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Anesth Analg 2000;91:601-605
© 2000 International Anesthesia Research Society

OBSTETRIC ANESTHESIA

Advantages of Intrathecal Nalbuphine, Compared with Intrathecal Morphine, After Cesarean Delivery: An Evaluation of Postoperative Analgesia and Adverse Effects

Xavier Culebras, MD*, Giovanni Gaggero, MD{dagger}, Jiri Zatloukal, MD{dagger}, Christian Kern, MD*, and René-Andréas Marti, MD*

*Division of Anesthesiology, Department APSIC, Geneva University Hospitals, Geneva; and {dagger}Department of Anesthesia, Hôpital de la Gruyère, La Riaz, Switzerland

Address correspondence and reprint requests to Dr. X. Culebras, Division of Anesthesiology, Geneva University Hospitals, 24, Rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Address e-mail to xavier.culebras{at}hcuge.ch


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We performed a prospective, randomized, double-blinded, multicenter study to compare the analgesic efficacy and adverse effects of intrathecal nalbuphine, at three different doses, and intrathecal morphine for postoperative pain relief after cesarean deliveries. Ninety healthy patients at full term who were scheduled for elective cesarean delivery with spinal anesthesia were enrolled in the study. They received 10 mg of hyperbaric bupivacaine 0.5% with either morphine 0.2 mg (Group 1), nalbuphine 0.2 mg (Group 2), nalbuphine 0.8 mg (Group 3), or nalbuphine 1.6 mg (Group 4). Only patients in Groups 1 and 2 reported pain during surgery. Postoperative analgesia lasted significantly longer in the morphine group, compared with the nalbuphine groups (P < 0.0001). In the nalbuphine groups, postoperative analgesia lasted longest with the 0.8-mg dose. The additional increase to 1.6 mg did not increase efficacy. The incidence of pruritus was significantly higher in Group 1 (11 of 22), compared with Group 2 (0 of 22, P < 0.0002), Group 3 (0 of 23, P < 0.0001), and Group 4 (3 of 20, P < 0.02). Postoperative nausea and vomiting were more frequent in Group 1 (5 of 22), compared with Group 2 (0 of 22, P < 0.05), Group 3 (0 of 23, P < 0.05), and Group 4 (3 of 23, not significant). There was no maternal or newborn respiratory depression. Neonatal conditions (Apgar scores and umbilical vein and artery blood gas values) were similar for all groups. This study suggests that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects. However, only morphine provides long-lasting analgesia.

Implications: Small doses of intrathecal nalbuphine produce fewer adverse effects, such as pruritus and postoperative nausea and vomiting, compared with intrathecal morphine. This may allow earlier discharge of patients from the recovery room.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
It is now well established that the addition of small doses of intrathecal morphine (0.05–0.5 mg) prolongs postoperative analgesia after cesarean deliveries (1–4). Furthermore, the use of small doses of morphine reduces the incidence of morphine-related adverse effects, particularly delayed respiratory depression (2). Despite the reduction of certain adverse effects, the incidences of postoperative nausea and vomiting (PONV) and of pruritus remain high. The incidence of PONV is between 10% and 41%, and the incidence of pruritus is between 40% and 78% and sometimes as high as 90% (5). Nalbuphine, a drug with mixed µ antagonist and {kappa} agonist properties, has been used to prevent or treat these morphine-related adverse effects, especially after epidural administration of morphine (5–7). The addition of intrathecal nalbuphine 0.4 mg to hyperbaric tetracaine, compared with intrathecal morphine 0.4 mg, for spinal anesthesia improved the quality of intraoperative and postoperative analgesia, with fewer side effects (8). In our institution, intrathecal nalbuphine is used for postoperative analgesia after orthopedic procedures (9). The aim of this prospective, randomized, double-blinded study was to test the responsiveness of intrathecal nalbuphine and its relative efficacy, compared with intrathecal morphine, after cesarean deliveries.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by our local institutional ethics committee, and written, informed consent was obtained from all women before participation. One hundred healthy, ASA physical status I or II parturients at full term who were scheduled for elective cesarean deliveries using spinal anesthesia were included in the study. Ranitidine 150 mg was administered orally before surgery. Lactated Ringer’s solution 10 mL/kg was infused IV, in 10 min, before the initiation of spinal anesthesia. Patients were placed in the left lateral position, and a spinal injection was performed at the L3-4 interspace by using a 27-gauge Whitacre spinal needle.

