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Acute tolerance to nitrous oxide in humans
Pain, 51(1992) 367-373 0 1992 Elsevier Science Publishers B.V. All rights reserved 0304-3959/92/$05.00
367
PAIN 02174
Acute tolerance to nitrous oxide in humans Douglas
S. Ramsay
apb,Arthur
C. Brown ’ and Stephen
C. Woods
a
a Department
of Psychology and b School of Dentistry, University of Washington, Seattle, WA 98195 @X4) and ’ The Oregon Health Sciences Universiv School of Dentistry, Portland, OR 97201 (USA)
(Received 30 March 1992, Revision received 29 June 1992, Accepted 1 July 1992)
Summary The goal of this research was to determine whether the level of analgesia produced by nitrous oxide remains constant for the duration of a typical dental procedure or whether acute tolerance reduces the drug’s efficacy. A computer-controlled stimulator delivered brief (approx. 1 msec) electrical pulses to a vital maxillary incisor which had been found to have normal sensitivity in a preliminary session. Subjects were trained to indicate the occurrence of a barely perceptible sensation (i.e., detection threshold) as well as a minimally painful sensation (i.e., pain threshold). On the experimental day, all subjects breathed a non-odorized placebo gas mixture during a lo-min baseline condition, and were then randomly assigned to receive either an odorized placebo gas mixture or an odorized 35-40% nitrous oxide/oxygen gas mixture for 46 min. Detection and pain thresholds were assessed repeatedly during the baseline and gas exposure conditions. Placebo control subjects had little change of either sensory threshold. Subjects breathing nitrous oxide significantly increased both detection and pain thresholds within 2-8 min following the onset of the drug. However, maintenance of the drug’s effect was not consistent between subjects, despite continuous administration of a constant concentration of nitrous oxide. Some subjects had a relatively constant elevation of sensory thresholds throughout the nitrous oxide administration period, and others returned to baseline sensitivity values and therefore were acutely tolerant.
Key words: Nitrous oxide; Analgesia; Tolerance
Introduction
Subanesthetic concentrations of nitrous oxide (N,O) are commonly used in dentistry and medicine to ameliorate pain and stress. The analgesic effects of N,O have been well documented in humans (Seevers et al. 1937; Chapman et al. 1943; Sonnenschein et al. 1948; Persson 1951; Haugen et al. 1959; Dundee and Moore 1960; Parkhouse et al. 1960; Dundee et al. 1962; Chapman et al. 1973; Yang et al. 1980; Dworkin et al. 1983a; Heft et al. 1984) and animals (Berkowitz et al. 1976, 1977, 1979; Wood et al. 1980; Lawrence and Livingston 1981; Smith and Rees 1981; Zuniga et al. 1987; Moody et al. 1989; Quack et al. 1990). However, little is known about the development of tolerance to N,O analgesia in humans.
Correspondence to: Dr. Douglas S. Ramsay, Department of Pediatric Dentistry, University of Washington, SB-26, Seattle, WA 98195, USA.
Acute tolerance is a change of “sensitivity to a drug within the duration of one continuous drug exposure” (Kalant et al. 1971, p. 147) and can most unambiguously be demonstrated when the drug concentration is maintained at a steady level. Thus, if a drug effect diminishes while the drug concentration is constant, acute tolerance has developed. N,O is well suited for such research since blood levels rapidly equilibrate with the inspired concentration and remain constant as long as the gas is administered (Eger 1985). In animals, acute tolerance develops to several effects of N,O (Mori and Winters 1975; Koblin et al. 1979; Smith et al. 1979; Oshima et al. 1982; Stevens et al. 1983). With respect to analgesia, some (Berkowitz et al. 1977, 1979; Rupreht et al. 1984; Ramsay et al. 1985) but not all (Shingu et al. 1985) animal studies have suggested that acute tolerance develops to N,O. Similarly, acute tolerance to N,O analgesia has been reported in some (Persson 1951; Whitwam et al. 1976; Rupreht et al. 1985) but not all (Yagi et al. 19891 human studies. Interpretation of these former experi-
368
ments is rendered difficult due to lack of consistent paradigms and conflicting findings. To provide a definitive answer, we used an experimental design with careful controls, a quantifiable stimulation and drug administration apparatus, and continuous automated pain and detection threshold tracking. 20.
Methods
~.~...~~..~~~~.~~~.~~....~~~~~~~~~~~~~~~~~~
-a OP 0
1
.
20
.
40
.
60
.
60
.
100
.
I
120
TIME (seconds)
Subjects Twenty-nine subjects (17 male, 12 female; 20-39 years old) were recruited from the Oregon Health Sciences University campus to participate in a study investigating the effects of an anesthetic gas on sensory thresholds in teeth. This study was approved by the human subjects review committees at the University of Washington and the Oregon Health Sciences University.
Apparatus Electrical tooth stimulator. A previously described computer-controlled, constant-charge stimulator (Brown et al. 1984, 1985) delivered electrical impulses to teeth. Stimuli were single pulses, approximately 1 msec in duration. In the present experiment, the amplitude of detectable stimuli ranged from 19 nC to a maximum possible stimulus of 325 nC (corresponding to a range of 19-325 pA current). Gas delivery unit. A standard N,O/O, delivery unit was modified (Nitrox Inc., Woodinville, WA) so that nitrogen (N,) could be substituted for N,O while holding the 0, concentration constant. Experimental subjects received between 35 and 40% N,O while control subjects received 35-40% Nz. Administered Oz concentration was monitored (Ventronics model no. 5570) to assure constant gas composition, and an odorant could be added to either gas mixture by bubbling the gas through a humidifier (Hudson model no. 3100) containing 315 ml of distilled water mixed with 0.5 ml of almond extract (Schilling). The odor provided subjects (experimental and control) with a common cue to suggest they were receiving an active (not placebo) substance and masked any odor associated with N,O administration. The gas was delivered via a standard nasal mask.
