New intravenous sedative combinations in oral surgery: A comparative study of nalbuphine or pentazocine with midazolam

British Journal of Oral and Maxillofacial 0 1988 The British Association of Oral

NEW INTRAVENOUS

Surgery

and

SEDATIVE

A COMPARATIVE

STUDY

(1988)

26,

Maxillofacial

95-106

Surgeons

COMBINATIONS

OF NALBUPHINE

WITH

IN ORAL

SURGERY:

OR PENTAZOCINE

MIDAZOLAM

P. C. G. HOOK’~ and K. M. LAVERY Department

of Oral and Maxillofacial Surgery, Queen Victoria Hospital, Grinstead. RH19 302 West Sussex

East

Summary. A randomised,

double blind study was conducted to compare the efficacy and safety of nalbuphine or pentazocine with midazolam in patients undergoing minor oral surgery under local analgesia. Forty patients, aged between 17 and 48 years and in American Society of Anesthesiologists A.S.A. Class I participated. The results confirmed that the use of either nalbuphine (0.2 mg/kg) or pentazocine (0.5 mg/kg) allowed for a significant reduction in the mean dosage of midazolam required to produce satisfactory sedation when compared with trials where midazolam was used alone. Thus a mean midazolam, 0.087 mg/kg (nalbuphine group) or 0.081 mgikg (pentazocine group) was required compared with 0.17 mg/kg (Aun et al., 1984) and 0.19 mgikg (Skelley et al., 1984). Inadvertent overdosage with midazolam is prevented as the onset of sedation and its end-point are more obvious. No adverse cardiovascular or respiratory side effects were noted. The recovery rate for both groups was At similar. Ninety-five per cent (39 of 40) of patients were able to walk unaided at 2 h post operation. this time significantly more patients in the nalbuphine group were pain free (p
Introduction

Many patients are fearful of investigations or procedures performed under local analgesia. This is particularly so in oral and dental surgery. Indeed, apprehension and previous unpleasant experiences often account for failure to attend for treatment (Liddel & My, 1984). In order to help apprehensive patients accept such treatments and procedures, intravenous sedative techniques have been used, as general anaesthesia is often unwarranted. The foremost of these intravenous sedative techniques was the Jorgensen technique (Jorgensen & Laffingwell, 1961) using pentobarbitone, pethidine and hyoscine. Forman (1965) introduced intermittent methohexitone sedation. Such techniques are seldom used today owing to their cardiovascular and respiratory side effects and the fine dividing line between sedation and general anaesthesia. The incremental techniques have been replaced by the benzodiazepines, in particular intravenous diazepam (Poswillo, 1967; Brown et al., 1968). Diazepam is more effective overall than the previously used agents particularly in producing a faster onset of drowsiness, smoother sedation, better amnesia and faster mean recover time (Keilty & Blackwood, 1969). Its main disadvantages are pain on injection in 30-80% of cases (Wood & Sheikh, 1986), post-injection thrombophlebitis and its long half-life (24-48 h). The latter results from its pharmacologically active metabolites and the secondary resurgence effect (Coral1 et al., 1979; Barclay

“Present address: L7 SXP.

