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MIDAZOLAM ACTS SYNERGISTICALLY WITH FENTANYL FOR INDUCTION OF ANAESTHESIA
British Journal of Anaesthesia 1990; 64: 45-47
MIDAZOLAM ACTS SYNERGISTICALLY WITH FENTANYL FOR INDUCTION OF ANAESTHESIA
PATIENTS AND METHODS
SUMMARY The induction dose-response of midazolam was compared with the dose-response of its combination with fentanyl and with that of fentanyl alone in three groups of 60 unpremeditated, ASA physical status I or II women undergoing minor gynaecological surgery. The end-point of induction of anaesthesia was inability to open eyes upon command. Dose-response curves were determined for each group with a probit procedure and compared with an isobolographic analysis. Midazolam was found to act in synergism with fentanyl for induction of anaesthesia. Twenty-five percent of the ED^ of fentanyl was required in combination with 23% of the EDX for midazolam to achieve the ED^ of the combination. This degree of synergism may explain mutual potentiation between opioids and benzodiazepines reported previously. KEY WORDS Hypnotics benzodiazepine: midazolam. Analgesics: fentanyl. Induction: midazolam, fentanyl.
Following informed consent, we studied 180 women (age 20-50 yr, ASA I or II) admitted for minor gynaecological procedures. The Institutional Review Board approved the study design. Dose regimens used for the study are shown in table I. Drugs were injected in a constant volume of 10 ml over 15-20 s. Two separate injections were administered at an interval of 1 min and the end-point of response to verbal command (open your eyes!) was evaluated 3 min after the first injection. In the combination group, midazolam was injected first, and in the other two groups saline was used as placebo. The drugs were labelled only as first and second, so that the administering physician was unaware of their nature. However, studies of the single-drug groups were concluded first, so that the doses for the combination could be planned. TABLE I. Dotes of midazolam, fentanyl, or a combination of the two, given to groups of 10 patients each in the study Combination Midazolam (mg kg"') 0.07
Fentanyl (Mgkg"1)
Midazolam + Fentanyl (mgkg- 1 ) (Jig kg"1)
5.0
0.02 + 1.9
Combinations of benzodiazepines and opioids are 0.10 0.03+1.9 6.0 0.13 0.04+1.9 7.0 used for induction of anaesthesia and sedation. 0.19 0.06+1.9 7.5 However, life threatening complications have 0.26 0.08+1.9 8.0 been reported, indicating the importance of 0.37 0.10+1.9 8.5 understanding the nature of their interaction. Although mutual potentiation of effects by specific drugs from these two groups was reported in IZHAR BEN-SHLOMO, M.D., SHIFRA ZOHAR, M.D. (Department several studies [1-6], none has attempted to define of Obstetrics and Gynaecology); HALED ABD-EL-KHALIM, M.D., JOSEF EZRY, M.D., MARK TVERSKOY, M.D., PH.D. (Deif this represents synergism or additivity. partment of Anaesthesia); The ' Rebecca Sieff' Government The present study was designed to examine the Hospital, Safed, Israel 13100. Accepted for Publication: May specific interaction for induction of anaesthesia 24, 1989. between midazolam and fentanyl. Correspondence to I.B.S.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
I. BEN-SHLOMO, H. ABD-EL-KHALIM, J. EZRY, S. ZOHAR AND M. TVERSKOY
46
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
The groups were comparable with respect to age and weight. The ED60 calculated from the fentanyl dose-response curve (fig. 1) was 7.7 ug kg"1 (95% confidence limits 7.5-8.0 ug kg"1). The dose—response curve of midazolam was displaced to the left by combination of midazolam with fentanyl 1.9 ug kg"1 (25 % of the calculated EDM)
991 M+F M+S
t; 40
§3
Q05
U1 0.2 Q3 Midazolam (mgkjf1)
Q4 05
FIG. 2. Midazolam quantal dose-response curves for induction of anaesthesia with the addition of fentanyl 0.019 mg kg"1 (M + F) or saline (M + S). Each point represents a subgroup of 10 patients at the indicated dosage.