Procedure Tooth stimulation. A rubber dam, stabilized with a ‘Wizard’ type of frame and placed over the maxillary anterior teeth and both maxillary first premolars, was used to minimize salivary interference with the measurements. This type of rubber dam and frame effectively sealed the entire oral cavity and therefore minimized the possibility that mouth breathing would dilute the nasally administered NzO. Electrical stimuli were delivered to the tooth being tested through a 30-ga silver-plated copper wire abutting the labial surface of the middle incisal third of the tooth by means of an acrylic splint containing circular holes (2.5-mm diameter) filled with conducting paste. This wire served as the negative electrode and a positive ECG electrode attached to the cheek completed the circuit. Tooth electrode resistance was measured with an impedance bridge (ES1 SP2596) throughout the procedure to verify that the impedance had not changed. When a human tooth is stimulated electrically with a series of pulses of gradually increasing amplitude, the subject eventually reports a non-painful, indeterminate sensation prior to reporting pain at a higher stimulus intensity (Shimizu 1964; Mumford and Stanley 1981; McGrath et al. 1983; Brown et al. 1985). Subjects in the present study held a response button and received a series of electrical impulses of gradually increasing charge. They were instructed: (1) not to press the button unless they felt a tooth sensa-
Fig. 1. The estimation of detection and pain thresholds is graphically depicted using a repeating staircase procedure. This subject received a total of 63 electrical stimuli delivered to a single maxillary incisor over a 123~set period. Open circles (0) indicate that the subject did not perceive the stimulus, solid circles (01 represent a perceptible but not painful stimulus, and open triangles (A ) indicate that the subject considered the stimulus to be painful. Five staircases were run on this subject’s tooth; the mean detection threshold was 58.6 nC (range: 55.8-61.8) and the mean pain threshold was 85.7 nC (range: 77.6-97.5).
tion; (2) to depress the button once each time they felt a tooth sensation that they would describe as discernible but not painful; and (3) to depress the button twice each time the sensation was painful. Subjects received training on this procedure with stimuli that were separated by a constant interpulse interval (2 set) and that increased by a constant amount of charge on successive stimulations. The increments were sufficiently small that several perceptible but nonpainful sensations were experienced prior to reaching pain threshold. This ‘staircase’ pattern always began with an intensity well below the subject’s detection threshold and ended when the subject first reported feeling pain, i.e., responded with 2 presses. For the actual experiment, both the time between successive stimuli (mean: 2 set) and the increase of intensity were randomized to preclude anticipatory responses. With this pattern, the charge typically increased monotonically but occasionally decreased for 1 or 2 stimulations. Typical data are depicted in Fig. 1. A subject’s detection threshold and pain threshold were both derived. Detection threshold was calculated as the mean of the highest intensity non-detectable stimulation and that of the first detected sensation. Pain threshold was calculated as the mean of the highest perceived but non-painful stimulus and the first painful stimulus. A single detection and pain threshold value was determined for each staircase. Individual detection and pain thresholds were averaged over the several staircases completed during each 2-min period. In principle, subjects would respond with a single button depression to each stimulus falling between their detection and pain thresholds. Failure to do so, and/or responding inappropriately to a stimulus well below detection threshold, were recorded as responding errors by a rater blind to the experimental condition. Experimental protocol. Subjects participated in 3 sessions. During the screening session, the experimental procedures were described, health and drug histories were taken, a clinical dental exam was performed, consent was obtained, and the acrylic splints for tooth stimulation were fabricated. During the training session. subjects practiced the tooth stimulation protocols until they could reliably distinguish detection and pain thresholds. Subjects were excluded from further participation if they could not reliably distinguish the 2 thresholds or if their pain threshold was beyond the limits of maximal charge generated by the stimulator. The testing session (at least 1 week later) began with a lo-min administration of a non-odorized placebo gas mixture. Two maxillary incisors which had been used for training were randomly designated as teeth ‘A’ and ‘B’ to denote
369 TABLE
I
NITROUS
OXIDE
INCREASES Tooth
Time (mini
4- 6 10-12 14-16 20-22 24-26 28-30 32-34 38-40 42-44 46-48 50-52
* * * * * * + * *
Tooth site B
detection
threshold
(nC1
Time (mini
Placebo
tn, S.E.M.1
N,O
(n, S.E.M.1
66.97 74.06 67.76 65.01 66.15 65.40 64.38 71.82 73.54 70.48 77.85
(10, 7.83) (10, 8.061 (10, 8.671 (10, 7.761 (10, 8.241 (IO, 9.701 (IO, 8.911 (10, 7.881 (10, 10.161 (10, 8.00) (10, 8.39)
68.64 72.16 89.76 91.65 99.00 102.97 105.21 95.84 101.70 100.76 105.91
(14, (14, (14, (14, (14, (14, (14, (14, (14, (14, (14.
P < 0.05, Mann-Whitney P < 0.025, Mann-Whitney
’ indicates * indicates
THRESHOLD
site A
Median
(base1 ine)
DETECTION
7.26) 8.521 9.101 10.941 9.691 8.831 9.101 9.56) 11.84) 14.961 10.971
Results Of the 19 N,O subjects, 5 (2 male, 3 female) withdrew from the study shortly after the onset of the drug (range: 11% 194 set) because of anxiety experienced on
threshold
(nC1
(n, S.E.M.)
NzO
tn, S.E.M.)
56.12 60.46 66.03 63.32 66.77 62.57 58.85 59.24 62.77 68.97 72.22
(9, (9, (9, (9, (9, (9. (9, (9, (9. (9, (9,
70.32 103.99 115.10 107.11 lb8.17 116.13 124.26 108.24 113.70 123.80 126.98
(14, t 14, (14, (14, t 14, (14, (14, (14, (14, (14, (14,
7.18) 6.411 7.501 6.541 6.38) 6.821 7.441 8.221 8.721 7.41) 7.60)
9.041 14.581 13.101 12.34) 12.751 13.251 16.391 14.121 14.971 14.621 15.271
N,O administration. None of the 10 placebo subjects withdrew. Due to salivary contamination, 1 tooth in the placebo condition was excluded from the analyses. Sensitivity data were analyzed with non-parametric statistics due to heterogeneity of variance between the 2 gas conditions. Since N,O reliably increases pain and detection thresholds, a l-tailed test of significance was employed. All other analyses used 2-tailed parametric tests. Detection and pain thresholds
Baseline detection and pain thresholds did not differ between the 2 groups (Tables I and II). Median detection threshold significantly increased during N,O inhalation. This was apparent within 4 min and persisted throughout the administration (Table I>. Median pain threshold also increased during N,O inhalation (Table II) and was significantly greater than for the
II
NITROUS
OXIDE
INCREASES Tooth
Time (mini
4- 6 IO-12 14-16 20-22 24-26 28-30 32-34 38-40 42-44 46-48 50-52
(baseline :) * * * * * * * * * *
detection
Placebo
LI (l-tailed). Li (l-tailed).
their temporal order of stimulation. Baseline detection and pain thresholds were determined for teeth A and B between minutes 4-6 and 6-8, respectively. After 10 min. subjects were randomly assigned to receive either odorized placebo or N,O/Oz with the proviso that twice as many N,O as placebo subjects were run. Both the subject and the experimenter operating the tooth stimulator were blind to the condition. Between minutes 4 and 54, assessments alternated between teeth A and B every 2 min with 4 interspersed time-out periods. Alternately stimulating 2 teeth permitted twice as much data collection per experiment while still permitting tracking of threshold change. Also, alternating teeth gave each tooth a ‘rest period’ which reduces the possibility of sensory adaptation that might have occurred with continuous tooth stimulation.
