Secondary Logo

Journal Logo

Anesthetic Pharmacology: Review Article

Is Synergy the Rule? A Review of Anesthetic Interactions Producing Hypnosis and Immobility

Hendrickx, Jan F. A. MD, PhD*; Eger, Edmond I II MD; Sonner, James M. MD; Shafer, Steven L. MD

Author Information
doi: 10.1213/ane.0b013e31817b859e
  • Free

All general anesthetics produce two critical clinical end-points: hypnosis and immobility. Two or more drugs are often combined to achieve these end-points, producing interactions labeled as “synergistic,” “additive,” or “infra-additive” when their combined effect exceeds, equals, or is less than that of the sum of the effects of the individual drugs, respectively. Infra-additive is also referred to as “antagonistic.”

Synergistic interactions may be clinically useful because they allow the use of smaller doses of the individual drug and thus potentially decrease side effects. However, synergy can also be associated with adverse effects, such as profound ventilatory depression when midazolam is combined with fentanyl.1 Documentation of net benefit or risk with synergy is scant, with “… very few studies that demonstrate that a particular anesthetic drug interaction makes a meaningful improvement in cost, safety, or patient comfort.”2

Beyond clinical uses, drug interactions may provide insights into mechanisms of anesthetic action. Strictly additive interactions must occur when anesthetics act identically at a single site. Thus, strict additivity supports, but does not prove, a single site of action. Deviations from strict additivity suggest different sites of action.2–8

This review summarizes published interaction data for the end-points of hypnosis and immobility (particularly suppression of movement after “supramaximal” noxious stimulation). We will define common trends in drug interactions between different drug classes, and identify where new information is needed to guide clinical care and studies of mechanism of action.

METHODS

We searched the entire PubMed database for animal and human data describing anesthetic combinations producing hypnosis and immobility. We considered drugs that act on γ-aminobutyric acid type A (GABAA) receptors (propofol, etomidate, methohexital, thiopental, midazolam, and diazepam), an N-methyl-d-aspartate (NMDA) receptor antagonist (ketamine), α2 adrenoceptor agonists (dexmedetomidine, clonidine), μ-opioid receptors (morphine, fentanyl, sufentanil, alfentanil, and remifentanil), dopamine receptor antagonists (droperidol and metoclopramide), and a sodium channel blocker (lidocaine). We added inhaled anesthetics (halothane, enflurane, isoflurane, sevoflurane, desflurane, nitrous oxide [N2O], and xenon [Xe]), compounds whose site of action is less clear. Every pair of these drugs was entered as a search term, combined with each of these terms: interaction, additive, additivity, synergy, synergism, synergistic, antagonism, antagonistic, isobologram, isobolographic, regression, movement, minimum alveolar concentration (MAC), incision, awareness, hypnosis, and memory.

In humans, we defined hypnosis as loss of appropriate response to verbal command or as “syringe drop,” and immobility as suppression of movement in response to surgical incision or tetanic electrical pulses. In animals, we defined hypnosis as loss of the righting reflex, and immobility as suppression of movement in response to tail clamping or electrical stimulation.

We applied the definitions of addition, synergy, and infra-additivity used in the two companion studies.9,10 After determining the dose (or concentration) that abolishes the target response (e.g., movement) in 50% of subjects (ED50) for each of two paired drugs A and B individually, we analyzed the dose (or concentration) of both drugs given together that produced exactly the same effect. The doses of each of the two drugs, A and B, were normalized to the ED50 for each drug (EDEP,A and EDEP,B) when given alone. The normalized doses were summed:

A normalized sum <0.9 was defined as synergy. A normalized sum between 0.9 and 1.1 was defined as additivity. A normalized sum more than 1.1 was defined as infra-additivity or antagonism. Although such a sum supplies only one point on the isobologram, it is particularly attractive because that single number provides a simple and clear definition applicable to most published data. Using these criteria, we reanalyzed the data from all studies identified in our literature search. When full dose–response data for both drugs and their combination were published (an infrequent event), our reanalysis also applied response surface modeling.11 Raw data supplied by several investigators allowed a more accurate reanalysis. All analyses are available as a web supplement to this manuscript (available online at www.anesthesia-analgesia.org).

When one or both drugs could not produce the target response alone (i.e., a ceiling effect was found), but the drugs given together could produce the target response, this was considered synergy by definition. An example is the relationship between inhaled anesthetics and opioids. Opioids can reduce the MAC of inhaled anesthetics, but they cannot reduce it to 0. There is a ceiling on the interaction. The Appendix explains why a ceiling effect by definition demonstrates synergy.

Some data (e.g., measures of the time to loss of consciousness when using drug X with or without drug Y) did not permit assessment of the nature of the interaction, and we excluded these studies. We also excluded studies that only examined a single dose of either drug, because a single dose cannot imply the nature of an interaction (i.e., in the absence of a knowledge of the ED50 for the test compound). Studies of inhaled anesthetics provide an exception because the ED50 (MAC) for these drugs is known.

For our presentation of results, absence of a description of interactions of a particular compound with other study compounds indicates that no such interaction reports were found. Similarly, the absence of statements for results with animals or with humans indicates that no interpretable data were found.

RESULTS

The text below describes the interaction between individual drug pairs. An excel spreadsheet summarizing the detailed results by study is available as a web supplement (available at www.anesthesia-analgesia.org). Figure 1 presents the interaction grid between drugs in various drug classes for human and animal studies.

Figure 1.
Figure 1.:
Interaction grid summarizing the available data on drug interactions in humans and animals for hypnosis and immobility. Drugs are organized by pharmacological class. Gamma-aminobutyric acid (GABA) = GABA acting drugs (propofol, thiopental, methohexital, and etomidate); GABABDZ = agents acting at the benzodiazepine binding site (midazolam, diazepam); N-methyl-d-aspartate (NMDA) = NMDA receptor antagonist (ketamine); α2 = α2 adrenergic agonists (dexmetedomidine, clonidine); opioid = drugs acting at μ-opioid receptor (morphine, alfentanil, fentanyl, sufentanil, and remifentanil); dopamine = dopamine antagonists (droperidol, metoclopramide); Na+ channel = sodium channel blockers (lidocaine, bupivacaine); and anesthetic gases. The right upper half of the grid (above the thick diagonal) summarizes interactions for the end-point of immobility; the left lower half (below the thick diagonal) summarizes interactions for the end-point of hypnosis. Synergy is coded as green, additivity as gray, and infra-additivity as red. The number refers to the number of studies attesting to a particular interaction; if one study documents two interactions (e.g., isoflurane with both fentanyl and alfentanil), they are counted separately. Animal data carry the suffix “a” after the number of studies, human data have no suffix. *Reanalysis: propofol–ketamine interaction in humans is infra-additive for immobility.19 **Reanalysis: thiopental – midazolam interaction in humans is additive for hypnosis.37 ¶, ¶¶Reanalysis: ketamine–midazolam interaction in humans is infra-additive for hypnosis and additive for immobility.51 †Because the MAC of Xe in swine is uncertain, data in swine149,150 are not included (see Discussion). §Infra-additivity between desflurane and N2O has been suggested in a small subgroup of 18–30-yr old patients.139

One or Both Drugs Acting at the GABAA Receptor (But Not Necessarily at the Same Site on the Receptor)