Patients were randomly allocated to one of four groups. They received either morphine 0.2 mg (Group 1), nalbuphine 0.2 mg (Group 2), nalbuphine 0.8 mg (Group 3), or nalbuphine 1.6 mg (Group 4), in a 1-mL volume, mixed with 10 mg of hyperbaric bupivacaine 0.5% (total volume, 3 mL). Ampules identical in color, form, and size were prepared and randomized by using a computer-generated code, by a private pharmacy (SOS Pharmacie, Geneva, Switzerland).

The anesthesiologist who performed the spinal injections took no further part in the study. Both patients and observers were blinded to the treatments.

Immediately after the intrathecal injection, patients were placed in the supine position, with a wedge under the right hip to maintain left uterine displacement. IV ephedrine 5 mg was administered prophylactically to all patients at the end of the intrathecal injection. Supplemental ephedrine was administered to treat arterial hypotension, which was defined as systolic blood pressure of <100 mm Hg or a reduction in systolic pressure of >20%, compared with baseline values. Bradycardia was defined as a reduction in heart rate to <60 bpm, and atropine (0.5 mg) IV was administered in cases in which the heart rate decreased to <55 bpm.

Oxygen 4 L/min was administered via a face mask until delivery. Blood pressure (measured noninvasively), heart rate, and oxygen saturation were recorded every 2 min for the first 12 min and every 5 min thereafter. The level of sensory response to an ether swab and the degree of motor block, as assessed with the Bromage scale (0 = none, 1 = just able to move the knee but not the hip, 2 = able to move the foot only, 3 = unable to move the knee or foot), were recorded every 2 min until skin incision. Surgery began as soon as the block reached the T-5 dermatome. At delivery, umbilical blood gas values were measured and Apgar scores were recorded at 1, 5, and 10 min.

Pain intensity was evaluated by using a visual analog scale (VAS) (0 = no pain and 10 = the worst imaginable pain) and was measured at skin and uterine incisions, at delivery, and at the end of the cesarean delivery. Patients were excluded from the study if supplemental IV fentanyl was required during surgery (VAS score > 3).

After surgery, blood pressure, heart rate, oxygen saturation, respiratory rate, pain, sensory level, and motor block were evaluated every 15 min during the first 90 min, every 30 min for the next 2 h, every 1 h for the next 4 h, and at 12 and 24 h after arrival in the recovery room. Side effects (pruritus, PONV, sedation, euphoria or dysphoria, and respiratory depression) were recorded for 24 h.

Sedation scores were defined as follows: 1 = awake and alert; 2 = sedated, responds to a verbal stimulus; 3 = sedated, responds to a mild physical stimulus; 4 = sedated, responds to a moderate or strong physical stimulus; 5 = not arousable. Pruritus was assessed using a four-point ordinal scale, as follows: 0 = none; 1 = mild; 2 = moderate; 3 = severe, treatment requested (clemastine 2 mg IV,). PONV were classified as follows: 0 = no symptoms present, 1 = symptoms present but treatment not required, 2 = symptoms present and treatment given (droperidol 0.625 mg IV). Maternal respiratory depression was defined as a respiratory rate of <10 breaths/min, and hypoxia was defined as an oxygen saturation of <95%.

The durations of complete analgesia (time from the intrathecal injection to the first pain report, VAS score > 0) and effective analgesia (time from the intrathecal injection to the first analgesic requirement, VAS score > 3) were noted. Propacetamol 2 g IV was administered when the VAS score was >3 or as requested by the patient. When VAS scores of >3 persisted for 45 min, ketorolac 30 mg IV was administered. If pain persisted, morphine (0.1 mg/kg) was administered subcutaneously. Overall satisfaction was evaluated with a VAS assessment at 24 h.

The incidence of pruritus was used as the main criterion for statistical analysis. By using the t-test and setting the {alpha} risk at 5% and the ß risk at 10%, a sample size of 20 would be sufficient to detect a reduction in the incidence of pruritus of at least 30% (compared with morphine). Statistical analysis was performed by using Statview® version 4.5 (Abacus Concepts, Inc., Apple Computer, Inc., Cuppertino, CA) for Macintosh. Variables were analyzed by using analysis of variance followed by the Scheffé test for intergroup comparisons. Frequency data were analyzed with the {chi}2 test and Fisher’s exact test with a Yates’ continuity correction, as appropriate. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
One hundred patients were enrolled. Ten were excluded from the study. Two patients in Group 1 and one in Group 2 were excluded for insufficient intraoperative analgesia, and four patients (one in Group 1, one in Group 2, and two in Group 3) were excluded for failure of the spinal anesthesia. One patient in Group 4 required general anesthesia because of rapid block regression during surgery. One patient in Group 2 was transferred postoperatively to another hospital, because her newborn needed to be admitted to the neonatal intensive care unit. One patient in Group 4 was excluded because of incomplete data. The remaining 90 patients were randomly allocated as follows: 22 in Group 1, 22 in Group 2, 23 in Group 3, and 23 in Group 4.