TABLE
6- 8 12-14 16-18 22-24 26-28 30-32 34-36 40-42 44-46 48-50 52-54
Median
Median
(baseline)
+ +
+
’ indicates * indicates
PAIN THRESHOLD Tooth site B
site A pain threshold
(nC)
Time (mini
Placebo
tn, S.E.M.)
NzO
(n, S.E.M.)
130.07 133.72 136.18 138.03 134.07 134.51 129.22 139.85 139.92 143.41 145.46
(10, (10, (10, (10, (10. (10. (10,
111.36 131.56 202.91 153.12 182.51 187.40 189.04 178.11 175.58 170.72 174.66
(14, (14, (13, (14, (14, (14, (14. (14, (14. (14, (14,
17.86) 17.11) 16.441 13.741 15.52) 15.021 14.54) (IO,15.67) (10, 19.071 (10, 10.77) (10. 12.901
P < 0.05, Mann-Whitney P < 0.025, Mann-Whitney
LI (l-tailed). u (l-tailed).
13.67) 15.571 24.321 21.511 21.611 20.991 22.06) 21.35) 23.021 21.861 21.771
6-8 (baseline) 12-14 16-18 * 22-24 26-28 + 30-32 + 34-36 * 40-42 44-46 48-50 52-54
Median
pain threshold
(nC1
Placebo
(n, S.E.M.1
N,O
(n, S.E.M.1
123.86 129.69 128.08 139.48 142.78 130.75 127.47 150.04 122.87 137.06 131.12
(9, (9, (9, (9, (9, (9, (9, (9, (9, (9, (9,
123.36 180.5 1 197.16 200.99 215.51 194.77 209.11 178.53 191.81 189.35 200.99
(14, (14, (14, (14, t 14, (14, (13, (14, (14, (14, f 14,
16.401 19.59) 14.101 15.911 17.871 15.411 16.391 19.24) 18.34) 15.48) 21.681
16.45) 22.96) 23.451 23.23) 23.541 23.551 22.78) 24.641 21.721 25.171 24.88)
370 200
-
320
DEtECTKIN AND PAIN
260
.
240
y
200 160
THRESHDLDS (nanocoulombs)
120 60
+
Odor and 35% Nitrous
Oxide 4 b
Odor and 40% Nitrous
Oxlde
4
00 0
4
12 16 20 24 26 32 36 40 44 46 52 56
6
TIME
0
4
6
12 16 20 24 26 32 36 40 44 46
(minutes)
62 56
TIME (minutes)
Fig. 2. Analgesic effects of N,O remain fairly constant throughout the gas administration for this subject. Detection (0) and pain (i?) ) thresholds were determined by stimulating the maxillary left (and right (. .) central incisors.
Fig. 4. Acute tolerance develops to the analgesic effects of N,O for this subject. Detection (0) and pain (I_?) thresholds were determined ) and left ( ) central by stimulating the maxillary right (incisors.
placebo group between 6-8, 16-26, and 36-38 min after the onset of NzO. Acute tolerance was assessed by comparing sensory thresholds between 4-18 and 32-42 min following the onset of NzO. A return toward baseline threshold (increasing sensitivity) in the second interval relative to the first was interpreted as acute tolerance since N,O reaches a steady-state concentration within the first time interval and the concentration is maintained throughout the remainder of the drug administration. Each of these intervals contains three 2-min assessments for both teeth. The highest mean detection and pain threshold value was determined for each tooth during each interval, and the respective detection and pain thresholds were then compared using a Wilcoxon sign test for differences between related samples. With all N,O subjects included, neither detection nor pain thresholds differed reliably between the 2 intervals (P > 0.05). Likewise pain threshold did not change reliably between the 2 time periods for placebo subjects (P > 0.05). However, the detection threshold for tooth A was significantly higher during the second than
the first interval (z = l.Y9, P < 0.051, but the detection threshold for tooth B did not differ between the 2 intervals (z = 1.72, P > 0.05). The grouped data (Tables I and II) mask considerable between-subject variation in detection and pain thresholds during N,O inhalation. Some subjects had a consistent elevation of their detection and pain thresholds throughout N,O exposure (Fig. 2), while others developed acute tolerance (Figs. 3 and 4). A single subject developed acute sensitization (Fig. 5). Of 14 subjects who received N,O, 4 developed acute tolerance to the detection threshold in both teeth and 1 additional subject developed tolerance in 1 of the 2 teeth. For the pain threshold, 4 of 14 subjects developed tolerance in both teeth and 2 additional subjects developed tolerance in 1 tooth only. Of the 9 subjects receiving placebo, none developed a tolerance-like pattern for the detection threshold and only a single tooth for a single subject would have been categorized as developing tolerance on the pain threshold. Given the parameters of this study, acute tolerance does not develop to the effects of N,O on detection
100
-
300
90 250
60 70 DEtECTION AND PAIN
60 50 -
THRESHOLDS 40 30 20 10 -
+
Odor and 40% Nitrous
Oxide
4
+
Odor and 35% Nitrous
Oxide 4
0 .,.,.,.,‘,.,.,.,‘,‘,.,.,‘,., 0
4
6
12 16 20 24 26 32 36 40
44 48 52 56
TIME (minutes)
Fig. 3. Acute tolerance develops to the analgesic effects of N,O for this subject. Detection (*) and pain (0) thresholds were determined ) and left t..,...)central by stimulating the maxillary right (-----incisors,
0
4
6
12 16 20 24 26 32 36 40 44 40 52 56 TIME
(minutes)
Fig. 5. Analgesic effects of N,O increase throughout the gas administration for this subject. Detection (0) and pain (0) thresholds were ) and left determined by stimulating the maxillary right () lateral incisors. (.
371
SNitrous
Placebo
4Mean Number of Errors Per Four
Oxide
M -
3:
. . Mhluie 21 Block
l-
o-
b
Nitrous
Oxide or Placebo
I I I I I I I I1 0
6
16
24
4
I I I I I I
32
40
46
56
Time (minutes)
Fig. 6. Subjects disruptive
receiving N20 become acutely tolerant to the drug’s effects on the tooth sensation assessment task.
and pain thresholds when all subjects receiving the gas are considered collectively. Except for a small increase in the detection threshold of tooth A (which was not replicated with tooth B), results from the placebo group suggest that baseline tooth sensitivity remained stable throughout the experimental session. This suggests that the present study’s inability to detect acute tolerance is not due to a changing baseline in tooth sensitivity. Response errors
Mean errors (inappropriate or inconsistent responses) per 4-min block are depicted in Fig. 6. The N,O group made significantly more errors than did the placebo group (2-factor repeated measures ANOVA: F (1, 21) = 4.30, P < 0.05). N,O caused an initial increase in error rate which later returned to control values. Post-hoc analysis indicated that the groups differed only during minutes 14-18 (t (21) = 2.13, P < 0.05) which suggests that acute tolerance developed to this effect of N,O. Response latency
The overall mean response latency (defined as the interval between tooth stimulus application and the subject’s response) was 0.46 sec. There were no response latency differences between the placebo and N,O groups at any interval (Tooth A: F (1, 22) = 0.06, P > 0.05; Tooth B: F (1, 22) = 0.05, P > 0.05).