Propofol

In humans, propofol and thiopental interact additively12,13 or synergistically14 for hypnosis, and synergistically for movement in response to noxious stimulation.12 Propofol and midazolam reportedly interact synergistically for hypnosis in humans,11,15–18 and where sufficient data were available, our reanalyses confirm some of these findings.11,15,16 Midazolam and propofol interact synergistically to produce immobility as indicated by a left shift in the dose–response curve15,16 more than 10% (since midazolam cannot produce immobility on its own, if the dose versus response relationship is left shifted by more than 10%, this is synergy by definition, as described in the Appendix). Propofol and ketamine reportedly interact additively in humans to produce hypnosis and immobility.19 On reanalysis, the interaction term for both hypnosis and immobility indicates infra-additivity, a finding significant for immobility (P = 0.02), but not hypnosis (P = 0.17). Propofol and clonidine appear to produce additivity for hypnosis in humans.20 In 11 of 13 studies, propofol and opioids produced hypnosis synergistically in humans (fentanyl,21 alfentanil,11,16,18,22,23 remifentanil24,25). Because fentanyl has a ceiling effect (i.e., in the absence of propofol no dose of fentanyl can exert a full hypnotic effect), the interaction in two studies26,27 is labeled “synergy by definition.” Two studies found additivity, one for fentanyl28 and one for sufentanil.29 Why these results differ from most results is unknown. For immobility, the 50% probability of a no-response isobole for the interaction of propofol with fentanyl19,26 and remifentanil30,31 bends towards the origin, demonstrating synergy. This is expected, of course, since no dose of opioid suppresses movement in all patients (i.e., the ability of opioids to produce immobility has a ceiling). In a study limited by muscle rigidity, the investigators interpreted the interaction of propofol with alfentanil16 as synergistic. These authors noted that interactions with drugs that are not full anesthetics (e.g., the ED50 of opioids, benzodiazepines cannot be defined for immobility) cannot have an isobologram applied to them to define the nature of their interactions. Therefore, the authors resorted to interpreting the shift in dose– response curves (shift and change in slope) to assess the nature of the interaction. As explained in the Methods section, these studies demonstrate synergy by definition. In the single available study on propofol and lidocaine's interaction, synergy was found for hypnosis in animals.32

The propofol–sevoflurane interaction was additive for hypnosis and immobility33 in humans. At 67% N2O or at least half of MAC, N2O decreased the propofol concentration that inhibited movement after skin incision in humans by 25% to 35%,34,35 indicating an infra-additive interaction.

Etomidate

In rats, etomidate is synergistic with morphine and with fentanyl for hypnosis and additive for suppression of movement from noxious stimulation. We would expect the interaction for suppression of movement to be “synergy by definition” because opioids cannot alone suppress movement, but data are insufficient to allow reanalysis.*

Methohexital

Methohexital interacts synergistically with midazolam for hypnosis in humans.36

Thiopental

Thiopental's interactions with propofol were described above. In humans37,38 and animals,39 thiopental and midazolam reportedly act synergistically for hypnosis. We confirmed synergy for one study in humans,38 but found additivity in another37 whereas the authors considered their findings a demonstration of synergy. The reason for the discrepancy is unclear. The limited effect of midazolam given alone, hampers studies of interaction on immobility, but a left shift in the thiopental dose–response relationship more than 10% (Appendix) is synergy by definition for immobility in humans.38 One study40 in humans described the interaction between thiopental and ketamine as additive both for hypnosis and immobility, but another study found infra-additivity for hypnosis.41 Reanalysis confirmed the findings of the latter study (infra-additivity, P < 0.001); raw data were unavailable for the former. Analgesic concentrations of fentanyl in humans do not affect the hypnotic concentration of thiopental, suggesting either no interaction (if one assumes that sedation and hypnosis are unrelated effects) or at most infra-additivity.42 Alfentanil decreases the dose of thiopental for hypnosis and immobility,43 but the nature of the interaction was not examined. In rats, thiopental and morphine or fentanyl interact synergistically for hypnosis44 and infra-additively for immobility.45 Droperidol has a ceiling in its ability to induce hypnosis, i.e., no dose of droperidol can induce full hypnotic drug effect.46 Since droperidol reduces the dose of thiopental for loss of consciousness by more than 10%,46 the interaction is synergistic by definition (Appendix). IM administration of lidocaine and bupivacaine decreases the dose of thiopental required to produce hypnosis in humans,47 but the nature of the interaction is unknown. In rats, the thiopental–lidocaine interaction is infra-additive for hypnosis.48 Thiopental decreases halothane MAC in rats, but with a ceiling according to the authors’ Figure 3.49 In humans, the interaction between N2O and thiopental appears to be infra-additive on MAC.50

Figure 3.
Figure 3.:
Drug B cannot cause the defined effect on its own. At least Δ units of drug A are required to produce the drug effect. Thus, drug B demonstrates a ceiling in its ability to produce the drug effect of interest.

Midazolam

The interactions of midazolam with propofol, methohexital, and thiopental are discussed in previous sections. The interaction between midazolam and ketamine in humans is reported as additive for hypnosis and infra-additive (no effect) for immobility.51 Reanalysis shows infra-additivity for hypnosis (P < 0.006) and additivity for immobility (P > 0.99). In rats, midazolam interacts synergistically with clonidine on hypnosis52 and synergistically with dexmedetomidine on both hypnosis and immobility.53 Opioids and midazolam interact synergistically to produce hypnosis in humans (fentanyl,54 alfentanil11,16,18,55) and animals (morphine56). Lidocaine increases the effect of midazolam on hypnosis in humans, but the nature of the interaction is unknown.57

Midazolam decreases the MAC of potent inhaled anesthetics in humans (halothane58,59) and animals (enflurane60). Again, the inability of midazolam to function as a full agonist by itself (i.e., a ceiling effect) combined with its reduction of the inhaled anesthetic concentration required for immobility demonstrates synergy by definition.

Diazepam

Diazepam interacts synergistically with dexmetedomidine61 and morphine on hypnosis61,62 in rats. In dogs, it decreases the amount of fentanyl that produces immobility, but the nature of the interaction is unclear.63 In rats, it produces an infra-additive interaction with fentanyl and morphine for immobility.64 The study in dogs used isoflurane MAC decreases to measure the interaction, whereas the study in rats may not have applied a supramaximal stimulus (400 g tail pressure).

Diazepam decreases the MAC of halothane in humans65,66 and animals,67 with only one study65 examining two diazepam doses instead of one. This last study suggests, within the limitations of exploring only two doses, that diazepam cannot function as a full agonist for immobility, again suggesting a ceiling effect and synergy by definition.

NMDA Receptor Antagonists—Ketamine

Ketamine's interactions with propofol, thiopental, and midazolam were described above. A study of ketamine and lidocaine interactions found synergy for hypnosis in mice.32 Ketamine decreases the MAC of halothane68,69 and enflurane70 in animals, with the isobolographic data bending towards the origin, indicating synergy.68,69 The study that explored doses of ketamine up to 100% MAC reduction (i.e., immobility with ketamine alone)70 found the best fit to the isobole was a log-linear relationship, one intrinsically curved towards the origin, demonstrating synergy. In dogs, ketamine clearly demonstrated synergy with isoflurane on MAC.71 Note that ketamine blocks more than NMDA receptors, perhaps explaining why ketamine alone can produce immobility, but MK-801, an NMDA antagonist that can completely block NMDA receptors, does not produce immobility by itself.72

α2-Adrenergic Agonists

Dexmetedomidine

Dexmedetomidine's interactions with propofol, midazolam, and diazepam were outlined above. Dexmedetomidine interacts synergistically with fentanyl to produce hypnosis in rats61 and immobility in dogs.73

In humans, dexmedetomidine decreases isoflurane and sevoflurane MAC by 35%–50%74,75 and 0%–17%,76 respectively. The type of interaction is unclear because of the lack of a full dose-response curve for dexmedetomidine.74–76 The concomitant use of alfentanil confounds the results of one study.74 In animals, dexmedetomidine decreases the MAC of potent inhaled anesthetics by 81%–100%,73,77–80 with the report by Vickery et al.77 showing synergy.

Clonidine

Studies of clonidine's interactions with propofol and midazolam were mentioned earlier. Although several studies describe interactions between opioids and clonidine for pain, no adequate studies examined the end-point of immobility. One study investigated the interaction of fentanyl and clonidine on hypnosis in animals. Alone, these two drugs did not provide hypnosis but did when combined,81 implying synergy by definition (the logical extension of the analysis in the Appendix for the case where neither drug can reach the given end-point).