(fig. 2). ED60 values were 0.19 mg kg"1 (0.17-0.22) and 0.044 mg kg"1 (0.037-0.051) for midazolam alone and in combination, respectively. The difference between the slopes was not significant by this method of analysis. However, the midazolam-fentanyl isobologram for ED60 doses (fig. 3) reveals that the combined ED60 point deviates to the left of the additivity line, indicating synergism (P < 0.001). Comparing the sum of fractional doses given of each drug alone with that given in the combination further demonstrates this synergism. Twenty-three percent of midazolam EDS0 combined with 25 % of fentanyl ED60 (48 % of EDJO) were included in the ED M of the combination (calculated degree of synergism = 2.1).
99 8i
S S. t* ~ S uj
S
60 50 40 30 20
I4 CO
5
M+F
5 6 7 Fentanyl (ugkg"1)
8
9
FIG. 1. Fentanyl quantal dose-response curve for induction of anaesthesia. Each point represents a subgroup of 10 patients at the indicated dosage.
010 Midazolam (mgkg~1)
O2O
FIG. 3. ED M isobologram for the anaesthetic interaction of midazolam and fentanyl. The dashed line connects the ED M values of each drug. See text for details.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
The percentage of patients in each dose group unable to open the eyes was converted into a probit value and plotted against a logarithmic value for the respective dose. Dose-response curves were determined with the use of probit analysis [7]. To define the type of interaction between midazolam and fentanyl, the three calculated ED50 values were plotted as an isobologram [8]. Singledrug ED 60 points were placed on the dose coordinates, the combined ED60 point in the dose field then representing the doses of each drug that were contained in the ED60 of the combination. A straight line joining the single-drug points is termed the "additivity line" and deviation of the ED60 of a combination to its left indicates synergism. This deviation is measured perpendicular to the additivity line. The standard error of this distance was computed by the method of propagation of error [9]. Error estimates from the combined ED60 point, in addition to singledrug EDN, points, were used. An approximate t test used to test the assumption of additivity was obtained as the ratio of measured distance to its standard error [10].
MIDAZOLAM-FENTANYL ANAESTHETIC SYNERGISM DISCUSSION
REFERENCES 1. Boldy DAR, English JSC, Lang GS, Hoare AM. Sedation for endoscopy: A comparison between diazepam, and diazepam plus pethidine with naloxone reversal. British Journal of Anaesthesia 1984; 56: 1109-1112. 2. Miller DL, Wall RT. Fentanyl and diazepam for analgesia and sedation during radiologic special procedures. Radiology 1987; 162: 195-198. 3. Ayre-Smith G. Fentanyl and midazolam: An alternative for diazepam. Radiology 1987; 164: 285.
4. Gamble JAS, Kawar P, Dundee JW, Moore J, Briggs LP, Evaluation of midazolam as an intravenous induction agent. Anaesthesia 1981; 36: 868-873. 5. Dundee JW, Halliday NJ, McMurray TJ, Harper RW. Pretreatment with opioids. Anaesthesia 1986;41: 159-161. 6. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: Pharmacology and uses. Anesthesiology 1985; 62: 310-314. 7. Finney DJ. Probit Analysis, Chapter 3. London: University Press, 1952. 8. Loewe S. Isobols of dose-effect relation in the combination of nikethamide and phenobarbital. Journal of Pharmacology and Experimental Therapeutics 1955; 115:
6-15. 9. Ku HH. Notes on the use of propagation of error formulas. Journal of Research of the National Bureau of Standards
