British Journal of Anaesthesia 1991; 66: 20-24
TEMAZEPAM ABSORPTION IN PATIENTS BEFORE SURGERY H. E. HOSIE AND W. S. NIMMO (AS ^ AT) [6]. In other words, those with increased anxiety tended to have delayed gastric emptying. The aims of this study were to compare the absorption and effects of temazepam in the capsule and elixir formulations in patients awaiting surgery, and to investigate the relationship between anxiety and absorption and the relationship between plasma concentration and effect.
We have compared the rates of absorption and efficacies of temazepam 30 mg in elixir and capsule formulations in 100 patients before surgery. Both formulations provided anxio/ysis and sedation, but there was wide variation in plasma concentrations of temazepam between individuals and between formulations. The presence or absence of anxiety did not influence the absorption of the preparations. It is suggested PATIENTS AND METHODS that plasma concentrations in excess of 200 ng 1 ml~ are required for sedation and anxio/ysis, and One hundred patients, aged 16-70 yr and ASA that this may be achieved more reliably using the grades I or II, having elective surgery gave written informed consent to take part in the study, which elixir formulation. KEY WORDS Premedication: temazepam.
Temazepam is used orally as a premedicant to provide anxiolysis and sedation. Its short duration of action allows rapid recovery without prolongation of sedation into the postoperative period [1]. Temazepam is available commercially in four forms in the United Kingdom and studies of its bioavailability and pharmacokinetics in different vehicles have been carried out in healthy volunteers [2-4]. In a previous study using an elixir formulation, wide variation in plasma concentration of temazepam was found at the time of surgery [5]. Preoperative anxiety may have an effect on gastric emptying and hence drug absorption [6, 7]. In a study of paracetamol absorption in patients awaiting operation, Simpson and Stakes showed that patients with low anxiety trait (AT) scores who had high anxiety state (AS) scores (AS > AT) before operation had delayed gastric emptying compared with patients who had anxiety state scores similar to or less than their trait scores
was approved by the local Ethics Committee. Patients were excluded if they had a history of hepatic or renal disease, previous gastric surgery or gastrointestinal disease, were taking concomitant benzodiazepine therapy or drugs known to affect gastric emptying, or were pregnant. Patients were allocated randomly to one of three groups: group 1 patients were given temazepam 30 mg in capsules with placebo elixir 15ml; group 2 received temazepam 30 mg in elixir with placebo capsules; group 3 received placebo capsules and elixir. Nursing staff and patients were unaware of which medication had been used. The premedication was timed to be given 1 h before the start of surgery, but in most instances surgery did not commence until 2 h after premedication. Venous blood samples were taken every 15 min for 2 h after premedication for assay of plasma
HEATHER E. HOSIE*, M.B., CH.B., F.C.ANAES.; W. S. NIMMO-J-,
B.SC, M.D., F.R.C.P., F.C.ANAES., F.F.A.R.A.C.S. ; Department of
Anaesthesia, University of Sheffield, Sheffield S10 2RX. Accepted for Publication: August 6, 1990. Present addresses: •Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF. fRoyal Infirmary, Lauriston Place, Edinburgh EH3 9YW.
