Pre-anaesthetic medication. Phenazocine and levo phenacylmorphan compared with morphine, pethidine and a placebo

Sections

Procedure
Results
Side Effects
Secretions
Changes in the Pupil
Changes in Vital Signs
Need for Postoperative Analgesic
Summary

Details

Author: Benjamin J. CILIBERTI ,, Phyllis SHROFF , , Nathan B. EDDY ,
Pages: 41 to 51
Creation Date: 1964/01/01

Pre-anaesthetic medication. Phenazocine and levo phenacylmorphan compared with morphine, pethidine and a placebo

M.D., Benjamin J. CILIBERTI [ 1] ,
M.D., Phyllis SHROFF [ 2] ,
M.D., Nathan B. EDDY [ 3] ,

In a previous report, Ciliberti & Eddy (3) described the use of anileridine, oxymorphone, morphine and placebo as pre-anaesthetic medication in a general hospital set-up. The conditions of administration were double blind, and the observers were the anaesthesia residents. While two dose-levels of each drug were employed, the purpose was not so much to establish a dose-effect relationship as to determine whether or not a difference between the drugs employed and placebo, between the several drugs, or definite advantage or disadvantage for any agent, could be recognized. It was noted that some anaesthetists tended to be generally pessimistic or optimistic in their evaluation of all preanaesthetic medication. Nevertheless, under the conditions of the study each narcotic was superior to the placebo in its satisfactory rating, but the three were not materially different when administered in equi-analgesic dose.

The study of pre-anaesthetic medication has been continued and extended to the surgical service of another Veterans Administration hospital, again comparing two new agents, phenazocine [ 4] and levophenacylmorphan, [ 5] with the usual standard, morphine, and with pethidine and a placebo. The procedure followed was essentially the same as in the earlier study. Anaesthesia residents again made the observations and the record form was very similar (see chart 1). The observations, as indicated on the chart, were made prior to the administration of the particular agent and at intervals through the period of an hour. Then the anaesthetist entered on the chart his judgement of the result and his reason for that judgement.

Procedure

Each agent was supplied to each hospital in 10-ml vials under 12 code numbers in such concentration that the desired dose was obtained by 0.01 ml for each two pounds body weight. The agents and concentrations were:


	mg/ml
Phenazocine hydrobromide	3.0
Levophenacylmorphan methane sulfonate	1.5
Morphine sulfate	20.0
Pethidine hydrochloride	100.0
Placebo	[ 6]

Phenazocine and levophenacylmorphan have similar pharmacologic properties and similar analgesic potency, taking into account that the former is a racemate and that its analgesic effect is brought about by its levocomponent (Fraser & Isbell, 5; Sadove, Schiffrin & Heller, 11; and Lasagna [ 7] ). The dose of morphine was increased for comparison with the 10 mg optimal dose (Lasagna & Beecher, 7) of the previous study and the dose of pethidine was that shown to be equi-analgesic with I0 mg of morphine (Lasagna & Beecher, 8).

The drugs were used in random sequence except that when a coded vial was opened its contents were used in successive patients until exhausted. Since the anaesthetist did not give the injection, he was not aware when the doses for two patients were from the same vial. It was, in addition, unusual for the same anaesthetist to be concerned with two successive patients. All doses were given intramuscularly.

Results

The results of the study are summarized in table 1 for the New York cases, and in table 2 for those observed in California, in percentage figures for satisfactoriness, reported sedation, etc. Other details will be given in subsequent tables.

TABLE 1

Percentage of satisfactoriness and of related factors with pre-anaesthetic medications, New York cases


	Phenazocine	Levophenacyl morphan	Morphine	Pethidine	Placebo
Dose mg/ml (0.01 ml/2 lb)	3.0	1.5	20.0	100.0	1.0ml
Number of patients	124	121	122	124	123
Satisfactory	64.5	68.6	83.6	78.2	39.0
Sedation:
None	24.2	24.8	10.6	12.9	43.1
Slight	43.5	43.0	36.1	47.6	39.0
Moderate	32.3	32.2	53.3	39.5	17.9
Time of onset, min	28.2	29.2	27.4	27.8	29.3
Sleep and/or drow- siness	51.6	50.4	62.3	62.9	26.0
Relaxation	46.0	46.4	54.1	52.4	37.4
Preoperative pain:
Incidence	15.3	16.5	13.1	14.5	13.8
Relieved	86.6	90.0	93.7	66.6	52.9