1966; 70: 263-273. 10. Kendall MGj Stuart A. The Advanced Theory of Statistics, Vol. 2. New York: Hafher, 1973; 44-^18. 11. Stanley TH, Webster LR. Anesthetic requirements and cardiovascular effects of fentanyl-oxygen anesthesia in men. Anesthesia and Analgesia 1978; 57: 411—416. 12. Reves JG, Kissin I, Smith LR. The effective dose of midazolam. Anesthesiology 1981; 55: 82. 13. Gross JB, Caldwell CB, Edwards MW. Induction doseresponse curves for midazolam and ketamine in premcdicated ASA class III and IV patients. Anesthesia and Analgesia 1985; 64: 795-800. 14. Tverskoy M, Fleyshman G, Ezry J, Bradley El jr, Kissin I. Midazolam-morphine sedative interaction in patients. Anesthesia and Analgesia 1989; 68: 282-285. 15. Silbert BS, Rosow CE, Keegan CR, Latta WB, Morphine AL, Moss J, Philbin DM. The effect of diazepam on induction of anesthesia with alfentanyl. Anesthesia and Analgesia 1986; 65: 71-77. 16. Kanto J, Sjovall S, Vuori A. Effect of different kinds of premedication on the induction properties of midazolam. British Journal of Anaesthesia 1982; 54: 507-511. 17. Bailey PL, Wibrink J, Zwanikken P, Pace NL, Stanley TH. Anesthetic induction with fentanyl. Anesthesia and Analgesia 1985; 64: 48-53. 18. Warning reemphasized in midazolam labeling. FDA Drug Bulletin, April 1987; 5. 19. Tverskoy M, Fleyshman G, Bradley EL jr, Kissin I. Midazolam-thiopental anesthetic interaction in patients. Anesthesia and Analgesia 1988; 67: 342-345. 20. Tverskoy M, Ben-Shlomo I, Ezry J, Finger J, Fleishman G. Midazolam acts synergistically with methohexitone for induction of anaesthesia. British Journal of Anaesthesia 1989; 63: 109-112.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
Fentanyl is used in anaesthesia mainly for its pronounced analgesic effect. Stanley and Webster [11] used fentanyl alone to achieve anaesthesia in all patients (the end-point was inability to open the eyes) and found that the average dose required was 11 ± 3 ug kg"1. Although derived by a different methodology, our dose-response curve agrees with this value. ED M value for midazolam calculated in this study (0.19 mg kg"1) is within the range of values described for this drug for the same end point [12, 13]. In a previous study we found that midazolam and morphine acted additively for sedation [14]. However, several studies report potentiation between opioids and benzodiazepines [15-17], leading in some cases to life-threatening complications such as respiratory and cardiac arrest [18]. The current study supports these qualitative reports and provides an estimation of the degree of synergism. We have no explanation for the different nature of the interactions between midazolam-morphine and midazolam-fentanyl. The difference between the two opioids may be attributable either to the differing end-points (anaesthesia vs sedation), or to their different structures, as differences in the degree of synergism between midazolam and agents from other groups are known to exist, for example with barbiturates [19, 20].
47
MIDAZOLAM ACTS SYNERGISTICALLY WITH FENTANYL FOR INDUCTION OF ANAESTHESIA
PATIENTS AND METHODS
SUMMARY The induction dose-response of midazolam was compared with the dose-response of its combination with fentanyl and with that of fentanyl alone in three groups of 60 unpremeditated, ASA physical status I or II women undergoing minor gynaecological surgery. The end-point of induction of anaesthesia was inability to open eyes upon command. Dose-response curves were determined for each group with a probit procedure and compared with an isobolographic analysis. Midazolam was found to act in synergism with fentanyl for induction of anaesthesia. Twenty-five percent of the ED^ of fentanyl was required in combination with 23% of the EDX for midazolam to achieve the ED^ of the combination. This degree of synergism may explain mutual potentiation between opioids and benzodiazepines reported previously. KEY WORDS Hypnotics benzodiazepine: midazolam. Analgesics: fentanyl. Induction: midazolam, fentanyl.