Although several studies found that clonidine decreases MAC (immobility) and MACawake (hypnosis) of inhaled anesthetics, the nature of the interaction remains unclear because of the limited dose ranges used (1 or 2 doses only). Clonidine decreases MACawake for isoflurane (30%)82 and sevoflurane (17%–21%)83,84 in humans. Clonidine alone cannot produce immobility, at least at doses explored clinically, as demonstrated by a study finding that doubling the dose of clonidine did not further decrease sevoflurane MACawake in children.85 If there is a ceiling to clonidine's effect on MACawake, the ability of clonidine to reduce MACawake of inhaled anesthetics demonstrates synergy by definition. Clonidine decreases the MAC of isoflurane86 and sevoflurane83,84 in humans by 30% and 17%–34%, respectively; this decrease is linear for sevoflurane over the limited dose range (two doses only) studied.87 In animals, clonidine decreases the halothane MAC by 16%–48%,88–90 with one study showing no further MAC reduction over a four-fold range89 and another over a 100-fold dose range,90 again showing a ceiling effect, and synergy by definition.

μ Opioid Receptor

Numerous studies have examined the interactions of morphine and the opioids fentanyl, alfentanil, sufentanil, and remifentanil with other drugs. Interaction data with IV anesthetics were described above.

Morphine does not affect MACawake for halothane,91 isoflurane,92 and sevoflurane93 in humans, suggesting an infra-additive relationship. In humans, morphine decreases halothane MAC by an unknown interaction.94 However, unpublished data from one of us (EIE) indicates a ceiling effect of morphine on halothane MAC in humans, indicating synergy by definition. In animals, morphine decreases the MAC of potent inhaled anesthetics,95–102 an effect that often reaches a ceiling.96–98,101

The nature of the interaction between fentanyl and sevoflurane on hypnosis in humans remains unclear. Although fentanyl decreased the MACawake of sevoflurane in humans in two studies,103,104 it had no effect at lower doses in one103 and caused a dose reduction described as “parabolic without manifest ceiling” in the other.104 All human interaction data for opioids and potent inhaled anesthetics show a dose-dependent decrease of MAC with a ceiling effect,103–111 thus demonstrating synergy. This has been shown for fentanyl, alfentanil, sufentanil, and remifentanil with isoflurane,105,106,110,111 and for fentanyl with isoflurane,105,106 sevoflurane,104,107 and desflurane.108,109 In animals, the effect on MAC is less consistent, but most studies find a decrease in MAC,63,73,96,112–120 usually demonstrating that opioids cannot produce immobility in the absence of some inhaled anesthetic,96,113–119 again demonstrating a ceiling and synergy in the ability of opioids alone to suppress movement. One exception found no effect of alfentanil on halothane MAC in horses.121 Although N2O and Xe can prevent awareness in studies determining the ED50 for opioids for several clinical end-points, these studies reveal little about the nature of the interaction between N2O or Xe, as these studies examined one fixed end-tidal concentration of Xe or N2O.122–126

Dopamine Antagonists

Droperidol and Metaclopromide

The interaction of droperidol and metaclopromide with thiopental for hypnosis in humans is synergistic by definition (see above).46

Sodium Channel Blockers

Lidocaine

Interactions with propofol, thiopental, midazolam, and ketamine were described above. Lidocaine administration decreases the MAC of halothane,127,128 enflurane,129 and isoflurane130,131 in animals, an effect usually described as additive.128–131 However, these studies explored lidocaine concentrations <10 μg/mL, probably because of the risk of seizure, and no study demonstrated more than a 70% reduction in halothane MAC. This could represent either additivity or synergy, depending on the unknown (and possibly unknowable) concentration of lidocaine given alone that produces immobility. However, one paper described a ceiling of 50% in halothane MAC with lidocaine concentrations ranging from 12 to 20 μg/mL in dogs127 and another presented similar data for rats for cyclopropane, halothane, isoflurane, and o-difluorobenzene.132 This constitutes synergy by definition. This finding of synergy is not inconsistent with the other studies suggesting additivity, because only these latter studies investigated high doses of lidocaine in an attempt to identify whether lidocaine alone could produce immobility (i.e., could produce 100% reduction in MAC). In humans,127 70% N2O was used to ensure hypnosis in a study of the ED50 of lidocaine for suppression of movement on incision. However, we do not know the effect of lidocaine alone because of the limited dose-range of lidocaine applied. Thus this study did not define the nature of the interaction between lidocaine and N2O.

Inhaled Anesthetics

Studies describing interactions of inhaled anesthetics with IV anesthetics were described previously.

In rats, interactions between inhaled anesthetics are additive for MAC for halothane with isoflurane,133 desflurane, and sevoflurane10 and for isoflurane with sevoflurane.10 Most human data show an additive effect of N2O on MAC for potent inhaled anesthetics (halothane,94,134 enflurane,135 isoflurane,136,137 sevoflurane,107,138 and desflurane139). Infra-additivity has been suggested between desflurane and N2O in 18 to 30-year old patients (only 45% MAC reduction) from the previously mentioned desflurane study in which the overall results showed additivity,139 and in pediatric patients (only a 25% MAC reduction) in a study flawed by the use of historical controls for the O2 only group.140 In contrast to the human data, older animal data suggest that higher concentrations of N2O act infra-additively with enflurane,141,142 halothane,142 and isoflurane.142,143 Recent animal studies find additivity with N2O for all inhaled anesthetics tested (sevoflurane in lizards144 and sevoflurane and desflurane in rats),10 except for isoflurane [infra-additivity in rats].10 In humans, the interaction between N2O and isoflurane145 and sevoflurane145,146 on hypnosis is infra-additive. Interaction studies between Xe and volatile inhaled anesthetics find additivity for hypnosis (isoflurane and sevoflurane145) and immobility (halothane,147 sevoflurane148) in humans. Although the results in the last study might statistically deviate from additivity, the deviation is <10%, and thus by our definition is additive. Two studies in swine by the same group of investigators came to opposing conclusions for immobility, showing additivity with sevoflurane149 but infra-additivity with isoflurane.150 The companion report to this paper10 finds additivity for Xe with isoflurane, sevoflurane, and halothane in rats.

DISCUSSION

What Trends Do the Data Reveal?

The grid in Figure 1 reveals several underlying trends. Opioids act synergistically with both IV and inhaled anesthetics,11,16,18,19,22–27,30,31,44,54,61–63,73,81,96–98,101,112–120 with two exceptions. In humans, opioids do not affect the MACawake of inhaled anesthetics (i.e., they are infra-additive).91–93 In animals, they are additive* (abstract only) or infra-additive for suppression of movement when combined with GABA-enhancing drugs,45,64 a finding possibly attributable to use of low (pronociceptive) concentrations of IV thiopental,45 acute opioid tolerance,151 or inframaximal stimulus intensities.64

Synergy is common when drugs acting on GABAA receptors are combined with drugs acting on non-GABAA receptors, but there are exceptions to this rule. As mentioned in the previous paragraph, GABA-enhancing drugs are additive or infra-additive on immobility with opioids in animals. The interaction with GABAA-enhancing drugs is also additive to infra-additive with N2O and with ketamine (see next paragraph).

In animals, ketamine acts synergistically with inhaled anesthetics on movement68–70 and with lidocaine32 on hypnosis, yet does not show synergy with drugs acting on GABAA receptors in any study. The interaction between ketamine and GABAA agonists ranges from additivity19,20,40 to infra-additivity19,41,51 (on reanalysis). Plausible explanations include the presence of an active ketamine metabolite (the effects of which may be difficult to account for without measuring blood concentrations), indirect effects (orthosympathic stimulation), and the fact that the methods used tended to skew the data towards additivity [“additivity by default”—see companion paper by Shafer et al.9].