TABLE 2

Percentage of satisfactoriness and of related factors with pre-anaesthetic medications, California cases


	Phenazocine	Levophenacyl morphan	Morphine	Pethidine	Placebo
Dose mg/ml (0.01 ml/2 lb)	3.0	1.5	20.0	100.0	1.0ml
Number of patients	123	129	123	121	129
Satisfactory	58.5	60.0	70.7	64.6	21.7
Sedation:
None	21.1	29.4	13.8	15.7	69.8
Slight	66.6	62.2	77.2	66.1	28.7
Moderate	12.2	8.4	9.0	18.2	1.5
Time of onset, min	44.0	46.0	47.3	40.3	49.4
Sleep and/or drowsiness	29.3	62.8	67.4	71.9	24.8
Relaxation	52.0	48.1	52.8	52.9	37.2
Preoperative pain:
Incidence	29.3	25.6	28.4	21.6	23.2
Relieved	100.0	87.8	100.0	88.5	39.6

For all medications, satisfactoriness was rated higher by the New York than by the California observers, and for both groups all narcotics were rated better than the placebo. Also for both groups the percentage satisfactoriness was a little less for phenazocine and levophenacylmorphan than for morphine or pethidine. The difference is less, however, than between any narcotic and the placebo. The satisfactoriness of the narcotics compared with the placebo and compared with each other was paralleled by the sedation, drowsiness and relaxation reported, except that in the California cases phenazocine produced as much drowsiness and relaxation as morphine or pethidine. At the New York hospital the larger dose of morphine used in the present series produced more sedation and was rated more satisfactory (83.6 vs. 58.6%) than the dose used in the previous series (Ciliberti & Eddy, 3). A higher incidence of side effects with the larger dose of morphine offset its apparent advantage.

The number of patients receiving each medication was very nearly the same in New York and in California. The diagnoses, or operative procedures undertaken, were similar per hospital and per drug, except that in California more prostatectomies and more orthopaedic procedures (except laminectomies) were carried out and in New York more abdominal and chest surgery and a greater number of laminectomies (see table 3). A significant difference at the two hospitals was a higher incidence of spinal anaesthesias in California, 60.4%, than in New York, 30.3%. However, a similar degree of satisfactoriness was reported generally for premedication for spinal and for general anaesthesia, with the same difference between the two hospitals previously noted for both types of anaesthesia (see table 4).

TABLE 3

Diagnosis or operative procedure per drug group. New York cases (col. 1); California cases (col. 2)


	Phenazocine	Levophenacyl morphan	Morphine	Pethidine	Placebo
Hernia	19-32	27-40	29-26	25-31	23-28
Prostatectomy	6-35	5-32	6-25	6-24	8-32
Other genitourinary	5-10	3-5	8-10	11-15	5-17
Laparotomy:
Gastrectomy and/or vagotomy	14-2	13-0	15-2	19-2	11-1
Cholecystectomy	10-1	14-2	8-6	6-5	11-2
Other	18-7	14-3	7-3	13-3	16-0
Chest surgery	6-0	9-1	3-0	2-1	7-1
Neurosurgery
Central nervous system	3-0	1-0	2-0	1-0	5-0
Sympathectomy	5-1	5-2	3-5	2-1	3-1
Peripheral nerve repair	2-1	4-0	3-0	3-1	0-0
Laminectomy	10-1	7-0	8-1	14-1	8-1
Orthopaedic	0-6	1-11	1-11	0-9	3-6
Plastic surgery	2-4	0-3	1-5	0-1	0-4
Tumors, miscellaneous	2-0	1-4	2-0	0-2	0-2
Varicose veins	5-2	1-2	7-5	3-2	2-2
Haemorrhoidectomy	4-11	5-6	7-6	1-6	7-6
Carcinoma of rectum	4-0	1-0	2-1	0-0	1-0
Face and neck dissection	2-0	2-1	4-1	4-0	5-0
Mastoidectomy	0-2	0-4	0-1	0-4	0-2
Thyroidectomy	2-0	3-1	1-0	2-0	0-0
Vascular surgery	2-0	2-0	1-0	5-1	1-0
Miscellaneous minor procedures	1-3	2-2	2-6	3-4	4-7
Surgery cancelled after premedication period	2-5	1-10	2-9	4-8	3-17

Another difference should be noted, which may account in part for the lower percent of statisfactoriness reported for the California cases. Because of difficulties in operating room scheduling there was a greater lapse of time between the giving of the premedication and the beginning of the anaesthesia in the California cases (see table 5). The anaesthetist was expected to make his judgement of the satisfactoriness of the premedication an hour after it had been given, but where there was considerable delay he must lack the responsiveness of the patient and the smoothness of induction of anaesthesia as parameters for his judgement. He sometimes commented on waning of the effect of the premedicant when anaesthesia was started. The differences in pre- medication time at the two hospitals occurred similarly with all premedications.