There were no significant differences in demographic data among the groups (Table 1). Breech presentation and previous cesarean delivery were the most frequent indications. Intervals between the intrathecal injection and the skin incision, delivery times, and surgical times were similar for all groups.


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  		Table 1. Patient Demographics
 
The durations of complete and effective analgesia were significantly increased in Group 1, compared with Groups 2, 3, and 4 (Figure 1, Table 2). Within the nalbuphine-treated groups, complete and effective analgesia was significantly longer in Groups 3 and 4, compared with Group 2 (Table 2). Nine patients reported pain during surgery; three of them received fentanyl during the cesarean delivery (Table 2).



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  		Figure 1. Time of effective analgesia (time from the intrathecal injection to the first analgesic intervention). Data represent mean ± SD. Mo = morphine, Nalb = nalbuphine.

 

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  		Table 2. Analgesic Data
 
The cumulative doses of different analgesics administered within the first 24 h are summarized in Table 3. No statistical differences were found for the total consumption of propacetamol among the groups. The administration of ketorolac and morphine was reduced in Group 1, compared with Group 2 (P < 0.05). One patient in Group 1 did not require any supplemental analgesics during the study period.


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  		Table 3. Supplemental Analgesic Requirements
 
Postoperative pruritus occurred only in Group 1 (50%) and Group 4 (15%) (Table 4). Three of the patients in the morphine-treated group but no patient in the nalbuphine-treated group needed to be treated for pruritus.


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  		Table 4. Adverse Effects in the Recovery Room
 
PONV was observed only in Group 1 (17%) and Group 4 (15%). Droperidol was used to treat two patients in Group 1 (Table 4).

The overall satisfaction of patients at 24 h, as evaluated with a VAS (10), showed no differences among groups. Respiratory rates were similar for all groups. Maternal oxygen desaturation to <95% was not observed. No headaches were recorded. Euphoria or dysphoria was not observed for any patient.

No differences were noted with respect to Apgar scores or neonatal umbilical blood gas values. There were no cases of newborn respiratory depression. Neither complaints nor neurological deficits were observed in the postoperative period.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We compared the efficacy and adverse effects of three different doses of intrathecal nalbuphine with those of intrathecal morphine 0.2 mg after cesarean deliveries. The longest durations of complete and effective analgesia among the nalbuphine-treated groups were provided by 0.8 mg added to bupivacaine. Increasing the nalbuphine dose to 1.6 mg did not further improve analgesia. We could not establish a dose-response curve with these three doses, but the asymptotic shape of the curve above 0.8 mg suggested a ceiling effect above this dose. Neither pruritus nor PONV were observed with nalbuphine 0.2 and 0.8 mg. It is noteworthy that intrathecal small doses of morphine (0.05–0.5 mg), fentanyl (2.5–50 µg), or sufentanil (2.5–5 µg) did not show such favorable adverse effect profiles (1–4,11,12).

Intrathecal nalbuphine 0.8–1.6 mg seems to improve the quality of intraoperative analgesia during cesarean deliveries. Intrathecal nalbuphine seems to provide a significantly faster onset of pain relief, compared with intrathecal morphine, probably because of its lipophilic properties (8,13). Previous studies in rats demonstrated that visceral analgesia is mediated by both µ and {kappa} receptors and that intrathecal nalbuphine suppresses responses to visceral pain (14,15).

Intrathecal nalbuphine does not seem to be as effective as intrathecal morphine in prolonging postoperative analgesia. Lin (8) reported that 0.4 mg of intrathecal nalbuphine prolonged postoperative analgesia to the same extent as did 0.4 mg of intrathecal morphine. Our results are not in accordance with that study, because morphine provided significantly longer postoperative analgesia. This could be attributable to the fact that we used a different patient population for a different type of surgery with a different local anesthetic. However, 0.8 mg of nalbuphine seems to provide a duration of postoperative analgesia after cesarean deliveries similar to that provided by 10 µg of intrathecal fentanyl or 2.5 µg of sufentanil (11,12,16), but without side effects.