The

(Received

24 October

Regional

Oral

1986; accepted

& Maxillofacial

95

Unit,

11 May Royal

1987) Liverpool

Hospital,

Liverpool

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et al., 198.5). Occasional reports of respiratory and cardiovascular collapse have been recorded (Coral1 et al., 1979). In order to try to reduce the side effects of diazepam and to increase the quality of sedation, diazepam has been used in conjunction with the opioid agonist/ antagonist, pentazocine (Dixon et al., 1970; Aldrete et al., 1971; Coral1 et al., 1979; Lawson & Milne, 1981). The synergistic effect of these two drugs improved sedation while the analgesia produced by pentazocine compensated for diazepam’s poor analgesic properties. In addition, Brown et al. (1975) noted that the administration of pentazocine significantly reduced the mean dose of diazepam required to produce satisfactory sedation, thus reducing some of its side effects. Although the combination of diazepam and pentazocine has been found in the main to be free of severe side effects, cardiopulmonary depression has been reported (Dixon et al., 1970; Coral1 et al., 1979; Lawson & Milne, 1981). There has also been some concern about the psychomimetic side effects of pentazocine (Economou et al., 1974), though these were low in the above mentioned trials. Recently midazolam,” a water soluble imidazobenzodiazepine, was introduced possessing the typical properties of the benzodiazepines; anxiolysis, hypnosis, amnesia and muscle relaxation. Its claimed advantages over diazepam for intravenous sedation are its faster onset of action, more consistent anterograde amnesia, more rapid recovery and almost no venous complications (McGimpsey et al., 1983; Aun et al., 1984; Barclay et al., 1985). Midazolam has a plasma half-life of 1.7-2.4 h, as its metabolites have little or no pharmacological activity and it has minimal enterohepatic circulation (Barclay et al., 1985). It is relatively free of side effects but respiratory depression has been noted in the elderly (Committee on Safety of Medicines, 1985) and with doses greater than 0.15 mg/kg (Forster et al., 1979). Nalbuphine hydrochloridet is a new semi-synthetic opioid agonist/antagonist analgesic, structurally related to oxymorphine. It is an agonist at the kappa opioid receptor and a competitive antagonist at the mu opioid receptor. It is devoid of activity at the sigma receptor (Jasinski, 1984). It is not a controlled drug and at present only a parenteral formulation is available for use in the UK. When administered intravenously its onset of action is 2-3 minutes and its half-life is about 5 h (Pallasch & Gill, 1985). However, at lower doses, studies have shown nalbuphine to be approximately equianalgesic to morphine on a weight for weight basis (Beaver & Feise, 1978). Its duration of action is slightly longer than morphine for equianalgesic doses. Nalbuphine is estimated to be about two to three times as potent as pentazocine with a slightly longer duration of action (Tammisto & Tigersteat, 1977). Its main side effects after short term administration are sedation 36% of cases, nausea 6% cases and psychomimetic effects 7% of cases (Errick & Heel, 1983). Nalbuphine and morphine given intravenously (0.1-0.5 mg/kg) produce similar degrees of respiratory depression. However, respiratory depression from nalbupine reaches a ‘ceiling’ in the 0.42-0.83 mg/kg dose range beyond which further increase in dosage does not further depress respiratory function (Romagnoli & Keats, 1980). Nalbuphine has no adverse haemodynamic side effects. It has been shown to increase heart rate slightly and reduce myocardial contractility (Lee et al., 1981). However Romagnoli and Keats (1980) have observed tachycardia and increased mean arterial pressure in a few post-operative patients. .Like other opioid agonists/antagonist analgesics its abuse potential is very low (Errick & Heel, 1983).

‘“‘Hypnovel’, Roche t’Nubain’,

DuPont.

Products

Limited.

NEW

INTRAVENOUS

SEDATIVE

97

As midazolam appears superior to diazepam as an intravenous sedative agent (Aun et al., 1984; Barclay et al., 1985; Wood & Sheikh, 1986), it was used in this trial in combination with either pentazocine or nalbuphine. The aim of the trial was to compare the efficacy and safety of the two combinations in patients undergoing minor oral surgery under local analgesia. A randomised, single dose, double blind, third party open parallel group investigation was undertaken. Patients and methods

