded. Maximum height of block (sensory) by using pinprick (tooth prick) was recorded every 30 s. Hemodynamic parameters were recorded every 5 min during surgery and every 30 min during postoperative period.
Time to attain highest motor blockade was recorded by using modified Bromage Scale as:
Duration of sensory block was recorded as regression of block to L1, using pinprick method.
Duration of motor blockade was recorded as time required to attain a Bromage Score (BS) of 1.
Duration of postoperative analgesia was recorded by using visual analog scale (VAS) during postoperation period every 30 min using the following scale: 0 - no pain, 1–3 - mild pain, 4–6 - moderate pain, and >6 severe pain.
Injection tramadol 100 mg i.v. was given slowly as rescue analgesic for pain relief.
Bradycardia (HR <50/min) was treated with injection atropine 0.6 mg i.v., if accompanied with hypotension. Intraoperative hypotension was defined as fall in mean arterial pressure (MAP) more than 20% from baseline; it was treated with i.v. bolus of 200 ml Ringer lactate and injection mephentermine 6 mg i.v., if required.
Postoperative monitoring for regression of sensory block to L1 (duration of subarachnoid block), BS, and postoperative pain using VAS, along with hemodynamic parameters were noted every 30 min till the VAS scores were >5. Effective analgesia, i.e., time from subarachnoid injection to first parenteral rescue analgesia at VAS ≥4 was noted.
Any adverse effect such as nausea and vomiting, shivering, pruritus, respiratory depression (i.e. relative risk <10/min at rest), dryness of mouth, and bradycardia that occurred during the observation period was noted down.
After 24 h, usual postoperative care followed. When patient complained pain and demanded for additional analgesia, i.e., VAS ≥4, i.v. tramadol 100 mg bolus was given slowly. The frequency of doses and time of such rescue analgesia were noted up to 24 h.
All values are reported as mean ± standard deviation (SD). Differences were considered statistically significant at a probability value P < 0.05. Unpaired Student's t-test was used for intergroup comparison of various data obtained such as time to sensory regression of the block to L1, duration of motor blockade, and duration of postoperative analgesia. Z-test was used for comparing intragroup data such as various heights of block attained and various degrees of motor block attained within the group.
| Results|| |
By comparing the mean ± SD and calculating the unpaired t-test (P > 0.05), all the three groups were found to be comparable with respect to age (years), weight (kg), height (cm), and sex ratio as shown in [Table 1].
The types of surgery in the three groups were almost similar in the two groups. The mean duration of operations between the three groups was comparable and not found to be statistically significant (P > 0.05). The mean length of operation in the Group A was 85.4 min, Group B was 99 min, and in Group C was 93.8 min.
The mean time of onset of action of the drugs in the groups (6.4 ± 3.0 min in Group A, 7.3 ± 3.2 min in Group B, 7.1 ± 3 min) was not found to be statistically significant (P > 0.05). Similarly, the mean time to attain highest Bromage Score in Group A was 10.9 ± 1.9 min and in Group B was 10.2 ± 3.7 min and in Group C was 10.3 ± 2.2 min (P > 0.05).
On comparing the various heights of block attained in the three groups, we found that significantly more patients in the study groups (Groups B and C) reached T9 level as compared to the patients in control group.
Out of total 25 patients in the each group, only one patient in the control Group A and three patients in the each of the study groups, B and C reached a Bromage Score of 3. All the remaining patients achieved a Bromage Score of 4. The result was not found to be statistically significant (P > 0.05).
The mean pulse rate varied from 74–83 beats/min in Group A, from 74 to 86/min in Group B, and from 76 to 86 bpm in the Group C, which was not statistically significant (P > 0.05) [Figure 2]. All the groups showed a steady downward trend of pulse rate after injection of the drug to the end of the operation. Single episode of bradycardia occurred in Group C at a point of time.
MAP varied from 88 to 96 mmHg in the Group A, from 86 to 92 mmHg in Group B, and from 84 to 93 mmHg in the Group C [Figure 3]. As shown graphically, the MAP values in the Group C were lower than that in the Group A. The maximum fall in the MAP (10%) that occurred in the Group A was after 4 h of the intrathecal injection. In the Group C, the maximum fall (15%) occurred after 5 h of the intrathecal drug whereas in Group B, the maximum fall (12%) occurred after 4 h of intrathecal drug.
|Figure 3: Comparison of mean arterial pressure (mmHg) between the three groups|
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We found statistically highly significant differences in mean time of sensory regression to L1, mean time to attain the BS of 1, and mean time of first rescue analgesic request as shown in [Table 2].