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
SUMMARY
TEMAZEPAM ABSORPTION
21
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
concentration of temazepam by high pressure TABLE I. Mean (range) age and toeight, and sex distribution of patients liquid chromatogTaphy (HPLC) [5]. Anxiety was assessed using the linear visual Weight Age analogue anxiety scale (VAS) and the Spielberger M F (kg) (yr) State Trait Anxiety Inventory (STAI) [8]. The VAS comprised a 100-mm line with anxious/ Group 1 8 32 68.5 Capsules 41 apprehensive and relaxed/confident end-points, (46.5-103) (n = 40) (16-68) and measurement from the "relaxed" end. The Group 2 STAI is a reliable method of assessing anxiety 42 71.2 Elixir 10 30 (17-64) (45.5-120) (n = 40) which gives two scores: the anxiety state, which measures anxiety to the acute situation, and the Group 3 67.9 46 Placebo 5 15 anxiety trait, which represents an individual's (18-65) 47-96.5) (n = 20) anxiety about everyday situations ("chronic" anxiety). Anxiety was assessed before premedication no significant differences between the groups with using the VAS and both parts of the STAI. respect to age, weight or sex (table I). Measurement of immediate anxiety was repeated 60 min after oral premedication using the VAS Plasma concentration of temazepam Plasma concentration of temazepam were and the state anxiety component of the STAI. Sedation was measured at 15-min intervals measured until induction of anaesthesia. Techafter premedication using a four-point self-rating nical problems or early operation prevented scale. Patients classified themselves as awake, analysis in three patients. In many patients drowsy or sleepy and the observer classified them temazepam was present in the first sample and as asleep if they did not respond to verbal contact. this reflected residual drug following adminisStatistical analysis of the data included analysis tration of a hypnotic dose on the previous of variance and unpaired t tests for parametric evening. data, Wilcoxon paired rank sum test and Mann— There were no significant differences between Whitney U test for non-parametric data, chi- the formulations, at any time, in mean plasma square analysis for nominal data and the Spear- concentration of temazepam. Mean peak plasma mann rank correlation coefficient. concentrations of about 800 ng ml~l occurred 30 min after premedication (table II). There were marked differences in plasma RESULTS concentrations both between individuals and Forty patients were given temazepam in capsules between those given capsules and those pre(group 1), 40 received temazepam in elixir medicated with elixir (figs 1, 2). Peak plasma (group 2) and 20 placebo (group 3). There were concentrations occurred at 15—105 min and varied
TABLE II. Mean (SEM) plasma concentrations of temazepam (ng ml'1) after oral temazepam 30 mg for the different formulations and in patients with low anxiety trail but high anxiety scores (AS > AT) and those with anxiety slate scores similar to or less than their anxiety trait scores (AS J£ AT) before operation. *P < 0.05 compared with AS > AT at same time Time (min) 0 Capsules Elixir AS>AT AS $ AT
30 (8) 57 (20) 38 (9) 62 (27)
15
30
384 (127) 528 (73) 410 (87) 547 (171)
869 (135) 796 (73) 938 (106) 681 (139)
45
60
75
90
105
120
660 (88) 774 (64) 789 (69) 546* (95)
694 (68) 740 (50) 111 (60) 614 (67)
689 (83) 701 (37) 674 (51) 753 (77)
683 (61) 658 (54) 608 (43) 764 (74)
596 (53) 624 (86) 549 (54) 682 (85)
577 (62) 617 (70) 575 (63) 619 (126)
BRITISH JOURNAL OF ANAESTHESIA
22
60
90
120
FIG. 1. Plasma concentrations of temazepam in patients given temazepam in capsule form. 3000
c
E 03 Q. O
Sedation For purposes of statistical analysis, patients were grouped as sedated (sleepy, drowsy and asleep) or unsedated (awake). Significant sedation was seen in the groups given active temazepam at 30,45 and 60 min. There was no overall difference between capsules and elixir and no significant sedation was seen in the placebo group.
2000-
1000-
E
0
30
60
90
120
Time after oral temazepam elixir (min)
FIG. 2. Plasma concentrations of temazepam in patients given temazepam in elixir form.
from undetectable to 3100 ng ml"1. The time to peak plasma concentration correlated inversely with age (r = -0.475; P < 0.002).
