Dextromethorphan and intrathecal morphine for analgesia after Caesarean section under spinal anaesthesia

D. M. A. Choi1, A. P. Kliffer and M. J. Douglas

Department of Anesthesia, British Columbia Women’s Hospital, Vancouver, British Columbia, Canada 1 Present address: Nuffield Department of Anaesthetics, Oxford Radcliffe Hospitals, Oxford OX3 9DU, UK

Corresponding author. E-mail: Desi.Choi@orh.nhs.uk

Accepted for publication: December 20, 2002


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

Background. Dextromethorphan is an N-methyl-D-aspartic acid antagonist which can attenuate acute pain with few side-effects. In this prospective, randomized, double-blind study of dextromethorphan and intrathecal morphine, we investigated postoperative pain, pruritus, nausea and vomiting in women undergoing Caesarean section under spinal anaesthesia.

Methods. Women were allocated randomly to one of six groups, to receive intrathecal morphine 0.05, 0.1 or 0.2 mg plus oral dextromethorphan 60 mg or placebo.

Results. The addition of dextromethorphan did not reduce postoperative pain scores (P=0.83). Compared with women receiving intrathecal morphine 0.05 mg, women receiving higher doses had a significantly higher incidence of nausea and vomiting [odds ratio for intrathecal morphine 0.1 mg, 4.0 (95% confidence interval 1.2–14.1); for intrathecal morphine 0.2 mg, 7.9 (2.3–27.1)]. Compared with women receiving intrathecal morphine 0.05 mg, women receiving higher doses also had a significantly higher incidence of pruritus [odds ratio for intrathecal morphine 0.1 mg, 3.2 (95% confidence interval 1.3–8.2); for intrathecal morphine 0.2 mg, 3.7 (1.4–9.5)]. Women receiving dextromethorphan had a lower incidence of nausea and vomiting [odds ratio 2.6 (1.1–6.3)].

Conclusions. Postoperative pain after Caesarean section under spinal anaesthesia was not reduced by the addition of oral dextromethorphan to a multimodal approach including intrathecal morphine.

Br J Anaesth 2003; 90: 653–8

Keywords: analgesic techniques, subarachnoid; analgesics opioid, morphine


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Since the first report of intrathecal opioid administration over 20 yr ago,1 the use of spinal opioids for analgesia has become widespread. Intrathecal morphine provides effective pain relief after Caesarean section, but maternal side-effects are common. Nausea and vomiting may occur in a third of patients and pruritus in more than 75%.24 The severity of side-effects can be reduced by decreasing the dose of intrathecal morphine,57 but this may be at the cost of decreased analgesia.8

Recently there has been interest in the role of dextromethorphan, a non-competitive N-methyl-D-aspartic acid (NMDA) antagonist, in pain management. A review by Weinbroum and colleagues9 concluded that dextromethorphan attenuates acute pain with few side-effects. Dextromethorphan is an over-the-counter cough suppressant which has been widely used for over 35 yr and has an established safety profile.10 It is the D isomer of the codeine analogue levorphanol but does not act through opioid receptors. It has no classical analgesic properties and little sedative activity, and does not inhibit ciliary function. Adverse effects are mild and uncommon, and may include dizziness and gastrointestinal disturbances such as nausea and vomiting.

Dextromethorphan as an antitussive is normally administered in a dose of 10–30 mg orally three to six times daily. The antitussive effect of a single dose of dextromethorphan 30 mg lasts 4–6 h, and 60 mg 6–8 h.11 Dextromethorphan undergoes extensive first-pass metabolism in the liver, where it is rapidly transformed to dextrorphan, a more potent NMDA antagonist. After a single oral dose of 60 mg in human volunteers, the peak concentrations of dextromethorphan in plasma were achieved at 2–3 h, and the peak concentrations of dextrorphan in plasma were achieved at 1.5 h. The elimination half-life of dextromethorphan was approximately 3.5 h.12

A multimodal approach for analgesia after Caesarean section under spinal anaesthesia, using intrathecal morphine, intrathecal fentanyl and rectal naproxen, is current practice at our institution. The aims of this prospective, randomized, double-blind trial were to determine if: (i) the addition of dextromethorphan reduced postoperative pain; (ii) a lower dose of intrathecal morphine reduced the incidence of nausea/vomiting; (iii) a lower dose of intrathecal morphine reduced the incidence of pruritus; and (iv) the addition of dextromethorphan to a low dose of intrathecal morphine provided equivalent postoperative analgesia to a higher dose of intrathecal morphine alone.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study was approved by the Clinical Research Ethics Board of the University of British Columbia. Parturients over 37 weeks’ gestation scheduled for elective Caesarean section under spinal anaesthesia were eligible for inclusion in the study. Women with preeclampsia, a history of gastrointestinal ulcers or bleeding, significant renal or hepatic impairment, allergy to any of the study medications, use of antitussives 48 h before surgery, chronic pain, regular analgesic use or drug dependency were not studied.

