- Email: [email protected]
Variations in amnesia with intravenous diazepam
oral surgery oral medicine oral pathology wh
onendodontics unddental radiology
XCC~~O~~
Volume 53, Number 4, April, 1982
oral surgery Editor: ROBERT 9. SHIRA, D.D.S. School of Dental Medicine, Tufts University I Kneeland Street Boston Massachusetts 021 I I
Variations in amnesia with intravenous diazepam J. K. Barclay, M. D.S., F.R.A. C.D.S., Dunedin, New Zealand SCHOOL
OF DENTISTRY,
Volunteer
senior
determine
whether
Profoundness exposure events
who
amnesia
of amnesia to the drug.
exposure
significantly are
students
in the immediate
second
UNIVERSITY
better
was
The
two
tested
recall
not previously
than
received
by the intravenous 24 hours
experiences
post-drug
to diazepam than
had
induced
OF OTAGO
after
were
administration following
drug
the first.
was It also
stimuli.
The
following
apart. likely
were
of diazepam
administration
set 28 days period
of cutaneous-tactile
a benzodiazepine administration
The
employed a first
study
showed
to be less
impaired
revealed clinical
that
recall
implications
to
remained
constant.
and that
second recall
following
of visual of these
stimuli
of a was
findings
discussed.
T
he benzodiazepine diazepam is probably regarded as the intravenous anxiolytic of choice for outpatient surgery. It is no exaggeration to suggest that this agent alone has revolutionized minor surgery performed under local analgesia. Whereas in the past patients often dreaded these procedures, many now find such surgery moderately acceptable. Diazepam, when administered intravenously, produces both tranquility and amnesia, and many patients are only too happy to have little or no memory of what they regard as an unpleasant event. It is now generally accepted that memory consists of three stages. Initially there must be storage or acquisition of new information, sometimes referred to as encoding. This is followed by retention, which is maintenance of stored material, and, finally, retrieval, or recovery of the information. Recent work indicates that diazepam acts principally, if not solely, on the first of these stages, acquisition.‘*2 0030-4220/82/040329
+ 06$00.60/O (3 I982 The C. V. Mosby Co.
Diazepam has been shown to produce greater than 70 percent amnesia for local analgesic administration following dose levels that have no significant effect on cardiopulmonary function3 It has also been demonstrated that an average dose of 30 mg. of diazepam administered intravenously will produce 100 percent amnesia,4a dose level in the region of half that required to induce anesthesia.j Additional central nervous system depressant drugs may also be used in conjunction with diazepam in order to raise the pain threshold or to further increase the profoundness and duration of amnesia. However, unsupplemented intravenous diazepam is not infrequently used in general dental practice,6 and it has been my impression that, when used in this way, amnesia is often more profound following the first exposure to the drug than following the second or subsequent exposures. This was first noted when some patients expressed disappointment at the lack 329
330
Barclay
Table I. Range of stimuli to be applied at predetermined times
-__
Time (min.) 2
6
8
IO
12
14
Subdivisions Stimulus
tested J&r rrrall
Group 1: Pin prick, 3 times Back of hand Left (I), right (2) Chin Left (3) right (4) Midline lip Upper (5). lower (6) Group 2: Picture cards (green on white) Car (I ), airplane (2) telephone (3). elephant (4). cat (5), number 4 (6) Group 3: Stroking three times with a spatula Ventral surface forearm Left (I), right (2) Mid cheek Left (3), right (4) Across wrist Left (5). right (6) Group 4: Recorded sounds Air rotor (I ), motor bike (2), dog (3). church bells (4), duck (5), jet plane (6) Group 5: Ethyl chloride spray 6 seconds from 18 inches Palm of hand Left (l), right (2) Dorsal surface forearm Left (3), right (4) Side of neck Left (5), right (6) Group 6: Picture cards (red on white) Horse (l), giraffe (2). boat (3) number 8 (4). turtle (5). Christmas tree (6)
of amnesia following their second experience with the drug, though all admitted to being tranquil. They were frequently patients who had impacted third molar teeth surgically removed one side at a time, with about 3 to 8 weeks between appointments. The duration of the operation on both visits was often similar, and comparable doses of diazepam had usually been administered. When this casual observation concerning amnesia was discussed with colleagues, some confirmed that they suspected much the same. A clinical trial was therefore conducted in order to confirm or refute this observation. METHOD
Medically fit fourth- and fifth-year dental students who had no previous experience of benzodiazepine therapy were asked to volunteer for the investigation. After giving their informed consent, they
site
Type
Object
Color
Site
Type
Request fo listen
Identification
Site
Object
Color
were assigned to Group A or B by a table of random numbers. There were fifteen students in Group A and fifteen students in Group B. Group A
Students assigned to this group received no drugs and were used to assessnormal memory loss over a 24-hour period. They were subjected to a seriesof six stimuli consisting of cutaneous, visual, and auditory stimulations. Each of the six principal stimuli was further subdivided into two (for example, cutaneous stimuli into “site and type,” and visual stimuli into “object and color,” Table I), thus producing a total of twelve factors that could subsequently be tested for recall. The choice of stimulus from within each group was determined by rolling dice, and the stimulus was then presented at the appropriate time. Subjects were not informed that they would subse-
Variations in amnesia with diazepam
Volume 53 Number 4
331
11
77 Q, = 2 ?! 5 .3 E .* v) % & e z’
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
SUBJECTS Fig. 1. Stimuli not recalled on the first and second occasions by subjects in Group B. First occasion, cross-hatched; second occasion, solid. The number of events not recalled is shown at the top of each column.