All the three groups demonstrated side effects, which were not significant P > 0.05 [Table 3]. Group A, i.e., control group experienced only 4% of sedation and nausea. Nausea was noted in 12% of patients in buprenorphine (B) group and 8% patients in clonidine (C) group. Vomiting was present in 4% of patients in buprenorphine group whereas none of the patients in clonidine group had vomiting. Other side effects noticed in clonidine group were hypotension in 4% patients, bradycardia in 4% of patients, and dryness of mouth in 8% of patients in clonidine group. Somnolence was noticed slightly higher in buprenorphine group, i.e., 12% whereas 8% in clonidine group.
| Discussion|| |
The difference of mean time of onset of action of the drugs and the mean time to attain highest BS was not statistically significant between the three groups. Similar results were also shown by Racle et al.
Patients who received intrathecal clonidine with bupivacaine (Group C) attained a higher dermatomal block level than Groups A and B patients. Benhamou et al. also demonstrated that clonidine increased the spread of the sensory block, intraoperatively. Nicol and Holdcroft  tried to explain this in their study on parturients, postulating that because clonidine becomes slightly hypobaric at body temperature, rostral spread might have occurred with the patient in the sitting position for several minutes after the intrathecal injection.
In the present study, a total of five patients (1 in Group A, 1 in Group B, and 3 in Group C) out of total 75 patients studied, attained a BS of 3. All other patients in the three groups attained the BS of 4. Although the result was not found to be statistically significant (P > 0.05), other investigators observed a complete motor blockade of the lower extremities in all patients. This difference could be due to the difference in the amount of drug delivered intrathecally. They used a total drug volume of 4.6 ml with 18 mg of bupivacaine, whereas in our study, a total of 3 ml of drug and 12.5 mg of bupivacaine were used.
Similar study was conducted to compare the efficacy of intrathecal buprenorphine with intrathecal dexmedetomidine for prolonging the duration of postoperative analgesia.
The hemodynamic parameters were stable in all the groups. Both pulse rate and MAP were lower in the clonidine Group C than that of Groups A and B. BP was responsive to i.v. fluid administration as is evident from the fact that there was significant difference in the i.v. fluid requirement in the clonidine Group C than in the other two groups. Clonidine, after neuraxial or systemic administration, affects arterial BP in a complex manner because of opposing actions at multiple sites. The α2-adrenergic agonists produce sympatholysis and reduce arterial BP through effects at specific brainstem nuclei and on sympathetic preganglionic neurons in the spinal cord, effects that are counteracted by direct vasoconstriction resulting from the α2-adrenergic agonists on the peripheral vasculature. As a result, the dose response for neuraxial clonidine on arterial BP in humans is generally considered to be U-shaped., Furthermore, combining α2-adrenergic receptor agonists with local anesthetics can potentially increase the degree of sympatholysis and resulting hypotension.
The difference in the meantime of sensory regression to L1 in our study was found to be statistically highly significant (P < 0.001), with regression occurring more slowly in buprenorphine group (209 min) than in the clonidine group (183 min). Sethi et al., in a similar study in gynecological patients found that the mean time from injection to regression of the level of sensory analgesia by two segments was longer in the clonidine group than in control group (P < 0.001). The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) and postsynaptic (enhancing hyperpolarization), effects. Although clonidine might have a vasoconstrictive effect in large concentrations, the role of vasoconstriction in prolonging sensory block seems to be minor, even in usual clinical doses (1–2 µg/kg).
The duration of motor block was prolonged (P < 0.001) with addition of clonidine (228 min) and buprenorphine (262 min) to a local anesthetic solution for intrathecal block. Similar result was demonstrated by Bonnet et al. who studied the effect of different concentrations of clonidine, an α2 agonist, on sensory and motor blockade during spinal anesthesia. Racle et al. and Bonnet et al. also demonstrated that intrathecal clonidine combined with local anesthetic significantly potentiates the intensity and duration of motor blockade. The explanation for this could be that the α2-adrenoceptor agonists induce cellular modification in the ventral horn of the spinal cord (motor neuron hyperpolarization) and facilitate the local anesthetic action.
There was a statistically significant difference (P < 0.001) between the mean time of first rescue analgesic request among the buprenorphine Group B (383 ± 38.9), clonidine Group C (278.2 ± 56.4), and control Group A (175.6 ± 26.1). Similar results were also demonstrated by Strebel et al. while studying the effect of varying doses of intrathecal clonidine (37.5 µg, 75 µg, 150 µg) along with bupivacaine (in 8% glucose). van Tuijl et al. have also demonstrated that addition of 75 µg clonidine to hyperbaric bupivacaine prolongs spinal analgesia and the motor block after cesarean section and improves early analgesia. In their study, immediate postoperative analgesia was better with the combination of bupivacaine and clonidine as demonstrated by a significantly later first request for analgesia, less need for morphine top-ups in the recovery period, and lower VAS scores in the bupivacaine–clonidine group. The analgesic effect following its intrathecal administration is mediated spinally through the activation of postsynaptic α2 receptors in substantia gelatinosa of spinal cord. The rationale behind intrathecal administration of clonidine is to achieve a high drug concentration in the vicinity of α2-adrenoreceptors in the spinal cord and it works by blocking the conduction of C and Aδ fibers, increases potassium conductance in isolated neurons in vitro, and intensifies the conduction block of local anesthetics.