Discussion
The most striking finding was the large intersubject variability observed in the maintenance of the analgesic effectiveness of N,O during a continuous administration. While it is clear that some subjects developed acute tolerance, the effect was not reliable for the group as a whole. Similar findings were reported by Whitwam et al. (1976) who found acute tolerance in 2 of 7 subjects given 33% N,O for 1 h. They concluded
that “with respect to analgesia, adaptation of the nervous system to a constant concentration of nitrous oxide can occur in some subjects” (p. 425). Similarly, Persson (1951) observed that pain thresholds during 30% N,O administration sometimes cease to rise and often decrease. He suggested that there may be organismic ‘accommodation’ (p. 85) to the drug or that “another factor prevails which counteracts the hypalgesic action of nitrous oxide” (p. 56). A single study (Rupreht et al. 1985) has demonstrated the development of acute tolerance to the antinociceptive effects of N,O in a group of human subjects. Using concentrations of N,O sufficiently high to induce loss of consciousness (60-80%), Rupreht and colleagues observed acute tolerance within 45 minutes, and by 150 minutes none of the subjects differed from their pre-drug baseline values. However, generalizing results using anesthetic concentrations of N,O to those obtained at analgesic concentrations may be inappropriate (Gillman and Footerman 1981). Large individual differences have been reported for many effects of N,O (Robson et al. 1960; Garfield et al. 1975; Atkinson and Green 1983), including analgesia. With regards to analgesia, Dworkin et al. (1983a) reported the occasional subject who experienced no analgesia whatsoever to 45% N,O. Benedetti et al. (1982, p. 364) emphasize these individual differences quite clearly, “On the average, the effect of nitrous oxide is very predictable, but at the level of the individual it can affect pain sensations erratically.” Hypotheses have been proposed to account for the large degree of intersubject variability observed during the administration of N,O. Atkinson and Green (1983) hypothesized that specific personality traits of the individual may be responsible for the variable effects of N,O. Alternatively, Dworkin et al. (1983b, 1984) have suggested that individual cognitive interpretations of N,O’s non-specific alteration of perceived bodily sensations accounts for the variable reactions to the drug. They demonstrated experimentally that the analgesic and subjective effects of N,O could be altered by manipulating subjects’ expectations. An appreciation of the individual differences that occur during N,O administration is important clinically. Findings from the present investigation emphasize that clinicians should not assume that the initial analgesic efficacy of N,O will be constant throughout the duration of its administration. Patients should be asked frequently to report their comfort level and the concentration of N,O should be adjusted accordingly to maintain its effectiveness. Acute tolerance unambiguously developed to the disruption of normal performance by N,O as estimated by response errors, and this did not correlate with tolerance to the analgesic effects of N,O. N,O is known to impair psychomotor performance (Steinberg
1954; Garfield et aI. 1975; Kortilia et al. 1981), and Sonnenschein et al. (1948) reported that an increase of pain threshold is correiated with a decrease of psychomotor performance. However, no previous research has reported the development of acute tolerance to N,O-induced psychomotor deficits. Although the cause of the acute tolerance is unknown, it is possible that subjects were able to improve their performance with repeated drugged practice. For example, drugged practice has been shown previously to contribute to the development of tolerance to ethanol’s psychomotor impairment (Wenger et al. 1981). Whatever the mechanism, it appears that tolerance to psychomotor disruption occurred independently of tolerance to analgesia. N,O has several characteristics which make it particularly useful for studying drug tolerance in humans. N,O has a high safety index (Gillman 1982); repeated measurements can be made while maintaining a steady-state drug concentration; and the only human metabolic pathway for N,O is by anaerobic bacteria in the intestine (Trudell 1985), thus limiting dispositional (i.e., pharmacokinetic) exptanations for whatever is observed. Future research should be aimed at identi~ing the subset of individuals who develop tolerance to N,O analgesia and investigating traits that distinguish them from those who do not.
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R.M.
Toler-
and pain in human teeth, Pain. 71
Arrowcrod,
of nitrous
trrsen.
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Ngai.
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The authors wish to thank B. Evan McAllister, President of Nitrox Inc., Woodinville, WA, for the design and construction of our unique gas delivery system; Robert C. Bolles, Irwin G. Sarason, and Philip Weinstein for their helpful comments on earlier versions of the manuscript; and the faculty and staff at the Oregon Health Sciences University School of Dentistry for providing the facilities and support necessary to conduct this research. This inv~tigation was supported in part by NIH Grant DE 00161 and by NIDA Grant DA 07391.
Berkowitz,
A.<‘.
oxide on decision-strategy
Acknowledgements
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373 action and its acute tolerance of nitrous oxide in the experimental models of epilepsy in cats, Masui, 31 (1982) S306. Parkhouse, J., Henrie, J.R., Duncan, G.M. and Rome, H.P., Nitrous oxide analgesia in relation to mental performance. J. Pharmacol. Exp. Ther., 128 (1960) 44-54. Persson, P., Nitrous oxide hypalgesia in man, Acta Odontolog. Stand., 9 (1951) l-98. Quack. R.M., Walczak, C.K., Henry, R.J. and Chen, D.C., Effect of subtype-selective opioid receptor blockers on nitrous oxide antinociception in rats. Pharmacol. Res., 22 (1990) 351-357. Ramsay. D.S., Bolles, R.C., Weinstein, P. and LaCour, F., Exploring the relationship between nitrous oxide and the opiate system, J. Dent. Res., 64 (1985) 249. Robson, J.G., Burns, B.D. and Welt, P.J.L., The effect of inhaling dilute nitrous oxide upon recent memory and time estimation, Can. Anaesth. Sot. J., 7 (1960) 399-410. Rupreht, J.. Ukponmwan, E.O., Dworacek, B., Admiraal. P.V. and Dzoljic, M.R., Enkephalinase inhibition prevented tolerance to nitrous oxide analgesia in rats, Acta Anaesthesiol. Stand., 28 (1984) 617-620. Rupreht, J., Dworacek, B., Bonke, B., Dzoljic, M.R., van Eijndhoven, J.H.M. and de Vlieger, M., Tolerance to nitrous oxide in volunteers, Acta Anaesthesiol. Stand., 29 (1985) 635-638. Seevers, M.H., Bennett, J.H., Pohle, H.W. and Reinardy, E.W., The analgesia produced by nitrous oxide, ethylene, and cyclopropane in the normal human subject, J. Pharmacol. Exp. Ther., 59 (1937) 291-300. Shimizu, T.. Tooth pre-pain sensations elicited by electrical stimulation, J. Dent. Res., 43 (1964) 467-475. Shingu, K., Osawa, M.. Fukuda, K. and Mori, K., Acute tolerance to the analgesic action of nitrous oxide does not develop in rats, Anesthesiology, 62 (1985) 502-504. Smith, E.H. and Rees, J.M.H., The effects of naloxone on the