Sedation scores were comparable among the groups. No other adverse effects, such as euphoria, dysphoria, maternal depression, or neurological deficits, were observed in any group.

With respect to the neurotoxicity of intrathecal nalbuphine, Rawal et al. (17) showed, in a sheep model using histopathological methods, that intrathecal nalbuphine was not neurotoxic. Even large doses (15–24 mg) of intrathecal nalbuphine were not associated with histopathological changes of the spinal cord. In the same study, however, the smallest dose of intrathecal sufentanil was associated with inflammatory changes, axonal swelling, and shrunken neurons. With the largest dose of sufentanil, there were signs of meningitis and arachnoiditis.

Although we received institutional ethics committee approval, and although none of our patients exhibited neurotoxic sequelae, there are probably still insufficient data to guarantee the safety of intrathecal nalbuphine in human patients. The delivery of novel drugs into the spinal space of human subjects requires preclinical studies with several animal models by using appropriate concentrations and adequate exposures. Although there is preliminary evidence suggesting that intrathecal nalbuphine is not associated with neurotoxicity in sheep, corroborating studies have not been published. Therefore, although preservative-free nalbuphine is now being used clinically by some anesthesiologists, there is controversy regarding whether the current literature supports the safety of intrathecal injection of nalbuphine in human subjects.

We conclude that 0.8 mg of intrathecal nalbuphine improves intraoperative analgesia and prolongs early postoperative analgesia, without increasing the risk of side effects. The delay to complete and effective analgesia is significantly shorter, compared with 0.2 mg of morphine. Intrathecal nalbuphine may thus be a reasonable alternative to intrathecal morphine.


   Acknowledgments
 
We thank Dr. Martin Tramèr, Division of Anesthesiology, University of Geneva, for his help in statistical analysis.


   Footnotes
 
Financial support (randomization cost and drug samples) was provided by Opopharma Pharmazeutika SA (Glattburgg, Switzerland).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  2. Abboud TK, Dror A, Mosaad P, et al. Mini-dose intrathecal morphine for the relief of post-cesarean section pain: safety, efficacy and ventilatory responses to carbon dioxide. Anesth Analg 1988; 67: 137–43.[Abstract/Free Full Text]
  3. Uchiyama A, Ueyama H, Nakano S, et al. Low dose intrathecal morphine and pain relief following caesarean section. Int J Obstet Anesth 1994; 3: 87–91.
  4. Chadwick HS, Ready LB. Intrathecal and epidural morphine sulfate for post-cesarean analgesia: a clinical comparison. Anesthesiology 1988; 68: 925–9.[Web of Science][Medline]
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  6. Wittels B, Glosten B, Faure EAM, et al. Opioid antagonist adjuncts to epidural morphine for postcesarean analgesia: maternal outcomes. Anesth Analg 1993; 77: 925–32.[Abstract/Free Full Text]
  7. Cohen SE, Ratner EF, Kreitzman TR, et al. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg 1992; 75: 747–52.[Abstract/Free Full Text]
  8. Lin ML. The analgesic effect of subarachnoid administration of tetracaine combined with low dose of morphine or nalbuphine for spinal anaesthesia. Ma Tsui Hsueh Tsa Chi 1992; 30: 101–5.
  9. Fournier R, Gamulin Z, Macksay M, Van Gessel E. Intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement [abstract]. Anesthesiology 1998; 89: A867.
  10. Cohen S, Amar D, Pantuck CB, et al. Epidural analgesia for labour and delivery: fentanyl or sufentanil? Can J Anaesth 1996; 43: 341–6.[Web of Science][Medline]
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  15. Schmauss C, Doherty C, Yaksh TL. In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. J Pharmacol Exp Ther 1984; 228: 1–12.[Abstract/Free Full Text]
  16. Connelly NR, Dunn SM, Ingold V, Villa EA. The use of fentanyl added to morphine-lidocaine-epinephrine spinal solution in patients undergoing cesarean section. Anesth Analg 1994; 78: 918–20.[Abstract/Free Full Text]
  17. Rawal N, Nuutinen L, Lovering SL. Behavioral and histopathologic effects following intrathecal administration of butorphanol, sufentanil, and nalbuphine in sheep. Anesthesiology 1991; 75: 1025–34.[Web of Science][Medline]
Accepted for publication April 21, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press