A random numbers table was used to prepare a series of sealed, opaque envelopes containing the randomization slips. After giving written informed consent, patients were randomized to one of six groups: (group 1) intrathecal morphine 0.05 mg plus oral placebo; (group 2) intrathecal morphine 0.05 mg plus oral dextromethorphan 60 mg; (group 3) intrathecal morphine 0.1 mg plus oral placebo; (group 4) intrathecal morphine 0.1 mg plus oral dextromethorphan 60 mg; (group 5) intrathecal morphine 0.2 mg plus oral placebo; (group 6) intrathecal morphine 0.2 mg plus oral dextromethorphan 60 mg.

Surgeons, patients and the evaluating anaesthetist were blinded to the group allocation. Patients received the oral study medication (fruit-flavoured placebo or dextromethorphan 60 mg) 1 h before surgery and at 6 and 12 h after surgery. The oral study medication was prepared by the hospital pharmacy, and the placebo and dextromethorphan were similar in appearance and taste.

All patients received premedication with sodium citrate 30 ml. Spinal anaesthesia was performed using a standardized technique with a 25G Whitacre needle at the L2/3 or L3/4 interspace. Patients received hyperbaric bupivacaine 0.75% 1.2–1.6 ml mixed with fentanyl 10 µg plus the allocated dose of preservative-free morphine. Hypotension was treated with incremental doses of i.v. ephedrine. After delivery, oxytocin 20 U litre–1 was added to the i.v. crystalloid infusion, which continued into the immediate post-partum period. Patients were given rectal naproxen 500 mg after completion of surgery and again 12 h later.

Treatment of postoperative pain and side-effects was at patient request. Analgesia was provided in the form of tablets of codeine phosphate 30 mg combined with acetaminophen 300 mg and caffeine 15 mg (Tylenol No. 3, McNeil Consumer Healthcare, Guelph, Ontario, Canada) at intervals of 3 h as required. Nausea and vomiting was treated with i.v. metoclopramide 10 mg at intervals of 4 h as required. Pruritus was treated with i.v. nalbuphine 5–10 mg at intervals of 3 h. Monitoring for late-onset respiratory depression was done in all study groups according to hospital protocol.

Pain at rest and on movement was measured using a 100 mm visual analogue scale (VAS) at 6, 12, 24, 36, 48 h after surgery. Pain VAS on movement at 48 h and the incidence of nausea, vomiting and pruritus at 24 h were the primary outcomes. Pain VAS at rest and on movement at the time of the first request for analgesia, additional analgesic requests, and interventions for side-effects were recorded. The incidence of dizziness during the 48 h study period was also explored.

Power calculations were performed before data collection. Bonferroni correction was used for multiple hypothesis testing, giving a type I error ({alpha}) of 0.0125. With a factorial design, a sample size of 20 per group was calculated to detect a difference in mean pain VAS of 20 mm between groups with 80% power, assuming a standard deviation of 20 mm (from previous studies at our institution). We used two-way analysis of variance (ANOVA) to analyse the 48 h pain scores. As these scores were not normally distributed we transformed them with a square root transformation so that the normality assumption of ANOVA was satisfied. ANOVA was carried out with SAS statistical software (SAS Institute Inc., Cary, NC, USA). This analysis provided a statistical test of significance and means and confidence intervals for the pain VAS data. As the analysis was carried out on the square root of the pain VAS data, which is not directly interpretable, we transformed the results back into original units for presentation. Splus (Insightful Corporation, Seattle, WA, USA) was used to run a generalized linear model in order to assess the effect of dextromethorphan and intrathecal morphine on the incidence of nausea and vomiting and pruritus.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
One hundred and twenty-three patients were enrolled and 120 patients completed the study, with 20 in each group. In one case, the spinal anaesthesia was inadequate for surgery and was converted to general anaesthesia. One patient had a major post-partum haemorrhage; uterine packs were left in situ and another spinal anaesthetic was required for removal of the packs at 24 h. One patient withdrew from the study and did not complete the postoperative assessments: after giving initial consent, she declined to complete the study and was excluded from assessment. In general the oral study medication was tolerated well. Only two women were unable to drink the study drug after surgery because of nausea and vomiting. These women were included as the analysis was on an intention-to-treat basis (one patient from the placebo group, one from the dextromethorphan group).

The groups were similar in terms of age, height, weight, parity, dose of intrathecal bupivacaine, block height and duration of oxytocin infusion (Table 1).


