Acla anaesth. scand. 1977, 21, 470-480
Antagonism of Fentanyl with Naloxone during N,O+O,+ Halothane Anaesthesia IRMATIGERSTEDT Department of Anaesthesia, Helsinki University Central Hospital, Helsinki, Finland
T o investigate the antagonistic effect of naloxone on fentanyl-induced respiratory depression, 55 patients (randomly divided into various study and control groups) were studied during nitrous-oxide-oxygen-halothaneanaesthesia. Respiratory depression after 0.1 mg of fentanyl was totally reversed by 10 pg/kg of naloxone, measured as 100% restoration of spontaneous respiration, normal minute volumes and end-tidal C 0 2 , while 15 pg/kg of naloxone was needed to antagonize 0.2 mg of fentanyl. The respective control groups remained apnoeic. If no fentanyl had previously been administered, there was no difference in the respiratory behaviour of naloxone-treated and control patients, which indicates that no unspecific analeptic effect of naloxone could be demonstrated. T h e circulatory changes after fentanyl were nearly reversed by naloxone, as has been found earlier with other narcotics. Recovery from anaesthesia was scored from 0 to 10 (using a modification of Apgar scores for newborns), and somewhat higher mean scores were obtained with the naloxone-treated patients than with their controls. However, higher postoperative pain scores were recorded in these patients as well as a higher incidence of nausea and vomiting. The study demonstrates the dose-relationships of fentanyl and naloxone for estimation of total antagonism ;however, the use of naloxone for partial antagonism a t the termination of anaesthesia cannot be based on these findings.
Received 31 January, accepted for publication 28 Februav 1977
Naloxone (N-allyl-nor-oxymorphone) is a spiratory depression of both natural (HASpotent new analgesic antagonist. After ex- BROUCK 1971, HEISTERKAMP & COHEN1972) and synthetic narcotic analgesics, including tensive experimental studies with animals started by BLUMBERGet al. in 1961, more propoxyphene (KERSCH 1973, LOVEJOY et al. than a decade of clinical research has proved 1974), cyclazocine (JASINSKI et al. 1968) its superiority to previous agents, as it is the and pentazocine (KALLOS& SMITH1968). first pure antagonist devoid of any agonist It is also capable of antagonizing the agonist effect (FOLDESet al. 1963, JASINSKI et al. effects of the partial narcotic antagonists 1967, KALLOS& SMITH 1968). The analgesic levallorphan and nalorphine (BLUMBERG & WATT 1968). activity of narcotic action is promptly blocked et al. 1966, KOSTERLITZ by naloxone (BLUMBERGet al. 1966, TAKE- Circulatory depression and sedation after MORI et al. 1969, SMITS & TAKEMORI 1970, narcotics are reversed by naloxone (EVANSet et al. 1969). In contrast to EVANSet al. 1974, GIRVAN & DUNDEE 1976). al. 1974, FOLDES On a molar basis, the antagonistic effect of nalorphine, levallorphan and cyclazocine, naloxone seems to be six times more potent naloxone does not constrict the pupils than levallorphan or 30 times more effective (JASINSKI et al. 1967). It is claimed that it than nalorphine (FOLUESet al. 1963). causes no nausea when given alone (LONGNaloxone reverses the narcotic-induced re- NECKER et al. 1973), but when it is given after
ANTAGONISM OF FENTANYL WITH NALOXONE
narcotics the frequency of nausea and vomiting would be the same as after the respective analgesics ( FOLDES1964). Two case reports (Moss 1973, BELL1975), and a recent study by STEPHEN et al. (1976) with dyspnoeic newborn rabbits, suggest some unspecific central stiniulating effect of naloxone. Very mild analgesia after high doses (2 mg) of naloxone has been suggested (LASAGNA1965), as well as mild sleepiness after chronic use of naloxone (JASINSKI et al. 1967). The reversal of narcotic intoxications and obstetric analgesia by naloxone has recently been well documented in the literature. The use of naloxone after morphine anaesthesia has also been studied (HASBROUCK 1971, LONGNECKER et al. 1973, JOHNSTONE et al. 1974). As shorter-acting narcotic analgesics are frequently used for supplementation of combined anaesthesia, this study was undertaken in order to investigate dose relationships between different doses of naloxone and fentanyl, our primary intraoperative analgesic. MATERIAL AND METHODS Fifty-five patients scheduled for elective general
