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Drug Interactions: Volatile Anesthetics and Opioids
Drug Interactions: Volatile Anesthetics and Opioids Peter S.A. Glass, MB, ChB, FFA (SA),* Tong J. Gan, MD,† Scott Howell, MD,† Brian Ginsberg, MD* Department of Anesthesiology, Duke University Medical Center, Durham, NC.
Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (ie, within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided. © 1997 by Elsevier Science Inc. Keywords: Amnesia; analgesia; anesthesia, intravenous; anesthetics, volatile: pharmacodynamic, pharmacokinetic interactions; drug interactions; fentanyl; hypnosis; isoflurane; opioids; propofol; remifentanil.
*Associate Professor †Assistant Professor Address correspondence to Dr. Glass at the Department of Anesthesiology, Duke University Medical Center, P.O. Box 3094, Durham, NC 27710, USA. Received for publication March 19, 1997; revised manuscript accepted for publication April 22, 1997.
Anesthesia consists of hypnosis, analgesia, and amnesia. As yet, there is no single intravenous (IV) anesthetic drug that can effectively and safely provide all of these three components of anesthesia. Thus, to provide the anesthetic state, usually two or more drugs are combined. It is well known that one drug may readily alter the disposition (pharmacokinetics) of a second drug. In addition, because the anesthetic state may be produced by drugs acting at a variety of receptor sites, it is not unexpected that their resultant combined effect (pharmacodynamics) will produce complex interactions. The interaction between two volatile anesthetics has been shown to be simply additive; that is, their combined effect is the result of adding their individual effects.1 However, because of both the pharmacokinetic and pharmacodynamic interactions, when combining IV drugs with volatile anesthetic drugs, this simple additive effect is unusual, and a more complex interaction is normally observed. A pharmacodynamic interaction implies a change in the observed effect when one drug is combined with another, compared with their effect when given alone, and this change in the observed effect is not a result of changes in the drugs’ concentration in the biophase (effect) site. Thus, pharmacodynamic interactions exclude interactions occurring as a result of one drug altering the pharmacokinetics of the second drug. Pharmacodynamic interactions occur as a result of several mechanisms, most of which are presently ill understood.2,3 At the cellular level, one drug may enhance the binding of a second drug to its receptor or conversely inhibit its binding (eg, agonist, antagonist). A drug also may alter the intracellular signal transduction pathway of another drug (eg, the
Journal of Clinical Anesthesia 9:18S–22S, 1997 © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0952-8180/97/$17.00 PII S0952-8180(97)00122-0
Volatile anesthetics and opioids: Glass et al.
potentiation of the arrhythmogenic effects of beta-agonists by volatile anesthetics by both increasing adenyl cyclase activity, or the increased minimum alveolar concentration (MAC) in alcoholics due to development of tolerance of the GABAergic receptor), or one drug may effect the uptake or production of neurotransmitters whose release is altered by the second drug (eg, reversal of neuromuscular blockers by anticholinesterases). A pharmacodynamic interaction also may occur as a result of two drugs acting on two separate receptor systems, but whose final common pathway either at the cellular or subcellular levels is similar. This later mechanism is probably the most common cause for the pharmacodynamic drug interactions seen between drugs used to provide anesthesia. To establish the concentration of a volatile anesthetic that provides adequate anesthesia, the end-tidal concentration that is in equilibrium with its effect site and will inhibit movement in 50% of patients at skin incision is used (ie, MAC). To establish the interaction between volatile anesthetics and opioids, the reduction in MAC can be utilized. When performing such studies, it is important that both the volatile anesthetic and the opioid are maintained at stable concentrations and have equilibrated with their effect site. For the volatile anesthetic, this is readily achieved using a calibrated vaporizer. For the opioid, computer assisted continuous infusion (CACI) or similar target-controlled delivery devices are used to maintain constant opioid concentration.4 Probably the most commonly used combination of anesthetics is isoflurane and fentanyl. McEwan et al.5 recently demonstrated that the MAC of isoflurane is reduced markedly by low opioid concentrations (Figure 1). A 50% MAC reduction was achieved by 1.7 ng/ml (fentanyl-loading dose of 4 mg/kg followed by 1.75 mg/kg/hr). The minimum effective analgesic concentration of fentanyl is 0.6 ng/ml, so that the steepest reduction in MAC occurs within the analgesic concentration range of fentanyl (ie, 0.5 to 2 ng/ml).6 Clinically significant respiratory depression may occur with plasma fentanyl concentrations above 2 ng/ml. This study by McEwan et al. also demonstrated that beyond 5 ng/ml a plateau or ceiling effect is seen with a maximum MAC reduction of approximately 80%. The maximum reduction in isoflurane was to a concentration of 60.3%, close to the MAC awake for isoflurane.7 Alfentanil,8 sufentanil,9 and remifentanil10 produce similar reductions in isoflurane MAC, with an initial steep reduction at lower concentrations and a plateau effect at higher concentrations. The concentration producing a 50% reduction of the MAC of isoflurane also provides a means of determining equipotency (in the concentration domain) between the opiates thus far tested (Table 1). Remifentanil is a new esterase metabolized opioid.11–13 The MAC reduction of isoflurane by remifentanil has recently been published and is illustrated in Figure 2.10 The results of this drug interaction are identical to those with the other opioids thus far tested. Again, even with these very high concentrations (.30 ng/ml), a ceiling effect was still observed, with the ceiling at an isoflurane concentration of 0.2% to 0.3%.
