Intrathecal morphine is commonly used for pain relief after cesarean delivery. This method affords long-lasting analgesia without sedation. However, side effects such as pruritus, nausea, and vomiting are common1 and have been shown to be the most common causes for dissatisfaction with postoperative analgesia.2
Pruritus, a subjective unpleasant and irritating sensation that provokes an urge to scratch, is usually localized to facial areas innervated by the trigeminal nerve.3 It is often difficult to treat and is refractory to conventional antipruritic treatment.4,5 The exact mechanism of intrathecal morphine-induced pruritus is unclear. More than one mechanism may be responsible for the development of this unpleasant symptom.6 Drugs with different mechanisms of action have been used for prophylaxis or treatment of neuraxial opioid-induced pruritus.7–9 We found that ondansetron is effective for patients in the treatment of intrathecal morphine-induced pruritus after cesarean delivery.8 Evidence suggests that activation of κ-opioid receptors inhibits pruritus evoked by intradermal, subcutaneous, or intrathecal morphine in animal models.10,11 Pentazocine, a κ-opioid receptor agonist and partial μ-opioid receptor agonist,12 has been used as an analgesic in obstetric patients for decades. Pentazocine 15 mg has been successfully used to treat pruritus secondary to neuraxial opioid administration in our institution. We therefore performed a randomized, double-blind, clinical study to compare the efficacy of pentazocine and ondansetron in the treatment of intrathecal morphine-induced pruritus in parturients undergoing cesarean delivery.
After approval from the institutional ethical committee, we obtained written informed consent from each parturient before performing spinal anesthesia. This prospective, randomized, double-blind study was performed at the King Chulalongkorn Memorial Hospital, a 1500-bed university hospital. ASA physical status I or II parturients scheduled for cesarean delivery under spinal anesthesia and intrathecal morphine were recruited for this study. We excluded patients who had known allergy to pentazocine, ondansetron, morphine, or bupivacaine and those with preexisting pruritus due to pregnancy or a coexisting skin disorder or other pruritogenic systemic diseases. Patients with inadequate spinal anesthesia necessitating conversion to general anesthesia were also excluded.
No premedication was administered. All parturients were hydrated with 500–1000 mL of normal saline solution before administration of spinal anesthesia. Spinal anesthesia was induced with hyperbaric bupivacaine 11 mg (5 mg/mL; 2.2 mL) and preservative-free morphine 0.2 mg (1 mg/mL; 0.2 mL), mixed in the same syringe. After a satisfactory spinal block was verified by loss of sensation to cold or pinprick, cesarean delivery was performed.
In the postanesthesia care unit (PACU), vital signs were recorded every 15 min for 4 h. All data were collected by a single investigator (DT). Patients were observed for scratching and its location. The degree of pruritus was evaluated at 15-min intervals by asking about the presence and severity of pruritus and whether treatment was desired (1 = no pruritus; 2 = mild pruritus, treatment not requested; 3 = moderate pruritus, treatment requested; 4 = severe pruritus, treatment requested).7 Patients whose pruritus score was ≥3 were randomly assigned, by a computer-generated random number table, in blocks of 4 to one of 2 groups. The patients in the pentazocine group received IV pentazocine (15 mg; 2 mL), whereas patients in the ondansetron group received ondansetron (4 mg; 2 mL). Group assignment was sealed in an opaque envelope that was opened at the time the patient complained of moderate to severe pruritus. Coded syringes were prepared by a nurse anesthetist not involved in the study and were administered in a double-blind fashion. Pruritus scores, arterial blood pressure, heart rate, and oxygen saturation were recorded at 15-min intervals. An 11-point verbal numeric pain score (0 = no pain, 10 = worst imaginable pain), a 4-point sedation score (1 = fully awake; 2 = somnolent, responds to voice; 3 = somnolent, responds to tactile stimulation; 4 = asleep, responds to painful stimulation),13 a 4-point rating scale for nausea and vomiting (1 = no nausea or vomiting; 2 = queasy; 3 = severe nausea; 4 = vomiting),14 and a 4-point rating scale for shivering (1 = no shivering; 2 = mild shivering, treatment not necessary; 3 = moderate shivering, treatment desirable; 4 = severe shivering)15 were also recorded immediately before and 15 min after the administration of the study drugs.