analgesic activities of general anaesthetics, Experientia, 37 (1981) 289-290. Smith, R.A., Winter, P.M., Smith, M. and Eger, II, E.I., Rapidly developing tolerance to acute exposures to anesthetic agents, Anesthesiology, 50 (1979) 496-500. Sonnenschein, R.R., Jamison. R., Loveseth, L.J., Cassels. W.H. and Ivy, A.C., A study on the mechanism of nitrous oxide analgesia, J. Appl. Physiol., 1 (1948) 254-258. Steinberg, H., Selective effects of an anaesthetic drug on cognitive behaviour, Quart. J. Exp. Psychol., 6 (19.54) 170-180. Stevens, J.E., Oshima, E. and Mori, K., Effects of nitrous oxide on the epileptogenic property of enflurane in cats., Br. J. Anaesth., 55 (1983) 145-154. Trudell. J.R., Metabolism of nitrous oxide. In: E.I. Eger. II (Ed.), Nitrous oxide/N,O, Elsevier, New York, 1985, pp. 203-210. Wenger. J.R., Tiffany, T.M., Bombardier, C., Nicholls, K. and Woods, S.C., Ethanol tolerance in the rat is learned, Science, 213 (1981) 575-577. Whitwam, J.G., Morgan, M., Hall, G.M. and Petrie, A., Pain during continuous nitrous oxide administration, Br. J. Anaesth., 48 (1976) 425-428. Wood, R.W., Warren, P.H. and Weiss, B., Attenuated aversiveness of electric shock during nitrous oxide exposure, J. Pharmacol. Exp. Ther.. 213 (1980) 128-132. Yagi, M., Tashiro, C., Tomi, K. and Yoshiya, I., Analgesia and anesthesia induced by subanesthetic concentration of nitrous oxide, Masui. 38 (1989) 724-729. Yang, J.C., Clark, W.C. and Ngai, S.H., Antagonism of nitrous oxide analgesia by naloxone in man, Anesthesiology, 52 (1980) 414-417. Zuniga, J., Joseph, S. and Knigge. K., Nitrous oxide analgesia: partial antagonism by naloxone and total reversal after periaqueductal grey lesions in the rat, Eur. J. Pharmacol., 142 (1987) 51-60.
367
PAIN 02174
Acute tolerance to nitrous oxide in humans Douglas
S. Ramsay
apb,Arthur
C. Brown ’ and Stephen
C. Woods
a
a Department
of Psychology and b School of Dentistry, University of Washington, Seattle, WA 98195 @X4) and ’ The Oregon Health Sciences Universiv School of Dentistry, Portland, OR 97201 (USA)
(Received 30 March 1992, Revision received 29 June 1992, Accepted 1 July 1992)
Summary The goal of this research was to determine whether the level of analgesia produced by nitrous oxide remains constant for the duration of a typical dental procedure or whether acute tolerance reduces the drug’s efficacy. A computer-controlled stimulator delivered brief (approx. 1 msec) electrical pulses to a vital maxillary incisor which had been found to have normal sensitivity in a preliminary session. Subjects were trained to indicate the occurrence of a barely perceptible sensation (i.e., detection threshold) as well as a minimally painful sensation (i.e., pain threshold). On the experimental day, all subjects breathed a non-odorized placebo gas mixture during a lo-min baseline condition, and were then randomly assigned to receive either an odorized placebo gas mixture or an odorized 35-40% nitrous oxide/oxygen gas mixture for 46 min. Detection and pain thresholds were assessed repeatedly during the baseline and gas exposure conditions. Placebo control subjects had little change of either sensory threshold. Subjects breathing nitrous oxide significantly increased both detection and pain thresholds within 2-8 min following the onset of the drug. However, maintenance of the drug’s effect was not consistent between subjects, despite continuous administration of a constant concentration of nitrous oxide. Some subjects had a relatively constant elevation of sensory thresholds throughout the nitrous oxide administration period, and others returned to baseline sensitivity values and therefore were acutely tolerant.
Key words: Nitrous oxide; Analgesia; Tolerance
Introduction
Subanesthetic concentrations of nitrous oxide (N,O) are commonly used in dentistry and medicine to ameliorate pain and stress. The analgesic effects of N,O have been well documented in humans (Seevers et al. 1937; Chapman et al. 1943; Sonnenschein et al. 1948; Persson 1951; Haugen et al. 1959; Dundee and Moore 1960; Parkhouse et al. 1960; Dundee et al. 1962; Chapman et al. 1973; Yang et al. 1980; Dworkin et al. 1983a; Heft et al. 1984) and animals (Berkowitz et al. 1976, 1977, 1979; Wood et al. 1980; Lawrence and Livingston 1981; Smith and Rees 1981; Zuniga et al. 1987; Moody et al. 1989; Quack et al. 1990). However, little is known about the development of tolerance to N,O analgesia in humans.
Correspondence to: Dr. Douglas S. Ramsay, Department of Pediatric Dentistry, University of Washington, SB-26, Seattle, WA 98195, USA.
Acute tolerance is a change of “sensitivity to a drug within the duration of one continuous drug exposure” (Kalant et al. 1971, p. 147) and can most unambiguously be demonstrated when the drug concentration is maintained at a steady level. Thus, if a drug effect diminishes while the drug concentration is constant, acute tolerance has developed. N,O is well suited for such research since blood levels rapidly equilibrate with the inspired concentration and remain constant as long as the gas is administered (Eger 1985). In animals, acute tolerance develops to several effects of N,O (Mori and Winters 1975; Koblin et al. 1979; Smith et al. 1979; Oshima et al. 1982; Stevens et al. 1983). With respect to analgesia, some (Berkowitz et al. 1977, 1979; Rupreht et al. 1984; Ramsay et al. 1985) but not all (Shingu et al. 1985) animal studies have suggested that acute tolerance develops to N,O. Similarly, acute tolerance to N,O analgesia has been reported in some (Persson 1951; Whitwam et al. 1976; Rupreht et al. 1985) but not all (Yagi et al. 19891 human studies. Interpretation of these former experi-
368
ments is rendered difficult due to lack of consistent paradigms and conflicting findings. To provide a definitive answer, we used an experimental design with careful controls, a quantifiable stimulation and drug administration apparatus, and continuous automated pain and detection threshold tracking. 20.
Methods
~.~...~~..~~~~.~~~.~~....~~~~~~~~~~~~~~~~~~
-a OP 0
1
.
20
.
40
.
60
.
60
.
100
.