Figure 1. The interaction between fentanyl and isoflurane. The solid line represents the concentration of the two drugs that will prevent movement at skin incision in 50% of patients. Reproduced with permission from McEwan A, Smith C, Goodman D, Smith LR, Glass PS: Anesthesiology 1993;78: 864 –9.
From the above, it would appear that to provide an adequate anesthetic, a minimal concentration of the volatile anesthetic is required to ensure loss of consciousness (ie, an end-tidal concentration above MAC awake). Of interest is the recent introduction and Food and Drug Administration approval of the bispectral monitor. The bispectral index has been shown to provide a very strong correlation between increasing sedation and loss of consciousness14 and, thus, may help clinicians titrate the Table 1. The Relative Potencies of the Potent m-Specific Opioid Agonists Based on their Ability to Reduce the Minimum Alveolar Concentration (MAC) of Isoflurane by 50%
Opioid Fentanyl Sufentanil Alfentanil Remifentanil
Plasma Concentration (ng/ml) Resulting in 50% MAC Reduction of Isoflurane 1.67 0.14 28.8* 1.37‡
Calculated Potency 1 12 1/16 (61/25)† 1.2
Reproduced with permission from Brunner MD, Braithwaite P, Jhaveri R, et al: Br J Anaesth 1994;72:42– 6. *The 50% MAC reduction of isoflurane by alfentanil was determined following induction of anesthesia with thiopental and, thus, underestimates the alfentanil concentration. †The potency in parentheses is that calculated for alfentanil when corrected for the presence of thiopental. ‡Remifentanil was measured as the whole blood concentration. J. Clin. Anesth., vol. 9, September 1997
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Figure 2. The reduction in isoflurane concentration to prevent movement at skin incision in 50% of patients by increasing measured remifentanil whole blood concentrations. F 5 a patient who moved, and S 5 a patient who did not move. The solid line is the logistic regression solution for a patient aged 40 years. The three patients not receiving any isoflurane are illustrated in the figure, but are not used in determining the logistic regression line. Reprinted with permission from Lang E, Kapila A, Shlugman D, et al: Anesthesiology 1996;85:721– 8.10
volatile anesthetic to loss of consciousness. The above studies on the interaction of opioids with volatile anesthetics also demonstrate that there is very little advantage in administering the opioid to higher concentrations once the ceiling effect is reached. For fentanyl and remifentanil, this is a concentration of approximately 5 ng/ml, for alfentanil 400 ng/ml and for sufentanil 0.5 ng/ml. However, when administering such high opioid concentrations, recovery from anesthesia and return of spontaneous ventilation may be markedly delayed. Thus, the ideal combination of opioid plus volatile anesthetic is that which provides adequate intraoperative anesthesia and allows for the most rapid recovery. Because the dose (concentration) of the opioid markedly affects the amount of volatile anesthetic required to provide adequate anesthesia, recovery from anesthesia will depend on the amount of opioid and volatile anesthetic administered, the rate of decrease of both drugs, and the concentration at which awakening/spontaneous ventilation occurs. Our understanding of the pharmacokinetic processes that determine the recovery from drug effect recently have also been more clearly defined.15,16 The concentration of a drug in the plasma and the biophase is dependent on those processes that add drug to the body and on the disposition of drug within the body. When the administration of drug to the body is terminated, the concentration 20S
