Failure of nalbuphine to antagonize morphine: a double-blind comparison with naloxone

The authors studied the respiratory and analgesic effects of nalbuphine (0.21 mg/kg, intravenous), naloxone (0.014 mg/kg, intravenous), and placebo (normal saline) when given after morphine (0.21 mg/kg, intravenous) in a double-blind, randomized fashion. Resting end-tidal CO2 (PETCO2), ventilatory and occlusion pressure responses to CO2 rebreathing, and pain threshold were measured in 12 healthy adult volunteers before, 5 min, and 30 min after morphine. Nalbuphine, naloxone, or saline were administered 55 min after morphine, and the above measurements were repeated 5 min later (60 min after morphine) as well as 90, 120, 180, and 240 min after morphine. Whereas naloxone reversed respiratory depression as measured by all three respiratory parameters, nalbuphine either further depressed (resting PETCO2) or did not affect (ventilatory and occlusion pressure responses to CO2 rebreathing) respiratory drive. Morphine produced a significant elevation of the pain threshold. Significant decreases in the pain threshold were seen only after naloxone. Saline and nalbuphine did not significantly alter the pain threshold. The data indicate that nalbuphine may not reliably antagonize moderate doses of morphine.     

Antagonism of postoperative opioid-induced respiratory depression: nalbuphine versus naloxone

The authors compared naloxone and nalbuphine as antagonists of opioid-induced respiratory depression to determine the relative efficacies and safety of the two agents. In a double-blind, randomized fashion, 90 anesthetized patients received a mean dose of 25 micrograms/kg fentanyl during surgery. Inadequate spontaneous respirations at the end of anesthesia were treated with either naloxone 0.08 mg or nalbuphine 2.5 mg IV every 2 min while heart rate (HR), systolic and diastolic blood pressures (SBP, DBP), respiratory rate (RR), and tidal volume (TV) were measured at 2-min intervals. Arterial blood samples for analysis of PaCO2, PaO2, and pH were drawn when spontaneous ventilation resumed, and 30 and 60 min later. Narcotic antagonism and respiration were deemed adequate when TV was greater than or equal to 4 ml/kg and RR greater than or equal to 8 breaths/min. Heart rate, SBP, DBP, TV and RR were recorded, as were the occurrence of renarcotization (RR less than 8) and analgesic requirements every 5 min during the recovery room stay. Sixty of 90 patients required narcotic antagonism at the end of surgery. No patient required more than three doses (0.24 mg) of naloxone or four doses (10 mg) of nalbuphine. Both antagonists produced similar and moderate increases in SBP and HR while restoring adequate spontaneous ventilation. There were no significant differences in TV, RR, or arterial blood gases (ABGS) between the two groups after narcotic reversal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of fentanyl reversal by naloxone at varying arterial carbon dioxide tensions in dogs

Clinical reports, as well as animal studies, have described cardiovascular and sympathetic stimulation after the administration of naloxone (NX) to reverse opioid-induced respiratory depression. This investigation examines the effect of PaCO2 on hemodynamic and adrenergic responses to NX, by means of 24 experiments carried out in six dogs. Each dog underwent NX reversal of fentanyl (FEN) at three different PaCO2 levels: 20, 35, and 60 mm Hg. In a final series of six experiments, the dogs were exposed to increasing PaCO2 after autonomic block by total spinal anesthesia and vagotomy. During enflurane anesthesia, 50 micrograms/kg FEN decreased mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine (EPI) significantly. NX 0.4 mg promptly returned HR and MAP to baseline or above in all experiments; catecholamine (CA) levels increased only in hypercapnic dogs. Increases in HR were the same in all series. MAP, EPI, and NE levels were significantly greater than pre-FEN baseline values only in hypercapnic dogs 1 minute after NX and were also significantly higher in hypercapnic than in hypocapnic dogs at this time. NE levels were greater in hypercapnic dogs at all time periods after NX. In blocked dogs, neither F nor NX had any effects on hemodynamic functions or plasma CA levels; the institution of hypercapnia caused significant decreases in HR, MAP, and systemic vascular resistance. This direct circulatory depressant action of an elevated PCO2 may have attenuated the indirectly mediated excitatory hemodynamic effects of NX in intact dogs, thus explaining the relatively greater effect of hypercapnia on adrenergic than on hemodynamic responses to reversal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antagonism of flunitrazepam and fentanyl by flumazenil, naloxone or nalbuphine