surgery were included in the study and randomly assigned to eight different treatment and control groups (Table 1). They were all in good general condition (physical status ASA I or 11). Informed consent was obtained from every patient. For premedication, 1 mg/kg of pethidine, 25-50 mg of promethazine and 0.1 mg/lO kg of atropine were given intramuscularly. Anaesthesia was induced with 3-5 mg/kg of thiopental; 1 mg/kg of suxamethonium was given for endotracheal intubation; and anaesthesia was maintained with nitrous oxide (70%) and oxygen (30%), using intermittent positive pressure ventilation (IPPV). D-tubocurarine was used for muscle relaxation, the need being estimated by a peripheral neurostimulator (R. G. Wakeling & Co. Ltd.). When required, halothane was given for supplementation (0.5-1 %). No analgesics were administered during the surgery. End-tidal carbon dioxide was continuously registered with an infra-red COz analyzer (Uras, Hartman-Braun) to ensure normocapnia. At the end of the operative procedure, muscle relaxation was reversed with 2 mg of neostigmine and 1 mg of atropine, the need for additional reversal being assessed with the neurostimulator (ALI & SAVARESE 1976). Anaesthesia was continued with 0.3% halothane, and fentanyl was administered intravenously in doses of none, 0.05 mg, 0.1 mg or 0.2 mg. If the patient belonged to the naloxone group, 5 pg/kg of naloxone was given intravenously 15 min later. A second dose of 5 pg/kg of naloxone was administered 10 min after the first dose, and a third dose of 5 pg/kg of naloxone was given after another 10 minutes. Systolic and diastolic blood pressure,
Table 1 Characteristics of the different treatment groups (mean (range)). Treatment groups Naloxone
Control
Fentanyl (mg) 0
No. of patients
Age (yr)
5
0.05
10
0.1
10
0.2
10
0 0.05
5 5
0.1
5
0.2
5
471
Sex F/M
Weight (kg)
Height (cm)
27 (2 1-55) 36 ( 18-60) 43 ( 18-64) 36 (21-48)
67 (48-79) 65 (51-98) 75 (53-95) 73 (60-1 10)
173 (158-179) 162 (154-181) 171 (158-190) 173 (I6 1-1 92)
31 (2249) 58 (43-73) 51 (40-66) 43 (40-49)
71 (55585)
( 160- 178)
71 (59-78) 64 (5367) 78 (65-97)
I70 169 (155-177) 162 ( I6 1-I 65) 170 (162-1 78)
472
I. TIGORSTEDT
Table 2 Postanaesthetic recovery score & KROULIK 1970) (ALDRETE 1. Respiration
2. Circulation
3. Consciousness
4. Colour
5. Activity
Lowest score Maximum score
2 = Able to breathe and cough freely 1 = Dyspnoea or limited breathing 0 = Apnoea 2 = Blood pressure+20% of preanaesthetic level 1 = Blood pressure+20-50% of preanaesthetic level 0 = Blood pressure over +50% of preanaesthetic level 2 = Fully awake 1 = Arousable on calling 0 = not responding 2 = Pink 1 = Pale (jaundiced) 0 = Cyanotic 2 = Able to move 4 extremities 1 = Able to move 2 extremities 0 = Able to move 0 extremities 0 10
pulse rate, end-tidal C 0 2 , respiratory minute volume (Wright respirometer) and rate were measured before the administration of fentanyl, and 10 min after it, and 2 min after each dose of naloxone. If spontaneous respiration was absent, ventilation was maintained manually in a semiclosed, C02-absorption anaesthesia system; but during the respiratory measurements, patients were left without any ventilation assistance unless end-tidal C 0 2 rose above 7.8%=PCo2- 7.3 pKa (55 mmHg). The patients in each control group were managed in a similar way, and the measurements were carried out a t the same intervals, except that they were given no naloxone. After the last recordings, all patients were allowed to regain consciousness, extubated and removed to the recovery room, where they stayed for a minimum of 2 hours. The postanaesthetic recovery score (PARS), described by ALDRETE& KROULIKin 1970, was applied to test the patients’ recovery from anaesthesia. The PARS scoring system evaluates the patients’ five vital functions like the Apgar scores for newborns (APOAR1953). Respiration, circulation, consciousness, colour and activity are scored as follows: 0 = serious derangement, 1 = moderate disorder, 2 = normal. The five scores are added together, and a PARS score of 0-10 is achieved. A score of 10 indicates a patient in the best possible condition (see details in Table 2). The intensity of pain was scored from the scale: 0 = no pain, 1 = slight, 2 = moderate and, 3 = severe pain. Conventional analgesic and spasmolytic
agents were given when needed for pain relief, but the pain score for the rest of the observation period was considered to be that prior to the analgesic. Any other untoward effects were carefully observed. All these observations were made immediately after removal to the recovery room, and after 30 and 60 min. A postanaesthetic visit was paid to every patient on the first postoperative day to obtain the patient’s subjective opinion. Statistics
One-way analysis of variance or Student’s t-test (whenever appropriate) were used to test the statistical significance of the differences between the means of parametric variables. The x 2 test was used for comparison of non-parametric data.