I
120
TIME (seconds)
Subjects Twenty-nine subjects (17 male, 12 female; 20-39 years old) were recruited from the Oregon Health Sciences University campus to participate in a study investigating the effects of an anesthetic gas on sensory thresholds in teeth. This study was approved by the human subjects review committees at the University of Washington and the Oregon Health Sciences University.
Apparatus Electrical tooth stimulator. A previously described computer-controlled, constant-charge stimulator (Brown et al. 1984, 1985) delivered electrical impulses to teeth. Stimuli were single pulses, approximately 1 msec in duration. In the present experiment, the amplitude of detectable stimuli ranged from 19 nC to a maximum possible stimulus of 325 nC (corresponding to a range of 19-325 pA current). Gas delivery unit. A standard N,O/O, delivery unit was modified (Nitrox Inc., Woodinville, WA) so that nitrogen (N,) could be substituted for N,O while holding the 0, concentration constant. Experimental subjects received between 35 and 40% N,O while control subjects received 35-40% Nz. Administered Oz concentration was monitored (Ventronics model no. 5570) to assure constant gas composition, and an odorant could be added to either gas mixture by bubbling the gas through a humidifier (Hudson model no. 3100) containing 315 ml of distilled water mixed with 0.5 ml of almond extract (Schilling). The odor provided subjects (experimental and control) with a common cue to suggest they were receiving an active (not placebo) substance and masked any odor associated with N,O administration. The gas was delivered via a standard nasal mask.
Procedure Tooth stimulation. A rubber dam, stabilized with a ‘Wizard’ type of frame and placed over the maxillary anterior teeth and both maxillary first premolars, was used to minimize salivary interference with the measurements. This type of rubber dam and frame effectively sealed the entire oral cavity and therefore minimized the possibility that mouth breathing would dilute the nasally administered NzO. Electrical stimuli were delivered to the tooth being tested through a 30-ga silver-plated copper wire abutting the labial surface of the middle incisal third of the tooth by means of an acrylic splint containing circular holes (2.5-mm diameter) filled with conducting paste. This wire served as the negative electrode and a positive ECG electrode attached to the cheek completed the circuit. Tooth electrode resistance was measured with an impedance bridge (ES1 SP2596) throughout the procedure to verify that the impedance had not changed. When a human tooth is stimulated electrically with a series of pulses of gradually increasing amplitude, the subject eventually reports a non-painful, indeterminate sensation prior to reporting pain at a higher stimulus intensity (Shimizu 1964; Mumford and Stanley 1981; McGrath et al. 1983; Brown et al. 1985). Subjects in the present study held a response button and received a series of electrical impulses of gradually increasing charge. They were instructed: (1) not to press the button unless they felt a tooth sensa-
Fig. 1. The estimation of detection and pain thresholds is graphically depicted using a repeating staircase procedure. This subject received a total of 63 electrical stimuli delivered to a single maxillary incisor over a 123~set period. Open circles (0) indicate that the subject did not perceive the stimulus, solid circles (01 represent a perceptible but not painful stimulus, and open triangles (A ) indicate that the subject considered the stimulus to be painful. Five staircases were run on this subject’s tooth; the mean detection threshold was 58.6 nC (range: 55.8-61.8) and the mean pain threshold was 85.7 nC (range: 77.6-97.5).
tion; (2) to depress the button once each time they felt a tooth sensation that they would describe as discernible but not painful; and (3) to depress the button twice each time the sensation was painful. Subjects received training on this procedure with stimuli that were separated by a constant interpulse interval (2 set) and that increased by a constant amount of charge on successive stimulations. The increments were sufficiently small that several perceptible but nonpainful sensations were experienced prior to reaching pain threshold. This ‘staircase’ pattern always began with an intensity well below the subject’s detection threshold and ended when the subject first reported feeling pain, i.e., responded with 2 presses. For the actual experiment, both the time between successive stimuli (mean: 2 set) and the increase of intensity were randomized to preclude anticipatory responses. With this pattern, the charge typically increased monotonically but occasionally decreased for 1 or 2 stimulations. Typical data are depicted in Fig. 1. A subject’s detection threshold and pain threshold were both derived. Detection threshold was calculated as the mean of the highest intensity non-detectable stimulation and that of the first detected sensation. Pain threshold was calculated as the mean of the highest perceived but non-painful stimulus and the first painful stimulus. A single detection and pain threshold value was determined for each staircase. Individual detection and pain thresholds were averaged over the several staircases completed during each 2-min period. In principle, subjects would respond with a single button depression to each stimulus falling between their detection and pain thresholds. Failure to do so, and/or responding inappropriately to a stimulus well below detection threshold, were recorded as responding errors by a rater blind to the experimental condition. Experimental protocol. Subjects participated in 3 sessions. During the screening session, the experimental procedures were described, health and drug histories were taken, a clinical dental exam was performed, consent was obtained, and the acrylic splints for tooth stimulation were fabricated. During the training session. subjects practiced the tooth stimulation protocols until they could reliably distinguish detection and pain thresholds. Subjects were excluded from further participation if they could not reliably distinguish the 2 thresholds or if their pain threshold was beyond the limits of maximal charge generated by the stimulator. The testing session (at least 1 week later) began with a lo-min administration of a non-odorized placebo gas mixture. Two maxillary incisors which had been used for training were randomly designated as teeth ‘A’ and ‘B’ to denote
369 TABLE
I
NITROUS
OXIDE
INCREASES Tooth
Time (mini
4- 6 10-12 14-16 20-22 24-26 28-30 32-34 38-40 42-44 46-48 50-52
* * * * * * + * *
Tooth site B
detection
threshold
(nC1
Time (mini
Placebo
tn, S.E.M.1
N,O
(n, S.E.M.1
66.97 74.06 67.76 65.01 66.15 65.40 64.38 71.82 73.54 70.48 77.85
(10, 7.83) (10, 8.061 (10, 8.671 (10, 7.761 (10, 8.241 (IO, 9.701 (IO, 8.911 (10, 7.881 (10, 10.161 (10, 8.00) (10, 8.39)
68.64 72.16 89.76 91.65 99.00 102.97 105.21 95.84 101.70 100.76 105.91
(14, (14, (14, (14, (14, (14, (14, (14, (14, (14, (14.
P < 0.05, Mann-Whitney P < 0.025, Mann-Whitney
’ indicates * indicates
THRESHOLD
site A
Median
(base1 ine)
DETECTION
7.26) 8.521 9.101 10.941 9.691 8.831 9.101 9.56) 11.84) 14.961 10.971
Results Of the 19 N,O subjects, 5 (2 male, 3 female) withdrew from the study shortly after the onset of the drug (range: 11% 194 set) because of anxiety experienced on
threshold
(nC1
(n, S.E.M.)
NzO
tn, S.E.M.)