TABLE 4

Incidence of spinal and general anaesthesias and percentage of satisfactoriness of premedication for each

	New York patients			California patients
Medication and anaesthesia	Sat.	Unsat.	% sat	Sat	Unsat.	% sat.
Phenazocine
Spinal	22	13	62.9	54	30	63.3
General	55	26	67.9	15	9	62.5
Levophenacylmor-
phan
Spinal	18	16	52.9	46	35	56.8
General	62	20	75.6	16	14	53.3
Morphine
Spinal	35	7	83.3	50	14	78.1
General	59	13	81.9	25	12	67.6
Pethidine
Spinal	28	8	77.7	44	27	62.0
General	65	16	80.2	22	12	64.7
Placebo
Spinal	16	23	41.0	24	54	30.8
General	28	49	36.8	3	20	13.0

TABLE 5

Time elapsing between giving of premedication and beginning of anaesthesia

	90 minutes or less Average incidence		90-150 minutes Average incidence		>150 minutes Average incidence		Total Average
	Minutes	%	Minutes	%	Minutes	%	Minutes
New York cases
Phenazocine	74	73.5	105	24.8	205	1.6	84
Levophenacylmorphan	74	75.4	109	23.0	167	1.6	84
Morphine	75	68.9	110	30.7	170	0.8	87
Pethidine	75	75.9	105	22.3	165	1.8	84
Placebo	75	79.3	106	20.0	170	0.8	82
Total	74	74.6	107	24.0	177	1.8	84
California cases
Phenazocine	80	26.5	118	59.0	182	14.5	117
Levophenacylmorphan	73	29.1	117	43.3	184	27.5	122
Morphine	77	31.0	109	54.3	191	14.7	111
Pethidine	79	26.7	118	48.2	200	25.0	128
Placebo	77	37.8	118	50.4	171	11.7	109
Total	77	30.2	116	51.0	178	18.7	116

Pre-anaesthetic medication 45

The age distribution of the patients in this study and the per cent satisfactoriness of the several agents for the four age groups are shown in table 6. The figures do not suggest a difference in effectiveness with age.

As in the previous study, there is indication that some anaesthetists tended to be over-enthusiastic and others over-pessimistic in their judgement of the satisfactoriness of the various medications in comparison with the judgement of the group as a whole. The records of all anaesthetists who participated in the study of each agent are presented in table 7. In the New York group, J. G. always, and A. S. for three of the five medications, overestimated, while Gi and B. C. tended to underestimate satisfactoriness. The number of patients observed that the last two are small, and the result may be coloured accordingly. For the California group, J. C. over-estimated for all agents except morphine, and H. K. under-estimated for all except pethidine. Both of these investigators were among those who saw a fair number of patients with each agent.

Side Effects

Side effects reported with the five medications in the two groups of cases are listed with their incidence in table 8. A few points are worth noting. A local reaction as a wheal and/or flare occurred most frequently with morphine. Curiously burning or stinging at the site of injection was noted very frequently in 104 of 129 patients in California, who received the placebo injection and very infrequently otherwise in any group, a finding for which we have no explanation, especially since the solution which was used as a placebo was the solvent for each of the narcotics. Nausea was noted with about equal frequency for each of the narcotics, but vomiting occurred four times after morphine, three times after pethidine, twice after levophenacylmorphan, and not at all after phenazocine. Nausea present before premedication was said to have been relieved within twenty minutes after injection in seven patients, three times after morphine, twice after pethidine and once each after phenazocine and levophenacylmorphan. Side effects as a whole occurred less frequently after phenazocine and levophenacylmorphan than after morphine and pethidine. Hypotension as a side effect will be discussed in connexion with observed changes in vital signs.