The new benzodiazepine antagonist flumazenil represents another approach to the ever-present problem of recurring respiratory depression after anesthesia with flunitrazepam and fentanyl. Objective and subjective side effects of flumazenil were studied in comparison with the opiate antagonists naloxone and nalbuphine. METHODS. One hundred fifty surgical patients, ASA I or II, aged 18-65 years were studied. After premedication with atropine 0.5 mg and flunitrazepam 0.5 mg anesthesia was induced with flunitrazepam 0.5 mg, fentanyl 0.1 mg and etomidate 10 mg and maintained with N2O/O2 2:1 and additional increments of 0.1 mg fentanyl as required. Relaxation for intubation and surgery was obtained with non depolarizing muscle relaxants. After the operation the patients were extubated and then flumazenil 0.4 mg, naloxone 0.05 mg, or nalbuphine 20 mg was given i.v. (randomized and double-blind). In 15 patients blood pressure and heart rate were monitored. In all patients postoperative pain was assessed by the time interval between administration of the antagonist and need for the first analgesic medication. On the 1st postoperative day recall of postoperative events and of pictures shown 5, 30, 60, 120, and 240 min after administration of the antagonist was tested. The patients were interviewed a second time for side effects on day 3-6 after the operation. RESULTS. The three antagonists produced no significant effects on arterial pressure and heart rate. There were no differences between the antagonists in the incidence of postoperative nausea and/or vomiting or postoperative pain. After flumazenil, a significant transient increase in vigilance and better recall of postoperative events was noted within 5 and 30 min after administration of the drug. CONCLUSION. On the basis of the objective clinical findings, there is no reason to prefer either benzodiazepine or opiate antagonists after flunitrazepam and fentanyl. However, postoperative amnesia can be reduced by flumazenil if this is desirable.     

Respiratory depression following diazepam: reversal with high-dose naloxone

The authors compared the effects of naloxone and saline solution on the respiratory changes following diazepam in a double-blind crossover trial in six subjects. Following baseline measurements of respiration, each subject was given diazepam, 15 mg, intravenously. Sixty and ninety-five minutes later each subject received either two doses of naloxone, 15 mg, intravenously, or two doses of the equivalent volume of saline solution. Forty-five minutes after diazepam administration the slopes of the curves of the ventilatory responses to rebreathing carbon dioxide (VE/PETCO2) were depressed to 53 per cent of control (P < 0.05). Following the two doses of naloxone, the slopes of VE/PETCO2 recovered, until, 120 minutes after the second dose of naloxone, slopes had returned to control values. After saline solution, however, slopes remained depressed at 68 per cent of control (P < 0.05). A similar recovery following naloxone was observed in the PETCO2 intercept of the VE/PETCO2 response curve and in the slope of the mouth-occlusion-pressure response curve to rebreathing carbon dioxide. End-tidal carbon dioxide during quiet breathing and during inspiratory resistive-loaded breathing (80 cm H2O/l/s) showed small increases after diazepam, which were not significantly reduced by naloxone. The results of this study show that diazepam produces respiratory depression, and that this may be relieved by large doses of naloxone.     

The cardiovascular effects of naloxone administration after fentanyl anesthesia in hypercapnic patients

Hemodynamic changes and plasma catecholamine levels after naloxone administration were studied in seventeen postoperative patients who received nitrous oxide, oxygen, and fentanyl anesthesia combined with epidural block. Group I consisted of ten postoperative hypercapnic (Pa_{CO 2} = 55.2 ± 2.4 torr) and group II seven postoperative normocapnic patients (Pa_{CO 2} = 38.4 ± 2.1 torr), respectively. In group I, naloxone reversal resulted in significant increases in heart rate (13.5%), mean arterial pressure (46.6%), systemic vascular resistance (32.1%), and rate pressure product (68.8%), whereas mean pulmonary artery pressure and pulmonary vascular resistance were significantly decreased. No significant hemodynamic changes after naloxone administration were observed in group II. There were no significant differences in arterial norepinephrine and epinephrine levels either before or after naloxone administration in the both groups. This study indicates that the postoperative hypercapnia elicits the cardiovascular stimulation after fentanyl reversal by naloxone.(Kishikawa K, Namiki A, Iwasaki H: The cardiovascular effects of naloxone administration after fentanyl anesthesia in hypercapnic patients. J Anesth 3: 48–53, 1989)     