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Table 1 Patient characteristics. Values are mean (SD or range) or number (%). No significant differences
 
The addition of dextromethorphan did not reduce pain scores on movement at 48 h [F(1,113)=0.05, P=0.83]. The adjusted mean VAS for group 2 (intrathecal morphine 0.05 mg plus dextromethorphan) was 27 [95% confidence interval (CI) 19–38], whereas the adjusted mean pain VAS in group 5 (intrathecal morphine 0.2 mg plus placebo) was 39 (95% CI 28–52). As the two confidence intervals overlap, it could be concluded that the addition of oral dextromethorphan to a lower dose of intrathecal morphine appeared to provide equivalent postoperative pain relief to a higher dose of intrathecal morphine alone. However, the adjusted mean pain of group 1 (intrathecal morphine 0.05 mg plus placebo) was 22 (95% CI 14.1–32.1), which is very similar to group 2 (Fig. 1).



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Fig 1 Boxplots of pain VAS on movement 48 h after surgery. DM=dextromethorphan; ITM=intrathecal morphine.

 
Increasing the dose of intrathecal morphine significantly increased the incidence of side-effects (Table 2). Compared with women receiving intrathecal morphine 0.05 mg, women receiving higher doses had a significantly higher incidence of nausea and vomiting [odds ratio for intrathecal morphine 0.1 mg, 4.0 (95% CI 1.2–14.1); for 0.2 mg, 7.9 (95% CI 2.3–27.1)]. Compared with women receiving intrathecal morphine 0.05 mg, women receiving higher doses also had a significantly higher incidence of pruritus [odds ratio for intrathecal morphine 0.1 mg, 3.2 (95% CI 1.3–8.2); for 0.2 mg, 3.7 (95% CI 1.4–9.5)]. This is reflected in the number of women requiring treatment for pruritus with nalbuphine (Table 2).


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Table 2 Incidence of nausea and vomiting, pruritus and nalbuphine treatment for pruritus in women receiving intrathecal morphine (ITM). Values are number (%)
 
Nausea and vomiting occurred in 22 (37%) women receiving placebo compared with 12 (20%) women receiving dextromethorphan [odds ratio 2.6 (95% CI 1.1–6.3)].


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The action of dextromethorphan as an orally administered NMDA antagonist with few side-effects makes it attractive as an addition to our current multimodal approach to analgesia after Caesarean section. However, we have been unable to show that the addition of oral dextromethorphan 60 mg given 1 h before surgery and 6 and 12 h after operation reduces 48 h pain scores after Caesarean section under spinal anaesthesia. The addition of dextromethorphan to the lowest dose of intrathecal morphine appeared to provide equivalent postoperative analgesia to the highest dose of intrathecal morphine plus placebo. However, as women receiving intrathecal morphine 0.05 mg and placebo had very similar pain scores to those receiving intrathecal morphine 0.05 mg and dextromethorphan, no positive conclusions can be drawn from these results.

We assessed the effect of dextromethorphan on pain at 48 h, as positive results in the late postoperative period had been shown in several previous studies.1317 Therefore, we chose pain VAS at 48 h as one of the primary outcomes in our study. We also planned to explore any effects of dextromethorphan in the immediate postoperative period. However, as our study produced a negative conclusion for the primary outcome for pain, the other pain VAS data collected were not analysed. The greater mean pain VAS in group 5 (intrathecal morphine 0.2 mg and placebo) was not statistically significant and is probably attributable to chance. We used pain VAS to assess analgesic efficacy instead of the total amount of postoperative analgesics consumed or time to first analgesic request, as we anticipated that a proportion of women would not require additional analgesia. Indeed, the median number of analgesic requests during the first 24 h was four or fewer in all groups.

We chose to use the 60 mg oral dose of dextromethorphan because previous studies looking at the effect of lower-dose dextromethorphan regimens on postoperative pain and analgesic use were inconclusive. Preoperative oral dextromethorphan 45 mg reduced pain for 7 days after tonsillectomy.13 In one study, pain scores and analgesic use after abdominal hysterectomy were reduced by oral dextromethorphan 40 mg given preoperatively and then at 8 h intervals for 48 h,16 but not by oral dextromethorphan 27 mg given preoperatively and 8, 16 and 24 h postoperatively in another study.18 However, we also aimed to avoid the side-effects associated with higher doses of oral dextromethorphan.