RESULTS
Incidence of sbontaneous respiration As halothane was used during anaesthesia in order to avoid intraoperative use of narcotics, only a few patients breathed spontaneously immediately after surgery, even when muscle relaxation was adequately reversed and end-tidal CO,% showed normocapnia (Fig. 1). Twenty minutes later,
ANTAGONISM OF FENTANYL WITH NALOXONE
i
473
J-
Fig. 1. Incidence (%) of spontaneous respiration. F = mg of rentanyl, N = 5 &kg of naloxone. -- naloxone, - - - - - = control.
however, the restoration of spontaneous respiration seemed to be equal in the naloxone and control groups when no fentanyl was given (Fig. IA). One patient in the naloxone group did not begin to breathe spontaneously during the study period even when end-tidal CO, showed maximally 7.8%. However, after termination of halo-
Fig. 2. Minute ventilation ( I / min). Mean+s.e. mean. F = mg of fentanyl, N = 5 pg/kg of naloxone. - naloxone, - - - - - = control. ~
thane and nitrous oxide, the patient awoke rapidly and could be extubated normally. In the group fentanyl-0.05, the first 5 pg/kg of naloxone initiated spontaneous respiration and/or coughing in eight patients, while in the control group only one patient began to breathe at that time. The difference was statistically significant ( P
Antagonism of Fentanyl with Naloxone during N,O+O,+ Halothane Anaesthesia IRMATIGERSTEDT Department of Anaesthesia, Helsinki University Central Hospital, Helsinki, Finland
T o investigate the antagonistic effect of naloxone on fentanyl-induced respiratory depression, 55 patients (randomly divided into various study and control groups) were studied during nitrous-oxide-oxygen-halothaneanaesthesia. Respiratory depression after 0.1 mg of fentanyl was totally reversed by 10 pg/kg of naloxone, measured as 100% restoration of spontaneous respiration, normal minute volumes and end-tidal C 0 2 , while 15 pg/kg of naloxone was needed to antagonize 0.2 mg of fentanyl. The respective control groups remained apnoeic. If no fentanyl had previously been administered, there was no difference in the respiratory behaviour of naloxone-treated and control patients, which indicates that no unspecific analeptic effect of naloxone could be demonstrated. T h e circulatory changes after fentanyl were nearly reversed by naloxone, as has been found earlier with other narcotics. Recovery from anaesthesia was scored from 0 to 10 (using a modification of Apgar scores for newborns), and somewhat higher mean scores were obtained with the naloxone-treated patients than with their controls. However, higher postoperative pain scores were recorded in these patients as well as a higher incidence of nausea and vomiting. The study demonstrates the dose-relationships of fentanyl and naloxone for estimation of total antagonism ;however, the use of naloxone for partial antagonism a t the termination of anaesthesia cannot be based on these findings.