Patients were included in the study if after assessment they seemed unable to accept minor oral surgery under local analgesia alone because of fear or anxiety. They had to meet the ASAt Class I criteria and be aged between 1665 years. They were required to have made arrangements to be accompanied home 2 h after the procedure. Patients in the following groups were excluded:1. patients not in ASAt Class I - _ patients receiving and who had received within 2 weeks of entering the study monoamine oxidase inhibitors, tricyclic antidepressants, or any other treatment for anxiety or depression. patients who had received sedative or analgesic drugs, or central nervous system depressants within 24 h prior to the study. patients with a history of hypersensitivity to the study drugs or opioidagonists or agonists/antagonists or any other benzodiazepine. pregnant or lactating female or fertile females not practising adequate contraception. The study was approved by the local ethical committee and conformed to the requirements of the Declaration of Helsinki (1964). Informed consent was obtained from each patient before entering the study. The patient was placed comfortably in the supine position and a 21 gauge bufferfly needle inserted in a medium to large peripheral vein in the forearm. The study drug, either pentazocine 0.5 mg/kg or nalbuphine 0.2 mg/kg was administered. This was followed by midazolam (10 mg/2 mls) in doses titrated to produce the required sedation using the Data sheet recommendations as a guide. Signs used to assess the point of sedation were nystagmus, ptosis, Verrill’s sign, (Verrill, 1969), s1urred speech and drowsiness. The total dose of midazolam did not exceed 7.5 mg. No supplementary dose of any drug was given. Once sedation had been attained local analgesia was achieved by nerve blocks and infiltration with 2% lignocaine, 1:80,000 adrenaline. Any sign of pain upon injection was noted during the administration of all drugs. The procedures performed included the surgical removal of teeth; teeth roots; third molars; apicectomies and retrograde root fillings. The operative conditions and quality of the sedation were evaluated by assessing the patients response and cooperation during the administration of the local analgesia and throughout the procedure. Verbal contact was maintained throughout the procedure. Blood pressure*, heart rate” and respiratory rate were monitored throughout the procedure and recorded at the stages shown in Figures 1 and 2. The degree of sedation was classified as 0, awake; 1, slight drowsiness; 2, moderate drowsiness; 3, marked drowsiness; 4, asleep not responding to spoken command but to physical “Copal.

Digital

tA.S.A.

American

sphygmomanometer Society

& pulse

of Anesthesiologists.

monitor

UA 251

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NALBUPHINE 50 BLOOD PRESSURE

mm. 4

1 T2

c! Tl

T4

T3

T5

Tl i

BASELINE

T2:

SEDATION BEFORE

TX=

PROCEDURE

EO-

130

ESTABLISHED/ LOCAL ANALGESIC. COMMENCED.

T4 i ELEVATION OF TOOTH ROOT OR APICECTOMY.

-

T5=

END

OF

i

PROCEDURE.

110 -

90

-

70

-

PENTAZOCINE

501

o;-

I

’

74

T3

T2

Tl

T5

TIME

Fig. Figure

l-Systolic with

I

and diastolic blood pressure measurements following administration of midazolam nalbuphine or pentazocine. (Median and upper and lower quartiles).

PENTALSCINE HEART WTE BEATS/MIN

60

_

0 _ 120

I Tl

T2

13

I T4

75

-

110

BASELINE

T2=

SEDATION ESTABLISHED, BEFORE LOCAL ANALGESIC.

T3=

PROCEDURE

COMMENCED.

T4 = ELEVATION OF TOOTH, ROOT OR APICECTOMY.

T

100

Tl i

T5=

END

OF

PROCEDURE,

90 80 70 ‘O;:_

NALBUPHINE

60 0

T2

Tl

T3

74

T5

TIME

Fig. 2 Figure

2-Heart

rate

measurements following administration of midazolam pentazocine (median and upper and lower quartile).

with

nalbuphine

or

NEW

INTRAVENOUS

99

SEDATIVE P

N

15 NO, OF

0

AWAKE

PATIENTS m

SLIGHT MODERATE MARKED

2 HOURS ADMINISTRATION

(Tl)

Fig. Figure

3-Drowsiness

Age

(years)

Weight

(kg)

Sex

Table

scores (number of patients) T,=during administration T,=during surgery, Ti=2 h post-operation.

Time

Table

data

Median Range Median Range Male Female Total

(mins)

Nalbuphine

Pentazocine

24.2 17.G48.0 60.0 44.G82.5 2 18 20

21.2 20.9-46.1 60.0 45.0-92.5 4 16 20

of the procedure

Median Range

Nalbuphine

Pentazocine

36 13-89

34 15-55

III

Clinical assessment

TlON

3

II

Duration

OPE

(T3)

