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Inhaled Anesthetics Have Hyperalgesic Effects at 0.1 Minimum Alveolar Anesthetic Concentration

Zhang, Yi, MD; Eger, Edmond I II, MD; Dutton, Robert C., MD; Sonner, James M., MD

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doi: 10.1213/00000539-200008000-00044
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At subanesthetic partial pressures, some inhaled anesthetics (e.g., nitrous oxide and diethyl ether) provide analgesia (antinociception) (1), whereas others (e.g., halothane) (2) appear to produce hyperalgesia (antianalgesia). Using the tail flick technique, we previously found a small hyperalgesic effect of desflurane (3). Thus, there appear to be differences among anesthetics in their capacity to provide analgesia.

We examined whether this difference exists for a particular model of pain, the hind paw withdrawal latency (HPWL) response to thermal nociceptive stimulation (4). This model has an advantage over the tail flick model we used previously, in that HPWL is tested in the unrestrained animal. We tested whether four inhaled anesthetics would produce hyperalgesia at small concentrations (would shorten HPWL), and antinociception (analgesia) at larger concentrations.


With approval of the University of California at San Francisco Committee on Animal Research, we studied male Sprague-Dawley rats (Crl:CD®[SD]Br) weighing 300–450 g (Charles River Breeding Laboratories, Wilmington, MA).

We measured HPWL with a modification of the automatic device (Plantar Tes; Ugo Basile Biological Research Apparatus, Comerio, Italy) described by Hargreaves et al. (4). Up to three unrestrained rats were studied at a time in individual clear plastic enclosures. The enclosures rested on a clear glass plate. Over the enclosures we placed a clear plexiglas box which was open at the bottom and which rested on a silicone rubber gasket on top of the glass plate. A circuit for delivery and scavenging of anesthetics was connected to the enclosure via gas-tight fittings at each end of the plexiglas box. To diminish exploratory activity, the rats were allowed at least 5 min to become accustomed to this environment. After this time of initial acclimation, a movable source of radiant heat was applied from a radium tungsten halogen lamp (EJY 19V 80 W; General Electric, Glen Allen, VA) through a 7-mm aperture under the glass plate to the hind paw of the resting rat. A photocell within the housing that surrounds the lamp sensed the light reflecting from the hind paw of the rat (whether the paw remained in place). The device automatically measured the time from the onset of application of the light (heat) to the time the rat moved the hind limb (as determined by the moment the light no longer reflected from the paw to the photocell).

Each measurement of HPWL for each hind paw was made five times (total of 10 measurements per animal per each dose of test drug). The five readings for each paw were averaged to produce the value for each control or anesthetic level. The initial measurements (5 min after introduction of the rat into the enclosure) were discarded, and control measurements were made after another 30 min of rest. This was done because preliminary studies revealed that this approach was needed to obtain consistent control readings. During this time, either oxygen or air was delivered to the enclosed system (see below). After control measurements were obtained, anesthetics were delivered in a stepwise manner at inspired concentrations equal to 0.05 MAC (not all anesthetics), 0.1 MAC, 0.2 MAC, 0.4 MAC, and, in some cases, 0.8 MAC. MAC for the nonimmobilizer 2N was estimated from its lipophilicity (5). MAC for diethyl ether was taken as 3.2% atmospheres (atm) partial pressure; for nitrous oxide, 220% atm; for isoflurane, 1.46% atm; and for halothane, 0.9% atm (6–8). Each step was held for 30 min to 40 min—the longer times used with the more soluble anesthetics. This was done to reduce the difference between brain partial pressure of anesthetic and the inhaled MAC fraction, although the exact difference between these partial pressures was not determined. At the end of each equilibration, we redetermined HPWL. After the final equilibration, anesthetic delivery was discontinued, and after 30 min to 120 min (increasing time with greater anesthetic solubility) we again measured HPWL.

We studied the effects of isoflurane, halothane, nitrous oxide, diethyl ether, and the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) in groups of six to nine rats. Some rats were used for more than one study (one anesthetic), and at least a week elapsed between the study of such rats. The vapors were delivered to the enclosed system from variable-bypass vaporizers and the nitrous oxide from a tank. All were delivered with oxygen as the background gas, except for diethyl ether which, because of the risk of explosion, was delivered in air. The concentrations of the vapors/gases were monitored with an infrared analyzer (RGM; Datex-Ohmeda, Madison, WI) and were analyzed at the end of each concentration step with gas chromatography. The chromatograph reading was accepted as the value for the exposure concentration. The chromatograph was calibrated with either secondary standards from tanks or from primary volumetric standards.