TABLE 6

Age distribution and satisfactoriness of premedication per age group


Age group	Phenazocine	Levo-phenacyl-morphan	Morphine	Pethidine	Placebo	Age incidence
	S/U	S/U	S/U	S/U	S/U	Per cent
30 or under
New York	1/3	7/3	8/2	5/1	4/2	5.9
California	2/3	4/5	4/2	5/5	1/2	5.3
Total	3/6	11/8	12/4	10/6	5/4	5.6
Per cent satisfactory	33.3	57.9	75.0	62.5	55.6
31-50
New York	29/19	29/8	43/10	40/8	23/36	39.9
California	22/20	18/12	26/14	19/13	6/35	30.0
Total	51/39	47/30	69/24	59/21	29/71	34.9
Per cent satisfactory	56.6	61.0	74.2	73.8	29.0
51-70
New York	44/28	44/25	46/7	33/20	17/31	48.6
California	31/22	40/32	49/15	43/24	16/47	51.4
Total	75/50	84/57	95/22	76/44	33/78	50.0
Per cent satisfactory	60.0	59.5	81.2	63.3	30.0
Over 70
New York	6/4	3/2	5/1	3/3	4/6	6.0
California	15/6	15/3	8/5	10/0	5/16	13.4
Total	21/10	18/5	13/6	13/3	9/22	9.7
Per cent satisfactory	67.7	78.3	68 4	81.3	29.0
Per cent satisfactory, all cases	58.7	61.2	77.1	77.6	30.3

TABLE 7

Judgement of the satisfactoriness of premedications as reported by individual anaesthetists,

	Phenazocine			Levo-phenacyl-morphan			Morphine			Pethidine			Placebo
Anaesthetist	Sat.	Unsat.	%sat.	Sat.	Unsat.	%sat.	Sat.	Unsat.	%sat	Sat.	Unsat.	%sat.	Sat.	Unsat.	% sat.
New York group
B. C.	3	3	50.0	3	4	42.8	5	1	83.3	8	2	80.0	0	6	0.0
G. T.	4	2	66.6	10	5	66.6	12	2	85.7	7	1	87.5	2	7	22.2
R. G.	11	6	64.7	8	5	61.5	10	5	66.6	9	2	81.8	5	8	38.2
E. M.	4	2	66.6	5	1	83.3	8	3	72.7	6	4	60.0	6	2	75.0
H. G.	8	7	53.3	8	2	80.0	9	0	100.0	6	3	66.6	2	8	20.0
A. S.	12	7	63.2	19	5	79.2	14	3	82.3	17	1	94.4	12	6	66.6
D. L.	3	0	100.0	6	1	85.7	3	0	100.0	3	1	75.0	1	2	33.3
O. S.	9	4	69.2	7	3	70.0	15	2	88.2	13	5	72.2	6	5	54.5
J. G.	14	3	82.3	15	1	93.8	15	0	100.0	16	1	94.1	7	7	50.0
S. F.	4	5	44.4	2	6	25.0	9	0	100.0	6	1	85.7	5	9	35.7
Gi.	2	3	40.0	0	4	0.0	1	3	25.0	3	3	50.0	0	6	0.0
E. F.	6	3	66.6	5	2	71.4	5	1	83.3	3	2	60.0	3	4	42.8
Sm.	7	2	77.7	2	4	33.3	5	0	100.0	5	1	83.3	3	5	37.5
All cases			64.5			68.6			83.6			78.2			39.0
California group				6	11	35.3	9	5	64.3	12	2	71.4	1	17	5.5
H. K .	10	8	55.5	13	2	86.6	8	3	72.7	22	2	91.6	11	9	55.0
J. C.	24	2	92.3	5	4	55.5	1	3	25.0	0	4	0.0	2	4	33.3
G. S.	8	2	80.0	8	4	66.6	8	4	66.6	3	6	33.3	1	10	9.0
J. V.	3	3	50.0	4	2	66.6	4	1	80.0	3	6	33.3	0	5	0.0
E. C.	4	6	40.0	0	3	0.0	1	3	25.0	2	5	28.6	0	5	0.0
J. B.	1	6	14.6	5	4	55.5	13	3	81.2	13	3	81.2	5	7	41.6
R. S.	7	10	41.2	5	10	33.3	9	3	75.0	5	3	62.5	3	11	21.4
R. V.	7	5	58.3	10	6	62.5	8	4	66.6	6	2	75.0	1	20	4.8
J. M.	1	4	25.0	3	1	75.0	7	1	87.5	6	3	66.6	1	3	25.0
R. F.	4	2	66.6	5	0	100.0	11	1	91.6	5	3	62.5	1	3	25.0
D. C.	1	1	50.0
All cases			58.5			60.0			70.7			64.6			21.7