Received 31 January, accepted for publication 28 Februav 1977
Naloxone (N-allyl-nor-oxymorphone) is a spiratory depression of both natural (HASpotent new analgesic antagonist. After ex- BROUCK 1971, HEISTERKAMP & COHEN1972) and synthetic narcotic analgesics, including tensive experimental studies with animals started by BLUMBERGet al. in 1961, more propoxyphene (KERSCH 1973, LOVEJOY et al. than a decade of clinical research has proved 1974), cyclazocine (JASINSKI et al. 1968) its superiority to previous agents, as it is the and pentazocine (KALLOS& SMITH1968). first pure antagonist devoid of any agonist It is also capable of antagonizing the agonist effect (FOLDESet al. 1963, JASINSKI et al. effects of the partial narcotic antagonists 1967, KALLOS& SMITH 1968). The analgesic levallorphan and nalorphine (BLUMBERG & WATT 1968). activity of narcotic action is promptly blocked et al. 1966, KOSTERLITZ by naloxone (BLUMBERGet al. 1966, TAKE- Circulatory depression and sedation after MORI et al. 1969, SMITS & TAKEMORI 1970, narcotics are reversed by naloxone (EVANSet et al. 1969). In contrast to EVANSet al. 1974, GIRVAN & DUNDEE 1976). al. 1974, FOLDES On a molar basis, the antagonistic effect of nalorphine, levallorphan and cyclazocine, naloxone seems to be six times more potent naloxone does not constrict the pupils than levallorphan or 30 times more effective (JASINSKI et al. 1967). It is claimed that it than nalorphine (FOLUESet al. 1963). causes no nausea when given alone (LONGNaloxone reverses the narcotic-induced re- NECKER et al. 1973), but when it is given after
ANTAGONISM OF FENTANYL WITH NALOXONE
narcotics the frequency of nausea and vomiting would be the same as after the respective analgesics ( FOLDES1964). Two case reports (Moss 1973, BELL1975), and a recent study by STEPHEN et al. (1976) with dyspnoeic newborn rabbits, suggest some unspecific central stiniulating effect of naloxone. Very mild analgesia after high doses (2 mg) of naloxone has been suggested (LASAGNA1965), as well as mild sleepiness after chronic use of naloxone (JASINSKI et al. 1967). The reversal of narcotic intoxications and obstetric analgesia by naloxone has recently been well documented in the literature. The use of naloxone after morphine anaesthesia has also been studied (HASBROUCK 1971, LONGNECKER et al. 1973, JOHNSTONE et al. 1974). As shorter-acting narcotic analgesics are frequently used for supplementation of combined anaesthesia, this study was undertaken in order to investigate dose relationships between different doses of naloxone and fentanyl, our primary intraoperative analgesic. MATERIAL AND METHODS Fifty-five patients scheduled for elective general
surgery were included in the study and randomly assigned to eight different treatment and control groups (Table 1). They were all in good general condition (physical status ASA I or 11). Informed consent was obtained from every patient. For premedication, 1 mg/kg of pethidine, 25-50 mg of promethazine and 0.1 mg/lO kg of atropine were given intramuscularly. Anaesthesia was induced with 3-5 mg/kg of thiopental; 1 mg/kg of suxamethonium was given for endotracheal intubation; and anaesthesia was maintained with nitrous oxide (70%) and oxygen (30%), using intermittent positive pressure ventilation (IPPV). D-tubocurarine was used for muscle relaxation, the need being estimated by a peripheral neurostimulator (R. G. Wakeling & Co. Ltd.). When required, halothane was given for supplementation (0.5-1 %). No analgesics were administered during the surgery. End-tidal carbon dioxide was continuously registered with an infra-red COz analyzer (Uras, Hartman-Braun) to ensure normocapnia. At the end of the operative procedure, muscle relaxation was reversed with 2 mg of neostigmine and 1 mg of atropine, the need for additional reversal being assessed with the neurostimulator (ALI & SAVARESE 1976). Anaesthesia was continued with 0.3% halothane, and fentanyl was administered intravenously in doses of none, 0.05 mg, 0.1 mg or 0.2 mg. If the patient belonged to the naloxone group, 5 pg/kg of naloxone was given intravenously 15 min later. A second dose of 5 pg/kg of naloxone was administered 10 min after the first dose, and a third dose of 5 pg/kg of naloxone was given after another 10 minutes. Systolic and diastolic blood pressure,
Table 1 Characteristics of the different treatment groups (mean (range)). Treatment groups Naloxone
Control
Fentanyl (mg) 0
No. of patients
Age (yr)
5
0.05
10
0.1
10