quently be tested for memory of events. No warning
was given before the administration of the cutaneous stimuli, but participants were requested when necessary to open their eyes and “look at the picture” for stimuli from Group 2 and Group 6. Likewise, they were requested to “listen” before recordings of readily recognized sounds were played. This is a recognized method of assessingamnesia and has been used in other investigations. ‘,a Twenty-four hours later participants were questioned with regard to the stimuli they had received and a record was kept of their responses. In the event of failure to recall a stimulus a prompt was used (for example, “Do you remember a pin prick anywhere?” or “Were you shown a picture?“) A positive was scored when a stimulus was remembered with or without the aid of a prompt. Failure to recall a stimulus was scored as a negative. The same method of testing was then repeated 28 days later with the same group of participants. They were asked not to discuss experimental procedures with anyone. Group B Participants in Group B received an intravenous injection of diazepam into a vein in the antecubital fossa at the rate of 5 mg. per minute. Prior to administration all subjects had received oral and written instructions regarding intricate machinery, alcohol consumption, and driving. Arrangements had been made for them to be taken home by car with an escort 2 hours after drug administration. The dose of diazepam was determined by noting responseto the drug (Table II), with the appearance of three or more signs signifying the need for no further incre-
II. Guidelines used to determine the dose of diazepam
Table
Visible relaxation Altered speech Slurred Garrulous Cessation Slowed movements Drowsiness Ptosis, Verrill sign
ment of diazepam. Cessation of drug administration was taken as zero time, and the dose was recorded. Participants were then subjected to a seriesof stimuli selectedfrom Group 1 to Group 6 and presented over a 1Cminute period (Table I). The selection of stimuli was determined as for Group A by rolling dice, and 24 hours later participants were questioned to determine their ability to recall stimuli. They were not forewarned that they would subsequently be tested for recall of events. A prompt was used, as in Group A, in the event of a stimulus not being recalled. If the prompt elicited accurate recall of the event, it was scored as a positive, with no differentiation being made between recall with or without a prompt. Twenty-eight days after the first exposure to diazepam subjects received the same dose administered over the same period of time, and were then presented with the same experimental procedure. Finally, they were questioned about the second experience 24 hours after diazepam administration as on the first occasion, and their responsesrecorded as positive for recall and negative for failure to recall a stimulus.
332
Barclay
Table
Ill. Recall of experimental procedure-pooled results -_ -___ 7’irne (min.) 2
6
8
IO
12
I4
Oral Surg. ,4pril. 19x2
First Stimulus Pinprick Site Type Total Card Object Color Total Stroking Site Type Total Sounds Request Identification Total Ethyl chloride Site Type Total Card Object Color Total
Negative
Positive
14 14 28
I
12
2
-2 21
-!
3 4 9
5
IO
3
I2
-2 12
s 18
-3 9
2 21
12
3
8
7
11 25
-2 5
2 IS
4 I5
II
4
7
8
-2 20
A IO
s 1s
1 I5
6
9
4
L? IO
11. 20
-2 6
5
IO
4
6
14 24
2? 8
-!