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of the drug in the plasma (and biophase) will decrease due to both the irreversible elimination of drug from the body and the redistribution of drug from the plasma to peripheral tissues. Conventional wisdom has been that the elimination half-life of the drug represents the measure of how rapidly recovery from drug occurs. The elimination half-life represents the terminal clearance of the drug and does not incorporate any redistribution of drug and, thus, clearly does not provide any quantitative measure of how long it will take for the drug to decrease by 50%. To provide an estimation of the time for recovery to occur with IV anesthetics, the concept of “context-sensitive halftime” has been proposed and represents the time required for the plasma concentration of a drug to decrease by 50% (for an infusion designed to maintain a constant concentration) for any given duration of the infusion.15 The context-sensitive half-times for the opioids is shown in Figure 3. It is noted in Figure 3 that the “context-sensitive half-time” can vary markedly according to the duration of the infusion: the longer the duration of infusion, the longer the time required for a 50% decrease. The actual percent decrease required at the termination of the procedure to provide awakening and adequate spontaneous ventilation varies according to the dose of opioid administered during the anesthetic. For example, if fentanyl is administered to a concentration of 2 ng/ml (loading dose 6 mg/kg followed by 2 mg/kg/hr), then only a
Volatile anesthetics and opioids: Glass et al.
Table 2.
Manual Opioid Infusion Schemes
Drug Fentanyl Fentanyl Alfentanil Alfentanil Sufentanil Sufentanil Remifentanil Remifentanil
Target Plasma Concentration (ng/ml)
Bolus (mg/kg)
Infusion Rate (mg/kg/min)
1 4 40 160 0.15 0.50 1 5–15
3 10 20 80* 0.15 0.50 0.25 1*
0.020 0.070 0.25 1.00 0.003 0.010 0.025 0.2–1.0
*Remifentanil and alfentanil bolus should given as a rapid infusion over 1–2 minutes.
Figure 3. Various context-sensitive decrement times for alfentanil, fentanyl, sufentanil, and remifentanil. Note the marked difference in decrement time according to the percent decrease in concentration that is required. Also note that, for remifentanil, the decrement time is virtually time independent, and even for an 80% decrease, only requires 12 minutes.
30% decrease will be required for adequate spontaneous ventilation. In a similar vein, simulations demonstrate that the time for, for example, 25%, 50%, or 75% decrease in plasma drug concentration is not linear (ie, a 25% decrease may take 5 minutes, a 50% decrease, 20 minutes, and a 75% decrease, 120 minutes). The context sensitive decrement times for several different percentage decreases for fentanyl, alfentanil, sufentanil, and remifentanil are shown in Figure 3. Vuyk et al.17 have performed studies to determine the interaction of alfentanil and propofol. The results for absence of movement at skin incision with the combination of these two drugs was very similar to that seen with isoflurane and opioids. Vuyk et al. took this interaction one step further in that they also observed the time to awakening at each of these combinations. Thus, not only were they able to define the optimal interaction for the prevention of a response to skin incision, but also the implication of these concentrations on recovery. The differences in recovery time according to which drug was used (ie, opioid or propofol) was well illustrated in this study. They showed that optimal recovery time occurs at an alfentanil concentration of approximately 80 ng/ml and a propofol concentration of approximately 3 mg/ml. When the concentration of propofol is increased, the concentration of alfentanil can be decreased, but the overall time to recovery increases. Similarly, as the concentration of alfentanil increases, the concentration of propofol can be decreased, but the time to recovery increases. When the concentration of alfentanil is increased beyond 80 ng/ml, even though the concentration of propofol can be reduced, there is a marked increase in the time to recovery. This increase in recovery time is much larger than the increase in recovery time that occurs when propofol is increased beyond 3 mg/ml. A propofol concentration of 3 mg/ml is just above its MAC awake value.17,18 The recovery profile (offset) of isoflurane is very similar to that of propofol. Thus, the clinical implication of the drug interaction between volatile anesthetics with either fentanyl, alfentanil, or sufentanil to provide anesthesia with the most rapid recovery is that the infusion regimen should provide an analgesic concentration of the opioid equivalent to 1 to 2 ng/ml of fentanyl (Table 2). The volatile J. Clin. Anesth., vol. 9, September 1997
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Volatile anesthetics and opioids: Glass et al.
