Original Articles

Effects of Intrathecal Midazolam on Postoperative Analgesia When Added to a Bupivacaine-Clonidine Mixture

Mehdi Boussofara, M.D., Ph.D., Michel Carls, M.D., Marc Raucoules-Aim, M.D., Ph.D., Mohamed Riadh Sellam, M.D., and Jean-Louis Horn, M.D.
Background: Previous clinical and experimental studies have shown that a midazolam-clonidine mixture has a synergistic antinociceptive effect. This study evaluated the postoperative analgesic effect of adding midazolam to an intrathecal bupivacaine-clonidine mixture. Methods: One hundred ten patients scheduled to undergo elective lower-extremity surgery were enrolled in this double-blind, randomized trial. Spinal anesthesia was administered by using 1 of 2 mixtures. Group B-C received 12.5 mg isobaric 0.5% bupivacaine, 30 g clonidine, and 0.4 mL 0.9% saline. Group B-C-M received the B-C mixture plus 2 mg of midazolam in a 0.4-mL solution. Motor and sensory block levels were assessed before, during, and after the procedure until regression of the block to S2. Sedation levels were determined before anesthesia, during surgery, and at the end of the procedure. Postoperative analgesia was assessed every 15 minutes by using a visual analog scale. Duration of sensory and motor blocks was determined based on a modied Bromage scale, and time of the rst pain relief request was noted. Results: Duration of sensory block, time of rst postoperative analgesic request, and amount of postoperative morphine administered were comparable between groups. However, the motor blockade lasted signicantly longer in the B-C-M group compared with the B-C group (287 73 minutes vs 257 72 minutes, respectively; P .05). Conclusion: Addition of midazolam to an intrathecal B-C mixture does not potentiate postoperative analgesia but prolongs the motor blockade. Reg Anesth Pain Med 2006;31:501-505. Key Words: Midazolam, Intrathecal anesthesia, Postoperative analgesia.

everal adjuvant drugs have been injected with intrathecal anesthesia to prolong postoperative analgesia, but many of these drug combinations

See Editorial page 489

From the Dpartement dAnesthsieRanimation, Hpital Aziza Othmana, Tunis, Tunisia (M.B., M.R.S.); Dpartement dAnesthsieRanimation, Centre Hospitalier Universitaire de Nice, Nice Cedex, France (M.C., M.R.-A.); and Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, OR (J.-L.H.). Accepted for publication May 31, 2006. Reprint requests: Jean-Louis Horn, M.D., Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., UHS-2, Portland, OR 97239-3098. E-mail: hornj@ohsu.edu 2006 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/06/3106-0001$32.00/0 doi:10.1016/j.rapm.2006.05.013

produce signicant side effects. Opioids prolong the duration of spinal anesthesia without delaying recovery to ambulation, and clonidine provides a coanalgesic effect, decreasing postoperative analgesic requirement and improving analgesic quality.1-3 However, many signicant side effects limit their use, including respiratory depression, hemodynamic instability, pruritus, urinary retention, nausea and vomiting, and sedation.4,5 Several clinical studies have shown that midazolam can be safely added to intrathecal local anesthetics to improve postoperative analgesia with minimal side effects.6-11 For this study, we postulated that adding midazolam to an intrathecal bupivacaine-clonidine mixture would prolong postoperative analgesia. To test this hypothesis, we administered spinal anesthesia to 2 groups of patients undergoing lower extremity surgery: group B-C received a bupivacaine-clonidine mixture only,

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and group B-C-M received the B-C mixture plus midazolam.