RESULTS Group A
Fourteen of the fifteen participants in Group A were able to recall accurately all the stimuli presented to them 24 hours after the event on both the first and second occasions. One participant failed to recall one stimulus on one occasion. Gioup
euperience
B
The number of events not recalled by each of the participants in Group B on the first and second occasions is shown in Fig. 1. The number of stimuli that could not be recalled 24 hours following the first experimental procedure is shown by the crosshatched bars, and the number of stimuli that could not be recalled on the second occasion is depicted by solid bars. For example, participant No. 1 could not recall ten of the twelve stimuli 24 hours after injection on the first occasion and sevenof the twelve stimuli on the second occasion. Although there is considerable subject variation with regard to the amount of amnesia it will be noted that ten subjects had greater recall following the second experimental procedure than following the first. Participant No. 9 had recall of an equal number of events on both occasions, and four participants (Nos. 5, 8, 12, and 13) could recall less on the second occasion than
II 13 24 II L! 22
following their first experience. There was therefore a bias toward better recall of events on the second occasion, but chi-square tests revealed no significant difference when participants’ results were checked individually. Results of participants’ recall were then pooled, as were the two subdivisions of each of the six principal stimuli, thus giving a total of thirty stimuli for the fifteen participants. This information is shown in Table III and is also presented in graph form in Fig. 2, where the first experience is shown as a continuous line and the secondexperience as a dotted line. With one exception, amnesia was observed to be more pronounced following the first than the second occasion. Chi-square tests of this material revealed that two of the six principal stimuli-“pin prick” at 2 minutes and “stroking” at 8 minutes-were recalled with significantly greater frequency following the second exposure to diazepam than following the first (0.02 < P < 0.05 and 0.01 < P < 0.02, respectively). Three of the other stimuli-“picture card” (green on white) at 6 minutes, “recorded sounds” at 10 minutes, and “ethyl chloride spray” at 12 minutesshowed a bias toward better recall on the second occasion than on the first, but the differences were not statistically significant. “Picture cards” (red on
Volume Number
Variations in amnesia with diazepam
53 4
white) presented at 14 minutes after injection were recalled with a marginally greater degree of accuracy by more participants following the first rather than the second exposure to diazepam. This difference was not statistically significant. Results for all fifteen participants were pooled, giving a total of 180 stimuli on the first and again on the secondoccasion. Chi-square tests between first and second occasions revealed a highly significant difference (x2 = 7.516, Yates correction 0.005 < P < O.Ol), with greater recall on the second occasion. Fig. 2 shows that amnesia was maximal on both occasionswhen first tested at 2 minutes after administration. It also reveals the well-recognized rapid decrease in amnesia with the passageof time?,“*” and this was present following both the first and secondexperiences.The exception to this generalized falloff in amnesia was recall of visual stimulus (green on white) presented at 6 minutes after drug administration. This event was generally recalled accurately and with greater frequency than other stimuli presented at 8 and 10 minutes following both the first and second experiences with diazepam. Standard error tests were used to determine whether this high frequency of recall for visual stimuli at 6 minutes was significant. Recall of stimuli at 2 and 8 minutes following the first experience was not significantly different, but memories of events that occurred at 2 and 6 minutes, and again at 6 and 8 minutes, were significantly different (P < 0.01 on both occasions). There was also a significant difference (P < 0.01) for recall of events presented at 2 and 6 minutes following the second experience with diazepam. DISCUSSION
Recall of events 24 hours after stimulation was all but total for subjects in Group A on both the first and second occasions. Gelfman and associates’*also found that their control group had accurate and total recall of visual and cutaneous-tactile stimuli when questioned 3 hours and 1 week after the event. In the undrugged state the type of subjects who participated in the present investigation also had accurate recall of the experimental procedure. It may therefore be concluded that any deviation from this pattern of recall was due to the administration of diazepam, as this was the only experimental factor that differed between Group A and Group B. Likewise, any difference in ability to recall events by participants in Group B following their first and second experienceswith diazepam may be attributed solely to the drug. The present study reveals that, for a short period after administration, memory of events is likely to be
-
3Or
333
Ftrst expertewe
26 221814 10 6I2
4
6
TIME IN MINUTES
8
10
12
14
POST-INJECTION
Fig. 2. Failure to recall stimuli, pooled results, in relation to time.
better following a second experience with intravenous diazepam than following the first. Presumably, a second experience, similar in nature to the first, reinforces the ability to recall events, even when the experience occurred in the drugged state. The study, however, does not indicate the length of time that this difference exists. It is probable that the difference is greatest in the immediate postadministration period, when amnesia is usually most profound. Nevertheless, this finding may need to be taken into account when a patient who seeksgood amnesia requires intravenous sedation with diazepam on a secondoccasion not too far removed in time from the first. Consideration may need to be given to either increasing the dose of diazepam or using additional and appropriate central nervous system depressant drugs to provide the desired amnesia.‘3Gelfman and associates” failed to demonstrate tolerance with regard to amnesia when using intravenous diazepam, but in their series they employed methohexitone, or fentanyl and methohexitone, in conjunction with diazepam. Although it has been stated that amnesia following intravenous diazepam is nonselective,14this was not found to be the case in the present investigation. Following the first exposure to diazepam, visual stimuli presented at 6 minutes after drug administration were recalled with significantly greater frequency than cutaneous-tactile-auditory stimuli that immediately preceded and followed the visual stimuli. After the second experience with diazepam this trend was also evident, as illustrated by the parallel
334
Barclay
nature of the graphs as seen in Fig. 2. On this occasion, however, recall of stimuli immediately before and after the visual stimulus was statistically different only between stimuli presented at 2 and 6 minutes and not between stimuli presented at 6 and 8 minutes. The present study provides further support for the earlier findings of Clark and associates,‘5Dundee and Pandit,i6 and more recently Conner and associates” that amnesia is pronounced immediately after intravenous administration of diazepam. In addition, it indicates that there is significantly better recall of visual stimuli during this period than there is for other forms of stimulation. The ability to recall visual stimuli more readily than cutaneous-tactile stimuli has already been noted.12As the majority of our learning experiencesare visual in nature, perhaps this observation should cause little surprise. However, it doeshave implications for the clinical situation, as the pattern of amnesia for controlled stimuli probably reflects the pattern of amnesia for the uncontrolled clinical situation.14 For the clinician who wishes to achieve maximal amnesia for his patient, there could be some merit in covering the patient’s eyes with a drape. It is likely that the less the patient sees, the less will be remembered. An appropriately sized and located window would provide accessto the mouth and still maintain shielding of the eyes.A statement to the effect that it is to keep the light from the eyes may be offered to the patient by way of explanation. It seems likely that this simple maneuver, which would interrupt visual stimulation, would enhance amnesia induced by intravenously administered diazepam. I wish to acknowledge the assistance of D.H. McClymont with the statistical analysis, and to thank the students who volunteered for the study. REFERENCES I. Clark, E. 0.. Glanzer, N., and Turndort, A.: The Pattern of Memory Loss Resulting From intravenously Administered Diazepam, Arch. Neurol 36: 296-300, 1979.