Secretions

The anaesthetists were asked to judge the secretions in mouth and throat as minimal (less than normal), moderate (normal or greater than normal, but not troublesome), or marked (excessive and troublesome to the anaesthetist). They reported accordingly for the majority of patients, failing to do so for some of the cases of spinal anaesthesia where secretions were of no concern. The results are summarized in table 9. Pethidine and morphine appear to have had some drying effect, probably a little greater for the former, consistent with the incidence of dry mouth noted after pethidine in the listing of side effects. Levophenacylmorphan probably had some drying effect also, about like that of morphine, but phenazocine did not differ from placebo in this respect. Atropine was administered to check secretions in some cases after all premedications and the frequency of its use was not entirely consistent with the reported incidence of marked (troublesome) secretions. The former exceeded the latter with all premedications except phenazocine, and the discrepancy was greatest for pethidine and morphine.

Changes in the Pupil

The pupil-size was measured at each observation against a pupilometer, a card with a series of black dots differing in diameter by 0.5 mm. The results are shown in table 10. The unusual finding is the degree of pupillary constriction noted when only a placebo had been given. Otherwise morphine caused the most, phenazocine and levophenacylmorphan similar butsomewhat less, and pethidine the least constriction.

Pre-anaesthetic medication 47

TABLE 8

Side effects

	Phenazocine		Levo-phenacyl-morphan		Morphine		Pethidine		Placebo
	N.Y.	Cal.	N.Y.	Cal.	N.Y.	Cal.	N.Y.	Cal.	N.Y.	Cal.
Number of patients	124	123	121	129	122	123	124	121	123	129
None	67	75	70	86	32	69	51	71	79	25
Local reaction:
Wheal and/or flare	3	2	4	2	30	5	7	5
Burning or stinging		4			8	13		2		104
Nausea	1	9	1	7	2	8	2	10
Vomiting			1	1		4		3
Dizziness	4	9	1	13	3	9	6	18		1
Lightheaded		1		1	1
Drymouth	45	3	43	4	37	7	65	5	39	1
Euphoria.	3	9	2	2	4	6	4	8
Grogginess	1	2		8		4	2	6	3
Tiredness					3		1
Heaviness	1		1		1		1	1
Numbness									1
Sweating.	5	12	3	5	4	10	1	22	1	1
Feeling of warmth		8		8		6		16		2
Hot flashes	1	1						1
Itching	2	2			2	2	1
Headache	1	4		1	2					3
Hiccup			1
Conjunctival injection
Visual disturbance	1	1
Nystagmus								1
Confused								2
Abdominal pain

TABLE 9

Effect of premedications on secretions

	New York		California		Total		New York		California		Total		New York		California		Total
	Incidence	%	Incidence	%	Incidence	%	Incidence	%	Incidence	%	Incidence	%	Incidence	%	Incidence	%	Incidence	%
	Phena-zocine						Levo-phenacyl-morphan						Morphine
Minimal	39	36.1	80	72.7	119	54.6	66	70.2	78	67.2	144	68.6	72	77.4	65	57.5	137	66.5
Moderate	51	47.2	26	23.6	77	35.3	21	22.3	26	22.4	47	22.4	19	20.4	38	33.6	57	27.6
Marked	18	16.7	4	3.6	22	10.1	7	7.4	12	10.3	19	9.0	+2	2.2	10	8.8	12	5.8
Not reported	16		13				27		13		40		29		10		39
Atropine given for excessive secretion					18						26						20
	Pethidine						Placebo
Minimal	63	61.2	87	79.8	150	75.0	50	51.6	62	58.5	112	55.1
Moderate	22	21.3	13	11.9	35	17.5	34	35.1	33	31.1	67	33.0
Marked	6	5.8	9	8.2	15	7.5	13	13.4	11	10.4	24	11.8
Not reported	33		12		45		26		23		49
Atropine given for excessive secretion					26						29

