European Journal of Clinical Pharmacology © Springer-Verlag1986
Eur J Clin Pharmacol (1986) 31:267-276
Patient-Controlled Analgesia with Nalbuphine, a New Narcotic Agonist-Antagonist, for the Treatment of Postoperative Pain K. A. Lehmann 1 and B. Tenbuhs z Department of Anaesthesiology, University of Cologne, Cologne and 2 Department of Anaesthesiology, RWTH, Aachen, Federal Republic of Germany
Summary. Patient-controlled analgesia (PCA, intravenous self-application of narcotics) has been studied during the early postoperative period in 40 ASA I-III patients recovering from elective major and minor surgery (20 abdominal and 20 orthopaedic operations). Doses of 3.7 mg of the new agonistantagonist opiod analgesic nalbuphine were available on demand, whenever the patients felt that pain relief was necessary, delivered by a microprocessorcontrolled injection pump (On-Demand Analgesia Computer, ODAC) in response to use of a patientcontrolled manual switch. The maximum dose/h was set at 28.2 rag, with a refractory time of 1 minute between successful demands. A continuous nalbuphine infusion (0.44 mg. h 1) was administered in addition in order to prevent obstruction of the catheter. The duration of the PCA period was 17.9 (0.4-28.0) h (median, range). During that time, 13.3 (1-45) demands per patient were recorded, resulting in median individual nalbuphine consumptions of 51.3 (8.1-1050.5)~tg-kg-t.hk Self-administration was characterized by considerable intra- and interindividual variability. Following abdominal surgery significantly more nalbuphine was needed compared to orthopaedic patients, but it resulted in poorer pain relief. There were no statistically significant differences in drug requirements or pain scores between the sexes. Overall efficacy and patient acceptance proved to be good. When compared with previous conventional postoperative analgesia, the effectiveness of PCA was judged superior by about 57% of patients. Side effects (nausea, sweating) occured in about 10% of patients but were usually of minor intensity. No serious circulatory or respiratory problems were observed during the period of PCA. Patient-controlled analgesia is a promising technique for the treatment of acute pain and for clinical pain research.
Key words: analgesia, nalbuphine; patient-controlled treatment, postoperative pain, narcotic analgesics
Postoperative analgesia is generally considered to be one of the most neglected aspects of anaesthesiology. Today, many patients are not so worried about anaesthesia as about the first few hours following surgery. The reasons for this include rigid, intramuscular dose regimens (usually given to the nursing staff in the form of strict instructions, and often based more on subjective preferences than objective investigations), which do not allow for any variation in the type of drug, dose or time interval between administrations according to the experience of individual patients. An effective form of treatment should take into account rapid onset of action as well as the pain intensity and threshold in each patient, which are known to be extremely variable. While the first of these aims can only be achieved by means of an intravenous injection, the second requires information which can only be provided by the patient and not by the physician. The most promising solution is patient-controlled, intravenous on-demand analgesia (PCA). This is usually delivered by means of a microprocessor-controlled infusion pump, which allows the patient himself to inject small intravenous boluses of analgesic into an infusion bypass by pressing a hand-button as often as he needs to achieve an acceptable level of analgesia. The intravenous injection of suitable drugs makes the patient aware that there is a direct connection between his demand for the analgesic and its effect; he no longer has to wait for the attentions of a nurse and the slow onset of action of the drug given by intramuscular injection. The patient is certain that he will experience
268
immediate pain relief, so he can determine the level of pain he will tolerate, and he might be more likely to be prepared to raise this gradually and to balance the level of analgesia against the side effects of the analgesic. In addition, PCA makes it possible for basic research to be more objective about certain aspects of subjective pain behaviour (i. e. drug consumption) and thus to compare the efficacy of various analgesics. Nalbuphine, a new morphine derivative with agonistic-antagonistic characteristics, and a proven maximum respiratory depressant effect in man, may have advantages in the treatment of pain by PCA. The aim of the present study was to determine the characteristics of such use: the efficacy, dose requirements and side effects when nalbuphine was used in patients suffering from pain after abdominal or orthopaedic surgery.
Patients and Methods
Patients Fourty patients in American Society of Anesthesiology (ASA) classes I-III who underwent elective abdominal or orthopaedic surgery (20 patients in each group) were included in the study. The evening before surgery they were given detailed information on the nature of the investigation, shown how to use the PCA-apparatus and were asked to give their verbal consent to participate in the study, which conformed to the Declaration of Helsinki. Patients with severe cardiac, pulmonary, renal or hepatic impairement, a history of chronic respiratory disease or cerebrovascular accident, treatment with monoamine oxidase inhibitors or tricyclic antidepressants within 2 weeks prior to the study, addiction to other drugs, pregnancy or breast-feeding were excluded, as were patients with motor disturbances making it impossible for them to operate the ODAC, and those who did not understand the PCA-technique.