Some of the adverse effects noted in our study were nausea and vomiting, dryness of mouth, and sedation. However, none of the adverse effects noted were found to be statistically significant in either groups. Buprenorphine (12%) caused sedation in significantly higher number of patients than in clonidine group (8%). The nausea and vomiting was not very marked and was settled after one dose of an antiemetic. Other side effects noticed in clonidine group were hypotension and bradycardia in a single patient.
| Conclusion|| |
Intrathecal buprenorphine 50 µg gives adequate analgesia up to 383 ± 38.9 min, which is significantly longer than that of intrathecal clonidine 50 µg, i.e., 278.2 ± 56.4 min. Quality of analgesia was acceptable to patients in both groups, although VAS assessment was better in buprenorphine group. Administration of buprenorphine and clonidine intrathecally does potentiate the duration of analgesia, sensory and motor block. The study suggests that combination of two or more drugs from different group (e.g., opioid and α2 agonist) can give better analgesia and less chance of side effects.
The authors acknowledge the great help received from the scholars whose articles were cited and included in the references of this manuscript. The authors are also grateful to authors/editors/publishers of all those articles, journals, and books from where the literature for this article has been reviewed and discussed.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Lizasoain I, Leza JC, Lorenzo P. Buprenorphine: Bell-shaped dose-response curve for its antagonist effects. Gen Pharmacol 1991;22:297-300.
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;66:442-6.
Kamibayashi T, Maze M. Clinical uses of a2-Adrenergic agonists. Anesthesiology 2000; 93:1345-9.
Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth 1985;57:192-6.
Gradhe RP, Wig J, Yaddanapudi LN. Evaluation of bupivacaine-clonidine combination for unilateral anesthesia in lower limb orthipaedic surgery. J Anaesthesiol Clin Pharmacol 2008;24:155-8.
Dobrydnjov I, Samarütel J. Enhancement of intrathecal lidocaine by addition of local and systemic clonidine. Acta Anaesthesiol Scand 1999;43:556-62.
Bonnet F, Buisson VB, Francois Y, Catoire P, Saada M. Effects of oral and subarachnoid clonidine on spinal anesthesia with bupivacaine. Reg Anesth 1990;15:211-4.
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;38:724-8.
Dobrydnjov I, Axelsson K, Samarütel J, Holmström B. Postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine. Acta Anaesthesiol Scand 2002;46:806-14.
Chiari A, Lorber C, Eisenach JC, Wildling E, Krenn C, Zavrsky A, et al.
Analgesic and hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage of labor: A dose-response study. Anesthesiology 1999;91:388-96.
Eisenach JC, De Kock M, Klimscha W. alpha (2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996;85:655-74.
Benhamou D, Thorin D, Brichant JF, Dailland P, Milon D, Schneider M. Intrathecal clonidine and fentanyl with hyperbaric bupivacaine improves analgesia during cesarean section. Anesth Analg 1998;87:609-13.
Nicol ME, Holdcroft A. Density of intrathecal agents. Br J Anaesth 1992;68:60-3.
Strebel S, Gurzeler JA, Schneider MC, Aeschbach A, Kindler CH. Small-dose intrathecal clonidine and isobaric bupivacaine for orthopedic surgery: A dose-response study. Anesth Analg 2004;99:1231-8.
Soumya S, Rani P, Chandrasekar LJ, Jena SK. Intrathecal buprenorphine or intrathecal dexmedetomidine for postoperative analgesia: A comparative study. Health Agenda 2014;2:9-14.
Eisenach JC, Dewan DM. Intrathecal clonidine in obstetrics: Sheep studies. Anesthesiology 1990;72:663-8.
Sethi BS, Samuel M, Srivastava D. Efficacy of analgesic effects of low dose intrathecal clonidine as adjuvant to bupivacaine. Indian J Anaesth 2007;51:415-9.
Gaumann DM, Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesth Analg 1992;74:719-25.
Erne-Brand F, Jirounek P, Drewe J, Hampl K, Schneider MC. Mechanism of antinociceptive action of clonidine in nonmyelinated nerve fibres. Eur J Pharmacol 1999;383:1-8.
Acalovschi I, Bodolea C, Manoiu C. Spinal anesthesia with meperidine. Effects of added alpha-adrenergic agonists: Epinephrine versus clonidine. Anesth Analg 1997;84:1333-9.
Bonnet F, Brun-Buisson V, Saada M, Boico O, Rostaing S, Touboul C. Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg 1989;68:619-22.
van Tuijl I, van Klei WA, van der Werff DB, Kalkman CJ. The effect of addition of intrathecal clonidine to hyperbaric bupivacaine on postoperative pain and morphine requirements after caesarean section: A randomized controlled trial. Br J Anaesth 2006;97:365-70.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]