Table I

Demographic

POST

(12)

of the patient’s anxiety

Anxiety

Nalbuphine

Pentazocine

Total

Mild Moderate Severe Very severe Total

5 9 3 3 20

4 10 4 2 20

9 19 7 5 40

of local

analgesic,

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stimuli (Gamble et al., 1981). These scores were assessed during the administration of the local analgesic, during the surgery and at 2 h post-operatively (Fig. 3). Upon completion of the surgery the patients were recovered in the reclined position under observation. Two hours after the procedure the patients were assessed for drowsiness, ability to walk unaided, Rombergism and fitness for discharge. (Fig. 3 & Table VI) (Dundee et al., 1980; Aun et al., 1984; Wood & Skeikh, 1986). At this stage patients were asked to record the pain they experienced on a visual linear analogue (Fig. 5) (Aitken, 1969). They were also asked if they could recall anything of the procedure after the injection in the arm. These responses were graded as O! total recall; 1, amnesia of the surgery only; 2, amnesia for the surgery and local analgesia; 3, total amnesia (Table VII). Before the patients were discharged their evaluation of the sedative techniques was noted. Finally the operators global evaluation of the efficacy of the techniques were classified as excellent=patient relaxed, calm, cooperative, no resistance; good=slight restlessness, mild resistance; poor=very restless, activeresistance (Table VIII). M oreover, the operators global evaluation of the safety of the techniques were assessed. Results The two study groups were evenly matched for all parameters (Tables I and II). The predominance of female patients reflects the referral pattern to this Unit and

Figure 4-Mobility recovery scores at 2 h post-operation. (Number of patients). O=able to walk l=able to walk unaided but unaided without deviation from straight line or on turning around, unsteady when turning around, 2=able to walk unaided but deviates from straight line, 3=unable to walk unaided. Figure

5-Pain

scores

at 2 h post-operation

(number

of patients).

NEW

INTRAVENOUS

I-

,-

I

,-

-

101

SEDATIVE

. .b.I I N

P

,-

I

HOOK

WOOD 8 SHIEKH 19.86

8 LAVERY 1986

SKELLY et ai ,984

(TRIAL)

Fig. Figure

6

h-Mean dose of midazolam required to produce which midazolam was used alone. (Meanil

sedation. A comparison with other S.D.; maximum and minimum).

trials in

has been seen in other similar trials. (Kawar et al., 1982; McGimpsey et al., 1983; Skelly et al., 1984; Wood & Skeikh, 1986). The degree of anxiety as assessed by the operators was similar in both groups (Table III). Nalbuphine was regarded as being 2.5 times as potent as pentazocine, hence adjustments were made to give equipotent doses (Table IV). The dosage of midazalom required to produce satisfactory sedation in both groups was remarkably similar (Table V). No drug caused pain upon injection. The blood pressure recordings for both groups were fairly variable in time. However, there was no statistically significant difference between the groups (Fig. 1). In both, the systolic blood pressure rose throughout the procedure with a tendency to fall back to base line levels. The median diastolic blood pressure in both groups had a tendency to fall and rise to base line levels. As a result, the mean arterial pressures for both groups during the procedures remained fairly constant. None of these changes was clinically significant. There was only one episode of transient hypotension, (88/62), that occurred in a 29-year-old female who weighed 55 kg and who received pentazocine and 0.11 mg/kg of midazolam. This episode was self limiting and required no active intervention. In both groups the median heart rates tended to rise throughout the procedure then return to base line levels by the end. This was not clinically significant. Indeed

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Table IV Dosage of the trial

Dose

(mg)

OF

ORAL

&

MAXILLOFACIAL

SURGERY

drugs Nalbuphine

Pentazocine

12.0 9.9-16.5

31.3 22.5-46.3

12.5 9.C18.5

Nalbuphine

Pentazocine

Nalbuphine

Pentazocine

5.0 3.S7.5

5.0 1.0-7.5

0.09 0.05-0.16

0.08 0.02-O. 13

Median Range

= Nalbuphine

Table V Dosage of midazolam

Median Range

Table VI Rombergism

at 2 h post-operation

Rombergism

Nalbuphine

Pentazocine

Total

Yes No

14 6 20

15 2;

29 11 40

Amnesia*

Nalbuphine

Pentazocine

Total

0

1 4 10 5 20

2 3 13 2 20

3 7 23 7 40

Table

VII

1 2 3

*See text.

