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. 2016 Fall;63(3):147–155. doi: 10.2344/15-00034.1

Effective Dosage of Midazolam to Erase the Memory of Vascular Pain During Propofol Administration

Aiji Boku *, Mika Inoue †, Hiroshi Hanamoto †, Aiko Oyamaguchi †, Chiho Kudo †, Mitsutaka Sugimura †, Hitoshi Niwa †
PMCID: PMC5011957  PMID: 27585418

Abstract

Intravenous sedation with propofol is often administered to anxious patients in dental practice. Pain on injection of propofol is a common adverse effect. This study aimed to determine the age-adjusted doses of midazolam required to erase memory of vascular pain of propofol administration and assess whether the Ramsay Sedation Scale (RSS) after the pretreatment of midazolam was useful to predict amnesia of the vascular pain of propofol administration. A total of 246 patients with dental phobia requiring dental treatment under intravenous sedation were included. Patients were classified according to their age: 30s, 40s, 50s, and 60s. Three minutes after administration of a predetermined dose of midazolam, propofol was infused continuously. After completion of the dental procedure, patients were interviewed about the memory of any pain or discomfort in the injection site or forearm. The dosage of midazolam was determined using the Dixon up-down method. The first patient was administered 0.03 mg/kg, and if memory of vascular pain remained, the dosage was increased by 0.01 mg/kg for the next patient, and then if the memory was erased, the dosage was decreased by 0.01 mg/kg. The effective dosage of midazolam in 95% of each age group for erasing the memory of propofol vascular pain (ED95) was determined using logistic analysis. The accuracy of RSS to predict the amnesia of injection pain was assessed by receiver operating characteristic (ROC) analysis. The ED95 of midazolam to erase the memory of propofol vascular pain was 0.061 mg/kg in patients in their 30s, 0.049 mg/kg in patients in their 40s, 0.033 mg/kg in patients in their 50s, and 0.033 mg/kg in patients in their 60s. The area under the ROC curve was 0.31. The ED95 of midazolam required to erase the memory of propofol vascular pain demonstrated a downward trend with age. On the other hand, it was impossible to predict the amnesia of propofol vascular pain using the RSS.

Key Words: Midazolam, Propofol, ED95, Vascular pain

Propofol is one of the most commonly used sedative agents for intravenous sedation during dental procedures. By continuous infusion, propofol provides the ability to titrate to a desired level of sedation and provides a rapid recovery because of the short context-sensitive half-time and the short effect-site equilibration time.1 However, propofol causes a high incidence of pain on injection, approximately 60% according to a recent review, with some patients recalling the induction of anesthesia as the most painful part of the perioperative period.2 Various methods of reducing vascular pain caused by propofol have long been the subject of investigation. Some reports have stated that a mixed injection with lidocaine is effective.3,4 Although intravenous lidocaine (0.5 mg/kg) with a rubber tourniquet on the forearm 30–120 seconds before the injection of propofol has been considered the most effective technique, the efficacy rate is only approximately 60%4; therefore, it has not become standard practice. Furthermore, propofol is prepared in a micellar state, and the micellar diameter reportedly increases with time following mixing with lidocaine solution.5 Because a pulmonary embolism can be caused when the micellar diameter exceeds 4–5 μm, mixing propofol with lidocaine solution is not a clinically useful method unless the combination is used soon after mixing.6

Jalota et al2 recommended the routine use of small doses of opioid before induction of anesthesia despite lesser efficacy than the lidocaine-tourniquet technique. However, opioids should be administered carefully because of potential ventilation concerns for dental outpatients when intravenous conscious sedation is the intended level of sedation.

Intravenous sedation is often administered to anxious patients in dental practice. For these patients, fear and anxiety about pain on injection of sedation medication may have a great impact on such patients. We believe that erasing the negative memory of the painful injection of propofol is therefore important. Ideally, sedation providers would like to either predict the susceptibility to propofol injection pain or prevent it completely.