Oral Surg. April, 1982 2. Petersen, R. C., and Choneim, M. M.: Diazepam and Human Memory, Influence on Acquisition, Retrieval and State Dependent Learning, Prog. Nemo-Psychopharm. 4: 81-88, 1980. 3. Driscole, E. J., Smilack, Z. Ii., Lightbody, P. M., Park, F., and Fiorucci, R. D.: Sedation With Intravenous Diazepam, J. Oral Surg. 30: 332-343, 1972. 4. Keiety, S. R., and Blackwood, S.: Sedation for Conservative Dentistry, Br. J. Clin. Pratt. 23: 365-367, 1969. 5. Brown, S. S., and Dundee, J. W.: Clinical Studies of Induction Agents. XXV. Diazepam, Br. J. Anaesth. 40: 108-I 12, 1968. 6. Barclay, J. K.: Pain and Anxiety Control in Dental Practice:
Report of a Survey, N. Z. Dent. J. 75: 87-93, 1979. 7. Dundee, J. W., and Pandit, S. K.: Anterograde Amnesic Effects of Pethidine Hyoscine and Diazepam in Adults, Br. J. Pharmacol. 44: 140-144, 1972. 8. Barclay, J. K., Hunter, K. MacD., and Jones, H.: Diazepam and Lorazepam Compared as Sedatives for Outpatient Third Molar Surgery, Br. J. Oral Surg. 18: 141-149, 1980. 9. Conner, J. T., Bellville, J. W., Wender, R. H., Wapner, S., and Katz, R. L. Evaluation of Intravenous Diazepam as a Surgical Premedicant, Anesth. Analg. 56: 21 l-215, 1977. 10. Henr, G. P., Conner, J. T., Katz, R. L. Dorey, J. L.‘Armand, and Schehl, D.: Diazepam and Dropenidol as I.V. Premedicants, Br. J. Anaesth. 51: 537-542, 1979. Il. George, K. A., and Dundee, J. W.: Relative Amnesic Actions of Diazepam, Flunitazepam and Lorazepam in Man, Br. J. Clin. Pharmacol. 4: 45-50, 1977. 12. Gelfman, S. S., Gracley, R. H., Driscoll, J., Windzek, P. R., Sweet, J. B., and Butler, D. P.: Conscious Sedation With Intravenous Drugs: A Study of Amnesia, J. Oral Surg. 36: 292-297, 1978. 13. Grainzer, J.. and Marshall, K.: The Jorgensen Technique Revisited, a Comparison With Intravenous Diazepam, Dent. Anaesth. Sed. 10: 75-78, 1981. 14. Gregg, J. M., Ryan, D. E., and Levin, K. H.: The Amnesic Actions of Diazepam, J. Oral Surg. 32: 651-664, 1974. 15. Clark, P. R. F., Eccersley, P. S., Frisby, J. P., and Thornton, J. A.: The Amnesic ElTects of Diazepam (Valium), Br. J. Anaesth. 42: 690-697, 1970. 16. Dundee, J. W., and Pandit, S. K.: Studies on Drug induced Amnesia With lntravenous Anaesthetic Agents in Man, Br. J. Clin. Pratt. 26: 164-166, 1972. 17. Conner, J. T., Katz, R. L.. Bellville, J. W., Graham, C., Pazano, R., and Dorey, F.: Diazepam and Lorazepam for Intravenous Surgical Premeditation, J. Clin. Pharmacol. 5-6: 285-292, 1978.