All combinations of potent inhaled anesthetics (halothane with isoflurane, desflurane, and sevoflurane or isoflurane with sevoflurane) are additive on MAC in rats.133 MAC for volatile anesthetics with N2O94,107,134–139,145,147,148 and Xe107,135–139,145,147,148 are usually additive in humans. The N2O/isoflurane interaction is infra-additive in rats,142 and this is the only exception to the general finding of additivity between inhaled drugs. Although the MAC of N2O in humans had been determined in 1982,152 older animal data on the interaction between N2O and volatile anesthetics had to be interpreted with caution because many of these studies estimated the MAC of N2O by extrapolation, possibly causing N2O MAC to be under-estimated and biasing the results towards infra-additivity.6 Nevertheless, when using hyperbaric conditions to determine the MAC of N2O, Russell and Graybeal143 confirmed the infra-additive nature of the isoflurane-N2O interaction, a finding corroborated in the companion paper.10 Studies in swine find additivity of MAC for the Xe/sevoflurane pair149 but infra-additivity for Xe/isoflurane.150 Again these results are difficult to interpret because the MAC for Xe in swine is unclear. In a subsequent study by the same authors, the MAC for Xe was found to be higher than previously estimated, but the MAC was determined using halothane MAC reduction assuming additivity for the halothane/Xe interaction.149,150,153 The companion report to this paper10 found additivity of MAC for Xe/isoflurane and Xe/sevoflurane pairs in rats, and for all potent inhaled anesthetic interactions tested (including pairs that were not part of our literature search), except for the combination of isoflurane with N2O where infra-additivity was found.10 Interestingly, N2O has significant NMDA antagonistic properties, and thus the failure to find synergy with isoflurane (which has more potent GABAA effects) parallels the lack of synergy observed with ketamine and IV hypnotics.

Interest in quantifying drug interactions and appropriate analysis methodology developed after 1980. This explains the limited data for older drugs like lidocaine, which is likely synergistic with inhaled anesthetics, as suggested by the demonstration of a ceiling effect,127 even though most studies examined modest doses and referred to the interaction as “additive.”128–131 Lidocaine has been shown to interact synergistically with cyclopropane.154 Some other older, but extensively used drug combinations, such as the opioid-droperidol combination to provide neuroleptanesthesia, have not been formally analyzed.

What Is Missing from Our Understanding of Drug Interactions

A study often provides interaction data for a single drug pair, and external validation (duplication or the use of a parallel drug pair) for many such studies is lacking. We compensated for this deficiency by combining data from drug pairs from the same drug classes (Fig. 1). Even this approach fails to cover interactions between certain drug classes. For other classes, only animal data are available, necessitating extrapolation from one species to another. There is a risk in such extrapolation since data from different species can produce conflicting results as illustrated by the different interaction between isoflurane and N2O on immobility in animals versus humans.

Only two studies investigated the interaction between volatile anesthetics and GABAA receptor-enhancing drugs: in animals, halothane, and thiopental are synergistic for immobility,49 whereas sevoflurane and propofol are additive for hypnosis and immobility in humans.33 Although both propofol and midazolam act on the GABAA receptor and additivity might therefore be expected, various evidence suggests that they affect different receptor sites.155–158 Propofol alone can produce immobility,23,25,26,31 whereas midazolam alone cannot completely obliterate movement to noxious stimulation.59,60 Thus, perhaps, the finding of synergy should not be surprising.

No human data were found for ketamine/volatile anesthetics and α2 adrenergicagonist/benzodiazepine combinations despite the clinical interest in the use of ketamine as an analgesic adjunct159 and the use of dexmedetomidine as a sedative in the intensive care setting.160

Our data apply to in vivo interactions in which specific responses potentially result from actions on multiple receptors. We have not examined in vitro effects for actions on a single receptor. In a companion paper exploring this issue, additivity was the predominant finding.161

We may not have retrieved some published interaction data because of the limitations of our search terms. Nevertheless, the large number of studies identified presents a clear overall picture of what we know and where future research efforts may be warranted.

What Can Interaction Studies Tell Us About the Underlying Mechanism of Action

Except, possibly, for ketamine, IV anesthetics that work at different receptors or receptor subtypes usually show synergy for hypnosis and suppression of movement from noxious stimulation. Our review supports the widely held belief that IV anesthetics that work at different receptors or receptor subunits usually, but not always, exhibit synergy to the end-point of interest, and that IV anesthetics that act at identical receptors show additivity.2–7

Our review findings may also allow some deductions regarding the mechanism of action of inhaled versus IV anesthetics, particularly as regards immobility. First, consistent with the analysis in the first companion paper9 suggesting that additivity should be an uncommon finding for drugs acting at different sites of action, IV anesthetics with known differing receptor effects usually, but not always, exhibit synergy for movement. Second, IV anesthetics acting at identical receptors or receptor subunits almost always show additivity, again supporting the analysis presented by Shafer et al.9 Third, the consistent lack of synergy among inhaled anesthetics on MAC, demonstrated in our literature review, and reinforced in the companion manuscript by Eger et al.,10 strongly suggests that inhaled anesthetics act at a common site to produce immobility despite considerable differences in receptor effects.

Clinical Implications

This analysis has only considered two clinically desirable interactions: hypnosis and immobility.162 The widespread practice of combining opioids with inhaled or IV hypnotics suggests that clinicians find the resulting synergy clinically useful. However, nothing in our analysis speaks to synergy for adverse events. There can be synergy for ventilatory depression,1 hypotension, loss of airway reflexes, and other common adverse effects. Little research has compared clinically useful with clinically undesirable forms of synergy.2

Summary

Interactions between drugs of different pharmacological classes often result in synergy. The type of interaction depends on the end-point examined. It also depends on the analysis technique, with “additivity by default” having different implications from clear demonstrations of additivity.9 The absence of synergy among inhaled anesthetics regarding MAC has no parallel with IV drugs with known mechanisms of action. This would support the notion that the mechanism of inhaled anesthetic action underlying immobility may result from an effect at a single, presently unidentified site of action.

ACKNOWLEDGMENTS

The authors are grateful to Drs. Igor Kissin, Timothy G. Short, and Giovanni Manani for providing the raw data of some of their interactions studies.

APPENDIX: WHY A “CEILING EFFECT” IS SYNERGY BY DEFINITION

Consider the interaction of inhaled anesthetics and opioids on the end-point of movement in response to a noxious stimulation (e.g., incision). By definition, inhaled anesthetics produce this effect in 50% of patients at 1 MAC, which is defined as the steady-state end-tidal concentration associated with 50% likelihood of no movement response to incision. Opioids can decrease the concentration of inhaled anesthetic required to ablate the response to noxious stimulus. Thus, there is an interaction. Is it synergistic, additive, or infra-additive?

Multiple studies demonstrate that opioids alone cannot suppress movement in 50% of patients. Figure 2 superimposes the results of two studies of inhaled anesthetic interaction with fentanyl on MAC: one studying the interaction between isoflurane and fentanyl,105 and one studying the interaction between desflurane and fentanyl.109 Both studies show the “ceiling effect” of opioids on MAC. Even with very large doses of fentanyl there is some requirement for inhaled anesthetic. The interaction plots are not straight lines, as would be seen with additivity, instead, curving in a concave manner towards the origin. It is visually obvious that the isobole bows towards the origin when describing a ceiling effect, such as the relationship between an inhaled anesthetic and an opioid. This concave bowing suggests synergy. However, can one demonstrate that it “proves” synergy in a statistically rigorous manner?

Figure 2.
Figure 2.:
The graph shows the interaction between isoflurane and fentanyl,105 desflurane, and fentanyl.109 Both studies show the “ceiling effect,” in that even with very large doses of fentanyl there is some requirement for inhaled anesthetic to prevent movement in response to incision.