Anaesthetic Techniques Surgery was performed under either general (n = 35) or spinal anaesthesia (n=5), depending on the wishes of the patient and the site of operation. Premedication consisted of oral diazepam 10 mg administered the evening before the operation and 2 ml Thalamonal (containing 0.1 mg fentanyl and 5 nag droperidol), or 2 ml Psyquil comp. (containing 50 nag pethidine and 20 mg triflupromazine) i.m. 60 min prior to surgery. General anaesthesia was induced with alcuronium (2 and 8 rag), diazepam (10-15 rag),
K. A. Lehmannand B.Tenbuhs:Analgesiawith Nalbuphine hexobarbital (2-3 mg/kg) and fentanyl (4-6 ~tg/kg). Endotracheal intubation was effected with succinyIcholine (tmg/kg). For maintenance fentanyl (0.1-0.2 mg) and alcuronium (3 rag) were administered as required; ventilation was controlled using NzO 60% in 02. If there were signs of insufficient anaesthesia, halothane (0.7-1.5 vol.%) was given. At the end of surgery, neuromuscular blockade was antagonized with atropine 0.5rag and neostigmine 1.0mg; narcotic antagonists were never required. Mepivacaine (hyperbaric Meaverin 4%, 2 ml, given between I52 and L4 was used for spinal anaesthesia.
Patient-Controlled Analgesia Post-operative analgesia was provided by use of an On-Demand Analgesia Computer (ODAC). By means of a mechanical syringe operated by a pushbutton, the microprocessor-controlled infusion system supplied small, preprogrammed boluses of analgesic solution, which are added to the usual postoperative infusion (demand volumes 0.1-5 ml, regulated in 0.1 ml steps, injection time 5-10s). The microcomputer controlled a previously prescribed hourly maximum dosage (volume of 1-99 ml, adjustable in 1 ml increments). After administering this dosage, the apparatus switched itself off and could only be restarted by the medical staff. In addition, a continuous infusion (independent of the demands by the patient, 0.01-0.99 ml/min, adjustable in steps of 0.01 ml/min) can be administered. A number of safety checks are intended to prevent an overdose: thus, the patient has to press the button twice within 1 second for the demand to be valid (disorientated patients are unable to do this); between two demands the apparatus remains refractory for a selected time period. The computer also checks the system for leaks, air bubbles or excessive resistance in the tubing, and controls the timely filling of the 10 ml syringe from an infusion bottle via a three-way valve. A built-in thermoprinter documents each valid demand together with its timing. 200rag naIbuphine (20ml) were diluted with 250 ml 0.9% saline solution. The demand dose was 3.7 mg (5 ml). To prevent catheter obstruction, the continuous infusion rate was set at 0.44 mg/h. The selected hourly maximum dose was 28.2 mg (38 ml), with a p u m p refractory time of 1 min. At this setting, it was not possible to make more than 7 demands per hour. The patients were connected up to the ODAC as soon as possible following surgery and were closely monitored until returning to complete orientation. A further explanation of how to handle the machine was given and then they followed normal ward rou-
K. A. Lehmann and B.Tenbuhs: Analgesia with Nalbuphine
269
Table 1. Demographic data and anaesthetic techniques (data as number in subgroups (n) or mean + SD)
n
Sex
Age (years)
Weight (kg)
(male/female)
n general
spinal
Duration of surgery (rain)
Totalgroup
40
(19/21)
46.6_+I4.5
69.8___12.9
35
5
150.1+79.2
Abdom Ortho
20 20
(8/12) (11/ 9)
48.0_+ 14.0 45.2-+15.3
65.3 -+ 10.5 74.3+13.7
20 15
0 5
194.5 -4-86.0 105.8+__36.5
42.5 +_t3.3 50.3 ± 14.9
74.5 + 13.1 65.5 + tl.3
17 18
2 3
141.6 + 68.6 157.9 +_88.7
44.7_+14.0 60.2+__11.6
67.8-+11.2 83.8+16.3
35 5
t59.0+80.5 88.0+22.5
Male Female
19 21
General Spinal
35 5
(17/I8) (2/ 3)
(abdom = abdominal surgery, ortho = orthopaedic surgery; general = genera} anaesthesia, spinal = spinal anaesthesia) Table 2. List of operations (number in brackets)
a) abdominal surgery: cholecystectomy (8), stomach (Billroth, vagotomy) (6), colectomy (1), resection of rectum (4), Whipple (1) b) orthopaedic surgery: osteosynthesis of the shoulder (1), femur (2), knee (5), lower leg (1), foot (4); discectomy (2), meniscectomy (5) c) inverventions performed under spinal anaesthesia: osteosynthesis of the knee (2), foot (2); meniscectomy (1) Table 3. Retrospective pain scores
0 1 2 3 4 5
no pain sometimes moderate pain always moderate pain sometimes severe pain always moderate, sometimes severe pain discontinuation due to inefficacy