The primary outcome variable was treatment success, defined as a pruritus score of 1 or 2 at 15 min after treatment. Patients continued to be evaluated every 15 min for 4 h to determine the duration of the antipruritic response. In the absence of a positive response (pruritus score of 3 or 4), the result was considered a treatment failure and those whose pruritus scores continued to be ≥3 were rescued with IV propofol 20 mg. A divided dose of naloxone (40 μg) was administered in case of rescue medication failure. Metoclopramide 10 mg was administered for nausea and vomiting as required. Tramadol 0.5 mg/kg was prescribed for shivering when needed, and tramadol 1 mg/kg was administered for pain (pain score more than 5 or on patient request). After each drug administration, arterial blood pressure, heart rate, respiratory rate, oxygen saturation, dizziness, extrapyramidal effects, mood changes, the presence of hallucination, other adverse effects, and the onset of pruritus were recorded.7 Demographic and surgical characteristics of the patients were also recorded. The study ended at 4 h after treatment and all patients were transferred to ward.
Sample size analysis was performed to determine the size of the study groups, with a probability of a Type II error of 0.1 and Type I error of 0.05, based on a two-tailed test (assuming the success rate of 84% for the pentazocine group and 62% for the ondansetron group from a pilot study) (STATA version 9.0). Allowing for a 10% dropout rate, we estimated that a minimum of 104 parturients was required for each group. Statistical analysis of the results was performed with χ2 test (Fisher’s exact test as appropriate) for categorical data and t-test or Wilcoxon’s ranked sum test for continuous data, with intention-to-treat approach. Differences were considered significant at P < 0.05.
There were 454 parturients who were scheduled for cesarean delivery (Fig. 1). Eight parturients were excluded because of inadequate spinal anesthesia necessitating induction of general anesthesia. Therefore, 446 parturients were enrolled in the study. Three hundred seventy-five parturients reported pruritus (84%) among whom 208 (46.6%) reported moderate to severe pruritus (pruritus score ≥3). These patients were allocated to the pentazocine and ondansetron groups. Both groups were comparable regarding demographic characteristics, surgical characteristics, and onset of intrathecal morphine-induced pruritus (Table 1). The onset of pruritus (score ≥2) ranged from 30 to 180 min (mean 94 ± 27 min) after the neuraxial administration of morphine. The common sites of pruritus were near the eyes (92.3%), nose (84.1%), and cheek (70.2%). Pruritus also occurred on the neck (17.8%), arms (13.9%), trunk (10.1%), and back (10.1%).
The treatment success rate was significantly higher in the pentazocine group (100 of 104 patients; 96.1%) than in the ondansetron group (84 of 104 patients; 80.8%) (difference in rate of treatment success 15.3% [95% confidence interval: 7.0%, 23.8%], P = 0.001) (Table 2). The distribution of pruritus scores after treatment is shown in Table 2 and is different between groups. The rate of recurrence of moderate to severe pruritus within 4 h of treatment was higher in the ondansetron group.
Propofol rescue treatment was successful in 3 of 4 patients (75%) in the pentazocine group and in 11 of 20 patients (55%) in the ondansetron group (P = 0.46). All patients with rescue treatment failure were successfully treated with incremental doses of naloxone. Five patients (4.8%) in each group experienced an increased pain score of 2 or more from baseline. Other side effects are shown in Table 3. No hallucinations, extrapyramidal effects, dizziness, or respiratory depression were observed in either group.
Neuraxial opioid analgesia is one of the significant breakthroughs in pain management, and spinal morphine is one of the most frequently used methods of analgesia after cesarean delivery and other surgical procedures. This study demonstrated an incidence of pruritus of 84%, which was high and consistent with other studies.8,13,14,16 Pregnant women seem to be more susceptible to pruritus after neuraxial opioid administration than other populations, with an incidence of 60%–100%.5,6,17 In contrast, after orthopedic surgery, the incidence of pruritus after intrathecal opioid ranged from 30% to 60%.18–20 A recent systemic review revealed that the mean incidence of pruritus is 83% in postpartum patients and 69% in nonpregnant patients including males and females.21 Possible explanations are increased cephalic spread of spinally administered drug14 and change of metenkephalin concentrations at opioid receptor sites.22 We observed the parturients for 4 h in the PACU because pruritus usually occurs within a few hours of intrathecal morphine injection.23 The onset of pruritus in our study ranged from 30 to 180 min, which is also consistent with our previous studies.7,8 However, we also observed that some parturients not enrolled in the study developed pruritus after discharge from the PACU.
The primary finding of this study was that the success rate of pruritus treatment with pentazocine was significantly greater than with ondansetron, as was the percentage of patients with complete recovery. The recurrence rate of moderate to severe pruritus within 4 h was also lower in the pentazocine group.