anesthetic should be administered to the lowest concentration required to provide adequate anesthesia but to an absolute minimal end-tidal concentration equivalent to its MAC awake value (eg, for isoflurane a minimal concentration of 0.3%). If the patient demonstrates signs of inadequate anesthesia, it is preferable to increase the volatile anesthetic, because increasing these has less of an effect on prolonging wake-up time than increasing the opioid. Remifentanil, as previously stated, has an extremely short context-sensitive half-time of only 3 to 5 minutes and a context-sensitive 80% decrement time of 10 to 15 minutes irrespective of the duration of the infusion (Figure 3). This offset is quicker than that achieved with most of the volatile anesthetics; thus, with remifentanil the reverse is true. It is preferable to administer remifentanil to high opioid concentrations of 5 to 12 ng/ml (0.2 to 0.4 mg/kg/min), with just sufficient hypnotic given to ensure an unconscious patient. Also, if the patient responds, recovery time is less prolonged by increasing the remifentanil than by increasing the volatile anesthetic. However, it must be reiterated that, although for recovery it is preferable to increase remifentanil, the primary goal is to ensure that the patient is not conscious, and this effect is only achieved with the volatile anesthetic. In surgery in which immediate recovery is not required (eg, most cardiac procedures where postoperative ventilation is planned), and where surgical stimulation is profound, it is probably preferable to administer the opioid to its ceiling effect, thereby ablating any stress response to surgery. In studies in which remifentanil was administered at infusion rates of 1 mg/kg/min, plasma concentrations of epinephrine and norepinephrine (markers of the stress response) were unchanged or decreased from baseline at sternotomy. Thus, for cardiac anesthesia to minimize the stress response and yet provide fast track recovery, it is preferable to use a combination of volatile anesthetic and opioid rather than a pure high-dose opioid technique. In this instance, the opioid should be administered at a dose that will be just at the ceiling effect of the opioid (see above). In contrast, in instances in which the patient is expected to breathe spontaneously during surgery, the amount of opioid needs to be limited to avoid significant respiratory depression, and higher concentrations of the volatile anesthetic should be used to provide adequate anesthesia. Opioid concentrations should probably not exceed a fentanyl equivalent of 2 ng/ml (1 to 2 mg/kg loading dose followed by 1 mg/kg/hr). Anesthesia appears to consist of at least two components—analgesia and loss of consciousness. Combining an opioid with a volatile anesthetic achieves this objective. The interaction of volatile anesthetics and opioids in providing anesthesia is complex, but consistent. In addition, because two drugs are being used to provide anesthesia, recovery to an awake state is dependent on the decrease in concentration of both drugs. Thus, to provide adequate anesthesia and appropriate recovery, it is important to incorporate both the pharmacodynamic interac-
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tion that occurs between these drugs as well as their relative offset, as demonstrated by their context-sensitive decrement times.