Table VIII Surgeons assessment

of the operating

conditions

Assessment”;

Nalbuphine

Pentazocine

Total

Excellent Good Poor

19 1 0 20

19 1 0 20

38 2 0 40

*See

text.

equivalent

mgi2.5

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there was no statistically significant difference between the two groups though the nalbuphine group had marginally lower heart rates (Fig. 2). The majority of the patients in each group showed no gross fluctuation in respiratory rate. No patient recorded a respiratory rate of less than 10imin and there were no episodes of apnoea. No patient lost the cough reflex or hiccoughed. One patient experienced a 15 s bout of coughing at the beginning of the procedure and another had a short episode of snoring; both resolved spontaneously. No patient admitted to, or after direct questioning, to any psychomimetic effects during or after the procedure. Nausea was noted in three patients in the nalbuphine group and one in the pentazocine group but not during the first hour after the administration of the drug. One patient vomited 2 h post-operatively and this was attributed to swallowed blood. At 2 h post-operation, 15% (3 in 20) of the nalbuphine group and 55% (11 in 20) was statistically of the pentazocine group experienced pain. This difference significant p
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This study has clearly demonstrated that the addition of an opioid agonist/ antagonist, nalbuphine or pentazocine allowed for a significant reduction in the median dosage of midazolam required to produce satisfactory sedation. The median dosage of midazolam for each group was 5.0 mg or 0.09 mg/kg in the nalbuphine group and 0.08 mg/kg in the pentazocine group (Table V). This dosage is slightly higher than the 0.07 mg/kg recommended by the Data Sheet. However both groups dosage range compares very favourably with other trials in which midazolam was used alone and in larger doses (Aun et al., 1984; Bardham et al., 1984; Skelley et al., 1984; Rosenbaum, 1985; Wood 81 Sheikh, 1986) (Fig. 6). Thus the synergistic sedative side effects of the opioid agonist/antagonist allow for a significant reduction in midazolam’s dosage. This reduction may well overcome the problems of over dosage and subsequent side effects. No significant cardiovascular side effects were noted in the trial. The effects on blood pressure and heart rate were similar for both groups (Figs. 1 & 2). Comparable findings were noted by McGimpsey et al. (1983) and Skelly et al. (1984). The effects on respiration were minimal. No patient experienced any respiratory embarrassment or hiccoughing. Respiratory depression is well known with doses of midazolam 0.15 mg/kg (Forster et al., 1980) and marked hiccoughing has been recorded at doses of 0.1 mg/kg (Mendonca, 1984). Aun et al. (1984) using a mean dose of midazolam 0.17 mgikg reported a high incidence of respiratory side effects, hiccoughing, brief apnoea following induction and airway obstruction during maintenance. At present it is not known whether a drug such as midazolam may interfere with the upper ceilings of respiratory depression that is a feature of nalbuphine and pentazocine. Although Waye & Braunfeld (1982) reported no respiratory depression when using a combination of nalbuphine or pethidine with diazepam in patients aged from 18-82 years. Even so all due care should be taken when administrating such sedative agents. Nausea was the most noteable side effect but this occurred more than 1 h after the administration of the opioid drug. It was noted in three patients in the nalbuphine group and one in the pentazocine group. In this trial both combinations proved to have a high degree of safety as 92.5% of patient (19120) nalbuphine group, 18/20 pentazocine group) experienced no side effects. In the remaining 7.5% of patients (1 in 20 nalbuphine group, 2 in 20 pentazocine group) only mild and transient cardiovascular and respiratory abnormalities were noted. All of these were self limiting and did not require any active intervention. However, it behoves those who administer intravenous sedation to have the ability and the equipment to deal with respiratory depression. During the administration of the local analgesic and the surgical procedure the majority of both groups, i.e. 75% showed no visible signs of pain. However the pain scores 2 h post-operatively showed significantly fewer patients in pain in the nalbuphine group, 15% (3 in 20) than in the pentazocine group, 55% (11 in 20), (p
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found. In no case was anything other than very mild lack of co-operation encountered (Table VIII). This trial confirms that the use of nalbuphine or pentazocine with midazolam gives safe sedation and excellent operating conditions for out-patient minor oral surgery. The administration of nalbuphine or pentazocine allows for a marked reduction in the dose of midazolam necessary for excellent sedation. Inadvertent overdosage with midazolam is prevented as the onset of sedation and its end-point are more obvious. In addition, the effects of the opiate component of this technique can be rapidly reversed using the specific opiate antagonist naloxone should any signs of respiratory depression occur (Errick & Heel, 1983). This adds another element of safety over the use of midazolam alone, for which no specific antagonist is generally available. Ro 1.5-1788, a synthetic imidazodiazepine and benzediazepine antagonist/agonist is at present undergoing trials and has been shown to temporarily reverse the sedation of midazolam (Ashton, 1985). The reduction in the midazolam dosage will reduce the risk of Rombergism post-operatively. This should ensure that the patient could walk unaided from the clinic 2 h postoperation. Overall both trial groups had similar results but the greater analgesic effect of nalbuphine means that more patients will enjoy a more comfortable post-operative period. Consequently the combination of midazolam and nalbuphine is favoured.

