|Year : 2012 | Volume
| Issue : 4 | Page : 231-234
The role of intrathecal midazolam as an adjunct to bupivacaine in providing post-operative pain relief
Malavika Kulkarni1, Madhuri Kurdi2, Savithri Itagimath3, DA Sujatha1, MK Muralidhar4
1 Department of Anesthesia, Kasturba Medical College, Manipal, Karnataka, India
2 Department of Anesthesia, KIMS, Hubli, Karnataka, India
3 KIMS, Hubli, Karnataka, India
4 Department of Comunity Medicine, Kasturba Medical College, Manipal, Karnataka, India
|Date of Web Publication||27-Feb-2013|
Department of Anesthesia, Kasturba Medical College, Manipal University, Manipal, Karnataka
Source of Support: None, Conflict of Interest: None
Context: Post-operative analgesia forms an essential ingredient of perioperative care. Various adjuvants which include opioids and non-opioids have been used to prolong the post-operative analgesia of intrathecal bupivacaine. Aim: The study was conducted to study the effect of intrathecal midazolam in prolonging post-operative analgesia when used as an adjunct with bupivacaine. Settings and Design: The present study was a randomized control design conducted at Karnataka Institute of Medical Sciences, Hubli, Karnataka, India. Materials and Methods: A prospective randomized double blind placebo controlled study was undertaken to evaluate the efficacy of intrathecal midazolam as an adjunct intrathecal bupivacaine for post-operative analgesia on 150 adult patients of ASA grade I/II scheduled to undergo elective lower abdomen, lower limb, and urological surgeries. Patients in group A (n = 75) received 3 ml of intrathecal heavy bupivacaine with 0.2 ml of saline. In group B, patients received 3 ml of intrathecal heavy bupivacaine with 0.2 ml of preservative free 1 mg of midazolam. Statistical Analysis: Mean, Standard Deviation (SD), Z test, Chi-square test were done. Data was analyzed using Pc (XT) with minitab software version 13. Results: There was no significant difference observed in both the groups with respect to onset of sensory block, time taken to achieve maximum sensory block, or level of sensory block. The duration of sensory block was significantly longer in group B than group A (266.36 ± 22.56 min vs 187.8 ± 22.92 min). The duration of effective analgesia was prolonged in midazolam group than in the control group (232.75 ± 21.44 min vs 133.83 ± 16.23 min) with a P value <.0001. Conclusion: The duration of effective analgesia when midazolam is added to intrathecal bupivacaine is significantly prolonged thereby proving that midazolam is a useful adjunct to intrathecal bupivacaine for post-operative analgesia.
Keywords: Adjuvant, bupivacaine, intrathecal, midazolam, post-operative analgesia
|How to cite this article:|
Kulkarni M, Kurdi M, Itagimath S, Sujatha D A, Muralidhar M K. The role of intrathecal midazolam as an adjunct to bupivacaine in providing post-operative pain relief. Int J Health Allied Sci 2012;1:231-4
|How to cite this URL:|
Kulkarni M, Kurdi M, Itagimath S, Sujatha D A, Muralidhar M K. The role of intrathecal midazolam as an adjunct to bupivacaine in providing post-operative pain relief. Int J Health Allied Sci [serial online] 2012 [cited 2021 Dec 2];1:231-4. Available from: https://www.ijhas.in/text.asp?2012/1/4/231/107852
| Introduction|| |
Post-operative analgesia is an important challenge in peri-operative care. Pain results in physiological and psychological responses in the patient, the majority of which are detrimental to post-operative outcome.  Inadequate relief of post-operative pain can prolong recovery, increase the duration of stay in hospital, and increase in the health care cost.  It is therefore the responsibility of the modern anesthesiologist as a perioperative physician to ensure patient comfort throughout the pre-operative, intra-operative, and post-operative period.  Among the various methods of providing post-operative analgesia, the benefits of intrathecal opioids and non-opioids as adjuncts in spinal anesthesia are well documented. The addition of intrathecal opioids is however associated with dose-related adverse effects such as respiratory depression, nausea, vomiting, urinary retention, pruritus, and sedation.  Therefore, the use of non-opioids such as ketamine, clonidine, neostigmine, magnesium sulfate, midazolam have become popular adjuncts for post-operative analgesia. Several investigations have shown that intrathecal or epidural administration of midazolam produces a dose-dependent modulation of spinal nociceptive processing in animals and humans and is not associated with neurotoxicity, respiratory depression, or sedation.  A method of post-operative analgesia, which requires minimum technical intervention and expertise, gives good quality analgesia, is safe, that requires easily available drugs and equipment, is cheap and cost effective, has least side effects, and thereby has good patient and surgeon acceptance is the need of the hour today. With this in mind, we conducted a study to evaluate the effects of intrathecal midazolam-bupivacaine combination on post-operative analgesia.
| Materials and Methods|| |
After approval from the hospital ethics committee, a prospective randomized double blind placebo controlled study was carried out on 150 (ASA1 and 2) adults aged between 18 and 60 years scheduled to undergo elective surgical procedures on lower abdomen, lower extremity, or urological procedures under subarachnoid block.