Correlation of plasma concentration with effect Plasma concentrations of temazepam at 60 min correlated with change in anxiety and sedation using the Spearmann rank correlation. Rank correlation coefficients for anxiety were not statistically significant, but there was a significant correlation (r = 0.339; P < 0.005) between plasma temazepam concentration and sedation. The mean plasma concentration of temazepam was calculated for each sedation rating (table III)—"awake" was associated with a mean plasma concentration of temazepam 211 ngml"1,
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
30
Time after oral temazepam capsules (min)
Anxiety Patients were classified into two groups on the basis of their scores using the STAI. There was no difference in patient characteristics between the two groups. Overall, there was no significant difference in mean plasma concentrations between patients whose anxiety state score was greater than their anxiety trait score (AS > AT) and patients whose anxiety state was lower than or similar to their anxiety trait (AS < AT), except at 45 min following premedication, when the concentration was significantly greater in the group AS > AT (P < 0.05) (table II). Most patients were able to complete both the STAI and the visual linear analogue scale. Seven patients were unable to complete the assessments satisfactorily. One patient was transferred to theatre before the second anxiety assessment was made. The state score of the STAI and the visual analogue scale correlated well (r = 0.668; P < 0.005). All three groups were found to have a similar degree of anxiety before premedication, using both methods of assessment. One hour after premedication, all three groups had reduced anxiety. This was significant in the groups given active temazepam, as judged with the visual linear analogue scale (P < 0.01), but was significant also in the group given placebo when assessment was made using the STAI score (P < 0.05) (figs 3, 4).
TEMAZEPAM ABSORPTION
23
100 -i I
80 -
• E E
60-
x
40 -
tt I It
? 1
0
t
t
60 Capsules
0
60
0
Elixir
60 Placebo
FIG. 3. Mean (SD) anxiety scores using the visual analogue scale before (0) and 60 min (60) after premedication. 80-j 70•
60H • •
i •
40H
30-
Xt
• •• •
•
•
•
JL • V •
*
•
20
-
•
•
0 60 60 Elixir Placebo Capsules FIG. 4. Mean (SD) anxiety state scores using the Spielberger State Trait Anxiety Inventory before (0) and 60 min (60) after premedication. 0
60
0
"sedated" ratings with concentrations greater than 785 ngml"1. TABLE III. Mean (SEM) plasma concentrations of temazepam associated with sedation scores
Sedation score Awake Sleepy Drowsy Asleep
Plasma concn (ng ml"1) 211 (20) 785 (65) 790(50) 940(85)
DISCUSSION
There was no overall difference in the rate of absorption of temazepam between the two formulations. The time to peak plasma concentration was 30 min, which is shorter than has been found in volunteers (1.6 h [9]). The mean peak plasma concentration of 800 ng ml"1 after temazepam 30 mg corresponds well with peak plasma concen-
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
20 -
A
24
BRITISH JOURNAL OF ANAESTHESIA 1
suggests that a concentration in excess of 200 ng ml"1 is needed in order to ensure sedation. This may be achieved more reliably in patients awaiting surgery by giving temazepam in the elixir formulation, which results in less variable absorption. Further studies may be required to elucidate optimal timing of premedication. ACKNOWLEDGEMENTS We arc grateful to Farmitalia Carlo Erba for the placebo capsules and elixir and to Miss Tracey Kidd for the temazepam assays. REFERENCES 1. Kanto J. The use of oral benzodiazepines as premedications: the usefulness of temazepam. Acta Psychiatrica Scandinavica 1986; 74: 159S-166S. 2. Fuccella LM. Bioavailability of temazepam in soft gelatin capsules. British Journal of Clinical Pharmacology 1979; 8: 31S-35S. 3. Jochemsen R, Breimer DD. Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics — some clinical consequences. Acta Psychiatrica Scandinavica 1986; 74: 20S-31S. 4. Saletu B, Gruneberger J, Sieghart W. Pharmaco-EEG, behavioral methods and blood levels in the comparison of temazepam andfiunitrazepam.Acta Psychiatrica Scandinavica 1986; 74: 67S-94S. 5. Hosie HE, Brook IM, Nimmo WS. Comparison of sedation with temazepam by mouth and diazemuls i.v. for dental surgery. British Journal of Anaesthesia 1988; 60: 18-23. 6. Simpson KH, Stakes AF. Effect of anxiety on gastric emptying in preoperative patients. British Journal of Anaesthesia 1987; 59: 540-544. 7. Nakano S, Ogawa N, Kawazu Y. Influence of neuroticism on oral absorption of diazepam. Clinical Pharmacology and Therapeutics 1980; 27: 370-374. 8. Spielberger CD, Gorsuch RL, Lushene RE. STAI Manual. Palo Alto, California: Consulting Psychologists Press Inc., 1970. 9. Pickup ME, Rogers MS, Launchbury AP. Temazepam elixir: comparative bioavailability with a capsule formulation. International Journal of Pharmacology 1984; 22: 311-319.