Midazolam has a great advantage in eliminating unpleasant perioperative memories because of its strong anterograde amnesic properties. Furthermore, in addition to its anxiolytic effect, intravenous preadministration of midazolam has been reported to reduce postoperative nausea and vomiting and increase patient satisfaction.7 Thus, these secondary effects can also be advantageous in improving the patient's perioperative experience. Pretreatment with midazolam may also be useful to erase the memory of propofol injection pain. Earlier studies demonstrated that intravenous midazolam 2 mg prior to a propofol infusion decreased recollection of uncomfortable intraoperative events, including pain on propofol injection.8 On the other hand, because it is well known that elderly patients are more sensitive to the sedative action of midazolam compared with younger patients,9,10 determining the age-adjusted dose of midazolam for amnesia for propofol injection pain would be beneficial. The purpose of this study was to determine the effective dosage of midazolam in 95% of an age-adjusted population for erasing the memory of propofol injection pain. We also assessed whether the Ramsay Sedation Scale (RSS; see Table 1) after the pretreatment of midazolam was useful to predict amnesia of the pain of injection of propofol.

Table 1.

Ramsay Sedation Scale

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METHODS

Study Design

After approval from the Institutional Review Board and Ethical Committee of Osaka University Dental Hospital (H24-E12), this study was registered with the UMIN Clinical Trials Registry (UMIN000009894). Written informed consent was obtained from 246 patients, aged 30–69 years, with ASA physical status 1 or 2, undergoing dental procedures of less than 60 minutes under intravenous sedation from February 2013 to March 2014. Exclusion criteria were the following: allergy to propofol, soybean or egg; significant obesity (body mass index of 30 or higher); and use of sedative drugs.

Study Protocol

Patients were classified into 4 groups according to age: patients in their 30s, 40s, 50s, and 60s. As is customary in our institution, patients were nothing per os (NPO) for 4 hours for conscious sedation. On patients' arrival at the treatment room without preanesthetic medication, a 22-gauge cannula was inserted into the largest and straightest antecubital vein available and a predetermined dose of midazolam was administered. Three minutes later, the level of sedation was assessed using the RSS (Table 1). We chose 3 minutes, as in a previous pilot study we found that some patients were too sedated for effective verbal communication if we waited longer than 4 minutes after administration of midazolam. Then, we informed the patient about the start of propofol administration and propofol (Maruishi Pharmaceutical) was injected continuously at a rate of 3 mg/kg/h (50 mcg/kg/min). Patients were then tapped on their shoulder gently and asked if they felt vascular pain during the propofol injection. At this point, patients were sedated essentially by midazolam only; the sedation level at that time was RSS 2 or 3, so verbal communication was possible. Patients were kept sedated until completion of surgery with a continuous infusion of propofol at 2–4 mg/kg/h. The intended sedation level with this continuous infusion of propofol was considered moderate as described by the American Society of Anesthesiologists.11 Patients were then kept at an adequate sedation level (RSS 3 or 4) during the dental procedure by adjustment of the infusion rate of propofol. After completion of surgery, patients who complained of vascular pain were interviewed by a research team member who was blinded to dose of midazolam. Patients were asked about the memory of pain or discomfort at the injection site or forearm. In the present study, patients who received propofol and complained of vascular pain were assessed of their memory and patients who did not complain of vascular pain were excluded from data analysis.

The dosage of midazolam was determined using the modified Dixon up-down method.12 A dose of 0.03 mg/kg of midazolam was administered to the first patient in each age group and if memories of injection pain remained, the dosage was increased by 0.01 mg/kg for the second patient, and then if memories were erased, the dosage was decreased by 0.01 mg/kg. The maximum dose of midazolam was set at 0.08 mg/kg, as in Japan, the maximum dose of midazolam as a single bolus administration is 5 mg. In each age group, this process was repeated until 15th crossover points,13 where all independent pairs of patients manifested a crossover from residual memories to memory loss or the reverse, were obtained. In addition, we assessed cutoff values for RSS to erase memory of injection pain using a receiver operating characteristic (ROC) curve.