References 1. Eger EI 2d, Saidman LJ, Brandstater B: Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:756 – 63. 2. Sear JW: Drug interactions and adverse reactions. In: Bailliere’s Clinical Anaesthesiol (Bailliere Tindall) 1991;5:703–33. 3. Mueller RA, Lundberg DB: Philosophy and theory. In: Mueller RA, Lundberg DBA (eds): Drug Interactions for Anesthesiology (2d ed), New York: Churchill Livingstone, 1992:3–19. 4. Glass PS, Shafer SL, Jacobs JR, Reves JG: Intravenous drug delivery systems. In: Miller RD, (ed.) Anesthesia 4th ed. New York: Churchill Livingstone, 1994:389 – 416. 5. McEwan AI, Smith C, Dyar O, Goodman D, Smith LR, Glass PS: Isoflurane minimum alveolar concentration reduction by fentanyl. Anesthesiology 1993;78:864 –9. 6. Lehmann KA, Heinrich C, van Heiss R: Balanced anesthesia and patient-controlled postoperative analgesia with fentanyl: minimum effective concentrations, accumulation and acute tolerance. Acta Anaesthesiol Belg 1988;39:11–23. 7. Dwyer R, Bennett HL, Eger EI 2d, Peterson N: Isoflurane anesthesia prevents unconscious learning. Anesth Analg 1992;75: 107–12. 8. Westmoreland CL, Sebel PS, Gropper A: Fentanyl or alfentanil decreases the minimal alveolar anesthetic concentration of isoflurane in surgical patients. Anesth Analg 1994;78:23– 8. 9. Brunner MD, Braithwaite P, Jhaveri R, et al: MAC reduction of isoflurane by sufentanil. Br J Anaesth 1994;72:42– 6. 10. Lang E, Kapila A, Shlugman D, Hoke JF, Sebel PS, Glass PS: Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996;85:721– 8. 11. Glass PS, Hardman D, Kamiyama Y, et al: Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993;77:1031– 40. 12. Westmoreland CL, Hoke JF, Sebel PS, Hug CC Jr, Muir KT: Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993;79:893–903. 13. Egan TD, Lemmens HJ, Fiset P, et al: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993;80:881–92. 14. Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P: Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane and alfentanil in normal volunteers. Anesthesiology, (in press). 15. Hughes MA, Glass PS, Jacobs JR: Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992;76:334 – 41. 16. Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 1991;74:53– 63. 17. Vuyk J, Lim T, Engbers FH, Burm AG, Vletter AA, Bovill JG: The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in female patients. Anesthesiology 1995; 83:8 –22. 18. Smith C, McEwan AI, Jhaveri R, et al: The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994;81:820 – 8.
Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (ie, within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided. © 1997 by Elsevier Science Inc. Keywords: Amnesia; analgesia; anesthesia, intravenous; anesthetics, volatile: pharmacodynamic, pharmacokinetic interactions; drug interactions; fentanyl; hypnosis; isoflurane; opioids; propofol; remifentanil.
*Associate Professor †Assistant Professor Address correspondence to Dr. Glass at the Department of Anesthesiology, Duke University Medical Center, P.O. Box 3094, Durham, NC 27710, USA. Received for publication March 19, 1997; revised manuscript accepted for publication April 22, 1997.
Anesthesia consists of hypnosis, analgesia, and amnesia. As yet, there is no single intravenous (IV) anesthetic drug that can effectively and safely provide all of these three components of anesthesia. Thus, to provide the anesthetic state, usually two or more drugs are combined. It is well known that one drug may readily alter the disposition (pharmacokinetics) of a second drug. In addition, because the anesthetic state may be produced by drugs acting at a variety of receptor sites, it is not unexpected that their resultant combined effect (pharmacodynamics) will produce complex interactions. The interaction between two volatile anesthetics has been shown to be simply additive; that is, their combined effect is the result of adding their individual effects.1 However, because of both the pharmacokinetic and pharmacodynamic interactions, when combining IV drugs with volatile anesthetic drugs, this simple additive effect is unusual, and a more complex interaction is normally observed. A pharmacodynamic interaction implies a change in the observed effect when one drug is combined with another, compared with their effect when given alone, and this change in the observed effect is not a result of changes in the drugs’ concentration in the biophase (effect) site. Thus, pharmacodynamic interactions exclude interactions occurring as a result of one drug altering the pharmacokinetics of the second drug. Pharmacodynamic interactions occur as a result of several mechanisms, most of which are presently ill understood.2,3 At the cellular level, one drug may enhance the binding of a second drug to its receptor or conversely inhibit its binding (eg, agonist, antagonist). A drug also may alter the intracellular signal transduction pathway of another drug (eg, the
Journal of Clinical Anesthesia 9:18S–22S, 1997 © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0952-8180/97/$17.00 PII S0952-8180(97)00122-0
Volatile anesthetics and opioids: Glass et al.