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
trations of around 500 ng ml" after temazepam 20 mg [9]. Individual variation in peak plasma concentration is seen in volunteers, but a more marked variation in peak plasma concentration and a greater variability in time to peak in preoperative patients has been found in this study. Although there was no statistical difference between the two formulations, there may be less individual variation in those patients given temazepam in elixir form (table II). Unlike Simpson and Stakes [6], we found that patients with low anxiety trait scores who became highly anxious before operation had peak plasma concentrations of temazepam earlier than patients with anxiety state scores lower than or similar to their trait scores. Our results suggest that high levels of anxiety increase absorption, possibly by hastening gastric emptying, and are more in accordance with the findings of Nakano and colleagues, who described increased plasma concentrations of diazepam in individuals with high neuroticism scores [7]. Although we have been unable to relate anxiolysis with plasma concentration of temazepam, we found a positive correlation between level of sedation and plasma concentration, patients being unsedated at mean plasma concentrations of 211 ng ml"1 and sedated at mean concentrations in excess of 785 ng ml"1. This corresponds closely to the finding by Saletu, Gruneberger and Sieghart that deterioration in psychometric performance and sedation occurred at blood concentrations of 250 ng ml"1, and that lesser concentrations were associated with enhanced performance [4]. In order to provide optimal conditions at induction of anaesthesia, it seems reasonable to attempt to achieve moderate sedation and anxiolysis. This study does not identify the concentration required to achieve anxiolysis, but it
TEMAZEPAM ABSORPTION IN PATIENTS BEFORE SURGERY H. E. HOSIE AND W. S. NIMMO (AS ^ AT) [6]. In other words, those with increased anxiety tended to have delayed gastric emptying. The aims of this study were to compare the absorption and effects of temazepam in the capsule and elixir formulations in patients awaiting surgery, and to investigate the relationship between anxiety and absorption and the relationship between plasma concentration and effect.
We have compared the rates of absorption and efficacies of temazepam 30 mg in elixir and capsule formulations in 100 patients before surgery. Both formulations provided anxio/ysis and sedation, but there was wide variation in plasma concentrations of temazepam between individuals and between formulations. The presence or absence of anxiety did not influence the absorption of the preparations. It is suggested PATIENTS AND METHODS that plasma concentrations in excess of 200 ng 1 ml~ are required for sedation and anxio/ysis, and One hundred patients, aged 16-70 yr and ASA that this may be achieved more reliably using the grades I or II, having elective surgery gave written informed consent to take part in the study, which elixir formulation. KEY WORDS Premedication: temazepam.