56.12 60.46 66.03 63.32 66.77 62.57 58.85 59.24 62.77 68.97 72.22
(9, (9, (9, (9, (9, (9. (9, (9, (9. (9, (9,
70.32 103.99 115.10 107.11 lb8.17 116.13 124.26 108.24 113.70 123.80 126.98
(14, t 14, (14, (14, t 14, (14, (14, (14, (14, (14, (14,
7.18) 6.411 7.501 6.541 6.38) 6.821 7.441 8.221 8.721 7.41) 7.60)
9.041 14.581 13.101 12.34) 12.751 13.251 16.391 14.121 14.971 14.621 15.271
N,O administration. None of the 10 placebo subjects withdrew. Due to salivary contamination, 1 tooth in the placebo condition was excluded from the analyses. Sensitivity data were analyzed with non-parametric statistics due to heterogeneity of variance between the 2 gas conditions. Since N,O reliably increases pain and detection thresholds, a l-tailed test of significance was employed. All other analyses used 2-tailed parametric tests. Detection and pain thresholds
Baseline detection and pain thresholds did not differ between the 2 groups (Tables I and II). Median detection threshold significantly increased during N,O inhalation. This was apparent within 4 min and persisted throughout the administration (Table I>. Median pain threshold also increased during N,O inhalation (Table II) and was significantly greater than for the
II
NITROUS
OXIDE
INCREASES Tooth
Time (mini
4- 6 IO-12 14-16 20-22 24-26 28-30 32-34 38-40 42-44 46-48 50-52
(baseline :) * * * * * * * * * *
detection
Placebo
LI (l-tailed). Li (l-tailed).
their temporal order of stimulation. Baseline detection and pain thresholds were determined for teeth A and B between minutes 4-6 and 6-8, respectively. After 10 min. subjects were randomly assigned to receive either odorized placebo or N,O/Oz with the proviso that twice as many N,O as placebo subjects were run. Both the subject and the experimenter operating the tooth stimulator were blind to the condition. Between minutes 4 and 54, assessments alternated between teeth A and B every 2 min with 4 interspersed time-out periods. Alternately stimulating 2 teeth permitted twice as much data collection per experiment while still permitting tracking of threshold change. Also, alternating teeth gave each tooth a ‘rest period’ which reduces the possibility of sensory adaptation that might have occurred with continuous tooth stimulation.
TABLE
6- 8 12-14 16-18 22-24 26-28 30-32 34-36 40-42 44-46 48-50 52-54
Median
Median
(baseline)
+ +
+
’ indicates * indicates
PAIN THRESHOLD Tooth site B
site A pain threshold
(nC)
Time (mini
Placebo
tn, S.E.M.)
NzO
(n, S.E.M.)
130.07 133.72 136.18 138.03 134.07 134.51 129.22 139.85 139.92 143.41 145.46
(10, (10, (10, (10, (10. (10. (10,
111.36 131.56 202.91 153.12 182.51 187.40 189.04 178.11 175.58 170.72 174.66
(14, (14, (13, (14, (14, (14, (14. (14, (14. (14, (14,
17.86) 17.11) 16.441 13.741 15.52) 15.021 14.54) (IO,15.67) (10, 19.071 (10, 10.77) (10. 12.901
P < 0.05, Mann-Whitney P < 0.025, Mann-Whitney
LI (l-tailed). u (l-tailed).
13.67) 15.571 24.321 21.511 21.611 20.991 22.06) 21.35) 23.021 21.861 21.771
6-8 (baseline) 12-14 16-18 * 22-24 26-28 + 30-32 + 34-36 * 40-42 44-46 48-50 52-54
Median
pain threshold
(nC1
Placebo
(n, S.E.M.1
N,O
(n, S.E.M.1
123.86 129.69 128.08 139.48 142.78 130.75 127.47 150.04 122.87 137.06 131.12
(9, (9, (9, (9, (9, (9, (9, (9, (9, (9, (9,
123.36 180.5 1 197.16 200.99 215.51 194.77 209.11 178.53 191.81 189.35 200.99
(14, (14, (14, (14, t 14, (14, (13, (14, (14, (14, f 14,
16.401 19.59) 14.101 15.911 17.871 15.411 16.391 19.24) 18.34) 15.48) 21.681
16.45) 22.96) 23.451 23.23) 23.541 23.551 22.78) 24.641 21.721 25.171 24.88)
370 200
-
320
DEtECTKIN AND PAIN
260
.
240
y
200 160
THRESHDLDS (nanocoulombs)
120 60
+
Odor and 35% Nitrous
Oxide 4 b
Odor and 40% Nitrous
Oxlde
4
00 0
4
12 16 20 24 26 32 36 40 44 46 52 56
6
TIME
0
4
6
12 16 20 24 26 32 36 40 44 46
(minutes)
62 56
TIME (minutes)
Fig. 2. Analgesic effects of N,O remain fairly constant throughout the gas administration for this subject. Detection (0) and pain (i?) ) thresholds were determined by stimulating the maxillary left (and right (. .) central incisors.
Fig. 4. Acute tolerance develops to the analgesic effects of N,O for this subject. Detection (0) and pain (I_?) thresholds were determined ) and left ( ) central by stimulating the maxillary right (incisors.
placebo group between 6-8, 16-26, and 36-38 min after the onset of NzO. Acute tolerance was assessed by comparing sensory thresholds between 4-18 and 32-42 min following the onset of NzO. A return toward baseline threshold (increasing sensitivity) in the second interval relative to the first was interpreted as acute tolerance since N,O reaches a steady-state concentration within the first time interval and the concentration is maintained throughout the remainder of the drug administration. Each of these intervals contains three 2-min assessments for both teeth. The highest mean detection and pain threshold value was determined for each tooth during each interval, and the respective detection and pain thresholds were then compared using a Wilcoxon sign test for differences between related samples. With all N,O subjects included, neither detection nor pain thresholds differed reliably between the 2 intervals (P > 0.05). Likewise pain threshold did not change reliably between the 2 time periods for placebo subjects (P > 0.05). However, the detection threshold for tooth A was significantly higher during the second than
the first interval (z = l.Y9, P < 0.051, but the detection threshold for tooth B did not differ between the 2 intervals (z = 1.72, P > 0.05). The grouped data (Tables I and II) mask considerable between-subject variation in detection and pain thresholds during N,O inhalation. Some subjects had a consistent elevation of their detection and pain thresholds throughout N,O exposure (Fig. 2), while others developed acute tolerance (Figs. 3 and 4). A single subject developed acute sensitization (Fig. 5). Of 14 subjects who received N,O, 4 developed acute tolerance to the detection threshold in both teeth and 1 additional subject developed tolerance in 1 of the 2 teeth. For the pain threshold, 4 of 14 subjects developed tolerance in both teeth and 2 additional subjects developed tolerance in 1 tooth only. Of the 9 subjects receiving placebo, none developed a tolerance-like pattern for the detection threshold and only a single tooth for a single subject would have been categorized as developing tolerance on the pain threshold. Given the parameters of this study, acute tolerance does not develop to the effects of N,O on detection
100
-
300
90 250
60 70 DEtECTION AND PAIN
60 50 -
THRESHOLDS 40 30 20 10 -
+
Odor and 40% Nitrous
Oxide
4
+
Odor and 35% Nitrous
Oxide 4
0 .,.,.,.,‘,.,.,.,‘,‘,.,.,‘,., 0
4
6
12 16 20 24 26 32 36 40
44 48 52 56
TIME (minutes)
Fig. 3. Acute tolerance develops to the analgesic effects of N,O for this subject. Detection (*) and pain (0) thresholds were determined ) and left t..,...)central by stimulating the maxillary right (-----incisors,
0
4
6
12 16 20 24 26 32 36 40 44 40 52 56 TIME
(minutes)
Fig. 5. Analgesic effects of N,O increase throughout the gas administration for this subject. Detection (0) and pain (0) thresholds were ) and left determined by stimulating the maxillary right () lateral incisors. (.