sics, experience of previous operations were recorded, as well as acceptance of the PCA system (attitudes towards the apparatus as compared to treatment by the nursing staff, side-effects). Finally, a retrospective pain score was obtained using a sixpoint verbal scale (Table 3). All data were documented with a Commodore computer system. Cumulative doses were calculated from the times of successful demands and represented graphically as a function of time, site of operation and effectiveness. Arithmetic means + standard deviations, medians and ranges were calculated for statistical evaluation; subgroups were compared by means of the Mann-Whitney-Wilcoxon-test for independent samples (level of significance p = 0.05). Results
Table 4. Nalbuphine consumption as a function of time (arithmetic mean of mg nalbuphine for 4 hourly intervals starting with the connection of the patients to the ODAC)
Time (h)
1-4
5-8
9-12
Total group
20.6
13.8
9.8
Abdom Ortho
35.2 t 5.9
19.3 9.4
12.0 8.3
Male Female
25.6 25.1
9.4 17.8
General Spinal
26.7 15.9
14.5 9.2
13-16
17-20
21-24
12.5
12.3
10.1
18.7 7.8
18.6 8.5
8.3 9.4
9.4 t0.3
12.3 12.7
15.3 9.7
7.8 9.4
9.7 10.7
13.2 7.7
12.9 3.6
9.6 7.9
(abdom = abdominal surgery, ortho = orthopaedic surgery; general = general anaesthesia, spinal = spinal anaesthesia)
tine until the next morning; sedatives and additional analgesics were not allowed, except for an intramuscular injection of 15 mg piritramid should the PCA prove ineffective. On the following day all patients were questioned in a standardized interview. Smoking and drinking habits, pain history, basic attitude to analge-
Demographic data for the subgroups are shown in Table 1, and Table 2 lists the operations. Intraoperative fentanyl consumption during general anaesthesia was 0.075 _+0.044 lxg/kg/min. On average, patients were connected to the ODAC within 43 + 29 minutes of surgery being terminated and 71 _+32 min passed until the working of the apparatus was fully understood. The mean hourly doses (+_ SD) for the population of 40 patients are shown in Fig. 1. They comprised the continuous infusion and the self-administered nalbuphine boluses. After an initial "loading" period, during which a mean dose of nalbuphine 16 mg/h was required, the demand for nalbuphine became stable at about 2-5 mg/h. The large standard deviations, however, indicate marked individual variation in the demand pattern. There was a highly significant positive correlation between the dose of nalbuphine during the first hour of PCA treatment and intraoperative fentanyl consumption; according to y = a x + b , with y = m g nalbuphine, x = g g fentanyl.kg a.minq; a=202.3, b = - 0 . 0 4 , coeffi-
270
K.A. Lehmann and B.Tenbuhs: Analgesia with Nalbuphine
2t,
.£2
•~ Z0 £1_
F16
g },2
Fig.l. Mean hourly nalbuphineconsumpfion per patient during intravenous self-administration in the early postoperative period; mean + SD. Patients were connected to the ODAC at time t = 0. Numbers above the abscissa indicate how many patients remained in the study at the appropriate time
O
o 6 xZ £%
n=
t,
8
16
12
20
2,~
time(h)
E 80
'
120
0
E D tO
r~O
9()
AZ
60 O
30
f
o ~mo~e (2~11
y
0 orthopaedil: (201
O
. . . . . . . . . . .
4
8
12
16
,
20
Fig. 2. Mean cumulative nalbuphine consumption as a function of time for the sexes (a) and different sites of surgery (b)
2/,
~t,i~me I h )
Table 5. Natbuphine consumption and efficacy (arithmetic mean ± SD and median/range) Duration of PCA-treatment
Demands per patient
Nalbuphine consumption (p~g' kg -1" h q)
Retrospect. pain score
(h) Total group
17.4 _+6.9
16.0 + 12.3 13.3 (1-45)
117.5 _+201,0 51.3 (8.t-1050.5)
1.82 + 1.72 15 (0-5)
Abdom
15.3 ± 8.7
Ortho
19.5 ± 3.8
21.0 ± 11.6 17.0 (5-45) 11.t ± t 1,1 7.5 (1-42)
198.4 + 260.6 100.8 (24.3-1050.5) 36.7 ± 35.4 24,0 (8,1- 147.0)
2,45 ± t.82 2.1 (0-5) 1.20 ± 1.39 0.8 (0 4)
Male
16,9 _+6.2
Female
17.9 ± 7.7
15.5 _+12.3 13.3 (t-45) 16.6 +__12.5 13.3 (1-42)
95,4 _+143.7 41.0 (8.4- 520.1) 137.6 ± 243.6 56.6 (8.1-1050.5)
1,57 + 1.64 t.2(0-5) 2.04 ± 1.80 1.9 (0-5)
General
t7.5 +_7.4
Spinal
17.2:t:3.1
16.9 ± 12.6 13.4 (1-45) 10.2_+ 8,8 10.0 (1-20)
129.9 ± 212.2 56.6 (8.2--1050.5) 31.3± 23.5 22.4 (8.1- 60.9)
1.9t +_1.77 1.6 (0-5) 1.20+1.30 1.0 (0-3)
(abdom = abdominal surgery, ortho = orthopaedic surgery; general = general anaesthesia, spinal = spinal anaesthesia)
K. A. Lehmann and B. Tenbuhs: Analgesia with Nalbuphine
271
PCF:I Nt:::tLBUPHI NE 200
pLtn
eco~o
0
eco'r •
pLtn
%
2
160
120
80
I0
o
J
200 pLtn
~co?s
pe.|n sco'ro~
]
..~,4,$
160
120
60
O
41.
8
12
16
20
21
0
28
4
e
12
16
20
2/,.