TABLE 10

Changes in the size of the pupil

	New York			California			Total
			%			%			%
	Phena-zocine
Reported	124			123			247
Constricted	96		77.4	89		72.3	185		75.3
Constricted by: 1.0 mm. or more.	78		62.9	43		35.0	121		49.0
Initial diameter, mm		3.34			3.17			3.26
Minimal diameter, mm		2.26			2.52			2.39
Degree of constriction, per cent		32.2			20.5			26.7
	Levo-phenacyl-morphan
Reported	120			128			248
Constricted	98		81.6	89		69.5	187		75.4
Constricted by: 1.0 mm. or more	78		65.0	37		28.9	115		46.4
Initial diameter, mm		3.22			3.05			3.13
Minimal diameter, mm		2.01			2.47			2.25
Degree of constriction, per cent		37.5			19.0			28.1
	Morphine
Reported	122			120			242
Constricted	105		86.1	94		78.3	199		82.2
Constricted by: 1.0 mm. or more	98		80.3	45		37.5	143		59.1
Initial diameter, mm		3.38			3.13			3.25
Minimal diameter, mm		3.08			2.45			2.26
Degree of constriction, per cent		38.5			21.7			30.5
	Pethidine
Reported	123			118			242
Constricted	90		73.2	69		58.5	159		65.7
Constricted by: 1.0 mm. or more	71		57.7	23		19.5	94		38.8
Initial diameter, mm		3.24			3.03			3.14
Minimal diameter, mm		2.26			2.58			2.41
Degree of constriction, per cent		30.3			14.8			23.2
	Placebo
Reported	122			127			249
Constricted	74		66.5	47		37.0	121		48.6
Constricted by: 1.0 mm. or more	48		39.3	8		6.3	56		22.5
Initial diameter, mm		3.17			3.07			3.11
Minimal diameter, mm		2.56			2.94			2.74
Degree of constriction, per cent		19.2			4.2			11.9

Changes in Vital Signs

Blood pressure (table 11).- With any of the parameters examined phenazocine did not differ from placebo, and morphine and levophenacylmorphan were alike in their effect. Both were credited with producing more effect on systolic and diastolic blood pressure in incidence and degree than phenazocine or placebo, and each was reported to have produced a drop in blood pressure described-as a hypotensive episode in two cases. Pethidine had a greater effect on blood pressure, especially on diastolic blood pressure and in the production of hypotensive episodes (seven) than any of the other agents: The lack of effect of phenazocine on blood pressure in these cases is in accord with the findings of others on this point (Stephen & Macmillan, 12; Eckenhoff & Prevoznik, 4).

Heart rate (table 12).-The averages for degrees of change in heart rate after phenazocine or placebo on the one hand are very similar and those for the other three agents on the other hand are similar, and indicate a greater decrease in rate following the drug. The lowest individual rates were seen after morphine.

TABLE 11

Blood pressure changes after premedication


		Phenazocine	Levo-phenacyl-morphan	Morphine	Pethidine	Placebo
Decrease in systolic B.P. ^a	Number	82	105	103	109	87
	Per cent	33.2	42.0	42.0	44.5	34.5
Decrease in diastolic B.P ^b	Number	69	87	88	110	65
	Per cent	23.0	34.8	35.9	44.9	25.8
Simultaneous decrease in systolic and	Number	33	57	55	70	35
diastolic pressures	Per cent	13.3	22.8	22.4	28.6	13.9
Peak decrease in systolic pressure of	Number	26	45	50	57	27
20 mm or more	Per cent	10.5	18.0	20.4	23.3	10.7
Peak decrease in systolic pressure of	Number	5	12	11	15	7
30 mm or more	Per cent	2.0	4.8	4.5	6.1	2.4

Details of cases described as hypotensive after premedication c


Patient number	Degree of sedation	Initial	10'	20'	30'	45'	60'
		Phenazocine
None
		Levo-phenacyl-morphan
265	Slight	230/130/72	168/110/68	160/110/68	220/130/68	210/130/68	192/120/60
573	Slight	120/ 80/78	110/ 70/74	74/ 48/84	80/ 50/54	74/ 48/84	84/ 50/84
		Morphine
433	Slight	132/ 84/69	132/ 84/69	132/ 84/70	88/ 60/55	112/ 78/55	124/ 80/60
492	None	160/ 80/77	120/ 70/74	120/ 70/74	76/ 42/56	110/ 70/76	120/ 80/74
		Pethidine
93	Moderate	190/100/72	190/100/72	160/ 80/68	130/ 80/66	126/ 84/66	134/ 90/70
330	Moderate	125/ 60/92	120/ 60/84	110/ 60/80	90/ 50/76	100/ 60/78	100/ 60/68
434	None	160/ 70/76	130/ 60/76	120/ 50/72	120/ 50/72	104/ 50/72	110/ 60/68
438	Slight	110/ 70/76	105/ 60/78	80/ 50/72	82/ 50/72	88/ 60/68	92/ 60/76
608	Slight	152/ 90/90	135/ 75/90	110/ 70/70	110/ 60/74	110/ 60/74	105/ 55/82
201	Moderate	134/ 84/84	120/ 80/90	124/ 84/92	60/ ? /70	80/ ? /65	94/ 64/78
543	Slight	164/ 94/78	140/ 90/50	110/ 60/50	134/ 68/54	132/ 70/61	134/ 70/59
		Placebo
None

^aDecrease of 8 mm or more for two or more consecutive observations.