371
SNitrous
Placebo
4Mean Number of Errors Per Four
Oxide
M -
3:
. . Mhluie 21 Block
l-
o-
b
Nitrous
Oxide or Placebo
I I I I I I I I1 0
6
16
24
4
I I I I I I
32
40
46
56
Time (minutes)
Fig. 6. Subjects disruptive
receiving N20 become acutely tolerant to the drug’s effects on the tooth sensation assessment task.
and pain thresholds when all subjects receiving the gas are considered collectively. Except for a small increase in the detection threshold of tooth A (which was not replicated with tooth B), results from the placebo group suggest that baseline tooth sensitivity remained stable throughout the experimental session. This suggests that the present study’s inability to detect acute tolerance is not due to a changing baseline in tooth sensitivity. Response errors
Mean errors (inappropriate or inconsistent responses) per 4-min block are depicted in Fig. 6. The N,O group made significantly more errors than did the placebo group (2-factor repeated measures ANOVA: F (1, 21) = 4.30, P < 0.05). N,O caused an initial increase in error rate which later returned to control values. Post-hoc analysis indicated that the groups differed only during minutes 14-18 (t (21) = 2.13, P < 0.05) which suggests that acute tolerance developed to this effect of N,O. Response latency
The overall mean response latency (defined as the interval between tooth stimulus application and the subject’s response) was 0.46 sec. There were no response latency differences between the placebo and N,O groups at any interval (Tooth A: F (1, 22) = 0.06, P > 0.05; Tooth B: F (1, 22) = 0.05, P > 0.05).
Discussion
The most striking finding was the large intersubject variability observed in the maintenance of the analgesic effectiveness of N,O during a continuous administration. While it is clear that some subjects developed acute tolerance, the effect was not reliable for the group as a whole. Similar findings were reported by Whitwam et al. (1976) who found acute tolerance in 2 of 7 subjects given 33% N,O for 1 h. They concluded
that “with respect to analgesia, adaptation of the nervous system to a constant concentration of nitrous oxide can occur in some subjects” (p. 425). Similarly, Persson (1951) observed that pain thresholds during 30% N,O administration sometimes cease to rise and often decrease. He suggested that there may be organismic ‘accommodation’ (p. 85) to the drug or that “another factor prevails which counteracts the hypalgesic action of nitrous oxide” (p. 56). A single study (Rupreht et al. 1985) has demonstrated the development of acute tolerance to the antinociceptive effects of N,O in a group of human subjects. Using concentrations of N,O sufficiently high to induce loss of consciousness (60-80%), Rupreht and colleagues observed acute tolerance within 45 minutes, and by 150 minutes none of the subjects differed from their pre-drug baseline values. However, generalizing results using anesthetic concentrations of N,O to those obtained at analgesic concentrations may be inappropriate (Gillman and Footerman 1981). Large individual differences have been reported for many effects of N,O (Robson et al. 1960; Garfield et al. 1975; Atkinson and Green 1983), including analgesia. With regards to analgesia, Dworkin et al. (1983a) reported the occasional subject who experienced no analgesia whatsoever to 45% N,O. Benedetti et al. (1982, p. 364) emphasize these individual differences quite clearly, “On the average, the effect of nitrous oxide is very predictable, but at the level of the individual it can affect pain sensations erratically.” Hypotheses have been proposed to account for the large degree of intersubject variability observed during the administration of N,O. Atkinson and Green (1983) hypothesized that specific personality traits of the individual may be responsible for the variable effects of N,O. Alternatively, Dworkin et al. (1983b, 1984) have suggested that individual cognitive interpretations of N,O’s non-specific alteration of perceived bodily sensations accounts for the variable reactions to the drug. They demonstrated experimentally that the analgesic and subjective effects of N,O could be altered by manipulating subjects’ expectations. An appreciation of the individual differences that occur during N,O administration is important clinically. Findings from the present investigation emphasize that clinicians should not assume that the initial analgesic efficacy of N,O will be constant throughout the duration of its administration. Patients should be asked frequently to report their comfort level and the concentration of N,O should be adjusted accordingly to maintain its effectiveness. Acute tolerance unambiguously developed to the disruption of normal performance by N,O as estimated by response errors, and this did not correlate with tolerance to the analgesic effects of N,O. N,O is known to impair psychomotor performance (Steinberg
1954; Garfield et aI. 1975; Kortilia et al. 1981), and Sonnenschein et al. (1948) reported that an increase of pain threshold is correiated with a decrease of psychomotor performance. However, no previous research has reported the development of acute tolerance to N,O-induced psychomotor deficits. Although the cause of the acute tolerance is unknown, it is possible that subjects were able to improve their performance with repeated drugged practice. For example, drugged practice has been shown previously to contribute to the development of tolerance to ethanol’s psychomotor impairment (Wenger et al. 1981). Whatever the mechanism, it appears that tolerance to psychomotor disruption occurred independently of tolerance to analgesia. N,O has several characteristics which make it particularly useful for studying drug tolerance in humans. N,O has a high safety index (Gillman 1982); repeated measurements can be made while maintaining a steady-state drug concentration; and the only human metabolic pathway for N,O is by anaerobic bacteria in the intestine (Trudell 1985), thus limiting dispositional (i.e., pharmacokinetic) exptanations for whatever is observed. Future research should be aimed at identi~ing the subset of individuals who develop tolerance to N,O analgesia and investigating traits that distinguish them from those who do not.
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The authors wish to thank B. Evan McAllister, President of Nitrox Inc., Woodinville, WA, for the design and construction of our unique gas delivery system; Robert C. Bolles, Irwin G. Sarason, and Philip Weinstein for their helpful comments on earlier versions of the manuscript; and the faculty and staff at the Oregon Health Sciences University School of Dentistry for providing the facilities and support necessary to conduct this research. This inv~tigation was supported in part by NIH Grant DE 00161 and by NIDA Grant DA 07391.
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