20
time(h) Fig. 3. Individual cumulative dose-time plots for 40 patients broken down to the respective pain scores achieved (cf. Table 3). Bottom right graph: [] mean pain Score 3, A Score 4, X discontinuation due to inefficacy (Score 5). Each step is indicative of a vafid demand; curves gradually rise due to slow continuous infusion
cient of correlation r = 0.67; p = 0.00001 (35 patients operated under general anaesthesia). Considering all observed demands (n =642 for the population), a median duration of action of 19 (1-1255) min was calculated for each individual bolus. The time courses of the mean cumulative doses in different subgroups according to sex and site of operation are shown in Fig.2. The mean nalbuphine dosages at 4 hourly intervals are shown in Table 4. Table 5 shows duration of PCA treatment, demand frequency, drug consumption and retrospective pain scores. Statistically significant differences between the subgroups were only found for abdominal and orthopaedic patients in individual demand frequency, nalbuphine consumption (~.tg.kg q. h 1) and retrospective pain scores (Mann-Whitney-Wilcoxon). Patient acceptance is illustrated in Table 6. Individual cumulative dose-time-plots for all 40 patients differentiated according to the retrospec-
tive pain scores are displayed in Fig. 3. Side-effects observed during the PCA period were minor (15%) or major (2.5%) nausea, vomiting (7.5%), minor (5%) or major (7.5%) sweating, dysphoria (7.5%) and euphoria (2.5%). Itching was not observed. Clinically evident central respiratory depression never occurred, and the postoperative circulatory reaction pattern was always normal. Discussion
Treatment of pain in the early postoperative period often leaves much to be desired, as has been emphasised in numerous, usually extremely critical reports throughout the world [2, 34, 51, 62]. Most publications indicate a certain feeling of resignation, largely due to the unpredictability of individual pain intensity and tolerance [10, 58, 63]. So far it has been virtually impossible to establish the role played by age, sex,
272
K, A, Lehmann and B. Tenbuhs: Analgesia with Nalbuphine
Table 6. Patient acceptance (data in %; + better/positive, = comparable/uncertain, - worse/negative) Comparison PCA with conventional pain treatment
Continuation of present treatment desired
Total group
56.5
26.1
17.4
37.5
27.5
35
Abdom Ortho
44.4 64.3
22.2 28.6
33.3 7.1
50 25
25 30
25 45
15 0
Male Female
50 61.5
30 23.1
20 15.4
31.6 42.9
36.8 19
3t.6 38.1
10.5 4.8
General Spinal
55 66.7
30 0
15 33.3
37.1 40
28.6 20
34,3 40
8.6 0
Nurse preferred
7.5
(abdom = abdominal surgery, ortho = orthopaedic surgery; general = general anesthesia, spinal = spinal anesthesia)
anaesthetic technique and type or duration of surgery [32, 43], probably because psychological factors, such as previous experience, anxiety, depression, neuroticism and self-discipline on the part of the patient can seldom be satisfactorily standardised or recorded in an objective manner [8, 42, 46, 50, 60]. On the other hand, algesimetry itself involves considerable problems. Pain intensity and pain relief scales, as well as visual or acoustic analogue scales, require the patient to make a quantitative auto-analysis, which is unlikely to be reliable at all times [5, 18, 20, 31, 39, 44, 47, 49, 64]. If the number of postoperative administrations of analgesics were dependent on assessment and recording by the nursing staff [41, 43], there is the danger of too much importance being attached to stoicism ("you have to put with pain after surgery") and rigid dosage habits. In addition, the fact that polypharmacy is often practised during recovery (i.e. narcotics, non-steroidal antiphlogistics, tranquillizers etc.) means that it is difficult to make the necessary differentiation between objective pain intensity and subjective pain threshold [35]. It has long been known that it is difficult to predict the bioavailability of narcotic analgesics following intramuscular injection, and that there is often a considerable lag until their onset of action. On the basis of pharmacokinetic data, continuous intravenous infusions have often been recommended to maintain analgesia, but more and more studies have suggested that it is not possible to make generalizations about "'effective" plasma concentrations of narcotics for analgesia [9, 26, 36, 53]. Thus, the use of pharmacokinetic planning in the treatment of acute pain at present still appears to be unrealistic. The therapeutic concept of intravenous on-demand (or "pa~ient-corttrolled") analgesia should be considered an attempt to solve all the above-mentioned problems at once. If the patient himself decides how much pain he is suffering or is prepared to