The mechanism of intrathecal opioid-induced pruritus is not fully understood. The role of histamine is unclear. Intrathecal opioids do not release histamine, and antihistamines have little effect on centrally induced pruritus.6 The treatment success observed by Szarvas et al.6 may be due to antihistamines’ sedative effects. Another hypothesis is that pruritus from neuraxial opioids is related to the excitatory effects of opioids on the nocifensive and nonnocifensive neurons of the anterior and posterior spinal horn.24 Propofol may relieve pruritus related to neuraxial opioids because it has inhibitory effects on the dorsal horn of the spinal cord.25 A third theory is that the pain pathway and pruritus are transmitted by the same small unmyelinated sensory nerve fibers (C-fibers).26 Indeed, it is postulated that the antipruritic effect of nonsteroidal antiinflammatory drugs may be largely due to its analgesic action. Colbert et al.18 found that rectal diclofenac significantly reduced the incidence and severity of intrathecal morphine-induced pruritus. Another theory is that intrathecal morphine’s interaction with central 5-hydroxytryptamine subtype 3 receptors plays a role in the genesis of pruritus.6 Our previous study showed that ondansetron was effective for treating intrathecal morphine-induced pruritus with an 80% success rate.8 A recent systemic review showed that 5-hydroxytryptamine subtype 3 receptor antagonists may be effective in preventing neuraxial opioid-induced pruritus and postoperative nausea and vomiting (PONV).21
The most commonly cited theory is that pruritus is mediated by μ-opioid receptors. Intrathecal morphine-induced scratching in monkeys is mediated by this receptor.27 Naloxone’s reversibility of opioid-induced pruritus supports the existence of an opioid receptor-mediated central mechanism.28 However, the use of naloxone for the treatment of pruritus is limited to low doses, because high doses of naloxone may reverse the analgesic effect of opioids.
In 2002, Togashi et al.11 showed that TRK-820 had antipruritic activity that was mediated by κ-opioid receptors and was effective in both antihistamine-sensitive and antihistamine-resistant pruritus in mice. The κ-opioid receptor agonist also inhibited pruritus evoked by subcutaneous or intrathecal morphine in monkeys,10 drug-induced cholestasis in rats,29 and uremia in humans.30 Therefore, a possible explanation for the antipruritic activity of pentazocine in this study might be related to its κ-receptor agonist activity.12 We have not performed a dose-response study of pentazocine, but the dose of 15 mg pentazocine was shown to be effective in a pilot study. We elected to compare pentazocine with ondansetron 4 mg because this treatment was effective in a previous report.8
PONV is common after intrathecal morphine administration. However, we found a low incidence of PONV in both groups. Prophylactic ondansetron has been shown to decrease the incidence of intrathecal morphine-induced nausea and vomiting,8,20,21 and there was no difference in the incidence of PONV between the 2 groups. The frequently reported untoward effects of pentazocine are sedation, sweating, and dizziness, but vomiting is less common than with systemic morphine.31 Anxiety, nightmares, and hallucination can occur with parenteral doses of more than 60 mg of pentazocine.31 Patients may complain of irritation at the injection site.31 We found a low incidence of these side effects, and there was no difference between groups.
There were several limitations in our study design and conclusions. First, pruritus is a subjective symptom. Second, we have not studied the dose-response of antipruritic activity of pentazocine to determine the optimal dose. Third, our results can only be applied to postpartum women. A final limitation is the short follow-up period, because pruritus from intrathecal morphine usually lasts longer than 4 h.
In conclusion, IV pentazocine 15 mg was superior to IV ondansetron 4 mg for the treatment of moderate to severe pruritus induced by intrathecal morphine and had a lower recurrence rate. The incidence of PONV was low and similar to the ondansetron group. Side effects after treatment were mild. Therefore, pentazocine may be an alternative treatment to ondansetron for intrathecal morphine-induced pruritus after cesarean delivery.