Reprint requests to: J. K. Barclay, M.D.S., F.R.A.C.D.S. School of Dentistry, University of Otago P.O. Box 647 Dunedin, New Zealand
onendodontics unddental radiology
XCC~~O~~
Volume 53, Number 4, April, 1982
oral surgery Editor: ROBERT 9. SHIRA, D.D.S. School of Dental Medicine, Tufts University I Kneeland Street Boston Massachusetts 021 I I
Variations in amnesia with intravenous diazepam J. K. Barclay, M. D.S., F.R.A. C.D.S., Dunedin, New Zealand SCHOOL
OF DENTISTRY,
Volunteer
senior
determine
whether
Profoundness exposure events
who
amnesia
of amnesia to the drug.
exposure
significantly are
students
in the immediate
second
UNIVERSITY
better
was
The
two
tested
recall
not previously
than
received
by the intravenous 24 hours
experiences
post-drug
to diazepam than
had
induced
OF OTAGO
after
were
administration following
drug
the first.
was It also
stimuli.
The
following
apart. likely
were
of diazepam
administration
set 28 days period
of cutaneous-tactile
a benzodiazepine administration
The
employed a first
study
showed
to be less
impaired
revealed clinical
that
recall
implications
to
remained
constant.
and that
second recall
following
of visual of these
stimuli
of a was
findings
discussed.
T
he benzodiazepine diazepam is probably regarded as the intravenous anxiolytic of choice for outpatient surgery. It is no exaggeration to suggest that this agent alone has revolutionized minor surgery performed under local analgesia. Whereas in the past patients often dreaded these procedures, many now find such surgery moderately acceptable. Diazepam, when administered intravenously, produces both tranquility and amnesia, and many patients are only too happy to have little or no memory of what they regard as an unpleasant event. It is now generally accepted that memory consists of three stages. Initially there must be storage or acquisition of new information, sometimes referred to as encoding. This is followed by retention, which is maintenance of stored material, and, finally, retrieval, or recovery of the information. Recent work indicates that diazepam acts principally, if not solely, on the first of these stages, acquisition.‘*2 0030-4220/82/040329
+ 06$00.60/O (3 I982 The C. V. Mosby Co.
Diazepam has been shown to produce greater than 70 percent amnesia for local analgesic administration following dose levels that have no significant effect on cardiopulmonary function3 It has also been demonstrated that an average dose of 30 mg. of diazepam administered intravenously will produce 100 percent amnesia,4a dose level in the region of half that required to induce anesthesia.j Additional central nervous system depressant drugs may also be used in conjunction with diazepam in order to raise the pain threshold or to further increase the profoundness and duration of amnesia. However, unsupplemented intravenous diazepam is not infrequently used in general dental practice,6 and it has been my impression that, when used in this way, amnesia is often more profound following the first exposure to the drug than following the second or subsequent exposures. This was first noted when some patients expressed disappointment at the lack 329
330
Barclay
Table I. Range of stimuli to be applied at predetermined times
-__
Time (min.) 2
6
8
IO
12
14
Subdivisions Stimulus
tested J&r rrrall
Group 1: Pin prick, 3 times Back of hand Left (I), right (2) Chin Left (3) right (4) Midline lip Upper (5). lower (6) Group 2: Picture cards (green on white) Car (I ), airplane (2) telephone (3). elephant (4). cat (5), number 4 (6) Group 3: Stroking three times with a spatula Ventral surface forearm Left (I), right (2) Mid cheek Left (3), right (4) Across wrist Left (5). right (6) Group 4: Recorded sounds Air rotor (I ), motor bike (2), dog (3). church bells (4), duck (5), jet plane (6) Group 5: Ethyl chloride spray 6 seconds from 18 inches Palm of hand Left (l), right (2) Dorsal surface forearm Left (3), right (4) Side of neck Left (5), right (6) Group 6: Picture cards (red on white) Horse (l), giraffe (2). boat (3) number 8 (4). turtle (5). Christmas tree (6)
of amnesia following their second experience with the drug, though all admitted to being tranquil. They were frequently patients who had impacted third molar teeth surgically removed one side at a time, with about 3 to 8 weeks between appointments. The duration of the operation on both visits was often similar, and comparable doses of diazepam had usually been administered. When this casual observation concerning amnesia was discussed with colleagues, some confirmed that they suspected much the same. A clinical trial was therefore conducted in order to confirm or refute this observation. METHOD
Medically fit fourth- and fifth-year dental students who had no previous experience of benzodiazepine therapy were asked to volunteer for the investigation. After giving their informed consent, they
site
Type
Object
Color
Site
Type
Request fo listen
Identification
Site
Object
Color
were assigned to Group A or B by a table of random numbers. There were fifteen students in Group A and fifteen students in Group B. Group A
Students assigned to this group received no drugs and were used to assessnormal memory loss over a 24-hour period. They were subjected to a seriesof six stimuli consisting of cutaneous, visual, and auditory stimulations. Each of the six principal stimuli was further subdivided into two (for example, cutaneous stimuli into “site and type,” and visual stimuli into “object and color,” Table I), thus producing a total of twelve factors that could subsequently be tested for recall. The choice of stimulus from within each group was determined by rolling dice, and the stimulus was then presented at the appropriate time. Subjects were not informed that they would subse-
Variations in amnesia with diazepam
Volume 53 Number 4
331
11
77 Q, = 2 ?! 5 .3 E .* v) % & e z’
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
SUBJECTS Fig. 1. Stimuli not recalled on the first and second occasions by subjects in Group B. First occasion, cross-hatched; second occasion, solid. The number of events not recalled is shown at the top of each column.