Temazepam is used orally as a premedicant to provide anxiolysis and sedation. Its short duration of action allows rapid recovery without prolongation of sedation into the postoperative period [1]. Temazepam is available commercially in four forms in the United Kingdom and studies of its bioavailability and pharmacokinetics in different vehicles have been carried out in healthy volunteers [2-4]. In a previous study using an elixir formulation, wide variation in plasma concentration of temazepam was found at the time of surgery [5]. Preoperative anxiety may have an effect on gastric emptying and hence drug absorption [6, 7]. In a study of paracetamol absorption in patients awaiting operation, Simpson and Stakes showed that patients with low anxiety trait (AT) scores who had high anxiety state (AS) scores (AS > AT) before operation had delayed gastric emptying compared with patients who had anxiety state scores similar to or less than their trait scores
was approved by the local Ethics Committee. Patients were excluded if they had a history of hepatic or renal disease, previous gastric surgery or gastrointestinal disease, were taking concomitant benzodiazepine therapy or drugs known to affect gastric emptying, or were pregnant. Patients were allocated randomly to one of three groups: group 1 patients were given temazepam 30 mg in capsules with placebo elixir 15ml; group 2 received temazepam 30 mg in elixir with placebo capsules; group 3 received placebo capsules and elixir. Nursing staff and patients were unaware of which medication had been used. The premedication was timed to be given 1 h before the start of surgery, but in most instances surgery did not commence until 2 h after premedication. Venous blood samples were taken every 15 min for 2 h after premedication for assay of plasma
HEATHER E. HOSIE*, M.B., CH.B., F.C.ANAES.; W. S. NIMMO-J-,
B.SC, M.D., F.R.C.P., F.C.ANAES., F.F.A.R.A.C.S. ; Department of
Anaesthesia, University of Sheffield, Sheffield S10 2RX. Accepted for Publication: August 6, 1990. Present addresses: •Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF. fRoyal Infirmary, Lauriston Place, Edinburgh EH3 9YW.
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
SUMMARY
TEMAZEPAM ABSORPTION
21
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
concentration of temazepam by high pressure TABLE I. Mean (range) age and toeight, and sex distribution of patients liquid chromatogTaphy (HPLC) [5]. Anxiety was assessed using the linear visual Weight Age analogue anxiety scale (VAS) and the Spielberger M F (kg) (yr) State Trait Anxiety Inventory (STAI) [8]. The VAS comprised a 100-mm line with anxious/ Group 1 8 32 68.5 Capsules 41 apprehensive and relaxed/confident end-points, (46.5-103) (n = 40) (16-68) and measurement from the "relaxed" end. The Group 2 STAI is a reliable method of assessing anxiety 42 71.2 Elixir 10 30 (17-64) (45.5-120) (n = 40) which gives two scores: the anxiety state, which measures anxiety to the acute situation, and the Group 3 67.9 46 Placebo 5 15 anxiety trait, which represents an individual's (18-65) 47-96.5) (n = 20) anxiety about everyday situations ("chronic" anxiety). Anxiety was assessed before premedication no significant differences between the groups with using the VAS and both parts of the STAI. respect to age, weight or sex (table I). Measurement of immediate anxiety was repeated 60 min after oral premedication using the VAS Plasma concentration of temazepam Plasma concentration of temazepam were and the state anxiety component of the STAI. Sedation was measured at 15-min intervals measured until induction of anaesthesia. Techafter premedication using a four-point self-rating nical problems or early operation prevented scale. Patients classified themselves as awake, analysis in three patients. In many patients drowsy or sleepy and the observer classified them temazepam was present in the first sample and as asleep if they did not respond to verbal contact. this reflected residual drug following adminisStatistical analysis of the data included analysis tration of a hypnotic dose on the previous of variance and unpaired t tests for parametric evening. data, Wilcoxon paired rank sum test and Mann— There were no significant differences between Whitney U test for non-parametric data, chi- the formulations, at any time, in mean plasma square analysis for nominal data and the Spear- concentration of temazepam. Mean peak plasma mann rank correlation coefficient. concentrations of about 800 ng ml~l occurred 30 min after premedication (table II). There were marked differences in plasma RESULTS concentrations both between individuals and Forty patients were given temazepam in capsules between those given capsules and those pre(group 1), 40 received temazepam in elixir medicated with elixir (figs 1, 2). Peak plasma (group 2) and 20 placebo (group 3). There were concentrations occurred at 15—105 min and varied
TABLE II. Mean (SEM) plasma concentrations of temazepam (ng ml'1) after oral temazepam 30 mg for the different formulations and in patients with low anxiety trail but high anxiety scores (AS > AT) and those with anxiety slate scores similar to or less than their anxiety trait scores (AS J£ AT) before operation. *P < 0.05 compared with AS > AT at same time Time (min) 0 Capsules Elixir AS>AT AS $ AT
30 (8) 57 (20) 38 (9) 62 (27)
15
30
384 (127) 528 (73) 410 (87) 547 (171)
869 (135) 796 (73) 938 (106) 681 (139)
45
60
75
90
105
120
660 (88) 774 (64) 789 (69) 546* (95)
694 (68) 740 (50) 111 (60) 614 (67)
689 (83) 701 (37) 674 (51) 753 (77)
683 (61) 658 (54) 608 (43) 764 (74)
596 (53) 624 (86) 549 (54) 682 (85)
577 (62) 617 (70) 575 (63) 619 (126)
BRITISH JOURNAL OF ANAESTHESIA
22
60
90
120
FIG. 1. Plasma concentrations of temazepam in patients given temazepam in capsule form. 3000
c
E 03 Q. O
Sedation For purposes of statistical analysis, patients were grouped as sedated (sleepy, drowsy and asleep) or unsedated (awake). Significant sedation was seen in the groups given active temazepam at 30,45 and 60 min. There was no overall difference between capsules and elixir and no significant sedation was seen in the placebo group.