Throughout the sedation, heart rate, oxygen saturation, and arterial blood pressure were monitored and supplemental oxygen (3 L/min via a nasal cannula) was administered.

Statistical Analysis

In a pilot study, approximately 40% of patients complained of propofol vascular pain on injection in each age group (each group n = 10). Estimated sample size was calculated based on the results of this pilot study. It was determined that we needed approximately 60 patients in order to get the 15th crossover points from the 40% of patients who complained of propofol vascular pain in each age group.

Logistic regression analysis was used for statistical processing to compare each age group and calculations of effective dosage of midazolam in 95% of each group (ED95). A P value of <.05 was considered to indicate statistical significance. We also conducted an assessment using an ROC curve to investigate cutoff values for the level of sedation required to erase memories of propofol vascular pain on injection.

RESULTS

A flow diagram of the conduct of the study is shown in Figure 1. Of the 261 patients who were initially assessed, 246 patients were allocated to 4 groups according to their age, and 102 patients successfully completed the study without any complication.

Figure 1.

Figure 1

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The flow diagram of this study.

Table 2 shows demographic characteristics of the patients who were analyzed. There were no significant differences in sex, height, or weight among the 4 groups.

Table 2.

Patient Demographics*

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Table 3 shows the presence or absence of pain at the time of propofol injection. The numbers of patients who complained of pain were 28 (for patients in their 30s), 28 (for patients in their 40s), 20 (for patients in their 50s), and 26 (for patients in their 60s).

Table 3.

Number of Patients Who Complained of Presence or Absence of Pain at the Time of Propofol Injection

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Figures 2 through 5 show the consecutive dose of midazolam required to erase the memory of injection pain for each age group according to the up-down method.

Figure 2.

Figure 2

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The consecutive dose of midazolam according to the up-down method for patients in their 30s. The number of patients required to get the 15th crossover point (•→○ or ○→•) was 28. If memories of injection pain remained (•), the dosage was increased by 0.01 mg/kg for the next patient, and then if memories were erased (○), the dosage was decreased by 0.01 mg/kg.

Figure 5.

Figure 5

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The consecutive dose of midazolam according to the up-down method for patients in their 60s. The number of patients that was required to get the 15th crossover point (•→○ or ○→•) was 26. If memories of injection pain remained (•), the dosage was increased by 0.01 mg/kg for the next patient, and then if memories were erased (○), the dosage was decreased by 0.01 mg/kg.

Figure 3.

Figure 3

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The consecutive dose of midazolam according to the up-down method for patients in their 40s. The number of patients that was required to get the 15th crossover point (•→○ or ○→•) was 28. If memories of injection pain remained (•), the dosage was increased by 0.01 mg/kg for the next patient, and then if memories were erased (○), the dosage was decreased by 0.01 mg/kg.

Figure 4.

Figure 4

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The consecutive dose of midazolam according to the up-down method for patients in their 50s. The number of patients that was required to get the 15th crossover point (•→○ or ○→•) was 20. If memories of injection pain remained (•), the dosage was increased by 0.01 mg/kg for the next patient, and then if memories were erased (○), the dosage was decreased by 0.01 mg/kg.

The predictive ED95 of midazolam (dose mg/kg [95% CI]) required to erase the memory of injection pain calculated by the logistic regression analysis was 0.061 (0.047–0.304) mg/kg for patients in their 30s, 0.049 (0.038–0.163) mg/kg for patients in their 40s, 0.033 (0.028–0.067) mg/kg for patients in their 50s, and 0.033 (0.027–0.085) mg/kg for patients in their 60s (Figure 6). The amount of midazolam required to erase the memory of propofol injection pain demonstrated a downward trend with age, although there were no significant differences among the 4 groups (Table 4). Figure 7 shows the ROC curve produced by RSS at the time of propofol injection as independent variable and the presence or absence of memory of injection pain as the outcome based on data from all patients. The area under the curve (AUC) was 0.31, which shows that RSS was not a reliable predictor of amnesia.