Acknowledgements We wish to thank Mr M. D. Awty. Mr P. Banks and Mr A. E. Brown, Consultant Oral and Maxillofacial Surgeons for allowing patients under their care to be admitted to this trial. We are indebted to Dr J. Drake and MS M. Grace of Du Pont (UK) Ltd. Pharmaceuticals Division for their support and supplies of the trial drugs: to Mrs S. Cook and Mr D. 0. Chanter for assistance with the statistical analysis of the results; to Mrs J. Cooney for her patient secretarial assistance and to Mr T. Hill for the graphics.

References Aitken. R. C. B. (1969). Measurement of feelings using visual analogue scales. Proceedings of/he Royal Society of Medicine, 62, 989. Aldrate, J. A.. Clapp. H. W., Fishman, J. & O’Higgins. J. W. (1971). ‘Pentazepam’: A supplementary agent. Anaesthesia ‘and Analgesia, 50, 49X. Ashton. C. H. (1985). Benzodiazepine overdose: Are specific antagonists useful? British Medical Journal, 290, 805. Aun, C., Flynn, P. J.. Richards, J. & Major. E. (1984). A comparison of midazolam and diazepam for intravenous sedation in dentistry. Anaesthesia, 39, 589. Barclay. J. K.. Hunter. K. MacD. Kr McMillan. W. (1985). Midazolam and diazepam compared as sedatives for outpatient surgery under local analgesia. Oral Surgery, Oral Medicine, Oral Pathology, 69, 349. Bardhan. K. D., Morris. P.. Taylor. P. C. & Hinchcliffe, R. F. C. (1984). Intravenous sedation for upper gastrointestinal endoscopy: diazepam “emus midazolam. British Medical Journal, 288, 1046. Beaver, W. T. & Feise, G. A. (1978). A comparison of the analgesic effects of intramuscular nalbuphine and morphine in patients with post-operative pain. Journal of Pharmacology and Experimental Therapeutics, 204, 487. Brown, P. R. H., Main. D. M. G. & Lawson, J. I. M. (1968). Diazepam in dentistry. British Dental Journal. 125, 498. Brown, P. R. H., Main, D. M. G. & Wood, N. (1975). Intravenous sedation in dentistry: A study of 55 cases using pentazocine and diazeoam. British Dental Journal, 139, 59. Committee on Safety of Medicines (1985). Midazolam (Hypnovel)-respiratory depression and hypotension. Current Problems, 14. Corall. I. M., Strunin. L.. Ward, M. E.. Mason, S. A. & Alcalay, M. (1979). Sedation for outpatient conservative dentistry. Anaesthesia, 34, 855.