Sample size: After anticipating at least 1 h difference in the duration of analgesia between the two groups with a range of the duration of analgesia between 150 and 180 min for a power of 90% with 95% confidence level, a minimum sample size of 84 in each group is to be enrolled.
If loss to follow up of 10% is expected then the sample size would be 95 in each group. However, due to feasibility, a sample of 150 in each group is considered for our study.
Patients having any contraindications to regional anesthesia, sensitivity to the study drugs or any drugs that modify the pain perception were excluded from the study. Premedication with oral diazepam 0.2 mg/kg was given orally on the night before the surgery. The patients were randomly allocated into one of the two groups in a double blind manner using a sealed envelope, where group A was (n0 = 75) the bupivacaine group and group B was (n = 75) the bupivacaine midazolam group. The study solution was prepared by another anesthesiologist in order to ensure that the participant and the anesthesia provider were blinded to the treatment group.
Standard monitoring included an electrocardiogram (Lead 2 and V 5), non-invasive blood pressure, and pulse oximeter. Patients were preloaded with intravenous Ringer's lactate solution 15 ml/kg before administration of subarachnoid block. Baseline vital signs were recorded immediately before spinal anesthesia. Spinal anesthesia was performed on patients in the sitting/lateral position under aseptic conditions at the L 3 -L 4 or L 4 -L 5 interspace with a 25 G spinal needle.
The patients in group A received 3 ml of bupivacaine 0.5% (heavy) with 0.2 ml (1 mg) preservative free midazolam and in group B the patients received 3 ml of bupivacaine 0.5% (heavy) with 0.2 ml of normal saline. The drug was injected intrathecally over a period of 10 seconds with no barbotage. The following parameters were noted: Time of intrathecal injection once the patient was made supine, time of onset of sensory block-it is the time taken from intrathecal administration of the test drug solution to complete loss of sensation to pin prick, the level of sensory block as assessed by pin prick test bilaterally along the midclavicular line was performed at 2, 5, 10 and 15 min, time taken to achieve maximum level of sensory block was taken at the end of 15 min, the duration of sensory block was taken from the time of intrathecal injection to regression of the level of sensory block to S 1 dermatome. The level of sensory block as assessed by pin prick testing was performed every 15 min until regression by two segments and regression to S 1 dermatome. Post-operative analgesia was assessed using a visual analogue scale (VAS). The patient was asked to mark on a 10 cm horizontal scale with no pain corresponding to 0 at one end and the worst unbearable excruciating pain at the other end. This was explained to the patient in his vernacular language. The patient's mark of severity of pain on the line was measured. The duration of effective analgesia was taken from the time of intrathecal drug administration to the time of first supplementation with rescue analgesic. Injection diclofenac sodium 1.5 mg/kg intramuscular or injection tramadol 1 mg/kg intramuscular or intravenous was the rescue analgesic given if VAS was found to be 4 or more. Sedation scores were assessed every 15 min both intra and post-operatively using a four point scale (1 = awake, 2 = drowsy but responsive to verbal command, 3 = drowsy but responsive to physical stimulus, 4 = unresponsive to verbal/physical stimulus). Post-operatively, monitoring of vital signs, VAS scores, and sedation scores was continued every 15 min until the time of regression of sensory block to first sacral dermatome. The incidence of hypotension (arterial blood pressure <20% of baseline), bradycardia, pruritus, Nausea, vomiting and urinary retention were monitored in the recovery room and then shifted to the ward.
Neurological examination was done to rule out any neurological deficits at discharge.
| Results|| |
The two groups were similar with respect to the demographic characteristics and the type of surgery performed as no significant difference was observed as depicted in [Table 1].
The time of onset of sensory block, time to achieve maximum sensory block, and level of dermatomal sensory blockade was similar in both the groups and no significant difference was observed. However, the time taken for two segment regression of sensory block, regression of sensory block to S1 dermatome, and the duration of effective analgesia was significantly higher in the Group "B". This infers that the patients who were administered midazolam along with the bupivacaine had a prolonged sensory blockade than the bupivacaine only group. These results are shown in [Table 2].