Figure 6.

Figure 6

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Effective dosage of midazolam in 95% of each age group (ED95) required to erase the memory of injection pain calculated by logistic regression analysis. ED95 was 0.061 (95% CI, 0.047–0.304) mg/kg in patients in their 30s, 0.049 (95% CI, 0.038–0.163) mg/kg in patients in their 40s, 0.033 (95% CI, 0.028–0.067) mg/kg in patients in their 50s, and 0.033 (95% CI, 0.027–0.085) mg/kg in patients in their 60s. The left end of the graph indicates the lower end of 95% CI and the right end indicates the upper end of 95% CI. The amount of midazolam required to erase the memory of injection pain demonstrated a downward trend with age, although there were no significant differences among the 4 groups.

Table 4.

The Results of Logistic Analysis*

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Figure 7.

Figure 7

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The receiver operating characteristic (ROC) curve produced by RSS. The area under the curve (AUC) was 0.31. It is indicated by the gray zone, which shows that RSS was not a reliable predictor of amnesia.

After the administration of midazolam, oxygen saturation transiently dropped below 95% in 1 patient in the 40s, 1 patient in the 50s, and 3 patients in the 60s; however, this reduction was immediately improved in all patients by asking them to take a deep breath. All patients responded appropriately. There were no serious complications during the sedation.

DISCUSSION

Vascular pain at the time of propofol injection is a side effect associated with anesthesia that should be avoided.14 An explanation of vascular pain that occurs at the time of propofol injection should be given during the preanesthetic evaluation to minimize patient anxiety. Because erasing the memory of pain at the time of injection may prevent interference with the next anesthetic encounter for the patient in question or prevent communication of this adverse event with other patients, it is considered highly significant.

Memories typically consist of the acquisition, retention, and reproduction of information and are classified into short-term memories,15 where information is retained for less than 1 hour, and long-term memories, where information is retained for longer than 1 hour. Short-term memory is thought to be necessary in the acquisition of long-term memories.16

A previous study performed using intravenously administered midazolam (0.01, 0.02, 0.04, and 0.08 mg/kg) in order to erase the memory of lumbar puncture pain reported that short-term memories could be suppressed in a dose-dependent manner up to 20 minutes after administration of midazolam.17 This suggested that if we would like to prohibit the acquisition of an unpleasant memory, the unpleasant action should take place within 20 minutes of the administration of midazolam. In our study, we started administering propofol 3 minutes after administering midazolam. Therefore, our method had a reasonable likelihood of prohibiting the acquisition of the unpleasant memory of propofol vascular pain on injection.

In the present study, the incidence of pain of propofol injection was lower than has been previously reported. The incidence of pain on propofol injection is estimated to be around 70% in the setting of general anesthesia.4 On the other hand, Kwon et al18 reported that the intensity of injection pain appeared to be relatively mild during intravenous sedation for upper gastrointestinal endoscopy. We also had the same impression as Kwon et al18 during intravenous sedation for dental procedures. Although the reason for this difference is not yet understood, the rate and dose of propofol administration may be a determining factor. Picard and Tramèr4 determined from 56 randomized controlled trials during general anesthesia that the rate of propofol administration (mean rate 6 mg/s; range, 0.125–20 mg/s) had no impact on the incidence of pain. However, because the induction of general anesthesia requires a deeper level of sedation than that of intravenous sedation, a larger dose of propofol must be injected rapidly. In the present study, propofol was injected at a rate of approximately 0.05 mg/s and the initial propofol dose was so small that the incidence and intensity of injection pain would be expected to be lower and milder.