suffer, intravenous self-administration should satisfy the patient and reduce the nursing staff workload. In this way, the dynamic process of analgesia titration, with its ideal aim of complete pain relief, a decision which the patient can probably make better than any technique relying of attempted quantification of pain intensity, can be added to the static methods so far used in algesimetry. Various surveys have indicated increasing interest in the method, either because it should make it possible to give more effective treatment of acute and chronic pain than has been the case until now, or because it should enable more objective comparison of various analgesics with regard to effective dosage range [6, 23, 28, 591. Various microprocessor-controlled injection systems are now available. The investigations described here were performed with the On-Demand Analgesia Computer (ODAC) [451. Nalbuphine is a new agonistic-antagonistic opioid of the phenanthrene series; it is structurally related to oxymorphone and naloxone [12, 37]. In vitro and in vivo pharmacological studies have demonstrated that the analgesic potency of nalbuphine lies somewhere between morphine and pentazocine. In a study in dogs, Murphy and Hug [38] observed that it reduced the minimum alveolar concentration (MAC) of enflurane, by about 8%. This did not change when the dose was increased, whereas the same amount of morphine reduced the MAC by about 17%, a ceiling effect only occuring at 5 mg! kg. Gal et al. [16] gave male volunteers 0.15 mg/kg nalbuphine or morphine and observed similar effects with regard to analgesia and respiratory depression. When the dose was raised, the effect of nalbuphine only increased to a limited extent, whereas the effect of morphine increased in relation to dose. There was considerable individual variability in the analgesic effects of natbuphine. Romagnoli and Keats [48] also used volunteers to demonstrate that central respira-
K. A. Lehmann and B. Tenbuhs: Analgesia with Nalbuphine
273
Table 7. Discontinuationdue to inadequate analgesia (case reports) Patient
1 7 t0 15 17
Duration of surgery
Intraoperative fentanyl consumption
(min)
(rag)
100 180 210 180 120
0,9 1.1 1,8 1.5 0.8
(Ixg.kg-~•rain-~)
PCAdisc.ont. after (rain)
Cumulative nalbuphine dose
0.170 OAO0 0.136 0.098 0.090
57 595 1t0 98 23
30,1 74.8 60.1 63.7 29.8
tory depression was at its maximum after a dose of about 30 nag nalbuphine, while it increased when the dose of morphine was raised. It was possible rapidly to antagonise the effects of nalbuphine with nalorphine, levallorphane or naloxone, although rebound effects were noted. So far natbuphine has been used for premedication in anaesthesia [14, 24], for pain relief during surgery [13, 61], and for postoperative and postpartum analgesia [1, 3, 4, 7, 1t, 40, 55-58]. By comparison, little is known about its use in the treatment of chronic pain [54]. The most frequently reported side-effects have been sedation and, less commonly, nausea and vomiting; psychotomimetic effects have seldom occurred. It is estimated that there is only a slight risk of abuse [191. On the other hand, a number of authors have claimed that nalbuphine can reverse opioid-induced respiratory depression and reduced vigilance following administration of fentanyl during surgery', without analgesia being affected [t5, 25, 33]. The literature shows that, when comparable doses are given, parenterally administered nalbuphine has 0.7-0.9-times the analgesic potency of morphine and 3-times the potency of pentazocine. The studies by Murphy and Hug [38] as well as the opinions expressed by Fragen and Caldwell [14], who found nalbuphine considerably to be less effective as an analgesic than morphine when used for intravenous premedication prior to thiopental anaesthesia, make such equipotency data questionable. So far the use of nalbuphine has been reported twice in postoperative intravenous on-demand analgesia. Kay [21, 22] used demand doses of 5 mg (injection time 5 rain, refractory time 3 rain) after an initial loading dose of 20 nag in 20 patients who had undergone abdominal surgery. About half of them experienced sufficient analgesia after the first injection of 20 mg and afterwards only required a relatively low maintenance dose. The remaining patients, however, reported virtually no pain relief after the first bolus injection and later required high doses (up
(nag)
Table 8. Equipotency calculations. Comparison of nalbuphine data from the present study with results in identical studies using morphine [29] and pentazocine [30]: Relative equipotent doses are based on the product of mean analgesic consumption ([xg/kg/h) and retrospective pain score (morphine = I) Analgesic
Patients Consump- Retro(n) tion spect, (gg/kg/h) pain score
Morphine 40 Pentazocine 40 Natbuphine 40 Nalbuphinea 35
29.62 135.57 t17.52 55.75
t.52 t.60 1.82 1.37
Product
Relative equipot. dose
45.02 216.91 2t3.89 76.38
1 4.82 4.75 1.70
a patients with pain scores 0-4
to 100 mg nalbuphine in 90 rain), without experiencing effective pain relief. Sprigge and Otton [52] compared nalbuphine and pethidine in 13 postoperative patients after abdominal surgery (demand dose 2 mg, injection time 2 rain, refractory time 15 min). Their study, too, showed considerable individual variability in analgesic consumption. Analgesic efficacy was described as good and approximately equal for both medications; however, the sedative effect of nalbuphine sometimes prevented the patients from making optimal use of the apparatus. In the present investigation each patient had a total dose of 200 mg nalbuphine at his disposal; the maximum hourly dose was 28.2 mg. In view of the first clinical reports of the new analgesic, these doses may appear to be very high. However, it should be emphasised that this amount was an offer, and as shown in Fig. 3, it was only occasionally needed. Only 3 out of 40patients required more than 150mg nalbuphine in the treatment period. From the figures given in Table 3 (mean nalbuphine consumption in 4-h observation periods) it can be assumed that in conventional treatment of postoperative pain single injections of about 15 mg would be necessary every 4-6 h. However, from Figs. t and 3 it can be seen that there was marked intra- and interindividual variability in demand.