quently be tested for memory of events. No warning
was given before the administration of the cutaneous stimuli, but participants were requested when necessary to open their eyes and “look at the picture” for stimuli from Group 2 and Group 6. Likewise, they were requested to “listen” before recordings of readily recognized sounds were played. This is a recognized method of assessingamnesia and has been used in other investigations. ‘,a Twenty-four hours later participants were questioned with regard to the stimuli they had received and a record was kept of their responses. In the event of failure to recall a stimulus a prompt was used (for example, “Do you remember a pin prick anywhere?” or “Were you shown a picture?“) A positive was scored when a stimulus was remembered with or without the aid of a prompt. Failure to recall a stimulus was scored as a negative. The same method of testing was then repeated 28 days later with the same group of participants. They were asked not to discuss experimental procedures with anyone. Group B Participants in Group B received an intravenous injection of diazepam into a vein in the antecubital fossa at the rate of 5 mg. per minute. Prior to administration all subjects had received oral and written instructions regarding intricate machinery, alcohol consumption, and driving. Arrangements had been made for them to be taken home by car with an escort 2 hours after drug administration. The dose of diazepam was determined by noting responseto the drug (Table II), with the appearance of three or more signs signifying the need for no further incre-
II. Guidelines used to determine the dose of diazepam
Table
Visible relaxation Altered speech Slurred Garrulous Cessation Slowed movements Drowsiness Ptosis, Verrill sign
ment of diazepam. Cessation of drug administration was taken as zero time, and the dose was recorded. Participants were then subjected to a seriesof stimuli selectedfrom Group 1 to Group 6 and presented over a 1Cminute period (Table I). The selection of stimuli was determined as for Group A by rolling dice, and 24 hours later participants were questioned to determine their ability to recall stimuli. They were not forewarned that they would subsequently be tested for recall of events. A prompt was used, as in Group A, in the event of a stimulus not being recalled. If the prompt elicited accurate recall of the event, it was scored as a positive, with no differentiation being made between recall with or without a prompt. Twenty-eight days after the first exposure to diazepam subjects received the same dose administered over the same period of time, and were then presented with the same experimental procedure. Finally, they were questioned about the second experience 24 hours after diazepam administration as on the first occasion, and their responsesrecorded as positive for recall and negative for failure to recall a stimulus.
332
Barclay
Table
Ill. Recall of experimental procedure-pooled results -_ -___ 7’irne (min.) 2
6
8
IO
12
I4
Oral Surg. ,4pril. 19x2
First Stimulus Pinprick Site Type Total Card Object Color Total Stroking Site Type Total Sounds Request Identification Total Ethyl chloride Site Type Total Card Object Color Total
Negative
Positive
14 14 28
I
12
2
-2 21
-!
3 4 9
5
IO
3
I2
-2 12
s 18
-3 9
2 21
12
3
8
7
11 25
-2 5
2 IS
4 I5
II
4
7
8
-2 20
A IO
s 1s
1 I5
6
9
4
L? IO
11. 20
-2 6
5
IO
4
6
14 24
2? 8
-!