potentiation of the arrhythmogenic effects of beta-agonists by volatile anesthetics by both increasing adenyl cyclase activity, or the increased minimum alveolar concentration (MAC) in alcoholics due to development of tolerance of the GABAergic receptor), or one drug may effect the uptake or production of neurotransmitters whose release is altered by the second drug (eg, reversal of neuromuscular blockers by anticholinesterases). A pharmacodynamic interaction also may occur as a result of two drugs acting on two separate receptor systems, but whose final common pathway either at the cellular or subcellular levels is similar. This later mechanism is probably the most common cause for the pharmacodynamic drug interactions seen between drugs used to provide anesthesia. To establish the concentration of a volatile anesthetic that provides adequate anesthesia, the end-tidal concentration that is in equilibrium with its effect site and will inhibit movement in 50% of patients at skin incision is used (ie, MAC). To establish the interaction between volatile anesthetics and opioids, the reduction in MAC can be utilized. When performing such studies, it is important that both the volatile anesthetic and the opioid are maintained at stable concentrations and have equilibrated with their effect site. For the volatile anesthetic, this is readily achieved using a calibrated vaporizer. For the opioid, computer assisted continuous infusion (CACI) or similar target-controlled delivery devices are used to maintain constant opioid concentration.4 Probably the most commonly used combination of anesthetics is isoflurane and fentanyl. McEwan et al.5 recently demonstrated that the MAC of isoflurane is reduced markedly by low opioid concentrations (Figure 1). A 50% MAC reduction was achieved by 1.7 ng/ml (fentanyl-loading dose of 4 mg/kg followed by 1.75 mg/kg/hr). The minimum effective analgesic concentration of fentanyl is 0.6 ng/ml, so that the steepest reduction in MAC occurs within the analgesic concentration range of fentanyl (ie, 0.5 to 2 ng/ml).6 Clinically significant respiratory depression may occur with plasma fentanyl concentrations above 2 ng/ml. This study by McEwan et al. also demonstrated that beyond 5 ng/ml a plateau or ceiling effect is seen with a maximum MAC reduction of approximately 80%. The maximum reduction in isoflurane was to a concentration of 60.3%, close to the MAC awake for isoflurane.7 Alfentanil,8 sufentanil,9 and remifentanil10 produce similar reductions in isoflurane MAC, with an initial steep reduction at lower concentrations and a plateau effect at higher concentrations. The concentration producing a 50% reduction of the MAC of isoflurane also provides a means of determining equipotency (in the concentration domain) between the opiates thus far tested (Table 1). Remifentanil is a new esterase metabolized opioid.11–13 The MAC reduction of isoflurane by remifentanil has recently been published and is illustrated in Figure 2.10 The results of this drug interaction are identical to those with the other opioids thus far tested. Again, even with these very high concentrations (.30 ng/ml), a ceiling effect was still observed, with the ceiling at an isoflurane concentration of 0.2% to 0.3%.
Figure 1. The interaction between fentanyl and isoflurane. The solid line represents the concentration of the two drugs that will prevent movement at skin incision in 50% of patients. Reproduced with permission from McEwan A, Smith C, Goodman D, Smith LR, Glass PS: Anesthesiology 1993;78: 864 –9.
From the above, it would appear that to provide an adequate anesthetic, a minimal concentration of the volatile anesthetic is required to ensure loss of consciousness (ie, an end-tidal concentration above MAC awake). Of interest is the recent introduction and Food and Drug Administration approval of the bispectral monitor. The bispectral index has been shown to provide a very strong correlation between increasing sedation and loss of consciousness14 and, thus, may help clinicians titrate the Table 1. The Relative Potencies of the Potent m-Specific Opioid Agonists Based on their Ability to Reduce the Minimum Alveolar Concentration (MAC) of Isoflurane by 50%
Opioid Fentanyl Sufentanil Alfentanil Remifentanil
Plasma Concentration (ng/ml) Resulting in 50% MAC Reduction of Isoflurane 1.67 0.14 28.8* 1.37‡
Calculated Potency 1 12 1/16 (61/25)† 1.2
Reproduced with permission from Brunner MD, Braithwaite P, Jhaveri R, et al: Br J Anaesth 1994;72:42– 6. *The 50% MAC reduction of isoflurane by alfentanil was determined following induction of anesthesia with thiopental and, thus, underestimates the alfentanil concentration. †The potency in parentheses is that calculated for alfentanil when corrected for the presence of thiopental. ‡Remifentanil was measured as the whole blood concentration. J. Clin. Anesth., vol. 9, September 1997