274
In general, the results agree with those obtained previously and quoted above. As in the study by Kay, 5 patients did not experience adequate analgesia following abdominal surgery, even though high doses were sometimes required (Table 7). There were no such difficulties following orthopaedic surgery. It is possible that the poor pain relief in the cases described was due to the antagonistic component of nalbuphine acting on the residue of the relatively high doses of fentanyl administered during the surgery. This suggestion is confirmed by the significant positive correlation between the self-administered dose of nalbuphine during the first hour of PCA treatment and the intraoperative fentanyl consumption. If patients with insufficient pain relief are included in the calculation of time-related postoperative nalbuphine consumption (~tg-kg-l.h -1) and mean analgesic efficacy (retrospective pain scores), the evaluation of nalbuphine relative to morphine or pentazocine is less favourable than would be inferred from the literature. In Table 8 the data for nalbuphine are compared with results obtained in identical postoperative PCA studies with those two narcotics in which no discontinuation due to lack of efficacy (pain score 5) was observed. Since analgesia was different for each drug, equipotency has been calculated using the product of consumption and efficacy (morphine = 1). By this method, which gives equal weight to intensity and duration of action, nalbuphine appears to be about as potent as pentazocine and only about 1/5 as effective as morphine. However, if nalbuphine failures (score 5) are eliminated, nalbuphine appears to be about 2/3 as potent as morphine and 2.8 times as potent as pentazocine. In general, this corresponds to the results so far reported in the literature. Dividing the patient population into subgroups did not reveal any major differences in demand for nalbuphine, success of treatment or patient acceptance between the sexes (Fig. 2, Tables 4-6). Patients who had undergone abdominal surgery required significantly more nalbuphine than those recovering from orthopaedic operations, but the retrospective pain score was significantly worse than in the latter group. At present there does not appear to be any convincing explanation for this difference, especially as investigations with other opioid analgesics [281 have not always confirmed this tendency. In this connection, Fig. 3 also illustrates a number of questions which have hardly been considered so far; it shows the demands by those patients who reported no or only minor pain even after upper abdominal surgery, while relatively high doses often resulted in considerable variation in pain relief. It must be the task of fu-
K. A. Lehmann and B. Tenbuhs: Analgesia with Nalbuphine
ture investigations to establish which factors are of real importance; it seems, however, as if it will only be possible to solve the problems with the help of psychologists. The influence of anaesthetic technique on postoperative nalbuphine consumption was not statistically significant. The mean consumption data ~able 4) seem to indicate that there is a difference, but in view of the great individual variability and the relatively small numbers of patients in the subgroups, it was not possible to come to any definite conclusion. In addition, it should be emphasised that the difference between anaesthetic techniques reflects the difference between the site of operation (Fig. 2 b), as spinal anaesthesia was only employed in cases of orthopaedic surgery. Prospective studies are now under way to confirm these results. As can be seen from Table 5, there was a positive attitude towards PCA with natbuphine. Of those patients who had already experienced conventional postoperative analgesia, 57% rated PCA as better, and only 17% preferred conventional treatment. 38% of the patients would have liked to have stayed on the apparatus after the treatment period. On average, only 8% regarded "supplanting" of the nursing staff by a machine in a negative light; the possibility of a connection between attitude and quality of analgesia cannot be ruled out. The nursing staff themselves made varying evaluations of on-demand analgesia; their opinions ranged from strong approval (less work) to great scepticism. The observations of physiotherapists, particularly following orthopaedic surgery, should be emphasised; in their experience patients primarily treated with the ODAC tended to complain and behave in an uncooperative manner when mobilisation exercises became necessary. Patients and therapists will, however, probably disagree whether effective pain relief on the day following operation can really be considered a disadvantage. In the case of adverse reactions, it is difficult to distinguish between residual effects of anaesthesia and the action of nalbuphine. In general, there was the usual incidence of postoperative side effects. The marked sedation following nalbuphine reported by others Was not observed here. There were no cases of clinically relevant central respiratory depression, and certainly none requiring treatment. In view of the experience so far fear of this complication does not seem to be more justified than in conventional pain therapy with narcotics. Combination effects, e.g. hypovolaemia [9], concommitant sedative medication and other causes of reduced vigilance [17, 27], probably play an important role in this respect. On the other hand pain itself, the reason for further de-
K. A. Lehmann and B. Tenbuhs: Analgesia with Nalbuphine
mands, is considered as one of the most effective antagonists of opiate-induced respiratory depression. The rather high price of suitable PCA devices is an obstacle to wider application of this new form of pain treatment. With future series production and a reduction in size and price, however, its routine use would be conceivable and may be desirable. Until then, insight into the tremendous variability in the treatment of acute pain here described and documented objectively should be used for better adaptation than before of the conventional regimes to the needs of each individual patient. Abandoning traditional rigid dosage schemes (mostly without feedback to the prescribing doctor) would be a first step in the right direction. Acknowledgments. The authors are particularly indepted to the medical and nursing staff of their hospitals for their patience and cooperation, and to Dr E. Godehard (Institute of Documentation and Medical Statistics, University of Cologne) who performed the statistical analyses. Mrs R. Lade was most helpful with organizational problems. Two ODAC machines were provided and serviced by Janssen Pharmaceutica, Beerse (Belgium). We also thank Du Pont de Nemours (West Germany) for effective assistance.