Materials and Methods

After obtaining approval of the Medical Ethics Committee at Aziza Othmana Hospital where the study was conducted and written informed consent from each subject, 110 American Society of Anesthesiologists I to III patients scheduled to undergo elective lower-extremity surgery were enrolled in this double-blind, randomized trial. Criteria for study exclusion were any contraindication to regional anesthesia, chronic analgesic therapy with opioids or constant baseline pain score 40/100, serious spinal abnormality, or peripheral neuropathy. The anesthesia protocol was standardized; no premedication was given. Patients received 500 mL 0.9% saline as uid loaded over 20 minutes, and a Whitacre 25-gauge atraumatic needle was inserted at the L3-L4 intervertebral space with the patient in the sitting position. We administered anesthesia by using 1 of 2 intrathecal mixtures. Group B-C received 12.5 mg isobaric 0.5% bupivacaine with 30 g clonidine plus 0.4 mL 0.9% saline, and group B-C-M received 12.5 mg isobaric 0.5% bupivacaine with 30 g clonidine and 2 mg buffered preservative-free midazolam in a 0.4-mL solution (Hypnovel; Roche, Neuilly-sur-Seine, France). The total volume of each intrathecal injection was 3.9 mL. These solutions were prepared and blinded by a pharmacist independent of the study. The density of the intrathecal solutions (B-C and B-C-M) was measured at room temperature by using a picnometric technique. We monitored vital signs until each patient was discharged from the recovery room. An electrocardiogram and arterial oxygen saturation were recorded continuously by using a Datex Cardiocap monitor (Ohmeda, Madison, WI). Blood pressure was measured noninvasively every 5 minutes until the end of the surgical procedure and every 20 minutes thereafter. Intravenous crystalloids and ephedrine (in 3-mg increments) were given to treat hypotension (systolic blood pressure 70 mm Hg or 30% decrease from preanesthesia values). Motor and sensory block levels were assessed at 5, 10, 20, 40, and 60 minutes after intrathecal injection; at the end of the surgical procedure; and every 15 minutes thereafter until regression to S2. All assessments were performed by physicians blinded to the subjects study group. Motor block levels were based on a 6-point modied Bromage scale as follows: 1, complete motor block; 2, almost complete blockade (the patient is able to move his/

her feet only); 3, partial motor blockade (the patient is able to move his/her knees); 4, detectable weakness of hip exion (the patient is able to raise his/her leg but is unable to keep it raised); 5, no detectable weakness of hip exion; and 6, no weakness at all. Motor block was considered effective when the Bromage score was 2. Sensory block was assessed by pinprick testing. Sedation levels were evaluated before anesthesia, every 15 minutes during surgery, and at the end of the procedure by using a 4-point scale as follows: 1, awake; 2, drowsy but responsive to verbal command; 3, drowsy but responsive to physical stimulus; and 4, unresponsive to verbal and physical stimuli. Postoperative analgesia was assessed every 15 minutes by using a visual analog scale (VAS) from 0 to 100 mm (0 no pain at all and 100 maximum imaginable pain). When the VAS score was 40 mm, analgesia was provided with 1 mg intravenous morphine every 3 minutes until adequate pain relief was achieved. Patients stayed in the recovery room until the sensory block regressed below L1 (assessed by pinprick) and voluntary movements in the lower extremities returned. Onset of sensory and motor blocks, duration of sensory and motor blocks, length of surgical procedure, and time of rst pain relief request were recorded. To diagnose possible neurologic complications,
Table 1. Demographic and Perioperative Data
Bupivacaine Clonidine (n 55) 51 19 30/25 74 14 170 8 20 21 14 76 35 1,005 101 83 83 89 83 82 1,465 7 18 10 9 12 14 14 506 12 Bupivacaine Clonidine Midazolam (n 55) 49 20 28/27 71 10 169 8 19 16 20 79 37 1,005 98 82 79 88 82 78 1,555 4 14 10 15 16 15 14 696 10

Parameter Age (y) Sex (M/F), n Weight (kg) Height (cm) Surgery, n Femur Knee Tibia and ankle Surgery duration (min) Density of intrathecal solution (kg/m3) Mean arterial pressure (mm Hg) Before surgery During surgery End of surgery* Heart rate (beats/min) Before surgery During surgery End of surgery Volume loading (mL) Ephedrine (mg) NOTE. Values are means wise indicated. *P .047.

standard deviation unless other-

Intrathecal Midazolam and Postoperative Analgesia Table 2. Anesthesia and Postoperative Analgesia
Bupivacaine Clonidine (n 55) 7 9 290 257 265 6 48 13 19 5 2 2 6 7 71 72 118 6 14 12 (34.5) (9.1) (3.6) (3.6) Bupivacaine Clonidine Midazolam (n 55) 7 10 306 287 273 5 50 14 6 6 66 73 116 4 14 10

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Parameter Onset of sensory block (min) Onset of motor block (min) Sensory block duration (min) Motor block duration (min)* Time to rst analgesics (min) Dose of morphine (mg) VAS before opioids (mm) VAS after opioids (mm) Perioperative events, n (%) Hypotension Bradycardia Nausea and vomiting Urine retention NOTE. Values are means wise indicated. *P .037.

groups. However, duration of motor block was signicantly longer for the B-C-M group compared with the B-C group (287 73 minutes vs 257 72 minutes, respectively; P .05) (Table 2). No differences were noted in the frequency of hypotension, bradycardia, urine retention, or nausea and vomiting (Table 2). No neurologic decit was observed in any patient after neurologic examination during the postoperative period.