A double-blind comparison of intramuscular pethidine and nalbuphine in labour

A double-blind, between-patient comparison of intramuscular pethidine 100 mg and nalbuphine 20 mg for the relief of pain during labour in 80 patients is described. Severity of pain was assessed before and after treatment by subjective pain scores and visual analogue scales. Neither of these methods showed a significant difference between the treatments. Nalbuphine was associated with less maternal nausea and vomiting than pethidine, but this possible advantage was somewhat offset by a tendency of the drug to produce more maternal sedation and dizziness. The mean umbilical vein/maternal vein ratio was significantly higher for nalbuphine (0.78, SEM 0.03) than for pethidine (0.61, SEM 0.02), which suggests easier placental transfer of the former. This finding was reflected in significantly lower 2-4 hour neurobehavioural scores for the infants of mothers given nalbuphine, but there was no significant difference between these scores at 24 hours. On the basis of this study, nalbuphine does not offer a substantial improvement over pethidine for pain relief in labour.     

Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine-related side effects

Background and Objectives. Epidural morphine is accepted as an efficient means of postoperative pain management. However, development of side effects such as nausea and vomiting and pruritus has been reported. This study compared the efficacy of intravenous infusions of nalbuphine or naloxone in the prevention of epidural morphine-related side effects. Methods. Seventy-five female patients undergoing epidural anesthesia for total hysterectomy were enrolled in a randomized, double-blind study. At the end of the surgery, all patients received epidural 3 mg morphine (every 12 hours) for postoperative pain. Meanwhile, patients in group 1 received an adjuvant intravenous infusion of nalbuphine 60 μg/kg/h, patients in group 2 received intravenous infusion of naloxone 2 μg/kg/h, and patients in group 3 received intravenous saline infusion only. A rescue analgesic of intramuscular 50 mg meperidine (every 4 hours) was available for each patient. Patients were observed for 24 hours. Results. All patients had adequate postoperative pain relief. However, the proportion of patients requiring rescue analgesia and the total consumption of rescue analgesic were higher in group 2 than in the other two groups. The incidence of nausea and vomiting and pruritus was higher in group 3 than in the other two groups. Conclusions. We found that coadministration of either nalbuphine or naloxone with epidural morphine reduces the incidence of morphine-related side effects. However, unlike naloxone, nalbuphine did not attenuate the analgesic effect of epidural morphine.     

A comparison of nalbuphine and meperidine in treatment of postoperative pain

The analgesic efficacy and side effect profile of nalbuphine 20 mg IV and of nalbuphine 40 mg IV were compared to those of meperidine 75 mg IM in the immediate postoperative period. Pain intensity, pain relief, additional analgesic requirements and the overall acceptability of the treatment were recorded for 150 patients. No significant differences were found between the groups for any of the efficacy variables. Peak analgesic effects occurred at 15 minutes in both nalbuphine groups and at 30 minutes in the meperidine group. The mean time to additional analgesic medication was approximately 207 minutes in each group. The incidence of nausea and vomiting with meperidine was 22 per cent (95 per cent confidence interval 10 to 34 per cent) and with nalbuphine 20 mg the incidence was two per cent (95%CI -2 to 6 per cent). This difference was significant (p less than 0.01). The difference between nalbuphine 40 mg (10 per cent, 95%CI 1 to 19 per cent) and meperidine, was not considered statistically significant (p = 0.17). The analgesic efficacy of nalbuphine 20 mg was indistinguishable from that of nalbuphine 40 mg and from that of meperidine 75 mg. The significantly lower incidence of nausea and vomiting with nalbuphine is a major advantage for a recovery room analgesic.     

Controlled comparison of nalbuphine and morphine for post-tonsillectomy pain

A controlled investigation was conducted to compare the effectiveness of morphine and nalbuphine in the prevention of pain and restlessness after tonsillectomy in children. Sixty children between 4 and 12 years old were randomly allocated to receive intramuscular morphine 0.2 mg/kg, nalbuphine 0.3 mg/kg or no medication approximately 5 minutes before the conclusion of surgery. Pain and restlessness were assessed 1 and 2 hours after injection, and side effects were recorded. The assessments were made double-blind. Both nalbuphine and morphine decreased restlessness and pain 1 hour (p less than 0.01) and 2 hours (p less than 0.05) after surgery. No significant differences were found between the two groups of patients who received opioids. Both nalbuphine and morphine caused more drowsiness than placebo 2 hours after surgery (p less than 0.001). Other side effects were uncommon. Nalbuphine may offer advantages compared with morphine in regard to safety and convenience of use for the treatment of post-tonsillectomy pain in children.     