To establish a positive control for these studies, we measured the effect of sufentanil on HPWL. In five rats, we established venous access by placement of a PE-10 catheter into the internal jugular vein under isoflurane anesthesia. The end of the catheter was tunneled to the nape of the neck and sewed in place. The next day, we determined a control value for HPWL. Sufentanil was then administered IV at infusion rates of 0.001, 0.002, 0.004, 0.008, and 0.016 μg · kg−1 · min−1, measuring HPWL after infusion of sufentanil for 10 min at each step. After infusion at the highest rate, the administration of sufentanil was discontinued. The next day, HPWL was measured again.

We tested whether tolerance might develop to the conditions of study. In particular, we assessed whether the response during application of a subanesthetic concentration might change with time, and whether the elimination of anesthetic would be associated with a recovery to a different control value for HPWL. Control HPWL values were obtained in three rats. These rats then breathed 0.17% isoflurane (0.1 MAC) for slightly more than 2 h with HPWL measured at 0.5 h intervals. After elimination of the isoflurane, HPWL was measured again.

HPWL results were averaged for the left and right paw for each rat. This provided a single value for control and for each anesthetic step for each rat. For each group given a particular anesthetic, the percent of the control (no anesthetic) value at each concentration step for each rat was calculated. These values were averaged for the six to nine rats used with each anesthetic. A paired t-test was used to determine whether a given point differed from control (no anesthetic), accepting P < 0.01 as significant (a Bonferroni correction was applied for multiple comparisons).


The inhaled anesthetics all significantly decreased HPWL at 0.1 MAC (Fig. 1;Table 1); however, 2N did not, although the value at 0.1 of a MAC predicted from the oil/gas partition coefficient approached significance (P = 0.03). Neither lower nor higher MAC-fractions of the anesthetics produced a greater decrease than that produced by 0.1 MAC, and MAC-fractions of 0.4 MAC or 0.8 MAC significantly increased HPWL. HPWL returned to control values after discontinuing anesthetic administration. Sufentanil did not decrease HPWL at any dose, causing increases at larger doses (Fig. 2). Application of 0.1 MAC isoflurane for 2 h produced a stable decrease in HPWL (Fig. 3). The control value after this period of application did not differ from the control value before application.

Figure 1
Figure 1:
In rats, the antianalgesic effects of isoflurane, halothane, nitrous oxide, and diethyl ether were a function of the minimum alveolar anesthetic concentration (MAC)-fraction with the greatest effect on hind paw withdrawal latency (HPWL) (lowest HPWL) at 0.1 MAC. Analgesic effects (increased HPWL) were seen at MAC fractions of 0.2, 0.4, and 0.8. The nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) did not have a statistically significant effect on HPWL. The lines connecting points represent a smooth-curve fitting to the data rather than one derived from a mathematical fitting.
Table 1
Table 1:
Percent of Control Hind Paw Withdrawal Latency (mean ± sd)
Figure 2
Figure 2:
Infusion of smaller concentrations of sufentanil did not decrease hind paw withdrawal latency (HPWL), and infusion of larger concentrations increased HPWL. Values are given as the percentage change from the initial control value (mean, sd;n = 5).
Figure 3
Figure 3:
Tolerance did not develop to the hyperalgesic effects of isoflurane. Exposure of rats to 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane had a hyperalgesic effect on hind paw withdrawal latency (HPWL) (decreased HPWL) which did not vary significantly over a 2-h period of isoflurane administration. HPWL returned to control after elimination of isoflurane. Values are given as the percentage change from the initial control value (mean, sd;n = 3).


Our results using thermal stimulation (HPWL) suggest that all inhaled anesthetics can be hyperalgesic at approximately 0.1 MAC (Fig. 1;Table 1). This result appears to conflict with some clinical data which document the analgesic properties of anesthetics, such as diethyl ether. For example, diethyl ether can produce analgesia sufficient to allow cardiac surgery (9). The reported arterial ether concentration of 32 mg% for this state may be estimated from the ether blood/gas partition coefficient of 12 (10) to indicate that these patients were at a concentration equal to 0.92% of an atm or 0.48 MAC for normothermic humans (11). The patients studied by Ebersole and Artusio (9) probably were hypothermic and thus, at a still higher MAC-fraction (12). Our data suggest that analgesia (increased HPWL) would be present at such MAC-fractions (Fig. 1;Table 1).