Midazolam has a strong anterograde amnesic effect as well as a hypnotic effect. In the present study, age-adjusted doses of midazolam (ED95) required to erase the memory of injection pain were determined by logistic regression analysis and declined with increasing patient age. Bell et al19 also found a relatively linear decrease in midazolam required for sedation for upper gastrointestinal endoscopy with age. Jacobs et al10 reported that the steady-state plasma midazolam concentration at which 50% of patients would be expected not to respond to verbal command decreased with age because of increased pharmacodynamics sensitivity. Our results also reflect the effects of age on the amnestic effect of midazolam.

Although Nagahama et al17,20 have reported that a small bolus administration of midazolam (0.03 or 0.06 mg/kg) provided enough amnesia and sedation without any adverse effects for spinal anesthesia, no regard was given to the effects of aging on midazolam dose. Boku et al13 measured doses of midazolam required for loss of memory during lumbar spinal puncture in 50% of patients (0.043 mg/kg for patients in their 50s, 0.035 mg/kg for patients in their 60s, and 0.026 mg/kg for patients in their 70s) and concluded that aging increased sensitivity to the amnestic effects of midazolam. This report supports our result that the ED95 of midazolam decreases with age.

In the present study, we evaluated RSS for determining amnesia for propofol injection pain by calculating the AUC in ROC analysis in distinguishing between presence and absence of vascular pain. The calculated AUC was only 0.31 and the optimal cutoff value was not obtained. The calculated AUC of 0.31 means low correlation accuracy. Therefore, it is unpredictable to use RSS as an indicator of amnesia of propofol vascular pain. According to the study by Matsuki et al,21 a large distribution of bispectral index (BIS) value was seen within each sedation level on the RSS, with BIS values overlapping each other. There was such a wide range in sedation level in each RSS that we could not get an accurate cutoff value of RSS. On the other hand, there are some reports of a good relationship between amnesia and BIS value. Glass et al22 reported that 50% of healthy volunteers demonstrated a complete lack of recall at BIS values ranging from 84 to 86. Nakasuji et al23 recommended a BIS value below 90 to get amnesia of pain during lumbar epidural puncture with midazolam. The BIS value may be superior to the RSS for evaluating level of sedation and may enable anesthesiologists to predict amnesia during propofol injection.

Side effects associated with administration of midazolam include respiratory depression and oversedation. Although 4 patients experienced a transient decrease in oxygen saturation following administration of midazolam, it was improved quickly by arousal of the patient. No patients in any of the age groups experienced oversedation as a result of midazolam administration. The combination technique of midazolam and propofol has some advantages. Midazolam is reported to exert a synergistic effect when coadministered with propofol,24 which is associated with a high degree of patient comfort and rapid recovery time.8 A combined sedation regimen may be superior to sedation with propofol alone in terms of recovery, side effects, and costs because of a possibly lower total amount of propofol needed. However, Fanti et al25 reported that premedication with a low dose of midazolam does not reduce the total amount of propofol administered.25 However, Seifert et al26 reported that sedation with propofol and midazolam required a lower total dose of propofol, but otherwise has no superior sedation efficacy and is associated with a slower postprocedure recovery than sedation with propofol alone.

Future studies should evaluate the presence or absence of memory of propofol vascular pain on injection using BIS values instead of RSS for conscious sedation.

CONCLUSIONS

Although there were no significant differences in the ED95 of midazolam required to erase the memory of propofol vascular pain on injection, we demonstrated a downward trend in dosage with age (0.061 mg/kg in patients in their 30s, 0.049 mg/kg in patients in their 40s, 0.033 mg/kg in patients in their 50s, and 0.033 mg/kg in patients in their 60s). It was not possible to predict the amnesia of injection pain from the sedation level assessed by RSS.

ACKNOWLEDGMENT

This study was funded solely by department funds.

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