^bDecrease of 5 mm or more for two or more consecutive observations.

^cFirst figure systolic blood pressure, second figure diastolic blood pressure, third figure heart rate.

Atropine was given because of the low heart rate, in a small number of cases, consistent with the statement just made about changes in rate (with one exception); it was used most often after pethidine.

Respiratory rate (table 13).-Respiratory depression, or a trend towards it, in so far as it is indicated by a decrease in respiratory rate, was greater after each of the narcotics than after placebo. It was greatest with morphine, least with pethidine. On this point phenazocine was not free of adverse effect.In one case the rate fell to 5, lower than with any of the other agents. The similarity of respiratory effect of phenazocine indicated by these figures again is in accord with the observations of others (Bellville et al., 1; Greisheimer et al., 6; Berkowitz et al., 2; and Papadopoulos & Keats, 10).

Need for Postoperative Analgesic

The figures for the incidence and time of giving a postoperative narcotic (analgesic) medication are very slightly in favour of an effect of morphine as premedication decreasing the need for postoperative analgesia. There is another point in this connexion which favours morphine and, to a lesser extent, pethidine. In many cases the first postoperative narcotic dose was pethidine 25 mg or morphine 5 or 6 mg given most often within the first two hours after the completion of surgery. These doses would be considered generally of little use for analgesia and presumably were given mainly for postoperative restlessness. Since these small doses were used least often when the premedication was morphine and almost as infrequently when the premedication was pethidine, it would seem that the effect of each of these drugs carried over to some extent to the postoperative period, helping to allay post operative discomfort.

TABLE 12

Changes in heart rate after premedication


	Phenazocine	Levo-phenacyl-morphan	Morphine	Pethidine	Placebo
No consistent trend	188 = 76.4%	170 = 68.0%	157 = 64.1%	158 = 64.5 %	179 = 71.0%
Increase of 8/min. or more	18 = 6.5%	16 = 6.4%	26 = 10.6%	27 = 11.0%	19 = 7.5%
Decrease of 8/min. or more	41 = 16.6%	64 = 25.6%	62 = 25.3%	60 = 24.5%	54 = 21.0%
Change according to initial rate: ^a
Initially>80	18 (72)	31(78)	28 (80)	26 (81)	33 (92)
Decrease to<70	1 (84-66) ^b	3 (83-65)	1 (84-68)	5 (88-65)	None
Initially 70-80	19 (97)	22 (108)	26 (90)	27 (92)	18 (19)
Decrease to<60	None	1 (76-58)	1 (77-56)	6 (76-55)	None
Initially<70	4 (77)	11 (64)	8 (75)	7 (72)	3 (69)
Decrease to<60	3 (64-65)	6 (63-51)	7 (67-53)	6 (65-56)	3 (68-57)
Atropine or scopolamine given to increase heart rate	7	10	9	13	7

^aFirst figure is number showing the minimal decrease indicated above; second figure is number of patients in drug group having that initial rate.

^bFigures in parentheses are averages.

Summary

Two synthetic analgesics, phenazocine and levophenacylmorphan, have been used as pre-anaesthetic medication on a double-blind basis in comparison with morphine, pethidine and a placebo. Each of the narcotics was superior to the placebo in the anaesthetists' judgement of satisfactoriness and in the production of sedation, drowsiness and relaxation. The results with morphine were superior in these respects to those obtained in a previous study with the smaller dose of 10 mg per 60 kg body weight, but were obtained at the cost of a higher incidence of side effects. Phenazocine produced the fewest side effects among the narcotics and especially did not differ from the placebo in any apparent effect on the circulation. It was not, however, superior to the other narcotic agents in its effect on respiratory rate. Pethidine appeared to have the greatest disturbing effect on the circulation, lowering the blood pressure to an extent described as hypotensive episodes in seven cases. Such episodes occurred twice after morphine, twice after levophenacylmorphan, but not after phenazocine or placebo. It cannot be concluded that any one of the narcotics is outstandingly superior to the others or entirely free of disadvantage.