RESULTS Group A
Fourteen of the fifteen participants in Group A were able to recall accurately all the stimuli presented to them 24 hours after the event on both the first and second occasions. One participant failed to recall one stimulus on one occasion. Gioup
euperience
B
The number of events not recalled by each of the participants in Group B on the first and second occasions is shown in Fig. 1. The number of stimuli that could not be recalled 24 hours following the first experimental procedure is shown by the crosshatched bars, and the number of stimuli that could not be recalled on the second occasion is depicted by solid bars. For example, participant No. 1 could not recall ten of the twelve stimuli 24 hours after injection on the first occasion and sevenof the twelve stimuli on the second occasion. Although there is considerable subject variation with regard to the amount of amnesia it will be noted that ten subjects had greater recall following the second experimental procedure than following the first. Participant No. 9 had recall of an equal number of events on both occasions, and four participants (Nos. 5, 8, 12, and 13) could recall less on the second occasion than
II 13 24 II L! 22
following their first experience. There was therefore a bias toward better recall of events on the second occasion, but chi-square tests revealed no significant difference when participants’ results were checked individually. Results of participants’ recall were then pooled, as were the two subdivisions of each of the six principal stimuli, thus giving a total of thirty stimuli for the fifteen participants. This information is shown in Table III and is also presented in graph form in Fig. 2, where the first experience is shown as a continuous line and the secondexperience as a dotted line. With one exception, amnesia was observed to be more pronounced following the first than the second occasion. Chi-square tests of this material revealed that two of the six principal stimuli-“pin prick” at 2 minutes and “stroking” at 8 minutes-were recalled with significantly greater frequency following the second exposure to diazepam than following the first (0.02 < P < 0.05 and 0.01 < P < 0.02, respectively). Three of the other stimuli-“picture card” (green on white) at 6 minutes, “recorded sounds” at 10 minutes, and “ethyl chloride spray” at 12 minutesshowed a bias toward better recall on the second occasion than on the first, but the differences were not statistically significant. “Picture cards” (red on
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Variations in amnesia with diazepam
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white) presented at 14 minutes after injection were recalled with a marginally greater degree of accuracy by more participants following the first rather than the second exposure to diazepam. This difference was not statistically significant. Results for all fifteen participants were pooled, giving a total of 180 stimuli on the first and again on the secondoccasion. Chi-square tests between first and second occasions revealed a highly significant difference (x2 = 7.516, Yates correction 0.005 < P < O.Ol), with greater recall on the second occasion. Fig. 2 shows that amnesia was maximal on both occasionswhen first tested at 2 minutes after administration. It also reveals the well-recognized rapid decrease in amnesia with the passageof time?,“*” and this was present following both the first and secondexperiences.The exception to this generalized falloff in amnesia was recall of visual stimulus (green on white) presented at 6 minutes after drug administration. This event was generally recalled accurately and with greater frequency than other stimuli presented at 8 and 10 minutes following both the first and second experiences with diazepam. Standard error tests were used to determine whether this high frequency of recall for visual stimuli at 6 minutes was significant. Recall of stimuli at 2 and 8 minutes following the first experience was not significantly different, but memories of events that occurred at 2 and 6 minutes, and again at 6 and 8 minutes, were significantly different (P < 0.01 on both occasions). There was also a significant difference (P < 0.01) for recall of events presented at 2 and 6 minutes following the second experience with diazepam. DISCUSSION
Recall of events 24 hours after stimulation was all but total for subjects in Group A on both the first and second occasions. Gelfman and associates’*also found that their control group had accurate and total recall of visual and cutaneous-tactile stimuli when questioned 3 hours and 1 week after the event. In the undrugged state the type of subjects who participated in the present investigation also had accurate recall of the experimental procedure. It may therefore be concluded that any deviation from this pattern of recall was due to the administration of diazepam, as this was the only experimental factor that differed between Group A and Group B. Likewise, any difference in ability to recall events by participants in Group B following their first and second experienceswith diazepam may be attributed solely to the drug. The present study reveals that, for a short period after administration, memory of events is likely to be
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Fig. 2. Failure to recall stimuli, pooled results, in relation to time.
better following a second experience with intravenous diazepam than following the first. Presumably, a second experience, similar in nature to the first, reinforces the ability to recall events, even when the experience occurred in the drugged state. The study, however, does not indicate the length of time that this difference exists. It is probable that the difference is greatest in the immediate postadministration period, when amnesia is usually most profound. Nevertheless, this finding may need to be taken into account when a patient who seeksgood amnesia requires intravenous sedation with diazepam on a secondoccasion not too far removed in time from the first. Consideration may need to be given to either increasing the dose of diazepam or using additional and appropriate central nervous system depressant drugs to provide the desired amnesia.‘3Gelfman and associates” failed to demonstrate tolerance with regard to amnesia when using intravenous diazepam, but in their series they employed methohexitone, or fentanyl and methohexitone, in conjunction with diazepam. Although it has been stated that amnesia following intravenous diazepam is nonselective,14this was not found to be the case in the present investigation. Following the first exposure to diazepam, visual stimuli presented at 6 minutes after drug administration were recalled with significantly greater frequency than cutaneous-tactile-auditory stimuli that immediately preceded and followed the visual stimuli. After the second experience with diazepam this trend was also evident, as illustrated by the parallel
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nature of the graphs as seen in Fig. 2. On this occasion, however, recall of stimuli immediately before and after the visual stimulus was statistically different only between stimuli presented at 2 and 6 minutes and not between stimuli presented at 6 and 8 minutes. The present study provides further support for the earlier findings of Clark and associates,‘5Dundee and Pandit,i6 and more recently Conner and associates” that amnesia is pronounced immediately after intravenous administration of diazepam. In addition, it indicates that there is significantly better recall of visual stimuli during this period than there is for other forms of stimulation. The ability to recall visual stimuli more readily than cutaneous-tactile stimuli has already been noted.12As the majority of our learning experiencesare visual in nature, perhaps this observation should cause little surprise. However, it doeshave implications for the clinical situation, as the pattern of amnesia for controlled stimuli probably reflects the pattern of amnesia for the uncontrolled clinical situation.14 For the clinician who wishes to achieve maximal amnesia for his patient, there could be some merit in covering the patient’s eyes with a drape. It is likely that the less the patient sees, the less will be remembered. An appropriately sized and located window would provide accessto the mouth and still maintain shielding of the eyes.A statement to the effect that it is to keep the light from the eyes may be offered to the patient by way of explanation. It seems likely that this simple maneuver, which would interrupt visual stimulation, would enhance amnesia induced by intravenously administered diazepam. I wish to acknowledge the assistance of D.H. McClymont with the statistical analysis, and to thank the students who volunteered for the study. REFERENCES I. Clark, E. 0.. Glanzer, N., and Turndort, A.: The Pattern of Memory Loss Resulting From intravenously Administered Diazepam, Arch. Neurol 36: 296-300, 1979.