Discussion
Many adjuvant drugs are injected with intrathecal anesthesia to prolong postoperative analgesia. However, these often produce signicant side effects. Previous studies have shown analgesia with minimal side effects after administration of intrathecal midazolam.6-8,12,13 Potentiation of pain relief with no change in duration of the motor blockade has also been reported after adding intrathecal midazolam to bupivacaine.8 In a prospective study of the effects of adding midazolam (2 mg) to intrathecal hyperbaric 0.5% bupivacaine (10 mg) for arthroscopic knee surgery, Batra et al.7 observed prolonged sensory block in patients receiving a midazolambupivacaine mixture compared with those receiving bupivacaine alone (268 67 minutes vs 230 41 minutes, respectively; P .05). Furthermore, postoperative analgesia lasted up to 4 times longer in the midazolam-bupivacaine group compared with the bupivacaine group with no delay in recovery to ambulation and ability to void.7 In a prospective randomized study of patients undergoing proctologic surgery, Kim and Lee8 compared the effects of intrathecal hyperbaric 0.5% bupivacaine alone with intrathecal hyperbaric 0.5% bupivacaine with midazolam (1 mg and 2 mg). They observed that adding 1 or 2 mg of intrathecal midazolam prolonged the postoperative analgesic effects of bupivacaine by 2 and 4 hours, respectively, compared with the control group. Bharti et al.6 found the same signicant results for length and quality of postoperative analgesia and sensory block duration in patients receiving 1 mg midazolam in intrathecal hyperbaric bupivacaine (15 mg) for lower abdominal surgery. The mechanism by which midazolam provides analgesia has been explored in several recent studies. The main site of benzodiazepine action is the presynaptic GABAA receptors in the dorsal horn of the spinal cord.14,15 Midazolam reduces excitatory synaptic transmission resulting in decreased excitability of spinal dorsal horn neurons.16 Therefore, adding intrathecal midazolam may potentiate the antinociceptive effect of morphine-like agents. For women in the early stages of labor (cervical dila-

15 (27.3) 6 (10.9) 3 (5.4) 0

standard deviation unless other-

examinations were conducted by a senior neurologist on all patients before the administration of anesthesia and every day until hospital discharge. Neurologic examinations included assessment of reexes, muscular strength, persistent paranesthesia, motor and sensory decits, and bowel or bladder dysfunction. Statistical Analysis To detect a 30-minute difference in the duration of postoperative analgesia (for normal Gaussian distribution and a hypothesis of equality of variances), a minimum of 50 patients was required in each group (with an alpha error of 0.05 and a power of 0.90). Data are expressed as mean standard deviation. Comparisons between groups were evaluated with the chi-square test or Fisher exact test and Student t test, if required. Bonferronis correction was applied when multiple comparisons were made. A P .05 was considered signicant.

Results
The B-C (n 55) and B-C-M (n 55) groups were comparable for demographic data; type and duration of surgery; density of intrathecal solution; hemodynamic changes after intrathecal injection; volume loading; amount of ephedrine given; and sedation scores before, during, and after surgery (Table 1). Onset of sensory and motor blocks, duration of sensory block, sensory block levels at 10 minutes and at the end of surgery (data not shown), and time of rst pain relief request did not differ between groups (P .05). Postoperative morphine administered and VAS scores before and after morphine injection were also comparable for both

