Midazolam, a short-acting imidazobenzodiazipine derivative, enhances γ-aminobutyric acid (GABA) induced responses within the central nervous system (1). There may be a GABA-ergic pain modifying system descending from the periaqueductal gray matter (2). In vitro autoradiography has shown that there is a high density of benzo-diazepine (GABA-A) receptors in lamina II of the dorsal horn in the human spinal cord, suggesting a role in pain modulation (3). The GABA ionophore complex is also present in the superficial layer of the subnucleus caudalis (4), a brainstem region that processes nociceptive sensory information from the orofacial region. All these studies have lead to the speculation that midazolam could influence nociception. However, studies exploring this analgesic effect have shown conflicting results depending on the route and method of drug administration (5,6). Both hyperalgesic and antinociceptive effects of systemically administered midazolam have been reported (7–9). These discrepancies may be attributable to the diversity of experimental procedures and different dosing schedules of the drug.
Midazolam has been well established as a suitable sedative for use in patients undergoing dental surgery (10). The sedative and amnesia effects of midazolam are well established, but there is disagreement as to whether it has an analgesic effect. If midazolam sedation does have a pain-relieving effect, it will have a significant impact on the clinical practice of pain management and patient care. When severe pain is expected, midazolam sedation could be used as an adjunct to pain control. This could possibly result in reduced pain with better patient acceptance of treatment. In addition, less analgesic consumption may reduce the overall adverse effects of the analgesics. The present study evaluated the potential pain reducing effect of midazolam when given IV to patients undergoing third molar surgery.
The study was approved by our local IRB, and all patients provided informed written consent before surgery. Patients at least 16 yr of age, in generally good health, and scheduled for surgical removal of impacted third molars were eligible for this study. Inclusion criteria included the need for removal of one to two impacted mandibular third molars. All patients included were ASA I–II and had no contraindications to the study medications. Patients were excluded if they were pregnant, had any systemic diseases that increased the risks associated with parenteral sedation or oral surgery, had chronic use of central nervous system depressants or alcohol, or exceeded standard weight table norms by more than 20%. A sample of 125 patients undergoing elective surgical removal of impacted mandibular third molars in an outpatient setting was recruited.
Patients were allocated randomly to each treatment group. The study was of a single-blind design with an observer collecting the data being unaware of the category of treatment. All patients were operated upon by the same surgeon (KSO). A total of 125 patients were recruited and were randomized into 2 groups: 64 patients in the IV midazolam group and 61 patients in the control group.
For the midazolam group, an IV 20-gauge plastic catheter was placed in the antecubital fossa or dorsum of the hand. Midazolam (Dormicum; F.Hoffman-La Roche, Basel, Switzerland) was then administered at a rate of 1 mg/min until a clinical end-point, characterized by slurred speech, patient self-reports of relaxation, or drooping eyelids, or a maximum of 10 mg was reached. The midazolam was appropriately flushed with 2 mL of saline to ensure that the full dose was administered. At this point, local anesthetic 2% lidocaine with epinephrine 1:100,000 (Xylestesin™-A; 3M ESPE, Germany) was injected into the operation site for the anesthetic. The impacted mandibular third molars were surgically removed with a standardized technique and erupted upper third molars were extracted as required. Pulse and SaO2 were continuously monitored during the duration of the surgery and recovery using a pulse oximeter. Demographic and surgical data, including age, weight, gender, types and number of teeth extracted, duration of surgery, and amount of local anesthetic used were recorded.
Postoperative pain experience was assessed on the basis of four key end-points, which the patient was required to record in a pain diary.
- Pain Intensity. Patients were asked to record, on a 100-mm plain visual analog scale (VAS) and a 4-point categorized scale (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain), the intensity of pain every hour for 8 h after surgery. Serial VAS recorded over both the 4-h and 8-h investigation periods were complied into a graph of pain (mm) versus time (h). The area under the graph (AUC) was measured using the trapezoidal method and recorded as AUC0 – 4 and AUC0 – 8 respectively. Such a measure gives an overall assessment of each patient’s pain experience throughout the investigation time periods (11).
- Time to First Analgesic. Time to first analgesic was defined as the time from the end of surgery until intake of first analgesic became necessary for the patient. The patients were instructed to take 400 mg of ibuprofen (Brufen; The Boots Company, London, UK) when suffering from at least moderately severe pain and to wait for the next episode of pain if there was any before taking the next dose of ibuprofen.