Although this analysis might explain how diethyl ether produces analgesia sufficient to allow surgery, it does not explain why such analgesia has not been reported for anesthetics, such as desflurane, isoflurane, or sevoflurane, all compounds with an ether linkage. We suggest that the answer lies in another feature of these anesthetics—the MAC-fraction that suppresses appropriate responsiveness to command (MAC-Awake). The anesthetics for which surgical analgesia has been reported (e.g., diethyl ether and nitrous oxide) have the highest MAC-Awake values, values equal to 0.67 to 0.75 MAC (13,14). In contrast, MAC-Awake for desflurane, isoflurane, and sevoflurane is approximately 0.35 MAC (14–16). Thus, anesthetics, such as diethyl ether and nitrous oxide allow the imposition of higher MAC-fractions (analgesic concentrations) without loss of consciousness, whereas desflurane, isoflurane, and sevoflurane do not.

Although 0.1 MAC produced hyperalgesia with all test anesthetics, the magnitude differed somewhat among anesthetics (Fig. 1;Table 1), as did the concentrations producing analgesia. For example, the curve for diethyl ether is considerably to the right of that for isoflurane and nitrous oxide. At least part of these differences result from the higher solubility of diethyl ether (10). The measured inspired concentrations for ether overestimate the alveolar concentrations (the MAC-fraction is overestimated for ether). Similarly, although halothane’s solubility is less than that of ether (17), it is more than that for isoflurane (18) or nitrous oxide (19), and the curve for halothane lies between that for the more soluble ether and the less soluble nitrous oxide-isoflurane.

Based on the earlier work of Kandel et al. (20), we anticipated finding some analgesic effect from larger concentrations of 2N. Kandel et al. (20) found that 2N concentrations of 3% to 4% decreased jumping by rats in response to an electric shock. However, the highest concentration we applied (2.2%) was less than the concentrations found by Kandel et al. (20) to produce evidence of analgesia; at 2% 2N, they did not find analgesia.

How do inhaled anesthetics produce hyperalgesia? Other reports indicate that such anesthetics enhance C fiber activity at small (sub-MAC) concentrations (21,22), the enhancement continuing to increase at larger concentrations. At 0.1 MAC, isoflurane also increases the nociceptive-related slow ventral root potential in the rat spinal cord (23). However, larger concentrations depress the slow ventral root potentials. One could conjecture that the peripheral hyperalgesic effects of small anesthetic concentrations (e.g., 0.1 MAC) are not counterbalanced by depression of the spinal cord or higher centers, but that larger concentrations (>0.4 MAC) provide a counterbalancing depression. If so, analgesia would not become manifest unless these larger concentrations also permit awareness.

Alternatively, other reports suggest that larger concentrations of inhaled anesthetics suppress supraspinal modulating pathways, with the result that anesthetizing concentrations applied to the brain can increase MAC (24). Perhaps low partial pressures of inhaled anesthetics disrupt these modulating pathways and thereby, decrease the threshold for perception of a thermal stimulus.

One study in humans reports variable results for analgesia of nitrous oxide and xenon in humans (25). At approximately 0.1 MAC to 0.2 MAC, tolerance to ischemic pain decreased. However, tolerance to electrical or mechanical pain increased. Tolerance to cold pain gave variable results. Increasing concentrations of both gases appeared to produce increasing analgesia; however, larger concentrations were incompletely studied because of problems with nausea and vomiting.

If our results using thermal stimuli apply to humans after surgery, they have implications for recovery from anesthesia. When anesthetic concentrations (or combinations thereof) exceed 0.4 MAC, patients will be protected with an element of analgesia. As anesthetic elimination causes the central and peripheral nervous system concentrations to approach 0.1 MAC, patients will experience hyperalgesia. Such patients may perceive noxious stimulation from their wounds to be more intense than if no anesthetic were present. The longer such concentrations linger, the longer antianalgesia will be present. This would suggest that a more rapid elimination of anesthetics, as occurs with anesthetics having a low blood solubility, would decrease the duration of heightened perception of postoperative pain.


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