References I. Alon E, Krayer S, Hossli O (1984) Analgesie und Nebenwirkungen von Nalbuphin (Nubain) im Vergleich zu Morphin nach Hysterektomie. Anaesthesist 33:360~362 2. AngellM (1982) The quality of mercy. N Engl J Med 306: 98-99 3. Beaver WT0 Feise GA (1978) A comparison of the analgesic effect of intramuscular natbuphine and morphine in patients with postoperative pain. J Pharmacol Exp Ther 204:487-496 4. Beaver WT, Feise GA, Robb D 0981) Analgesic effect of intramuscular and oral nalbuphine in postoperative pain. Clin Pharmacol Ther 29: t 74- t80 5. Beaver WT (1983) Measurement of analgesic efficacy, in man. In: BonicaJJ (ed) Advances in pain research and therapy; vol 5. Raven Press, New York, pp 411-434 6. Bennett RL, Griffen WO (1983) Patient controlled analgesia. Contemp Surg 23:75-89 7. Bikhazi GB (1978) Comparison of morphine and nalbuphine in postoperative pediatric patients. Anesthesiol Rev 5: 34-36 8. CroninM, RedfernPA, OttingJE (1973) Psychometry and postoperative complaints in surgical patients. Br J Anaesth 45: 879-886 9. Dahlstrtm B, Tamsen A, Paalzow L, Hartvig P (1982) Patientcontrolled analgesic therapy, part IV: Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet 7:266--279 10. Donovan BD (1983) Patient attitudes to postoperative pain retier. Anaesth Intensive Care tl : 125-129 1L EngaltaJM, Jimenez H, Alejandro E (1982) Intramuscular natbuphine HC1 for the control of postoperative somatic pain. Phil J Ohstet GynecoI 6:44-49
275 12. Errick JK, Heel RC (t983) Nalbuphine. A preliminary report of its pharmacological properties and therapeutic efficacy. Drugs 26:I91-211 I3. Fahmy NR (1980) Nalbuphine in "balanced" anesthesia: Its analgesic efficacy and hemodynamie effects. Anesthesiology 53: $66 14. Fragen RJ, Caldwe|l N (1977) Acute intravenous premedication with nalbuphine. Anesth Analg 56:808-812 15. FreyeE, HartungE, SegethM (1984). Nalbuphine reverses fentanyl-related EEG-changes in man. Acta Anaesthesiol Belg 35: 25-36 16. Gal TI, DiFazio CA, Moscicki I (1982) Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine. Anesthesiology 57:36%374 17. Gibbs JM, Johnson HD, Davis FM (1982) Patient administration of i.v. buprenorphine for postoperative pain relief using the "Cardiff" demand analgesia apparatus. Br J Anaesth 54: 27%284 18. Houde RW, Wallenstein SL, Beaver WT (1965) Clinical measurement of pain. In: George DS (ed) Analgesics. Academic Press, New York, pp 75-122 19. JasinskiDR, Masky PA (1972) Evaluation of natbuphine for abuse potential. Clin Pharmacol Ther 13:78-90 20. Joyce CRB, Zutshi DW, Hrubes V, Mason RM (1975) Comparison of fixed intervals and visual analogue scales for rating chronic pain. Eur J Ctin Pharmacol 8:415--420 21. Kay B (I983) On-demand nalbuphine for post-operative pain. Anaesthesist 32 [Suppl]: 366-367 22. Kay B (1984) Patient-controlled analgesia. Can Anaesth Sue J 31 : 120-121 23. Keefi-Szanto M (1979) Drugs or drums: What relieves postoperative pain? Pain 6:217-230 24. Lake CL, Duckworth EN, DiFazio CA, Magruder MR (1984) Cardiorespiratory effects of nalbuphine and morphine premedication in adult cardiac surgical patients. Aeta Anaesthesiol Scand 28:305-309 25. Latasch L, Probst S, Dudziak R (1984) Reversal by nalbuphine of respiratory depression caused by fentanyl. Anesth Analg 63:814-816 26. Lehmann K_A,Gensior J, Daub D (1982) "Analgetische" Fentanyl-Blutkonzentrafionen unter Neuroleptanalgesie. Anaesthesist 31: 655-659 27. Lehmann KA, Neubauer ML, Daub D, KalffG (1983) CO2-Antwortkurven als Mag ftir eine opiatbedingte Atemdepression. Untersuchungen mit Fentanyl. ,~aaesthesist 32: 242-258 28. Lehmann KA (1984) On-Demand Analgesic: Neue MiSglichkeiten zur Behandlung akuter Schmerzen. Arzneimittelforsch 34:1108-1114 29. Lehmann KA, Gt~rdes B, Hoeckle W (1985) Postoperative OnDemand Analgesic mit Morphin. Anaesthesist 34:494-501 30. LehmannKA, TenbuhsB, HoeckleW (1985) Postoperative On-Demand Analgesic mit Pentazocin (Fortral). Langenbecks Arch Chit 367: 27 -40 31. Loan WB, Dundee JW (1967) The clinical assessment of pain. Practioner 198: 759-768 32. Loan WB, MorrisonJD (1967) The incidence and severity of postoperative pain. Br J Anaesth 39:695-698 33. Magruder MR, Delaney RD, DiFazio CA (1982) Reversal of narcotic-induced respiratory depression with nalbuphine hydrochloride. Anesthesiol Rev 9:34-37 34. Marks RM, Sachar EJ (1973.) Undertreatment of medical inpatients with narcotic analgesics. Ann lnt Med 78:173-181 35, Masson AHB (1967) The role of analgesic drugs in the treatment of postoperative pain. Br J Anesth 39:713-720 36. Mather LE (1983) Importance of blood concentrations of narcotics: Basis of understanding, controlling, and individualiz-