2000-
1000-
E
0
30
60
90
120
Time after oral temazepam elixir (min)
FIG. 2. Plasma concentrations of temazepam in patients given temazepam in elixir form.
from undetectable to 3100 ng ml"1. The time to peak plasma concentration correlated inversely with age (r = -0.475; P < 0.002).
Correlation of plasma concentration with effect Plasma concentrations of temazepam at 60 min correlated with change in anxiety and sedation using the Spearmann rank correlation. Rank correlation coefficients for anxiety were not statistically significant, but there was a significant correlation (r = 0.339; P < 0.005) between plasma temazepam concentration and sedation. The mean plasma concentration of temazepam was calculated for each sedation rating (table III)—"awake" was associated with a mean plasma concentration of temazepam 211 ngml"1,
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
30
Time after oral temazepam capsules (min)
Anxiety Patients were classified into two groups on the basis of their scores using the STAI. There was no difference in patient characteristics between the two groups. Overall, there was no significant difference in mean plasma concentrations between patients whose anxiety state score was greater than their anxiety trait score (AS > AT) and patients whose anxiety state was lower than or similar to their anxiety trait (AS < AT), except at 45 min following premedication, when the concentration was significantly greater in the group AS > AT (P < 0.05) (table II). Most patients were able to complete both the STAI and the visual linear analogue scale. Seven patients were unable to complete the assessments satisfactorily. One patient was transferred to theatre before the second anxiety assessment was made. The state score of the STAI and the visual analogue scale correlated well (r = 0.668; P < 0.005). All three groups were found to have a similar degree of anxiety before premedication, using both methods of assessment. One hour after premedication, all three groups had reduced anxiety. This was significant in the groups given active temazepam, as judged with the visual linear analogue scale (P < 0.01), but was significant also in the group given placebo when assessment was made using the STAI score (P < 0.05) (figs 3, 4).