Following informed consent, we studied 180 women (age 20-50 yr, ASA I or II) admitted for minor gynaecological procedures. The Institutional Review Board approved the study design. Dose regimens used for the study are shown in table I. Drugs were injected in a constant volume of 10 ml over 15-20 s. Two separate injections were administered at an interval of 1 min and the end-point of response to verbal command (open your eyes!) was evaluated 3 min after the first injection. In the combination group, midazolam was injected first, and in the other two groups saline was used as placebo. The drugs were labelled only as first and second, so that the administering physician was unaware of their nature. However, studies of the single-drug groups were concluded first, so that the doses for the combination could be planned. TABLE I. Dotes of midazolam, fentanyl, or a combination of the two, given to groups of 10 patients each in the study Combination Midazolam (mg kg"') 0.07
Fentanyl (Mgkg"1)
Midazolam + Fentanyl (mgkg- 1 ) (Jig kg"1)
5.0
0.02 + 1.9
Combinations of benzodiazepines and opioids are 0.10 0.03+1.9 6.0 0.13 0.04+1.9 7.0 used for induction of anaesthesia and sedation. 0.19 0.06+1.9 7.5 However, life threatening complications have 0.26 0.08+1.9 8.0 been reported, indicating the importance of 0.37 0.10+1.9 8.5 understanding the nature of their interaction. Although mutual potentiation of effects by specific drugs from these two groups was reported in IZHAR BEN-SHLOMO, M.D., SHIFRA ZOHAR, M.D. (Department several studies [1-6], none has attempted to define of Obstetrics and Gynaecology); HALED ABD-EL-KHALIM, M.D., JOSEF EZRY, M.D., MARK TVERSKOY, M.D., PH.D. (Deif this represents synergism or additivity. partment of Anaesthesia); The ' Rebecca Sieff' Government The present study was designed to examine the Hospital, Safed, Israel 13100. Accepted for Publication: May specific interaction for induction of anaesthesia 24, 1989. between midazolam and fentanyl. Correspondence to I.B.S.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
I. BEN-SHLOMO, H. ABD-EL-KHALIM, J. EZRY, S. ZOHAR AND M. TVERSKOY
46
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
The groups were comparable with respect to age and weight. The ED60 calculated from the fentanyl dose-response curve (fig. 1) was 7.7 ug kg"1 (95% confidence limits 7.5-8.0 ug kg"1). The dose—response curve of midazolam was displaced to the left by combination of midazolam with fentanyl 1.9 ug kg"1 (25 % of the calculated EDM)
991 M+F M+S
t; 40
§3
Q05
U1 0.2 Q3 Midazolam (mgkjf1)
Q4 05
FIG. 2. Midazolam quantal dose-response curves for induction of anaesthesia with the addition of fentanyl 0.019 mg kg"1 (M + F) or saline (M + S). Each point represents a subgroup of 10 patients at the indicated dosage.
(fig. 2). ED60 values were 0.19 mg kg"1 (0.17-0.22) and 0.044 mg kg"1 (0.037-0.051) for midazolam alone and in combination, respectively. The difference between the slopes was not significant by this method of analysis. However, the midazolam-fentanyl isobologram for ED60 doses (fig. 3) reveals that the combined ED60 point deviates to the left of the additivity line, indicating synergism (P < 0.001). Comparing the sum of fractional doses given of each drug alone with that given in the combination further demonstrates this synergism. Twenty-three percent of midazolam EDS0 combined with 25 % of fentanyl ED60 (48 % of EDJO) were included in the ED M of the combination (calculated degree of synergism = 2.1).
99 8i
S S. t* ~ S uj
S
60 50 40 30 20
I4 CO
5
M+F
5 6 7 Fentanyl (ugkg"1)
8
9
FIG. 1. Fentanyl quantal dose-response curve for induction of anaesthesia. Each point represents a subgroup of 10 patients at the indicated dosage.
010 Midazolam (mgkg~1)
O2O
FIG. 3. ED M isobologram for the anaesthetic interaction of midazolam and fentanyl. The dashed line connects the ED M values of each drug. See text for details.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
The percentage of patients in each dose group unable to open the eyes was converted into a probit value and plotted against a logarithmic value for the respective dose. Dose-response curves were determined with the use of probit analysis [7]. To define the type of interaction between midazolam and fentanyl, the three calculated ED50 values were plotted as an isobologram [8]. Singledrug ED 60 points were placed on the dose coordinates, the combined ED60 point in the dose field then representing the doses of each drug that were contained in the ED60 of the combination. A straight line joining the single-drug points is termed the "additivity line" and deviation of the ED60 of a combination to its left indicates synergism. This deviation is measured perpendicular to the additivity line. The standard error of this distance was computed by the method of propagation of error [9]. Error estimates from the combined ED60 point, in addition to singledrug EDN, points, were used. An approximate t test used to test the assumption of additivity was obtained as the ratio of measured distance to its standard error [10].
MIDAZOLAM-FENTANYL ANAESTHETIC SYNERGISM DISCUSSION
REFERENCES 1. Boldy DAR, English JSC, Lang GS, Hoare AM. Sedation for endoscopy: A comparison between diazepam, and diazepam plus pethidine with naloxone reversal. British Journal of Anaesthesia 1984; 56: 1109-1112. 2. Miller DL, Wall RT. Fentanyl and diazepam for analgesia and sedation during radiologic special procedures. Radiology 1987; 162: 195-198. 3. Ayre-Smith G. Fentanyl and midazolam: An alternative for diazepam. Radiology 1987; 164: 285.