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de Mendonca. M. J. T. (1984). Midazolam induced hiccoughs. British Dental Journal, 157, 49. Dixon, H. R. Jr., Tilton. B. E. & Briges. of the sedative and -- B. D. (1970). \ , A comparison cardiopulmonary effects of diazepam and pentazocine premeditation. Anaesthesia and Annlgesia, 49, 546. Dundee, J. W., Samuel, J. O., Toner, W. & Howard, P. J. (1980). Midazolam: a water-soluble benzodiazipine. Anamthesia, 35, 454. Dundee, J. W., Halliday, N. J., Loughran, P. G., & Harper. K. W. (1985). The influence of age on the onset of anaesthesia with midazolam. Anaesthesia, 40, 441. Economou, G., Monson, R., & Ward-McQuaid, J. N. (1971). Oral pentazocine and phenazocine: a comparison in post-operative pain. British Journal of Anaesthesia, 43, 486. Errick, J. K. & Heel, R. C. (1983). Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy. Drugs, 26, 191. Forman, P. A. (1965). Very light anaesthesia in dentistry. New Zealand Den/al Joumnl, 61, 18. Forster, A., Gardez, J. P., Suter, P. M. & Gemperle, M. (1979). Comparative respiratory effects of midazolam and diazepam. Anesthesiology, 51, 383. Gamble, J. A. S., Kawar, P., Dundee, J. W., Moore, J. & Briggs, L. P. (1981). Evaluation of midazolam as an intravenous induction agent. Anaesthesia, 36, 868. Jasinski, D. R. (1984). Opioid receptors and classification. In: W. S. Nimmo & G. Smith (Editors). Opioid agonist/antagonist drugs. Clinical Practice, pp. 24-30. Amsterdam: Excerpta Medica. Jorgensen, N. B. & Leffingwell. F. (1961). Premeditation in dentistry. Dental Clinics ofNorth Americn, 5, 229. Kawar, P., McGimpsey, J. G., Gamble, J. A. S., Browne, E. S. & Dundee. J. W. (1982). Midazolam as a sedative in dentistry. British Journal of Anaesthesia, 54, 1137. Keilty, S. R. & Blackwood, S. (1969). Sedation for conservative dentistry. The British Journnl of Clinical Praciice, 23, 365. Lawson, J. I. & Mime, M. K. (1981). Intravenous sedation with diazepam and pentazocine. British Dental Journal, 151, 379. Lee, G.. Low. R. I.. Amsterdam. E. A.. Demaria. A. N.. Huber. P. W. & Mason. D. T. (1981). Hemodynamic effects of morphine and nalbuphine in acute mycoardial infarction. &nick Pharmacology and Therapeutics, 29, 576. Liddell, A. & My. B. (1984). Some characteristics of regular and irregular attendance for dental check 23, 19. ups. British Journal of Clinicul Psychology, McGimpsey, J. G., Kawar, P., Gamble. J. A. S., Browne, E. S. & Dundee, J. W. (lY83). Midazolam in British Dentul Journal, 155, 47. dentistry. Pallasch, T. J. & Gill. C. J. (1985). Butorphanol and nalbuphine: a pharmacological comparison. Oral Surgery, Oral Medicine, Oral Pathology, 59, 15. Poswillo, D. E. (1967). Intravenous amnesia for dental and oral surgery. New Zenlnnd Dental Journal. 63, 265. Romagnoli, A. & Keats, A. S. (1980). Ceiling effect for respiratory depression by nalbuphine. Clinical Phurmacology & Therrtpeutics, 27, 478. Rosenbaum, N. L. (1985). The use of midazolam for intravenous sedation in general dental practice. British Dental Journul, 158, 139. Royal College of Surgeons of England (198.5). Guidelines for day case surgery. Commission on the provision of surgical services. Skelly, A M., Boscoe, M. J., Dawling. S. Kr Adams, A. P. (1984). A comparison of diazepam and midazolam as sedatives for minor oral surgery. European Journal of Atuwsthesiology, 1, 253. Tammisto, T. & Tigerstedt. I. (lY77). Comparison of the analgesic effects of intravenous nalbuphine and pentazocine in patients with post-operative pain. Acta Anuesthesiologicu Scmdinavica, 21,390. Verrill, P. J. (1969). Symposium on intravenous diazepam. British Dental Journnl, 127, 85. Waye, J. D. & Braunfeld, S. F. (1982). A randomised double-blind study of nalbuphine as an analgesic for colonscopy. Gustrointestinul Endoscopy, 28, 86. Wood, N. & Sheikh. A. (1986). Midazolam and diazepam for minor oral surgery. British Dentul Journal, 160, 9.