We defined synergy in terms of the sum of normalized “doses” (broadly defined to also include concentrations, if the experiment was conducted using concentrations rather than doses). Let EDEP,A be the “effective dose” of drug A associated with a given end-point, and EDEP,B be the effective dose of drug B associated with exactly the same end-point. There is synergy when, for some dose of drug A and some dose of drug B taken together, and producing exactly the same end-point,

< 0.9. This is readily applied to the relationship between two drugs that intersect the X and Y axes at EDEP,B and EDEP,A.

Assume that drug B has a ceiling (e.g., the ceiling for fentanyl effect in decreasing MAC seen in Fig. 2). That is, drug B cannot produce the given end-point without at least Δ units of drug A, regardless of the concentration of drug B. This is shown in Figure 3. The problem is that it does not intersect the X axis, so the definition of synergy given in

< 0.9 cannot be applied directly.

We can redraw our graph with different axes by subtracting Δ from all of the concentrations of drug A, as shown in Figure 4. Consider two choices of Δ. Δ1 yields an intersection with the X axis at infinity, and Δ2 yields in an intersection with the X axis at something less than infinity. This produces the set of three graphs, shown in Figure 5. Note that all three graphs describe exactly the same relationship. However, in the top graph the curve never intersections the X axis. In the middle graph Δ has been chosen to that the curve intersects with the X axis at infinity, and in the bottom graph Δ has been chosen so that the graph intersects with the curve at something less than infinity.

Figure 4.
Figure 4.:
The graph from Figure 3 can be redrawn using different Y axes, in which some fixed amount, Δ1 or Δ2, is subtracted from the dose (concentration) of Drug B. This does not change the underlying relationship between Drug A and Drug B. It simply changes how it is graphed, and the interpretation of the figure.
Figure 5.
Figure 5.:
Three ways of drawing the relationship between drug A and drug B. In the top graph, the ceiling effect is evident. In the middle graph, Δ from Figure 3 has been subtracted from the Y axis, producing a graph that intersects with the X axis at X = ∞. In the lower graph, a larger Δ has been subtracted, resulting in a graph that intersects the X axis. Although all three graphs depict exactly the same relationship between drugs A and B, the middle and lower graphs are most easily interpreted as the relationship between Drug B and incremental doses of drug A in excess of Δ1 and Δ2, respectively.

The three curves in Figure 5 all reflect exactly the same relationship between drugs A and B. However, because of the positioning of the axes on the relationship, there is a difference in interpretation. The middle and lower graphs in Figure 5 show the relationship between drug B and incremental doses of drug A above Δ1 and Δ2, respectively, always given in the presence of Δ1 and Δ2 units of drug A, respectively. For example, were this the relationship between isoflurane (drug A) and fentanyl (drug B), then we might have chosen Δ = 0.2% (Fig. 2) as the asymptope for the middle figure, and Δ = 0.4% for the lower figure. Thus, the middle figure would show the relationship between doses of isoflurane larger than 0.2% (Y axis) and fentanyl concentrations (X axis), given in the presence of the isoflurane dose on the Y axis plus an additional. 0.2% isoflurane. The lower figure would show the relationship between doses of isoflurane larger than 0.4% (Y axis) and fentanyl concentrations (X axis), given in the presence of the isoflurane dose on the Y axis plus an additional 0.4% isoflurane.

Our definition of synergy was deviation from the straight line isobole. We can generalize our synergy equation to permit adjustment of the Y axis as in Figure 5 by adjusting the dose of drug A, and the X intercept of drug A, by Δ:

. In our isoflurane/fentanyl example, Δ = 0 for the top graph, 0.2% isoflurane in the middle graph, and 0.4% isoflurane in the lower graph. Notice the different definition of the “effective dose” of drug B. A prime has been added to the term, ED′EP,B, because here the term ED is the effective dose of drug B in the presence of at least Δ units of drug A.

We will analyze the middle graph in Figure 5, because the dose of drug B conveniently disappears. Recall that in the middle graph, Δ1 was chosen so that the figure intersected with the X axis at infinity. Since

. Our equation for synergy thus reduces to

. This can be rearranged as

. If this equation is satisfied, then synergy exists.

Positive values of Δ decrease the left side of the equation, making the relationship more likely to be true and hence favoring a finding of synergy. Let's take the most conservative setting in which the equation is least likely to demonstrate synergy: Δ = 0. This reduces the relationship to

. This means is that if ANY dose of drug B can reduce the dose of drug A required to reach the stipulated end-point by 10%, then there is synergy for the relationship

. Since this relationship describes exactly the same relationship between the two drugs as described by

, a demonstration of synergy for one relationship describes synergy for all. Since this conclusion is based on our definition of synergy, we refer to this as “synergy by definition.”

In some settings, it might be possible to pick a theoretical dose of drug B, well beyond the measured data, and extrapolate from the measured data to predict that a high dose of drug B would yield a 10% reduction in the dose of drug A. As a practical matter, it seems reasonable to limit the conclusion that a ceiling effect implies synergy to those cases where the 10% reduction is observed at clinically relevant doses.