The mean arterial blood pressure and heart rate were comparable in both the groups. Similarly, the respiratory rate and oxygen saturation did not differ between the groups.
There were no statistical differences observed between the two groups with regard to minor complications like hypotension, bradycardia, drowsiness, nausea, vomiting or pruritis, though drowsiness was one of the features observed with Group B. However, there was no development of respiratory depression or signs of neurotoxicity (χ2 = 5.32, P > 0.05). The details are depicted in [Table 3].
| Discussion|| |
In this study, the inclusion of midazolam in intrathecal bupivacaine was shown to significantly enhance the duration of post-operative analgesia. However, the difference in time of onset of sensory blockade, time taken to achieve maximum sensory block, and the level of sensory block amongst the two groups was not statistically significant. Although different types of surgical procedures have been selected we have avoided bias by random distribution of cases.
Time to two segment regression in group B was significantly longer than in group A. The time of regression of sensory blockade to S 1 dermatome was significantly longer in the midazolam group when compared to the control group (266.36 ± 22.56 min vs 187.8 + 22.92 min) with theP value < 0.0001. The mean duration of effective analgesia in the midazolam group was much longer compared to the control (232.75 ± 21.44 vs 133.83 min ± 16.23) with a P value < 0.0001, hence statistically significant. The duration of post-operative analgesia was prolonged by approximately 2 h compared to the control.
Similar corroborative results were obtained in a study conducted by Prakash Smitha et al. to assess the post-operative analgesic efficacy in patients undergoing elective cesarean delivery. In the study, intrathecal bupivacaine (2 ml) along with midazolam in doses of 1 and 2 mg accounted for approximately 4 and 6 h of post-operative analgesia.  Kim. and Lee evaluated the post-operative analgesic effects of 1 and 2 mg midazolam with 1 ml of hyperbaric bupivacaine in patients undergoing hemorrhoidectomy and found that time to rescue analgesia was prolonged by 2 and 4.5 h, respectively,  thereby depicting a dose-dependent prolongation of post-operative analgesic effect. The study conducted by Bharti et al. showed that addition of 1 mg of midazolam to intrathecal bupivacaine improves the duration and quality of spinal anesthesia and provides prolonged perioperative analgesia without significant side effect in patients scheduled to undergo elective lower abdominal surgery. 
The mechanism of action of intrathecal midazolam is attributed to the potential role of spinal benzodiazepine receptors in sequential antinociceptive action. Administration of benzodiazepine antagonist (Bicuculline) has been reported to reverse the analgesic effect of intrathecal midazolam suggesting that the antinociceptive actions are mediated via BZD/GABA-A receptor complex which are present in lamina II of dorsal horn ganglia of spinal cord.  Intrathecal midazolam is involved in the release of endogenous opioid acting at spinal delta receptors. Its antinociceptive effect has been suppressed by delta selective opioid antagonist naltrindole.  Intrathecal midazolam besides causing analgesia has been found to be effective in suppressing reflex response to visceral distension in rabbits and visceral pain in humans in cesarean section. 
A cohort study conducted by Tucker et al. on eleven hundred patients who received intrathecal midazolam (2 mg) there was no increase in adverse neurological symptoms compared with conventional therapies.  Serrao, Marks et al. have safely used intrathecal midazolam on patients with chronic mechanical low back pain. Intrathecal midazolam has been used safely in humans for more than 10 years for treatment of chronic low back pain. Even long-term Administration (more than 2.5 years) of doses up to 6 mg/day of intrathecal midazolam did not cause any neurological deficits in patients with refractory musculoskeletal pain.  In our study, the dose of preservative free midazolam used was a low dose of 1 mg (0.2 ml) thereby contributing to post-operative analgesia without amounting to any neurotoxicity. The follow up of these patients was done for neurological deficits to the time of discharge.
Our study did not find a significant difference between the test and control group with regard to hemodynamic variables and occurrence of adverse effects such as hypotension, bradycardia, respiratory depression, nausea, vomiting, pruritus, urinary retention, and drowsiness.
Our study may be criticized for adopting a low dose of midazolam. This was done with the intention of providing safe and prolonged post-operative analgesia. The duration of motor block was not assessed as our objective was to determine effectiveness of midazolam as an adjunct to intrathecal bupivacaine in post-operative pain relief.
Further studies may be recommended with higher doses which may bring marked increase in the duration of post-operative analgesia. Studies with emphasis on the duration and quality of motor blockade may also be undertaken.
| Acknowledgement|| |
The authors acknowledge the subjects co-operation for having participated in the study.
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[Table 1], [Table 2], [Table 3]