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tion, 2-6 cm), the addition of midazolam (2 mg) to fentanyl (10 g) potentiated the analgesic effect compared with intrathecal administration of midazolam or fentanyl alone.17 Adding midazolam (1 mg) to intrathecal bupivacaine (15 mg) and diamorphine (0.2 mg) for elective cesarean delivery also reduced the postoperative opioid requirement. In that study, the only side effect noted was pruritus, attributable to intrathecal diamorphine groups.10 Intrathecal midazolam induces antinociception by acting as a direct agonist at kappa and delta opioid receptor sites in the spinal cord.18,19 A signicant synergistic effect on thermally induced acute pain and formalin-induced inammatory pain was shown in rats after intrathecal injection of a combination of midazolam and clonidine.20 However, experimental acute and inammatory pain in animal models may be different from postincisional pain in humans and may account for the difference in analgesic effects observed between the animal study and our study. Infusion of an intrathecal midazolam-clonidine mixture by Borg and Krijnen21 produced immediate and nearly complete pain relief in 4 patients with chronic benign neurogenic and musculoskeletal pain resistant to conventional analgesic therapy. They concluded that this intrathecal solution provides promising results in refractory chronic benign pain.21 In another study, 2 mg intrathecal midazolam was used to relieve chronic low backache.22 Most studies agree that 1 to 2 mg intrathecal midazolam is safe and efcacious.7,8,23 In the present study, we did not observe prolonged sensory block, postoperative analgesia, or time until morphine requirement with the B-C-M group. Yegin et al.23 found that adding 2 mg midazolam to bupivacaine for spinal anesthesia in perianal surgery did not prolong the sensory block; however, they showed a signicant increase in the time to rst analgesic requirement in the intrathecal midazolam group. In our study, the potentiation of the analgesic effect observed after intrathecal addition of midazolam to bupivacaine may be masked by clonidine.5 Similarly, Valentine et al.10 showed no difference in analgesia quality and morphine requirement between a group receiving an intrathecal bupivacaine-diamorphine mixture and another group receiving an intrathecal bupivacaine-diamorphine mixture with midazolam. The signicant prolongation of motor blockade in the B-C-M group compared with the B-C group could be explained by benzodiazepine-induced diminution of motor tonus at the ventral horn of the spinal cord.15 Bharti et al.6 also found that patients treated with midazolam experienced prolonged motor blockade. Furthermore, a few studies found that an intra-

thecal bupivacaine-midizolam mixture produced a statistically signicant sedative effect, probably resulting from supraspinal midazolam action.23 We did not observe a sedation effect in the midazolam group. This is most likely a result of the comparable baricity of the B-C and B-C-M intrathecal mixtures (1,005.2 kg/m3 and 1,005.1 kg/m3 at 25C, respectively) and the cerebrospinal uid (1,004 kg/m3 at 25C).24 It is important to note that a direct toxic effect of midazolam on nerve bers has been reported.25-27 Hypotonicity of the intrathecally injected solution could be the principal cause of these lesions.28 We found no neurotoxic effects using isotonic solutions in our clinical study. Moreover, Nishiyama et al.29 did not demonstrate any histopathological damage in the spinal cords of cats after direct exposure to 10 mg midazolam over 6 hours. Several human studies reported no neurologic decit after intrathecal injection of midazolam.21-23,30 In a cohort study on 1,100 patients, 547 received intrathecal midazolam (2 mg) in an isotonic solution without preservative. After 1 month of postoperative monitoring, Tucker et al.31 found no signicant difference between the intrathecal midazolam group and the control in neurologic complications, including cauda equina syndrome, adhesive arachnoiditis, transverse myelitis, paralysis, or bladder or bowel dysfunctions. Although our observations are consistent with studies that have found intrathecal midazolam to be safe in humans, we agree with Lin32 that it is prudent to take into account other experimental results25-27 and to consider that intrathecal midazolam may not be totally safe in humans. In conclusion, adding midazolam to an intrathecal bupivacaine-clonidine mixture does not potentiate postoperative analgesia but prolongs motor blockade. Furthermore, because of possible risks for neurotoxicity, we do not recommend adding midazolam to a bupivacaine-clonidine mixture for spinal anesthesia.

Acknowledgments
We thank M. Fredj, M.D., senior neurologist at Hpital Charles Nicolle, Tunis, Tunisia, for performing the neurologic examinations on the subjects of this study, and we also thank Hanne El Jebari, chemist at the Laboratoire de chimie analytique, at the Facult des sciences de Tunis, Tunisia, for measuring the density of the solutions tested in this study.

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