REFERENCES

1. Bailey P, Pace N, Ashburn M, Moll J, East K, Stanley T. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73:826–30
2. Rosow C. Anesthetic drug interaction: an overview. J Clin Anesth 1997;9:S27–S32
3. Kissin I. Anesthetic interactions following bolus injections. J Clin Anesth 1997;9:S14S–S7
4. Wardley-Smith B, Halsey MJ. Mixtures of inhalation and i.v. anaesthetics at high pressure. A test of the multi-site hypothesis of general anaesthes alia. Br J Anaesth 1985;57:1248–56
5. DiFazio C, Brown R, Ball C, Heckel C, Kennedy S. Additive effects of anesthetics and theories of anesthesia. Anesthesiology 1972;36:57–63
6. Eger EI II. Does 1 + 1 = 2? Anesth Analg 1989;68:551–2
7. Glass PS. Anesthetic drug interactions: an insight into general anesthesia–its mechanism and dosing strategies. Anesthesiology 1998;88:5–6
8. Hemmings HC Jr, Antognini JF. Do general anesthetics add up? Anesthesiology 2006;104:1120–2
9. Shafer S, Hendrickx J, Flood P, Sonner J, Eger EI II. Mass action, additivity, and synergy: theoretical analysis of implications for anesthetic mechanisms. Anesth Analg 2008
10. Eger EI II, Tang M, Liao M, Laster M, Solt K, Flood P, Jenkins A, Hendrickx J, Shafer S, Yasumasa T, Sonner JM. Inhaled anesthetics do not combine to produce synergistic effects regarding MAC in rats. Anesth Analg 2008
11. Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL. Response surface model for anesthetic drug interactions. Anesthesiology 2000;92:1603–16
12. Jones D, Prankerd R, Lang C, Chilvers M, Bignell S, Short T. Propofol-thiopentone admixture-hypnotic dose, pain on injection and effect on blood pressure. Anaesth Intensive Care 1999;27:346–56
13. Vinik HR, Bradley EL Jr, Kissin I. Isobolographic analysis of propofol-thiopental hypnotic interaction in surgical patients. Anesth Analg 1999;88:667–70
14. Naguib M, Sari-Kouzel A. Thiopentone-propofol hypnotic synergism in patients. Br J Anaesth 1991;67:4–6
15. Short TG, Chui PT. Propofol and midazolam act synergistically in combination. Br J Anaesth 1991;67:539–45
16. Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992;69:162–7
17. McClune S, McKay AC, Wright PM, Patterson CC, Clarke RS. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992;69:240–5
18. Vinik HR, Bradley EL Jr, Kissin I. Triple anesthetic combination: propofol-midazolam-alfentanil. Anesth Analg 1994;78: 354–8
19. Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J. Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 1995;82:641–8
20. Higuchi H, Adachi Y, Dahan A, Olofsen E, Arimura S, Mori T, Satoh T. The interaction between propofol and clonidine for loss of consciousness. Anesth Analg 2002;94:886–91
21. Kazama T, Ikeda K, Morita K. The pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses to skin incision, peritoneum incision, and abdominal wall retraction. Anesthesiology 1998;89:894–906
22. Vuyk J, Lim T, Englbers FH, Burm AG, Vletter AA, Bovill JG. The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women. Anesthesiology 1995;83:8–22
23. Vuyk J, Englbers FH, Burm AG, Vletter AA, Griever GE, Olofsen E, Bovill JG. Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia. Anesthesiology 1996;84:288–99
24. Mertens MJ, Olofsen E, Englbers FH, Burm AG, Bovill JG, Vuyk J. Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions. Anesthesiology 2003;99:347–59
25. Bouillon TW, Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, Shafer SL. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology 2004;100:1353–72
26. Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith LR, Canada AT, Glass PS. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994;81:820–8
27. Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology 1997;87:213–27
28. Ben-Shlomo I, Finger J, Bar-Av E, Perl AZ, Etchin A, Tverskoy M. Propofol and fentanyl act additively for induction of anaesthesia. Anaesthesia 1993;48:111–3
29. Schraag S, Mohl U, Bothner U, Georgieff M. Interaction modeling of propofol and sufentanil on loss of consciousness. J Clin Anesth 1999;11:391–6
30. Drover DR, Litalien C, Wellis V, Shafer SL, Hammer GB. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children. Anesthesiology 2004;100:1382–6
31. Kern SE, Xie G, White JL, Egan TD. A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology 2004;100:1373–81
32. Barak M, Ben-Shlomo I, Katz Y. Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice. J Basic Clin Physiol Pharmacol 2001;12:315–23
33. Harris R, Lazar O, Johansen J, Sebel P. Interaction of propofol and sevoflurane on loss of consciousness and movement to skin incision during general anesthesia. Anesthesiology 2006;104:1170–5
34. Stuart PC, Stott SM, Millar A, Kenny GN, Russell D. Cp50 of propofol with and without nitrous oxide 67%. Br J Anaesth 2000;84:638–9
35. Davidson JA, Macleod AD, Howie JC, White M, Kenny GN. Effective concentration 50 for propofol with and without 67% nitrous oxide. Acta Anaesthesiol Scand 1993;37:458–64
36. Tverskoy M, Ben-Shlomo I, Ezry J, Finger J, Fleyshman G. Midazolam acts synergistically with methohexitone for induction of anaesthesia. Br J Anaesth 1989;63:109–12
37. Tverskoy M, Fleyshman G, Bradley EL Jr. Kissin I. Midazolam-thiopental anesthetic interaction in patients. Anesth Analg 1988;67:342–5
38. Short TG, Galletly DC, Plummer JL. Hypnotic and anaesthetic action of thiopentone and midazolam alone and in combination. Br J Anaesth 1991;66:13–9
39. Kissin I, Mason JO III, Bradley EL Jr. Pentobarbital and thiopental anesthetic interactions with midazolam. Anesthesiology 1987;67:26–31
40. Roytblat L, Katz J, Rozentsveig V, Gesztes T, Bradley EL Jr, Kissin I. Anaesthetic interaction between thiopentone and ketamine. Eur J Anaesthesiol 1992;9:307–12
41. Manani G, Valenti S, Vincenti E, Segatto A, Zanette G, Giron GP, Galzigna L. Interaction between thiopentone and subhypnotic doses of ketamine. Eur J Anaesthesiol 1992;9:43–7
42. Telford RJ, Glass PS, Goodman D, Jacobs JR. Fentanyl does not alter the “sleep” plasma concentration of thiopental. Anesth Analg 1992;75:523–9
43. Mehta D, Bradley EL Jr, Kissin I. Effect of alfentanil on hypnotic and antinociceptive components of thiopental sodium anesthesia. J Clin Anesth 1991;3:280–4
44. Kissin I, Mason JO III, Bradley EL Jr. Morphine and fentanyl hypnotic interactions with thiopental. Anesthesiology 1987;67: 331–5
45. Kissin I, Mason JO III, Bradley EL Jr. Morphine and fentanyl interactions with thiopental in relation to movement response to noxious stimulation. Anesth Analg 1986;65:1149–54
46. Mehta D, Bradley EL Jr, Kissin I. Metoclopramide decreases thiopental hypnotic requirements. Anesth Analg 1993; 77:784–7
47. Tverskoy M, Ben-Shlomo I, Vainshtein M, Zohar S, Fleyshman G. Hypnotic effect of i.v. thiopentone is enhanced by i.m. administration of either lignocaine or bupivacaine. Br J Anaesth 1997;79:798–800
48. Kissin I, McGee T. Hypnotic effect of thiopental-lidocaine combination in the rat. Anesthesiology 1982;57:311–3
49. Stone DJ, Moscicki JC, DiFazio CA. Thiopental reduces halothane MAC in rats. Anesth Analg 1992;74:542–6
50. Katoh T, Ikeda K. Nitrous oxide produces a non-linear reduction in thiopentone requirements. Br J Anaesth 1996;77:265–7
51. Hong W, Short TG, Hui TW. Hypnotic and anesthetic interactions between ketamine and midazolam in female patients. Anesthesiology 1993;79:1227–32
52. Salonen M, Reid K, Maze M. Synergistic interaction between alpha 2-adrenergic agonists and benzodiazepines in rats. Anesthesiology 1992;76:1004–11
53. Bol CJ, Vogelaar JP, Tang JP, Mandema JW. Quantification of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat. J Pharmacol Exp Ther 2000;294:347–55
54. Ben-Shlomo I, abd-el-Khalim H, Ezry J, Zohar S, Tverskoy M. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br J Anaesth 1990;64:45–7
55. Vinik HR, Bradley EL Jr, Kissin I. Midazolam-alfentanil synergism for anesthetic induction in patients. Anesth Analg 1989;69:213–7