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Figure 2. The reduction in isoflurane concentration to prevent movement at skin incision in 50% of patients by increasing measured remifentanil whole blood concentrations. F 5 a patient who moved, and S 5 a patient who did not move. The solid line is the logistic regression solution for a patient aged 40 years. The three patients not receiving any isoflurane are illustrated in the figure, but are not used in determining the logistic regression line. Reprinted with permission from Lang E, Kapila A, Shlugman D, et al: Anesthesiology 1996;85:721– 8.10
volatile anesthetic to loss of consciousness. The above studies on the interaction of opioids with volatile anesthetics also demonstrate that there is very little advantage in administering the opioid to higher concentrations once the ceiling effect is reached. For fentanyl and remifentanil, this is a concentration of approximately 5 ng/ml, for alfentanil 400 ng/ml and for sufentanil 0.5 ng/ml. However, when administering such high opioid concentrations, recovery from anesthesia and return of spontaneous ventilation may be markedly delayed. Thus, the ideal combination of opioid plus volatile anesthetic is that which provides adequate intraoperative anesthesia and allows for the most rapid recovery. Because the dose (concentration) of the opioid markedly affects the amount of volatile anesthetic required to provide adequate anesthesia, recovery from anesthesia will depend on the amount of opioid and volatile anesthetic administered, the rate of decrease of both drugs, and the concentration at which awakening/spontaneous ventilation occurs. Our understanding of the pharmacokinetic processes that determine the recovery from drug effect recently have also been more clearly defined.15,16 The concentration of a drug in the plasma and the biophase is dependent on those processes that add drug to the body and on the disposition of drug within the body. When the administration of drug to the body is terminated, the concentration 20S
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of the drug in the plasma (and biophase) will decrease due to both the irreversible elimination of drug from the body and the redistribution of drug from the plasma to peripheral tissues. Conventional wisdom has been that the elimination half-life of the drug represents the measure of how rapidly recovery from drug occurs. The elimination half-life represents the terminal clearance of the drug and does not incorporate any redistribution of drug and, thus, clearly does not provide any quantitative measure of how long it will take for the drug to decrease by 50%. To provide an estimation of the time for recovery to occur with IV anesthetics, the concept of “context-sensitive halftime” has been proposed and represents the time required for the plasma concentration of a drug to decrease by 50% (for an infusion designed to maintain a constant concentration) for any given duration of the infusion.15 The context-sensitive half-times for the opioids is shown in Figure 3. It is noted in Figure 3 that the “context-sensitive half-time” can vary markedly according to the duration of the infusion: the longer the duration of infusion, the longer the time required for a 50% decrease. The actual percent decrease required at the termination of the procedure to provide awakening and adequate spontaneous ventilation varies according to the dose of opioid administered during the anesthetic. For example, if fentanyl is administered to a concentration of 2 ng/ml (loading dose 6 mg/kg followed by 2 mg/kg/hr), then only a
Volatile anesthetics and opioids: Glass et al.
Table 2.
Manual Opioid Infusion Schemes
Drug Fentanyl Fentanyl Alfentanil Alfentanil Sufentanil Sufentanil Remifentanil Remifentanil
Target Plasma Concentration (ng/ml)
Bolus (mg/kg)
Infusion Rate (mg/kg/min)
1 4 40 160 0.15 0.50 1 5–15
3 10 20 80* 0.15 0.50 0.25 1*
0.020 0.070 0.25 1.00 0.003 0.010 0.025 0.2–1.0
*Remifentanil and alfentanil bolus should given as a rapid infusion over 1–2 minutes.
Figure 3. Various context-sensitive decrement times for alfentanil, fentanyl, sufentanil, and remifentanil. Note the marked difference in decrement time according to the percent decrease in concentration that is required. Also note that, for remifentanil, the decrement time is virtually time independent, and even for an 80% decrease, only requires 12 minutes.