TEMAZEPAM ABSORPTION
23
100 -i I
80 -
• E E
60-
x
40 -
tt I It
? 1
0
t
t
60 Capsules
0
60
0
Elixir
60 Placebo
FIG. 3. Mean (SD) anxiety scores using the visual analogue scale before (0) and 60 min (60) after premedication. 80-j 70•
60H • •
i •
40H
30-
Xt
• •• •
•
•
•
JL • V •
*
•
20
-
•
•
0 60 60 Elixir Placebo Capsules FIG. 4. Mean (SD) anxiety state scores using the Spielberger State Trait Anxiety Inventory before (0) and 60 min (60) after premedication. 0
60
0
"sedated" ratings with concentrations greater than 785 ngml"1. TABLE III. Mean (SEM) plasma concentrations of temazepam associated with sedation scores
Sedation score Awake Sleepy Drowsy Asleep
Plasma concn (ng ml"1) 211 (20) 785 (65) 790(50) 940(85)
DISCUSSION
There was no overall difference in the rate of absorption of temazepam between the two formulations. The time to peak plasma concentration was 30 min, which is shorter than has been found in volunteers (1.6 h [9]). The mean peak plasma concentration of 800 ng ml"1 after temazepam 30 mg corresponds well with peak plasma concen-
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
20 -
A
24
BRITISH JOURNAL OF ANAESTHESIA 1
suggests that a concentration in excess of 200 ng ml"1 is needed in order to ensure sedation. This may be achieved more reliably in patients awaiting surgery by giving temazepam in the elixir formulation, which results in less variable absorption. Further studies may be required to elucidate optimal timing of premedication. ACKNOWLEDGEMENTS We arc grateful to Farmitalia Carlo Erba for the placebo capsules and elixir and to Miss Tracey Kidd for the temazepam assays. REFERENCES 1. Kanto J. The use of oral benzodiazepines as premedications: the usefulness of temazepam. Acta Psychiatrica Scandinavica 1986; 74: 159S-166S. 2. Fuccella LM. Bioavailability of temazepam in soft gelatin capsules. British Journal of Clinical Pharmacology 1979; 8: 31S-35S. 3. Jochemsen R, Breimer DD. Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics — some clinical consequences. Acta Psychiatrica Scandinavica 1986; 74: 20S-31S. 4. Saletu B, Gruneberger J, Sieghart W. Pharmaco-EEG, behavioral methods and blood levels in the comparison of temazepam andfiunitrazepam.Acta Psychiatrica Scandinavica 1986; 74: 67S-94S. 5. Hosie HE, Brook IM, Nimmo WS. Comparison of sedation with temazepam by mouth and diazemuls i.v. for dental surgery. British Journal of Anaesthesia 1988; 60: 18-23. 6. Simpson KH, Stakes AF. Effect of anxiety on gastric emptying in preoperative patients. British Journal of Anaesthesia 1987; 59: 540-544. 7. Nakano S, Ogawa N, Kawazu Y. Influence of neuroticism on oral absorption of diazepam. Clinical Pharmacology and Therapeutics 1980; 27: 370-374. 8. Spielberger CD, Gorsuch RL, Lushene RE. STAI Manual. Palo Alto, California: Consulting Psychologists Press Inc., 1970. 9. Pickup ME, Rogers MS, Launchbury AP. Temazepam elixir: comparative bioavailability with a capsule formulation. International Journal of Pharmacology 1984; 22: 311-319.
Downloaded from http://bja.oxfordjournals.org/ at University of Toronto Library on July 20, 2015
trations of around 500 ng ml" after temazepam 20 mg [9]. Individual variation in peak plasma concentration is seen in volunteers, but a more marked variation in peak plasma concentration and a greater variability in time to peak in preoperative patients has been found in this study. Although there was no statistical difference between the two formulations, there may be less individual variation in those patients given temazepam in elixir form (table II). Unlike Simpson and Stakes [6], we found that patients with low anxiety trait scores who became highly anxious before operation had peak plasma concentrations of temazepam earlier than patients with anxiety state scores lower than or similar to their trait scores. Our results suggest that high levels of anxiety increase absorption, possibly by hastening gastric emptying, and are more in accordance with the findings of Nakano and colleagues, who described increased plasma concentrations of diazepam in individuals with high neuroticism scores [7]. Although we have been unable to relate anxiolysis with plasma concentration of temazepam, we found a positive correlation between level of sedation and plasma concentration, patients being unsedated at mean plasma concentrations of 211 ng ml"1 and sedated at mean concentrations in excess of 785 ng ml"1. This corresponds closely to the finding by Saletu, Gruneberger and Sieghart that deterioration in psychometric performance and sedation occurred at blood concentrations of 250 ng ml"1, and that lesser concentrations were associated with enhanced performance [4]. In order to provide optimal conditions at induction of anaesthesia, it seems reasonable to attempt to achieve moderate sedation and anxiolysis. This study does not identify the concentration required to achieve anxiolysis, but it