- Total Analgesic Consumption During the First 48 H. As most patients with postsurgical pain have the most discomfort within the first 24 –48 h, the total amount of analgesic (ibuprofen) consumed during the first 48 h was recorded.
- Patient Global Assessment. Patients were asked to provide an overall evaluation of the pain experience on a 5-point categorical scale, at the end of the trial. The categories of scale were 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent; excellent = minimum pain versus poor = severe pain.
The same study was conducted for the control group with the same data collection. In the control group, only local anesthetic was given without any midazolam sedation for the surgery.
Using the principal variable, the VAS for postoperative pain and considering a difference of 15 mm as clinically significant, the sample size was calculated. Considering a type I α error of 0.05 and a type II β error of 0.1 and using an estimate of 25 mm for the sd, the sample size was calculated as 58 patients per treatment group.
Data were presented as the mean with their sd. Demographic data, duration of operation, and amount of local anesthetic used were evaluated with an unpaired Student’s t-test. The pain scores were analyzed using the Mann-Whitney U-test. The comparison of time to taking of first analgesic was based on log-rank test. The global assessment was assessed by the χ2 statistic. All tests were 2-sided and the level of significance was set at 0.05.
Of the 125 patients entered into the study, 8 were excluded from the analysis; 6 from the midazolam group and 2 from the control group were excluded due to incomplete pain diary form. Thus data were obtained from 117 patients; 58 patients for the midazolam group and 59 patients from the control group. Patient demographics and operation details, including the types and number of teeth extracted, are shown in Tables 1 and 2. Both groups were balanced for the demographic variables and there was no significant difference (P > 0.05) between the two groups for operating time and amount of local anesthetic used for the surgery.
The four primary end-points of the study were postoperative pain intensity, time to first analgesic, total analgesic consumption, and overall patient global assessment. The mean pain intensity scores (both VAS and categorical scores) and AUC for the VAS scores throughout the 8-h investigation period are shown in Table 3. It is noted that all the patients in the midazolam group experienced significantly less pain throughout the 8-h investigation period in terms of lower VAS scores (19.0 ± 13.2 mm versus 28.1 ± 12.8 mm) and 4-point categorized scores (0.98 ±0.48 versus 1.3 ± 0.51) (P < 0.05). For AUC0 – 4 and AUC0 – 8, the midazolam group was likewise superior to the control group.
All patients in this study required analgesic for pain control during the 8-h investigation period (Table 4). However, the midazolam group reported a longer time to first analgesic consumption compared with the control group (165.5 ± 56.5 min versus 202.2 ± 79.0 min, P < 0.05). The time to first analgesic consumption was delayed by a mean time of 37 min in the midazolam group when compared with the control group.
The mean total amount of analgesics (ibuprofen) consumed for the midazolam group was also significantly less than the control group (1275 ± 364 mg versus 1688 ± 407 mg, P < 0.001) as shown in Table 3. Figure 1 shows a violin plot that compares the median, the spread, and the distribution pattern of the analgesic consumption in the two treatment groups: the midazolam group (median, 1200 mg; range, 400 mg to 2000 mg) versus control group (median, 1600 mg; range, 800 mg to 2400 mg).
Patient’s overall assessment of the pain experience is shown in Figure 2. The midazolam group had a better global assessment score (3.34 ± 0.8 versus 2.4 ± 0.9, P < 0.001). The distribution of scores shows that more patients in the midazolam group (51.7%) scored the experience as excellent in relation to minimum pain after the surgery as compared with the control group (10.3%).
The IV administration of midazolam alone to 64 patients under the conditions of the trial did not produce any significant adverse events or premorbid changes. No patients suffered from respiratory depression as defined as a respiratory rate of <8 breaths/min. These findings, however, do not eliminate the risk of serious sequelae from administering the drug too quickly without appropriate physiological monitoring or professional supervision or the possibility of idiosyncratic responses that can occur at a frequency that is too small to be detected in a sample of only 64 patients.