30% decrease will be required for adequate spontaneous ventilation. In a similar vein, simulations demonstrate that the time for, for example, 25%, 50%, or 75% decrease in plasma drug concentration is not linear (ie, a 25% decrease may take 5 minutes, a 50% decrease, 20 minutes, and a 75% decrease, 120 minutes). The context sensitive decrement times for several different percentage decreases for fentanyl, alfentanil, sufentanil, and remifentanil are shown in Figure 3. Vuyk et al.17 have performed studies to determine the interaction of alfentanil and propofol. The results for absence of movement at skin incision with the combination of these two drugs was very similar to that seen with isoflurane and opioids. Vuyk et al. took this interaction one step further in that they also observed the time to awakening at each of these combinations. Thus, not only were they able to define the optimal interaction for the prevention of a response to skin incision, but also the implication of these concentrations on recovery. The differences in recovery time according to which drug was used (ie, opioid or propofol) was well illustrated in this study. They showed that optimal recovery time occurs at an alfentanil concentration of approximately 80 ng/ml and a propofol concentration of approximately 3 mg/ml. When the concentration of propofol is increased, the concentration of alfentanil can be decreased, but the overall time to recovery increases. Similarly, as the concentration of alfentanil increases, the concentration of propofol can be decreased, but the time to recovery increases. When the concentration of alfentanil is increased beyond 80 ng/ml, even though the concentration of propofol can be reduced, there is a marked increase in the time to recovery. This increase in recovery time is much larger than the increase in recovery time that occurs when propofol is increased beyond 3 mg/ml. A propofol concentration of 3 mg/ml is just above its MAC awake value.17,18 The recovery profile (offset) of isoflurane is very similar to that of propofol. Thus, the clinical implication of the drug interaction between volatile anesthetics with either fentanyl, alfentanil, or sufentanil to provide anesthesia with the most rapid recovery is that the infusion regimen should provide an analgesic concentration of the opioid equivalent to 1 to 2 ng/ml of fentanyl (Table 2). The volatile J. Clin. Anesth., vol. 9, September 1997
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anesthetic should be administered to the lowest concentration required to provide adequate anesthesia but to an absolute minimal end-tidal concentration equivalent to its MAC awake value (eg, for isoflurane a minimal concentration of 0.3%). If the patient demonstrates signs of inadequate anesthesia, it is preferable to increase the volatile anesthetic, because increasing these has less of an effect on prolonging wake-up time than increasing the opioid. Remifentanil, as previously stated, has an extremely short context-sensitive half-time of only 3 to 5 minutes and a context-sensitive 80% decrement time of 10 to 15 minutes irrespective of the duration of the infusion (Figure 3). This offset is quicker than that achieved with most of the volatile anesthetics; thus, with remifentanil the reverse is true. It is preferable to administer remifentanil to high opioid concentrations of 5 to 12 ng/ml (0.2 to 0.4 mg/kg/min), with just sufficient hypnotic given to ensure an unconscious patient. Also, if the patient responds, recovery time is less prolonged by increasing the remifentanil than by increasing the volatile anesthetic. However, it must be reiterated that, although for recovery it is preferable to increase remifentanil, the primary goal is to ensure that the patient is not conscious, and this effect is only achieved with the volatile anesthetic. In surgery in which immediate recovery is not required (eg, most cardiac procedures where postoperative ventilation is planned), and where surgical stimulation is profound, it is probably preferable to administer the opioid to its ceiling effect, thereby ablating any stress response to surgery. In studies in which remifentanil was administered at infusion rates of 1 mg/kg/min, plasma concentrations of epinephrine and norepinephrine (markers of the stress response) were unchanged or decreased from baseline at sternotomy. Thus, for cardiac anesthesia to minimize the stress response and yet provide fast track recovery, it is preferable to use a combination of volatile anesthetic and opioid rather than a pure high-dose opioid technique. In this instance, the opioid should be administered at a dose that will be just at the ceiling effect of the opioid (see above). In contrast, in instances in which the patient is expected to breathe spontaneously during surgery, the amount of opioid needs to be limited to avoid significant respiratory depression, and higher concentrations of the volatile anesthetic should be used to provide adequate anesthesia. Opioid concentrations should probably not exceed a fentanyl equivalent of 2 ng/ml (1 to 2 mg/kg loading dose followed by 1 mg/kg/hr). Anesthesia appears to consist of at least two components—analgesia and loss of consciousness. Combining an opioid with a volatile anesthetic achieves this objective. The interaction of volatile anesthetics and opioids in providing anesthesia is complex, but consistent. In addition, because two drugs are being used to provide anesthesia, recovery to an awake state is dependent on the decrease in concentration of both drugs. Thus, to provide adequate anesthesia and appropriate recovery, it is important to incorporate both the pharmacodynamic interac-
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tion that occurs between these drugs as well as their relative offset, as demonstrated by their context-sensitive decrement times.
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