1. Dahl JB, Jeppesen IS, Jorgensen H, Wetterslev J, Moiniche S. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia. Anesthesiology 1999;91:1919–27
2. Ayoub CM, Sinatra RS. Postoperative analgesia: epidural and spinal techniques. In: Chestnut DH, ed. Obstetric anesthesia: principles and practice. 3rd ed. Philadelphia: Mosby, 2004:472–97
3. Chadwick HS, Ready LB. Intrathecal and epidural morphine sulphate for post cesarean analgesia: a clinical comparison. Anesthesiology 1988;68:925–9
4. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988;33:149–60
5. Yeh HM, Chen YK, Lin CJ, Chan WH, Chen YP, Lin CS, Sun WZ, Wang MJ, Tsai SK. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg 2000;91:172–5
6. Szarvas S, Harmon D, Murphy D. Neuraxial opioid-induced pruritus: a review. J Clin Anesth 2003;15:234–9
7. Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2001;93:162–5
8. Charuluxananan S, Somboonviboon W, Kyokong O, Nimcharoendee K. Ondansetron for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Reg Anesth Pain Med 2000; 25:535–9
9. Charuluxananan S, Kyokong O, Pongpakdee K. Optimal dose of nalbuphine for treatment of intrathecal morphine-induced pruritus after cesarean section. J Obstet Gynaecol Res 1999:209–13
10. Ko MCH, Lee H, Song MS, Sobczyk-kojiro K, Mosberg HI, Kishioka S, Woods JH, Naughton NN. Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys. J Pharmacol Exp Ther 2003;305:173–9
11. Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endon T, Utsumi J, Kamei J, Tanaka T, Nagase H. Antipruritic activity of the kappa opioid receptor agonist, TRK-820. Eur J Pharmacol 2002;435:259–64
12. Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limberd LE, Gilman AG, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11 ed. New York: McGraw-Hill, 2006:547–90
13. Borgeat A, Eilder-Smith OH, Saiah M, Rifat K. Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine. Anesthesiology 1992;76:510–2
14. Warwick JP, Kearns CF, Scott WE. The effect of subhypnotic doses of propofol on the incidence of pruritus after intrathecal morphine for cesarean section. Anesthesia 1997;52:265–75
15. Kyokong O, Tamdee D, Charuluxananan S. Comparison of the efficacy of nalbuphine, tramadol, ondansetron, and placebo in the treatment of postanesthetic shivering after spinal anesthesia for cesarean delivery. Asian Biomed 2007;1:189–94
16. Charuluxananan S, Kyokong O, Somboonviboon W, Narasethakamol A, Promlok P. Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2003;96:1789–93
17. Shah MK, Sia AT, Chong JL. The effect of the addition of ropivacaine or bupivacaine upon pruritus induced by intrathecal fentanyl in labour. Anaesthesia 2000;55:1008–13
18. Colbert S, O’hanlon DM, Galvin S, Chambers F, Moriarty DC. The effect of rectal diclofenac on pruritus in patients receiving intrathecal morphine. Anaesthesia 1999;54:948–52
19. Torn K, Tuominen M, Tarkkila P, Lindgren L. Effects of subhypnotic dose of propofol on the side effects of intrathecal morphine. Br J Anaesth 1994;73:411–2
20. Dimitriou V, Voyagis GS. Opioid-induced pruritus: repeated vs single dose ondansetron administration in preventing pruritus after intrathecal morphine. Br J Anaesth 1999;83:822–3
21. Bonnet MP, Marret E, Josserand J, Mercier FJ. Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review. Br J Anaesth 2008; 101:311–9
22. Bromage PR. The price of intraspinal narcotic analgesia: basic constraints. Anesth Analg 1981;60:461–3
23. Bailey PL, Rhondeau S, Schafer PG. Dose-response pharmacology of intrathecal morphine in human volunteers. Anesthesiology 1993;79:49–59
24. Thomas DA, Williams GM, Iwata K, Kenshale DR, Dubner R. The medullary dorsal horn: a site of action or morphine in producing facial scratching in monkeys. Anesthesiology 1993; 79:548–54
25. Cavazzuti M, Porro CA, Barbieri A, Galetti A. Brain and spinal cord metabolic activity during propofol anesthesia. Br J Anaesth 1991;66:490–5
26. Lowit MH, Bernhard JD. Pruritus. Semin Neurol 1992;12:374–84
27. Ko MC, Naughton NN. An experimental itch model in monkey: characterization on intrathecal morphine-induced scratching and antinociception. Anesthesiology 2000;18:346–57
28. Lockington PF, Fa’aea P. Subcutaneous naloxone for the prevention of intrathecal morphine-induced pruritus in elective caesarean delivery. Anaesthesia 2007;62:672–6
29. Inan S, Cowan A. Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behaviour secondary to cholestasis induced by chronic ethynylestradiol injections in rats. Pharmacol Biochem Behav 2006;85:39–43
30. Wikstrom B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, Ogasawara M, Kawashima Y, Ueno K, Mori A, Ueno Y. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 2005;16:3742–7
31. Brogden RN, Speight TM, Avery GS. Pentazocine: a review of its pharmacological properties, therapeutic efficacy and dependence liability. Drugs 1973;5:6–91