The present study has demonstrated that a single dose of midazolam (mean dose of 5.9 mg or 0.09 mg/kg) given IV reduces postoperative pain after third molar surgery. This is evidenced by the lower pain intensity scores throughout the 8-hour investigation period. In addition, patients receiving IV midazolam also reported significantly longer time to first analgesic, lesser analgesic consumption, and better global assessment compared with the control group. Although IV midazolam increases the time to first analgesic consumption by a mean time of 37 minutes when compared with control, this may not be clinically significant. All the patients in the present study required an analgesic for pain relief in the 8-hour investigation period. The median time to first analgesic for the midazolam group was 180 minutes, compared with 150 minutes for the control. The peak postoperative pain for third molar surgery is usually 6 to 8 hours after surgery (12). Hence, delaying the pain onset by about 30 minutes, from 2.5 hours to 3 hours after the surgery, may not be clinically significant for this type of surgery. However, the overall lower pain intensity experience, smaller analgesic consumption, and better global assessment are clinically significant. In the midazolam group 51.7% of the patients reported the surgical experience as excellent in regard to pain (excellent = minimum pain versus poor = severe pain) as compared with 10.3% in the control group.
It has been shown that midazolam alters the thresholds for perception of tactile and painful stimulation (13). The authors showed that IV midazolam significantly increases the threshold of tactile and pain sensations on facial skin. Thresholds of tactile sensitivity and pain were statistically significantly different from control values at 10 minutes after injection of 0.05 mg/kg of midazolam. The authors concluded that their work supports previous studies reporting that midazolam has analgesic properties. It may be difficult for the authors of the above study to claim that midazolam has a direct antinociceptive effect based on their limited results. However, it is likely to have a direct effect on the affective-emotional component of pain. The mechanism of midazolam’s analgesic effect may be via its inhibitory effect on higher centers, which in turn influences the limbic and reticular systems responsible for the affective-emotional aspect of pain (9). Pain is a multidimensional experience with a sensory-discriminative and affective-emotional component. Midazolam could reduce pain perception by producing sedation, causing amnesia, and its anxiolytic effect could reduce the emotional component of pain. For postoperative pain, anxiety is the main emotional component involved. Anxiety and pain are intimately related (14) in that anxiety leads to an exacerbation of pain (15). The main thrust of our study was not to investigate the anxiolytic effect of midazolam but to look at its potential antinociceptive effect. Hence, anxiolysis was not formally measured and we could not conclude that it occurred in our study.
There have been very few studies done on the analgesic effects of midazolam apart from those studies that evaluated epidural administration. Only studies with midazolam administered epidurally showed consistent results on its analgesic effects (16,17). Studies done on the analgesic effect of IV midazolam showed conflicting results (17,18). These discrepancies may have been the result of the diversity of experimental procedures. For example, in a clinical study, it has been shown that midazolam by bolus and continuous infusion resulted in a reduction in morphine consumption and lower pain scores in 50 patients undergoing hysterectomy (17). The authors concluded that midazolam is effective in reducing postoperative pain. Our study supports the above finding but is contradictory to a previous investigation which concluded that midazolam sedation caused a significantly higher report of pain intensity in a sample of impacted third molar surgical patients when compared with placebo (17). However in that study, the conclusion was based on pain intensity assessed at 5 minutes intraoperatively by a 4-point categorical scale. No further measurement or pain assessments were taken. At 5 minutes after the administration of IV midazolam, the patients may not be able to report their pain intensity correctly because of the sedative and amnesic effect of the drug. Further investigations into pain intensity a few hours after the surgery may have provided more useful and pertinent information. It should be noted that the main objective of that particular study was not to investigate the pain reducing effect of midazolam but to establish the safety and relative efficacy of several sedative regimens, including midazolam sedation, for dental surgery.
In our study, IV midazolam appeared to have antinociceptive properties. Although the anxiolytic effect of midazolam was not measured in the study, the lower pain scores and analgesic consumption in the midazolam group versus control do suggest that midazolam sedation can lead to a less intense pain experience after surgery. This property of midazolam will be useful not only for surgical patients in general but also for a large variety of patients in pain. Evidence in palliative care has shown that temporary sedation with midazolam has resulted in good control of severe pain in patients with cancer-related pain that is not responsive to opioids (19,20).
It may be argued that our study was not adequately blinded, as both the patients and the operator were definitely aware whether or not IV midazolam was given, even if a placebo was administered. We deemed that a placebo injection of saline to the control group would do little to facilitate blinding of the study. Future studies in this area could consider incorporating two sedated groups, perhaps midazolam versus a barbiturate (e.g., methohexital, which has also been used as a sedative drug for dental surgery), with appropriate dummy solutions to allow a double-blind comparison.
We conclude from our present study that systematically administered midazolam is effective in reducing postoperative pain after third molar surgery.
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