4. Gamble JAS, Kawar P, Dundee JW, Moore J, Briggs LP, Evaluation of midazolam as an intravenous induction agent. Anaesthesia 1981; 36: 868-873. 5. Dundee JW, Halliday NJ, McMurray TJ, Harper RW. Pretreatment with opioids. Anaesthesia 1986;41: 159-161. 6. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: Pharmacology and uses. Anesthesiology 1985; 62: 310-314. 7. Finney DJ. Probit Analysis, Chapter 3. London: University Press, 1952. 8. Loewe S. Isobols of dose-effect relation in the combination of nikethamide and phenobarbital. Journal of Pharmacology and Experimental Therapeutics 1955; 115:
6-15. 9. Ku HH. Notes on the use of propagation of error formulas. Journal of Research of the National Bureau of Standards
1966; 70: 263-273. 10. Kendall MGj Stuart A. The Advanced Theory of Statistics, Vol. 2. New York: Hafher, 1973; 44-^18. 11. Stanley TH, Webster LR. Anesthetic requirements and cardiovascular effects of fentanyl-oxygen anesthesia in men. Anesthesia and Analgesia 1978; 57: 411—416. 12. Reves JG, Kissin I, Smith LR. The effective dose of midazolam. Anesthesiology 1981; 55: 82. 13. Gross JB, Caldwell CB, Edwards MW. Induction doseresponse curves for midazolam and ketamine in premcdicated ASA class III and IV patients. Anesthesia and Analgesia 1985; 64: 795-800. 14. Tverskoy M, Fleyshman G, Ezry J, Bradley El jr, Kissin I. Midazolam-morphine sedative interaction in patients. Anesthesia and Analgesia 1989; 68: 282-285. 15. Silbert BS, Rosow CE, Keegan CR, Latta WB, Morphine AL, Moss J, Philbin DM. The effect of diazepam on induction of anesthesia with alfentanyl. Anesthesia and Analgesia 1986; 65: 71-77. 16. Kanto J, Sjovall S, Vuori A. Effect of different kinds of premedication on the induction properties of midazolam. British Journal of Anaesthesia 1982; 54: 507-511. 17. Bailey PL, Wibrink J, Zwanikken P, Pace NL, Stanley TH. Anesthetic induction with fentanyl. Anesthesia and Analgesia 1985; 64: 48-53. 18. Warning reemphasized in midazolam labeling. FDA Drug Bulletin, April 1987; 5. 19. Tverskoy M, Fleyshman G, Bradley EL jr, Kissin I. Midazolam-thiopental anesthetic interaction in patients. Anesthesia and Analgesia 1988; 67: 342-345. 20. Tverskoy M, Ben-Shlomo I, Ezry J, Finger J, Fleishman G. Midazolam acts synergistically with methohexitone for induction of anaesthesia. British Journal of Anaesthesia 1989; 63: 109-112.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on May 29, 2015
Fentanyl is used in anaesthesia mainly for its pronounced analgesic effect. Stanley and Webster [11] used fentanyl alone to achieve anaesthesia in all patients (the end-point was inability to open the eyes) and found that the average dose required was 11 ± 3 ug kg"1. Although derived by a different methodology, our dose-response curve agrees with this value. ED M value for midazolam calculated in this study (0.19 mg kg"1) is within the range of values described for this drug for the same end point [12, 13]. In a previous study we found that midazolam and morphine acted additively for sedation [14]. However, several studies report potentiation between opioids and benzodiazepines [15-17], leading in some cases to life-threatening complications such as respiratory and cardiac arrest [18]. The current study supports these qualitative reports and provides an estimation of the degree of synergism. We have no explanation for the different nature of the interactions between midazolam-morphine and midazolam-fentanyl. The difference between the two opioids may be attributable either to the differing end-points (anaesthesia vs sedation), or to their different structures, as differences in the degree of synergism between midazolam and agents from other groups are known to exist, for example with barbiturates [19, 20].
47