56. Kissin I, Brown PT, Bradley EL Jr. Sedative and hypnotic midazolam-morphine interactions in rats. Anesth Analg 1990;71:137–43
57. Ben-Shlomo I, Tverskoy M, Fleyshman G, Melnicko V, Katz Y. Intramuscular administration of lidocaine or bupivacaine alters the effect of midazolam from sedation to hypnosis in a dose-dependent manner. J Basic Clin Physiol Pharmacol 2003;14:257–63
58. Melvin MA, Johnson BH, Quasha AL, Eger EI II. Induction of anesthesia with midazolam decreases halothane MAC in humans. Anesthesiology 1982;57:238–41
59. Inagaki Y, Sumikawa K, Yoshiya I. Anesthetic interaction between midazolam and halothane in humans. Anesth Analg 1993;76:613–7
60. Hall RI, Schwieger IM, Hug CC Jr. The anesthetic efficacy of midazolam in the enflurane-anesthetized dog. Anesthesiology 1988;68:862–6
61. Horvath G, Szikszay M, Rubicsek G, Benedek G. An isobolographic analysis of the hypnotic effects of combinations of dexmedetomidine with fentanyl or diazepam in rats. Life Sci 1992;50:PL215–PL220
62. Kissin I, Brown PT, Bradley EL Jr, Robinson CA, Cassady JL. Diazepam–morphine hypnotic synergism in rats. Anesthesiology 1989;70:689–94
63. Hellyer PW, Mama KR, Shafford HL, Wagner AE, Kollias-Baker C. Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or a combination of isoflurane and fentanyl. Am J Vet Res 2001;62:555–60
64. Kissin I, Brown PT, Bradley EL Jr. Morphine and fentanyl anesthetic interactions with diazepam: relative antagonism in rats. Anesth Analg 1990;71:236–41
65. Perisho JA, Buechel DR, Miller RD. The effect of diazepam (Valium) on minimum alveolar anaesthetic requirement (MAC) in man. Can Anaesth Soc J 1971;18:536–40
66. Tsunoda Y, Hattori Y, Takatsuka E, Sawa T, Hori T. Effects of hydroxyzine, diazepam, and pentazocine on halothane minimum alveolar anesthetic concentration. Anesth Analg 1973;52:390–4
67. Matthews NS, Dollar NS, Shawley RV. Halothane-sparing effect of benzodiazepines in ponies. Cornell Vet 1990;80: 259–65
68. White PF, Johnston RR, Pudwill CR. Interaction of ketamine and halothane in rats. Anesthesiology 1975;42:179–86
69. Muir WW III, Sams R. Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 1992;53:1802–6
70. Schwieger IM, Szlam F, Hug CC Jr. The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 1991;19:145–56
71. Solano AM, Pypendop BH, Boscan PL, Ilkiw JE. Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 2006;67:21–5
72. McFarlane C, Warner D, Dexter F. Interactions between NMDA and AMPA glutamate receptor antagonists during halothane anesthesia in the rat 1995;34:659–63
73. Salmenpera MT, Szlam F, Hug CC Jr. Anesthetic and hemodynamic interactions of dexmedetomidine and fentanyl in dogs. Anesthesiology 1994;80:837–46
74. Aantaa R, Jaakola ML, Kallio A, Kanto J. Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine. Anesthesiology 1997;86:1055–60
75. Khan ZP, Munday IT, Jones RM, Thornton C, Mant TG, Amin D. Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions. Br J Anaesth 1999;83:372–80
76. Fragen RJ, Fitzgerald PC. Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. J Clin Anesth 1999;11:466–70
77. Vickery RG, Sheridan BC, Segal IS, Maze M. Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an alpha 2-adrenergic agonist, in halothane-anesthetized dogs. Anesth Analg 1988;67:611–5
78. Segal IS, Vickery RG, Maze M. Dexmedetomidine decreases halothane anesthetic requirements in rats. Acta Vet Scand Suppl 1989;85:55–9
79. Weitz JD, Foster SD, Waugaman WR, Katz RL, Bloor BC. Anesthetic and hemodynamic effects of dexmedetomidine during isoflurane anesthesia in a canine model. Nurse Anesth 1991;2:19–27
80. Savola MK, MacIver MB, Doze VA, Kendig JJ, Maze M. The alpha 2-adrenoceptor agonist dexmedetomidine increases the apparent potency of the volatile anesthetic isoflurane in rats in vivo and in hippocampal slice in vitro. Brain Res 1991;548:23–8
81. Horvath G, Szikszay M, Benedek G. Potentiated hypnotic action with a combination of fentanyl, a calcium channel blocker and an alpha 2-agonist in rats. Acta Anaesthesiol Scand 1992;36:170–4
82. Goyagi T, Tanaka M, Nishikawa T. Oral clonidine premedication reduces the awakening concentration of isoflurane. Anesth Analg 1998;86:410–3
83. Katoh T, Ikeda K. The effect of clonidine on sevoflurane requirements for anaesthesia and hypnosis. Anaesthesia 1997;52:377–81
84. Inomata S, Yaguchi Y, Toyooka H. The effects of clonidine premedication on sevoflurane requirements and anesthetic induction time. Anesth Analg 1999;89:204–8
85. Kihara S, Inomata S, Yaguchi Y, Toyooka H, Baba Y, Kohda Y. The awakening concentration of sevoflurane in children. Anesth Analg 2000;91:305–8
86. El-Kerdawy HM, Zalingen EE, Bovill JG. The influence of the alpha2-adrenoceptor agonist, clonidine, on the EEG and on the MAC of isoflurane. Eur J Anaesthesiol 2000;17:105–10
87. Inomata S, Kihara S, Yaguchi Y, Baba Y, Kohda Y, Toyooka H. Reduction in standard MAC and MAC for intubation after clonidine premedication in children. Br J Anaesth 2000;85:700–4
88. Kaukinen S, Pyykko K. The potentiation of halothane anaesthesia by clonidine. Acta Anaesthesiol Scand 1979;23:107–11
89. Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an alpha-adrenergic agonist. Anesth Analg 1982;61:741–5
90. Maze M, Birch B, Vickery RG. Clonidine reduces halothane MAC in rats. Anesthesiology 1987;67:868–9
91. Watcha MF, Lagueruela RG, White PF. Effect of intraoperative analgesic therapy on end-expired concentrations of halothane associated with spontaneous eye opening in children. Anesth Analg 1991;72:190–3
92. Gross JB, Alexander CM. Awakening concentrations of isoflurane are not affected by analgesic doses of morphine. Anesth Analg 1988;67:27–30
93. Katoh T, Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. Can J Anaesth 1993;40:825–8
94. Saidman LJ, Eger EI II. Effect of Nitrous Oxide and of Narcotic Premedication on the Alveolar Concentration of Halothane Required for Anesthesia. Anesthesiology 1964;25:302–6
95. Kissin I, Kerr CR, Smith LR. Morphine-halothane interaction in rats. Anesthesiology 1984;60:553–61
96. Lake CL, DiFazio CA, Moscicki JC, Engle JS. Reduction in halothane MAC: comparison of morphine and alfentanil. Anesth Analg 1985;64:807–10
97. Murphy MR, Hug CC Jr. The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology 1982;57:489–92
98. Steffey EP, Baggot JD, Eisele JH, Willits N, Woliner MJ, Jarvis KA, Elliott AR, Tagawa M. Morphine-isoflurane interaction in dogs, swine and rhesus monkeys. J Vet Pharmacol Ther 1994;17:202–10
99. Criado AB, Gomez de Segura IA, Tendillo FJ, Marsico F. Reduction of isoflurane MAC with buprenorphine and morphine in rats. Lab Anim 2000;34:252–9
100. Ilkiw JE, Pascoe PJ, Tripp LD. Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 2002;63: 1198–202
101. Steffey EP, Eisele JH, Baggot JD. Interactions of morphine and isoflurane in horses. Am J Vet Res 2003;64:166–75
102. Muir WW III, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003;64:1155–60
103. Katoh T, Uchiyama T, Ikeda K. Effect of fentanyl on awakening concentration of sevoflurane. Br J Anaesth 1994;73:322–5
104. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998;88:18–24
105. McEwan AI, Smith C, Dyar O, Goodman D, Smith LR, Glass PS. Isoflurane minimum alveolar concentration reduction by fentanyl. Anesthesiology 1993;78:864–9
106. Westmoreland CL, Sebel PS, Gropper A. Fentanyl or alfentanil decreases the minimum alveolar anesthetic concentration of isoflurane in surgical patients. Anesth Analg 1994;78:23–8
107. Katoh T, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Ikeda K. The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999;90:398–405
108. Ghouri AF, White PF. Effect of fentanyl and nitrous oxide on the desflurane anesthetic requirement. Anesth Analg 1991;72: 377–81
109. Sebel PS, Glass PS, Fletcher JE, Murphy MR, Gallagher C, Quill T. Reduction of the MAC of desflurane with fentanyl. Anesthesiology 1992;76:52–9