TABLE 13

Changes in respiratory rate after premedication


	Phenazocine	Levo-phenacyl-morphan	Morphine	Pethidine	Placebo
No consistent trend	170 = 68.8%	178 = 71.2%	167 = 68.2%	168 = 68.6%	202 = 80.1%
Increase of 3/min. or more	6 = 2.4%	9 = 3.6%	8 = 3.3%	11 = 4.5%	19 = 7.5%
Decrease of 3/min. or more	71 = 28.7%	63 = 25.2%	70 = 28.6%	66 = 26.9%	21 = 8.3%
Minimal rate after drug of 12/min.
or less	18 (16-11)	16 (16-11)	23 (17-10)	22 (17-12)	4 (20-11)
Post-drug rate of<10	13-9	15-9	16-8	None	None
(Individual records)	20-5	13-7	14-9
		12-8	19-8
		14-8	14-8
			20-9

⁰¹

¹ Chief, Anaesthesia Section, Veterans Administration Hospital, Bronx, N.Y.

⁰²

²Chief, Anaesthesia Section, Veterans Administration Hospital, Los Angeles, Calif.

⁰³

³ Consultant, National Institutes of Health, Public Health Service, Department of Health, Education and Welfare, Bethesda, Md.

⁰⁴

⁴ Phenazocine is the generic and proposed international nonproprietary name for ( +)-2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan. Prepared originally at the National Institutes of Health (May & Eddy, 9), it was supplied for the present study through the courtesy of Smith, Kline & French Laboratories. It is marketed by them under the trade name of Prinadol.

⁰⁵

⁵Levophenacylmorphan is the generic and proposed international non-proprietary name for (-)-3-hydroxy-N-phenacylmorphinan. It was supplied through the courtesy of Hoffman-La Roche, Inc. It has not been marketed.

⁰⁶

⁶ Because of the low solubility of phenazocine and levophenacylmorphan, these agents were dissolved first in propylene glycol and normal saline added. The final concentration of propylene glycol was 25%. The propylene glycol-saline mixture was used for uniformity of conditions as the solvent for morphine and pethidine and for the placebo. We are indebted to the Parmacy Department of the National Institutes of Health for preparing all of the medications used in this study.

⁰⁷

⁷ Personal communication, 1960.

References

⁰⁰¹

BELLVILLE, J. W., WALLENSTEIN, S. L., HOUDE, R. L. & HOWLAND, W. S.: Anesthesiology, 13:401, 1956.

⁰⁰²

BERKOWITZ, R., RODMAN, T. & CLOSE, H. P.: J.A.M.A., 176:1092, 1961.

⁰⁰³

CILIBERTI, B. J. & EDDY, N. B.: Bull. Narc ., 13, No. 3:1, 1961.

⁰⁰⁴

ECKENHOFF, J. E. & PREVOZNIK, S. J.: Com. Drug Addict. & Narc., Min. Twenty-first Meet., Add. 3:60, 1960.

⁰⁰⁵

FRASER, H. F. & ISBELL, H.: Bull. Narc ., 12, No. 2:15, 1960.

⁰⁰⁶

GREISHEIMER, E. M., KRUMPERMAN, L. W., RUSY, B. F. & ELLIS, D. W.: Anesthesiology, 21:370, 1960.

⁰⁰⁷

LASAGNA, L. & BEECHER, H. K.: J.A.M.A., 156:230, 1954.

⁰⁰⁸

LASAGNA, L. & BEECHER, H. K.: J. Pharmacol. Exp. Ther ., 112:306, 1954.

⁰⁰⁹

MAY, E. L. & EDDY, N. B.: J. Org. Chem ., 24:294, 1959.

⁰¹⁰

PAPADOPOULOS, C. N. & KEATS, A. S.: Clin. Pharmacol. Therap ., 2:8, 1961.

⁰¹¹

SADOVE, M. S., SCHIFFRIN, M. J. & HELLER, Richard, Jr.: Curr. Ther. Res ., 1:109, 1959.

⁰¹²

STEPHEN, C. R. & MACMILLAN, R.: Com. Drug Addict. & Narc., Min. Twenty-first Meet., Add. 3:43, 1960.