Oral Surg. April, 1982 2. Petersen, R. C., and Choneim, M. M.: Diazepam and Human Memory, Influence on Acquisition, Retrieval and State Dependent Learning, Prog. Nemo-Psychopharm. 4: 81-88, 1980. 3. Driscole, E. J., Smilack, Z. Ii., Lightbody, P. M., Park, F., and Fiorucci, R. D.: Sedation With Intravenous Diazepam, J. Oral Surg. 30: 332-343, 1972. 4. Keiety, S. R., and Blackwood, S.: Sedation for Conservative Dentistry, Br. J. Clin. Pratt. 23: 365-367, 1969. 5. Brown, S. S., and Dundee, J. W.: Clinical Studies of Induction Agents. XXV. Diazepam, Br. J. Anaesth. 40: 108-I 12, 1968. 6. Barclay, J. K.: Pain and Anxiety Control in Dental Practice:
Report of a Survey, N. Z. Dent. J. 75: 87-93, 1979. 7. Dundee, J. W., and Pandit, S. K.: Anterograde Amnesic Effects of Pethidine Hyoscine and Diazepam in Adults, Br. J. Pharmacol. 44: 140-144, 1972. 8. Barclay, J. K., Hunter, K. MacD., and Jones, H.: Diazepam and Lorazepam Compared as Sedatives for Outpatient Third Molar Surgery, Br. J. Oral Surg. 18: 141-149, 1980. 9. Conner, J. T., Bellville, J. W., Wender, R. H., Wapner, S., and Katz, R. L. Evaluation of Intravenous Diazepam as a Surgical Premedicant, Anesth. Analg. 56: 21 l-215, 1977. 10. Henr, G. P., Conner, J. T., Katz, R. L. Dorey, J. L.‘Armand, and Schehl, D.: Diazepam and Dropenidol as I.V. Premedicants, Br. J. Anaesth. 51: 537-542, 1979. Il. George, K. A., and Dundee, J. W.: Relative Amnesic Actions of Diazepam, Flunitazepam and Lorazepam in Man, Br. J. Clin. Pharmacol. 4: 45-50, 1977. 12. Gelfman, S. S., Gracley, R. H., Driscoll, J., Windzek, P. R., Sweet, J. B., and Butler, D. P.: Conscious Sedation With Intravenous Drugs: A Study of Amnesia, J. Oral Surg. 36: 292-297, 1978. 13. Grainzer, J.. and Marshall, K.: The Jorgensen Technique Revisited, a Comparison With Intravenous Diazepam, Dent. Anaesth. Sed. 10: 75-78, 1981. 14. Gregg, J. M., Ryan, D. E., and Levin, K. H.: The Amnesic Actions of Diazepam, J. Oral Surg. 32: 651-664, 1974. 15. Clark, P. R. F., Eccersley, P. S., Frisby, J. P., and Thornton, J. A.: The Amnesic ElTects of Diazepam (Valium), Br. J. Anaesth. 42: 690-697, 1970. 16. Dundee, J. W., and Pandit, S. K.: Studies on Drug induced Amnesia With lntravenous Anaesthetic Agents in Man, Br. J. Clin. Pratt. 26: 164-166, 1972. 17. Conner, J. T., Katz, R. L.. Bellville, J. W., Graham, C., Pazano, R., and Dorey, F.: Diazepam and Lorazepam for Intravenous Surgical Premeditation, J. Clin. Pharmacol. 5-6: 285-292, 1978.
Reprint requests to: J. K. Barclay, M.D.S., F.R.A.C.D.S. School of Dentistry, University of Otago P.O. Box 647 Dunedin, New Zealand