110. Brunner MD, Braithwaite P, Jhaveri R, McEwan AI, Goodman DK, Smith LR, Glass PS. MAC reduction of isoflurane by sufentanil. Br J Anaesth 1994;72:42–6
111. 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
112. Schwieger IM, Hall RI, Hug CC Jr. Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs. Anesthesiology 1991;74:1060–6
113. Murphy MR, Hug CC Jr. The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 1982;57:485–8
114. Hecker BR, Lake CL, DiFazio CA, Moscicki JC, Engle JS. The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats. Anesth Analg 1983;62:987–90
115. Hall RI, Murphy MR, Hug CC Jr. The enflurane sparing effect of sufentanil in dogs. Anesthesiology 1987;67:518–25
116. Docquier MA, Lavand'homme P, Ledermann C, Collet V, De Kock M. Can determining the minimum alveolar anesthetic concentration of volatile anesthetic be used as an objective tool to assess antinociception in animals? Anesth Analg 2003; 97:1033–9
117. Hall RI, Szlam F, Hug CC Jr. The enflurane-sparing effect of alfentanil in dogs. Anesth Analg 1987;66:1287–91
118. Ilkiw JE, Pascoe PJ, Fisher LD. Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 1997;58:1274–9
119. Michelsen LG, Salmenpera M, Hug CC Jr, Szlam F, VanderMeer D. Anesthetic potency of remifentanil in dogs. Anesthesiology 1996;84:865–72
120. Criado AB, Gomez e Segura IA. Reduction of isoflurane MAC by fentanyl or remifentanil in rats. Vet Anaesth Analg 2003;30:250–6
121. Pascoe PJ, Steffey EP, Black WD, Claxton JM, Jacobs JR, Woliner MJ. Evaluation of the effect of alfentanil on the minimum alveolar concentration of halothane in horses. Am J Vet Res 1993;54:1327–32
122. Glass PS, Doherty M, Jacobs, Goodman D, Smith LR. Plasma concentration of fentanyl, with 70% nitrous oxide, to prevent movement at skin incision. Anesthesiology 1993;78:842–7
123. Nakata Y, Goto T, Saito H, Ishiguro Y, Terui K, Kawakami H, Tsuruta Y, Niimi Y, Morita S. Plasma concentration of fentanyl with xenon to block somatic and hemodynamic responses to surgical incision. Anesthesiology 2000;92:1043–8
124. Cork RC, Kihlstrom JF, Schacter DL. Absence of explicit or implicit memory in patients anesthetized with sufentanil/nitrous oxide. Anesthesiology 1992;76:892–8
125. Luginbuhl M, Petersen-Felix S, Zbinden AM, Schnider TW. Xenon does not reduce opioid requirement for orthopedic surgery. Can J Anaesth 2005;52:38–44
126. Drover DR, Lemmens HJ. Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery. Anesthesiology 1998;89:869–77
127. Himes RS Jr, DiFazio CA, Burney RG. Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Anesthesiology 1977;47:437–40
128. Doherty TJ, Frazier DL. Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Equine Vet J 1998;30:300–3
129. Himes RS Jr, Munson ES, Embro WJ. Enflurane requirement and ventilatory response to carbon dioxide during lidocaine infusion in dogs. Anesthesiology 1979;51:131–4
130. Valverde A, Doherty TJ, Hernandez J, Davies W. Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2004;31:264–71
131. Pypendop BH, Ilkiw JE. The effects of intravenous lidocaine administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 2005;100:97–101
132. Zhang Y, Laster MJ, Eger EI II, Sharma M, Sonner JM. Lidocaine, MK-801, and MAC. Anesth Analg 2007;104: 1098–102
133. Eger EI II, Xing Y, Laster M, Sonner J, Antognini JF, Carstens E. Halothane and isoflurane have additive minimum alveolar concentration (MAC) effects in rats. Anesth Analg 2003;96: 1350–3
134. Murray DJ, Mehta MP, Forbes RB, Dull DL. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990;71:120–4
135. Torri G, Damia G, Fabiani ML. Effect on nitrous oxide on the anaesthetic requirement of enflurane. Br J Anaesth 1974;46: 468–72
136. Stevens WD, Dolan WM, Gibbons RT, White A, Eger EI II, Miller RD, DeJong RH, Elashoff RM. Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 1975;42: 197–200
137. Murray DJ, Mehta MP, Forbes RB. The additive contribution of nitrous oxide to isoflurane MAC in infants and children. Anesthesiology 1991;75:186–90
138. Katoh T, Ikeda K. The minimum alveolar concentration (MAC) of sevoflurane in humans. Anesthesiology 1987;66:301–3
139. Rampil IJ, Lockhart SH, Zwass MS, Peterson N, Yasuda N, Eger EI II, Weiskopf RB, Damask MC. Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429–33
140. Fisher DM, Zwass MS. MAC of desflurane in 60% nitrous oxide in infants and children. Anesthesiology 1992;76:354–6
141. Cole DJ, Kalichman MW, Shapiro HM. The nonlinear contribution of nitrous oxide at sub-MAC concentrations to enflurane MAC in rats. Anesth Analg 1989;68:556–62
142. Cole DJ, Kalichman MW, Shapiro HM, Drummond JC. The nonlinear potency of sub-MAC concentrations of nitrous oxide in decreasing the anesthetic requirement of enflurane, halothane, and isoflurane in rats. Anesthesiology 1990;73:93–9
143. Russell GB, Graybeal JM. Nonlinear additivity of nitrous oxide and isoflurane potencies in rats. Can J Anaesth 1998;45:466–70
144. Bertelsen MF, Mosley CA, Crawshaw GJ, Dyson DH, Smith DA. Anesthetic potency of sevoflurane with and without nitrous oxide in mechanically ventilated Dumeril monitors. J Am Vet Med Assoc 2005;227:575–8
145. Goto T, Nakata Y, Ishiguro Y, Niimi Y, Suwa K, Morita S. Minimum alveolar concentration-awake of xenon alone and in combination with isoflurane or sevoflurane. Anesthesiology 2000;93:1188–93
146. Katoh T, Ikeda K, Bito H. Does nitrous oxide antagonize sevoflurane-induced hypnosis? Br J Anaesth 1997;79:465–8
147. Cullen SC, Eger EI II, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969;31:305–9
148. Nakata Y, Goto T, Ishiguro Y, Terui K, Kawakami H, Santo M, Niimi Y, Morita S. Minimum alveolar concentration (MAC) of xenon with sevoflurane in humans. Anesthesiology 2001;94: 611–4
149. Hecker KE, Baumert JH, Horn N, Reyle-Hahn M, Heussen N, Rossaint R. Minimum anesthetic concentration of sevoflurane with different xenon concentrations in swine. Anesth Analg 2003;97:1364–9
150. Hecker KE, Reyle-Hahn M, Baumert JH, Horn N, Heussen N, Rossaint R. Minimum alveolar anesthetic concentration of isoflurane with different xenon concentrations in swine. Anesth Analg 2003;96:119–24
151. Schwieger IM, Hall RI, Szlam F, Hug CC Jr. Anesthetic interactions of midazolam and fentanyl: is there acute tolerance to the opioid? Anesthesiology 1989;70:667–71
152. Hornbein TF, Eger EI II, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982;61:553–6
153. Hecker KE, Horn N, Baumert JH, Reyle-Hahn SM, Heussen N, Rossaint R. Minimum alveolar concentration (MAC) of xenon in intubated swine. Br J Anaesth 2004;92:421–4
154. DiFazio CA, Neiderlehner JR, Burney RG. The anesthetic potency of lidocaine in the rat. Anesth Analg 1976;55:818–21
155. Orser BA, McAdam LC, Roder S, MacDonald JF. General anaesthetics and their effects on GABA(A) receptor desensitization. Toxicol Lett 1998;100–101:217–24
156. Tanelian DL, Kosek P, Mody I, MacIver MB. The role of the GABAA receptor/chloride channel complex in anesthesia. Anesthesiology 1993;78:757–76
157. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Ledermann B, Antkowiak B, Rudolph U. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 2003;17:250–2
158. Sigel E. Mapping of the benzodiazepine recognition site on GABA(A) receptors. Curr Top Med Chem 2002;2:833–9
159. Sneyd JR. Recent advances in intravenous anaesthesia. Br J Anaesth 2004;93:725–36
160. Maze M, Scarfini C, Cavaliere F. New agents for sedation in the intensive care unit. Crit Care Clin 2001;17:881–97
161. Jenkins A, Lobo I, Gong D, Solt K, Harris RA, Eger EI II. General anesthetics have additive actions on three ligand gated ion channels. Anesth Analg 2008;107:486–93
162. Eger EI II, Sonner JM. Anaesthesia defined (gentlemen, this is no humbug). Best Pract Res Clin Anaesthesiol 2006;20:23–9

*Kissin I, Brown PT, Bradley EL. Morphine and fentanyl anesthetic interactions with etomidate. Anesthesiology 1987:67;A383 [abstract].
Cited Here

© 2008 International Anesthesia Research Society