0.2
10
0 0.05
5 5
0.1
5
0.2
5
471
Sex F/M
Weight (kg)
Height (cm)
27 (2 1-55) 36 ( 18-60) 43 ( 18-64) 36 (21-48)
67 (48-79) 65 (51-98) 75 (53-95) 73 (60-1 10)
173 (158-179) 162 (154-181) 171 (158-190) 173 (I6 1-1 92)
31 (2249) 58 (43-73) 51 (40-66) 43 (40-49)
71 (55585)
( 160- 178)
71 (59-78) 64 (5367) 78 (65-97)
I70 169 (155-177) 162 ( I6 1-I 65) 170 (162-1 78)
472
I. TIGORSTEDT
Table 2 Postanaesthetic recovery score & KROULIK 1970) (ALDRETE 1. Respiration
2. Circulation
3. Consciousness
4. Colour
5. Activity
Lowest score Maximum score
2 = Able to breathe and cough freely 1 = Dyspnoea or limited breathing 0 = Apnoea 2 = Blood pressure+20% of preanaesthetic level 1 = Blood pressure+20-50% of preanaesthetic level 0 = Blood pressure over +50% of preanaesthetic level 2 = Fully awake 1 = Arousable on calling 0 = not responding 2 = Pink 1 = Pale (jaundiced) 0 = Cyanotic 2 = Able to move 4 extremities 1 = Able to move 2 extremities 0 = Able to move 0 extremities 0 10
pulse rate, end-tidal C 0 2 , respiratory minute volume (Wright respirometer) and rate were measured before the administration of fentanyl, and 10 min after it, and 2 min after each dose of naloxone. If spontaneous respiration was absent, ventilation was maintained manually in a semiclosed, C02-absorption anaesthesia system; but during the respiratory measurements, patients were left without any ventilation assistance unless end-tidal C 0 2 rose above 7.8%=PCo2- 7.3 pKa (55 mmHg). The patients in each control group were managed in a similar way, and the measurements were carried out a t the same intervals, except that they were given no naloxone. After the last recordings, all patients were allowed to regain consciousness, extubated and removed to the recovery room, where they stayed for a minimum of 2 hours. The postanaesthetic recovery score (PARS), described by ALDRETE& KROULIKin 1970, was applied to test the patients’ recovery from anaesthesia. The PARS scoring system evaluates the patients’ five vital functions like the Apgar scores for newborns (APOAR1953). Respiration, circulation, consciousness, colour and activity are scored as follows: 0 = serious derangement, 1 = moderate disorder, 2 = normal. The five scores are added together, and a PARS score of 0-10 is achieved. A score of 10 indicates a patient in the best possible condition (see details in Table 2). The intensity of pain was scored from the scale: 0 = no pain, 1 = slight, 2 = moderate and, 3 = severe pain. Conventional analgesic and spasmolytic
agents were given when needed for pain relief, but the pain score for the rest of the observation period was considered to be that prior to the analgesic. Any other untoward effects were carefully observed. All these observations were made immediately after removal to the recovery room, and after 30 and 60 min. A postanaesthetic visit was paid to every patient on the first postoperative day to obtain the patient’s subjective opinion. Statistics
One-way analysis of variance or Student’s t-test (whenever appropriate) were used to test the statistical significance of the differences between the means of parametric variables. The x 2 test was used for comparison of non-parametric data.
RESULTS
Incidence of sbontaneous respiration As halothane was used during anaesthesia in order to avoid intraoperative use of narcotics, only a few patients breathed spontaneously immediately after surgery, even when muscle relaxation was adequately reversed and end-tidal CO,% showed normocapnia (Fig. 1). Twenty minutes later,
ANTAGONISM OF FENTANYL WITH NALOXONE
i
473
J-
Fig. 1. Incidence (%) of spontaneous respiration. F = mg of rentanyl, N = 5 &kg of naloxone. -- naloxone, - - - - - = control.
however, the restoration of spontaneous respiration seemed to be equal in the naloxone and control groups when no fentanyl was given (Fig. IA). One patient in the naloxone group did not begin to breathe spontaneously during the study period even when end-tidal CO, showed maximally 7.8%. However, after termination of halo-
Fig. 2. Minute ventilation ( I / min). Mean+s.e. mean. F = mg of fentanyl, N = 5 pg/kg of naloxone. - naloxone, - - - - - = control. ~
thane and nitrous oxide, the patient awoke rapidly and could be extubated normally. In the group fentanyl-0.05, the first 5 pg/kg of naloxone initiated spontaneous respiration and/or coughing in eight patients, while in the control group only one patient began to breathe at that time. The difference was statistically significant ( P