A comparison of nalbuphine with morphine for post-orchidopexy pain

A double-blind investigation was conducted to compare nalbuphine with morphine for the control of pain after unilateral orchidopexy. Fifty boys under 11 years of age were allocated randomly to receive intramuscular nalbuphine 0.2 mgkg-1 or morphine 0.2 mgkg-1 immediately after induction of anaesthesia. Pain was assessed on a three-point scale, 1, 2 and 4 h after injection and on the morning following operation. Side-effects were also recorded. There were no significant differences between the two drugs in either the provision of analgesia, or the incidence of the principal side-effects of vomiting and sweating. There was a high incidence of vomiting in both groups. Nalbuphine is a satisfactory alternative to morphine for post-orchidopexy pain and may offer the advantages of greater safety and convenience.     

Analgesia for adenotonsillectomy in children and young adults: a comparison of tramadol, pethidine and nalbuphine

A prospective, double-blind, randomized, controlled study was undertaken to compare the perioperative analgesic and recovery characteristics of equipotent doses of tramadol, pethidine and nalbuphine (3.0 mg kg-1, 1.5 mg kg-1 and 0.3 mg kg-1 respectively) with placebo (saline 0.02 ml kg-1) given at induction of anaesthesia in 152 ASA 1 children and young adults undergoing tonsillo-adenoidectomy. Premedication (temazepam and diclofenac), induction and maintenance of anaesthesia (thiopentone, atracurium, nitrous oxide and isoflurane), with controlled ventilation, were standardized. Variables monitored were heart rate (HR) and systolic arterial pressure (SAP) during surgery, time to recovery of spontaneous respiration at the termination of anaesthesia and restlessness, time to awakening, sedation and emesis in the recovery unit. Increases in HR or SAP > 33% of baseline during surgery were treated with esmolol 2.0 mg kg-1 intravenously (i.v.) and restlessness during recovery was treated with the same opioid i.v. given with an aesthesia, or pethidine i.v. in the placebo group. With placebo, there was a high requirement for esmolol during surgery and for pethidine in the recovery ward. Tramadol did not reduce the rate of intra-operative treatment with esmolol, but reduced the tramadol requirement during recovery (P < 0.05). Pethidine and nalbuphine reduced the intra-operative esmolol requirement more significantly (P < 0.025 and P < 0.005 respectively) and the need for treatment during recovery with opioids (P < 0.005 each). The time to recovery of spontaneous respiration at the end of anaesthesia was only delayed by pethidine. Other recovery variables were similar, except that restlessness-pain scores were reduced by tramadol (P < 0.02), pethidine (P < 0.005) and nalbuphine (P < 0.005). These results suggest that pethidine 1.5 mg kg-1 and nalbuphine 0.3 mg kg-1 given with induction of anaesthesia provide better analgesia during and after tonsillo-adenoidectomy than does tramadol 3.0 mg kg-1. The delay to recovery of spontaneous respiration with pethidine suggests a greater safety profile of nalbuphine and tramadol.     

Early extubation after high-dose fentanyl anaesthesia for aortocoronary bypass surgery: reversal of respiratory depression with low-dose nalbuphine

To investigate the possibility of selective reversal of narcotic-induced respiratory depression following fentanyl anaesthesia, we studied 20 patients after aortocoronary bypass surgery. All patients were anaesthetized with fentanyl, 40 micrograms . kg-1 and oxygen, with isoflurane as indicated. In a random double blind fashion either incremental doses of nalbuphine, or normal saline were administered approximately four hours after cardiopulmonary bypass. Respiratory depression was evaluated using blood gas and end tidal CO2 (PETCO2) measurement, and in addition, a ventilatory response to CO2 was obtained preoperatively and at selected intervals postoperatively. Despite randomization, patients with more respiratory depression were assigned to nalbuphine. There appeared to be a reversal of respiratory depression with nalbuphine, indicated by a fall in the resting PETCO2 value. This apparent reversal of respiratory depression was associated with a significant increase in pain, requiring treatment in three patients. We conclude that low-dose nalbuphine is not an acceptable method of antagonism of respiratory depression in this group of patients. Many patients who did not receive nalbuphine were able to breathe adequately at an earlier stage than was previously suspected. Close monitoring of the respiratory system may permit earlier extubation without the requirement of a narcotic antagonist after this dose of fentanyl.     