276 ing therapy. In: Bonica JJ (ed) Advances in pain research and therapy, vol 5. Raven Press, New York, pp 461-466 37. MitterRR (1980) Evaluation of nalbuphine hydrochloride. Am J Hosp Pharm 37:942-949 38. Murphy MR, Hug CC (1982) The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology 57: 489-492 39. Nayman J (1979) Measurement and control of postoperative pain. Ann R Coll Surg Engl 61 : 419-426 40. Okun R (1982) Analgesic effects of oral natbuphine and codeine in patients with postoperative pain. Clin Pharmacol Ther 32:517-524 41, Papper EM, BrodieBB, Rovenstine EA (1952) Postoperative pain; its use in the comparative evaluation of analgesics. Surgery 32:10%109 42. Parbrook GD, Steel DF, Dalrymple DG (1973) Factors predisposing to postoperative pain and pulmonary complications. A study of male patients undergoing elective gastric surgery. Br J Anaesth 45:21-23 43. ParkhouseJ, LambrechtsW, Simpson BRJ (1961) The incidence of postoperative pain. Br J Anaesth 33:345-353 44. Parkhouse J, Holmes CM (1963) Assessing post-operative pain relief. Proc R Soc Med 56:579-583 45. Peeters M, Brugmans J (1980) Postoperative pain relief by demand analgesia. Acta Anaesthesiol Belg 31 [Suppl]: 233-237 46. Pflug AE (1977) Pbysiopathology and control of postoperative pain. Arch Surg 112:773-781 47. RevilI SI, Robinson JO, Rosen M, Hogg MIJ (1976) The reliability of a linear analogue for evaluating pain. Anaesthesia 31 : 1191-1198 48. Romagnoli A, Keats AS (1980) Ceiling effect of respiratory depression by nalbuphine. Clin Pharmacol Ther 27:478-485 49. Scott J, Huskisson EC (1976) Graphic representation of pain. Pain 2:175-184 50. Scott LE, Clum GA, Peoples JB (1983) Preoperative predictors of postoperative pain. Pain 15: 283-293 51. Smith JM, UttingJE (1976) Postoperative pain. Br Med J 2: 875 52. Sprigge JS, Otton PE (1983) Nalbuphine versus meperidine for postoperative analgesia: a double-blind comparison using the patient controlled analgesic technique. Can Anaesth Soc J 30: 517-521 53. Stapleton JV, Austin KL, Mather LE (1979) A pharmacokinetic approach to postoperative pain: Continuous infusion of pethidine. Anaesth Intensive Care 7:25-32
K.A. Lehmann and B. Tenbuhs: Analgesia with Nalbuphine 54. Stambaugh JE (1982) Evaluation of nalbuphine. Efficacy and safety in the management of chronic pain associated with advanced malignancy. Curt Ther Res 31: 393-400 55. Sulit BNM (1982) Intravenous nalbuphine hydrochloride for the control of post-operative somatic pain among filipinos. Phil J Anesth 6:2-9 56. Sunshine A, Zighelboim I, de Sarrazin C, de Castro A (I983) A study of the analgesic efficacy of nalbuphine hydrochloride in patients with postpartum pain. Curr Ther Res 33: 108-114 57. Tammisto T, Tigerstedt I (1977) Comparison of the analgesic effects of intravenous nalbuphine and pentazocine in patients with postoperative pain. Acta Anaesthesiol Scand 21 : 390-394 58. Tammisto T, Tigerstedt I (1982) Narcotic analgesics in postoperative pain relief in adults. Acta Anaesthesiol Scand 74 [Suppl]: 161-164 59. Tamsen A, Hartvig P, Fagerlund C, Dahlstrrm B, Bondesson U (1982) Patient-controlled analgesic therapy: Clinical experience. Acta Anaesthesiol Scand 74 [Suppl]: 157-160 60. Wallace PGM, Norris W 0975) The management of postoperative pain. Br J Anaesth 47:113-120 61. WayeJD, BraunfeldSF (1982) A randomized double-blind study of nalbuphine as an analgesic for colonoscopy. Gastrointest Endosc 28: 86- 87 62. Weis OF, Sriwatanakul K, Alloza JL, Weintraub M, Lasagna L (1983) Attitudes of patients, housestaff, and nurses toward postoperative analgesic care. Anesth Analg 62:70-74 63. White DC (1982) The relief of postoperative pain. In: Atkinson RS, Hewer CL (eds) Recent advances in anaesthesia and analgesia. Churchill Livingstone, Edinburgh, London, Melbourne, New York, pp 121-139 64. WoodfordeJM, MerskeyH (1972) Some relationships between subjective measures of pain. J Psychosom Res t6: 173 178 Received: December 3, 1985 accepted in revised form: May 30, 1986 Prof. Dr. Dr. KIaus A. Lehmann Institute of Anaesthesiology University of Cologne Joseph-Stelzmann-Strasse 9 D-5000 KOln 41 Federal Republic of Germany