A comparison of clinical and psychological effects of fentanyl and nalbuphine in ambulatory gynecologic patients

Drug dosages, length of stay (LOS), and incidence of psychological side effects of fentanyl and nalbuphine were compared in a randomized, double-blind study using unpremedicated female day-surgery patients undergoing diagnostic laparoscopy. Patients received either fentanyl 1.5 micrograms/kg (F group; n = 142), low-dose nalbuphine 300 micrograms/kg (LN group; N = 103), or high-dose nalbuphine 500 micrograms/kg (HN group; n = 41), intravenously (IV) before anesthesia consisting of thiopental, N2O, O2, and a succinylcholine infusion. Additional IV intraoperative and IM postoperative opioids were given if required for signs of inadequate anesthesia or postoperative pain. The patients' clinical and psychological status was evaluated at 20-min intervals postoperatively by a team of trained interviewers. The low- and high-dose nalbuphine groups clinically resembled the fentanyl group in terms of dosing frequency and patients' self-ratings of postoperative analgesia. Length of stay and postoperative sedation were significantly greater with nalbuphine. The incidence of psychological side effects, including dreaming and postoperative anxiety, was also greater with nalbuphine. However, patient acceptance of nalbuphine was high and was similar to that observed in patients given fentanyl.     

A comparison of nalbuphine and morphine as premedication agents for minor gynaecological surgery

Nalbuphine 10 mg and morphine 10 mg were compared in a randomised double-blind trial as intramuscular premedication in 50 patients undergoing minor gynaecological surgery. Both nalbuphine and morphine produced significant sedation without anxiolysis as assessed by patient linear analogue scales, but there were no significant differences between the two drugs. Observer ratings demonstrated that nalbuphine produced calm/sleepy patients to a greater extent than morphine. There were no differences in untoward effects produced by each drug.     

Minidose lidocaine-fentanyl spinal anesthesia in ambulatory surgery: prophylactic nalbuphine versus nalbuphine plus droperidol

Minidose lidocaine-fentanyl spinal anesthesia (SAB(MLF)) is a safe, effective, and efficient anesthetic for ambulatory surgery. Unfortunately, it has a frequent incidence of pruritus and a substantial incidence of nausea and vomiting. Nalbuphine is effective in treating or preventing pruritus after intrathecal or epidural morphine but may or may not have a beneficial effect on nausea and vomiting. Droperidol has demonstrated antiemetic efficacy with neuraxial opiates. In this study, we examined the prophylactic use of nalbuphine alone compared with nalbuphine with droperidol after SAB(MLF). One-hundred-twenty-four patients having outpatient knee arthroscopy under SAB(MLF) with 20 mg of lidocaine 0.5% and 20 micro g of fentanyl were randomized to receive IV at the end of surgery either 4 mg of nalbuphine (Group N) or droperidol 0.625 mg plus nalbuphine 4 mg (Group ND). The incidences of early (before discharge) and late onset nausea were, respectively, 18% versus 5% and 32% versus 13%. The postoperative incidences of pruritus were 61% versus 40%, whereas 19% of patients in Group N compared with 2% of patients in Group ND requested treatment for this. Group ND had lower pain scores and had a longer delay until first use of analgesic. There were no differences in average times to discharge. The only side effect of the medications was an increased drowsiness in Group ND. In conclusion, as prophylactic medication for use in conjunction with SAB(MLF), the addition of droperidol 0.625 mg to nalbuphine 4 mg was superior to nalbuphine alone. The combination provided for reduced postoperative nausea, pruritus, and pain-benefits that persisted after discharge home. The combination also avoided isolated cases of extreme delay in discharge. IMPLICATIONS: Droperidol in combination with nalbuphine enhances analgesia and is more effective than nalbuphine alone in preventing pruritus, nausea, and vomiting after minidose lidocaine-fentanyl spinal anesthesia.     

A comparison of complications associated with colostomy reversal versus ileostomy reversal

BACKGROUND: The incidence of complications after reversal of Hartmann's procedure is unknown. This study compares the morbidity of Hartmann's reversal versus loop ileostomy reversal. METHODS: Two groups of 20 patients were studied retrospectively over a 5-year period. One group underwent Hartmann's takedown, and the other underwent loop ileostomy takedown. Postoperative complications were compared between the 2 groups. RESULTS: Similar demographics were noted between each group. The most common initial indications for Hartmann's procedure were diverticulosis (11 patients, 55%) and colon cancer (4 patients, 20%). For patients who had undergone colectomy with primary anastomosis and ileostomy, colon cancer was the most common indication (12 patients, 60%) followed by diverticulosis (3 patients, 15%). Complications were more common after Hartmann reversal than loop ileostomy reversal (16 complications/11 patients versus 6 complications/4 patients, P = .047). CONCLUSION: Segmental colonic excision with anastomosis and loop ileostomy may be an attractive alternative to minimize morbidity with stoma reversal.