Since our trial was carried out, positive results using a single preoperative dose of dextromethorphan 90 mg have been reported. Postoperative analgesic use and pain scores after laparoscopic cholecystectomy or inguinal hernioplasty were reduced.19 Oral dextromethorphan 90 mg given to patients undergoing lower body surgery with epidural anaesthesia or general anaesthesia also reduced analgesic requirements, both in the immediate (6 h) and late (24 h and 3 days) postoperative period.17 In a review of the clinical benefits of dextromethorphan in acute pain, Weinbroum and colleagues9 concluded that ‘dextromethorphan attenuated the sensation of acute pain at doses of 30–90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative dextromethorphan treated patients’.9

Studies of larger doses of oral dextromethorphan report conflicting results. Oral dextromethorphan 200 mg given at 8 h intervals led to a significant but modest reduction in morphine requirements but no reduction in postoperative pain after knee surgery.20 Oral dextromethorphan 150 mg reduced morphine use for 4 h after hysterectomy but had no prolonged effects on pain or wound hyperalgesia,21 and oral dextromethorphan 120 mg had no effect on pain after minor gynaecological surgery.22

Parenteral dextromethorphan administration for acute pain has also been studied. Preincisional intramuscular dextromethorphan 40 mg reduced pain and opioid use after modified radical mastectomy,15 and preincisional intramuscular dextromethorphan 120 mg reduced meperidine consumption and increased the time to first analgesia after upper abdominal surgery.23

In a double-blind, randomized study by Pan and colleagues,24 17 primiparous women in early labour were given either oral dextromethorphan 45 mg or placebo before intrathecal fentanyl 25 µg. Dextromethorphan prolonged the duration of labour analgesia of intrathecal fentanyl. To our knowledge, there have been no reports of the use of dextromethorphan in combination with intrathecal morphine and spinal anaesthesia.

NMDA antagonists prevent central sensitization of dorsal horn neurones in response to noxious stimulation, or wind-up.25 In healthy volunteers dextromethorphan reduced secondary hyperalgesia and had no effects on primary hyperalgesia.26 27 However, this effect has not been confirmed by other investigators.28 29 Dextromethorphan potentiated the antinociceptive effect of morphine in animal studies30 but not in a human experimental ischaemic pain model.31

Pruritus, nausea and vomiting are recognized side-effects of intrathecal opioids. In a study of male human volunteers receiving intrathecal morphine 0, 0.2, 0.4, or 0.6 mg, the incidence of emesis was dose-related.32 Intrathecal morphine can reach the vomiting centre and chemoreceptor trigger zone either by rostral spread in the cerebrospinal fluid or by uptake into the systemic circulation.33 34 All subjects receiving intrathecal morphine had pruritus but the severity of pruritus was not dose-dependent.32 In 1999 a systematic review of randomized controlled trials of intrathecal opioids in patients undergoing Caesarean section with spinal anaesthesia concluded that the relative risk of both pruritus and nausea and vomiting increased in a dose-dependent manner with intrathecal morphine.35 According to this meta-analysis, for every 100 women receiving intrathecal morphine 0.1 mg, 43 patients will experience pruritus, 10 will experience nausea, and 12 will experience vomiting. Two studies have reported no relationship between nausea and vomiting and intrathecal morphine.8 36 Both of these studies had a control group which received no intrathecal morphine but received i.v. morphine using a patient-controlled analgesia (PCA) device. The control group had an incidence of nausea and vomiting similar to groups receiving intrathecal morphine. This is not surprising as emesis is reported in 30–80% of patients receiving PCA i.v. morphine after Caesarean section.37 38

There was a lower incidence of nausea and vomiting in all dextromethorphan groups in our study. This was contrary to our expectations as gastrointestinal disturbances are said to be an adverse effect of dextromethorphan. In our study, dizziness was not increased by dextromethorphan and we did not directly assess sedation.

Previous studies have tried to define the optimal dose of intrathecal morphine for analgesia after Caesarean section.2 5 39 40 Non-steroidal anti-inflammatory drugs potentiate postoperative analgesia from intrathecal morphine40 41 and may also reduce pruritus.42 Therefore, the context in which the intrathecal morphine is given, whether as a sole agent or as part of a multimodal approach, should also be considered. However, in this study we were unable to show that the addition of oral dextromethorphan to our current multimodal approach reduced postoperative pain after Caesarean section under spinal anaesthesia.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–51[ISI][Medline]

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]

3 Abouleish E, Rawal N, Fallon K, Hernandez D. Combined intrathecal morphine and bupivacaine for cesarean section. Anesth Analg 1988; 67: 370–4[Abstract]

4 Chadwick HS, Ready LB. Intrathecal and epidural morphine sulfate for postcesarean analgesia—a clinical comparison. Anesthesiology 1988; 68: 925–9[ISI][Medline]

5 Uchiyama A, Ueyama H, Nakano S, Nishimura M, Tashiro C. Low dose intrathecal morphine and pain relief following caesarean section. Int J Obstet Anesth 1994; 3: 87–91

6 Milner AR, Bogod DG, Harwood RJ. Intrathecal administration of morphine for elective Caesarean section. A comparison between 0.1 mg and 0.2 mg. Anaesthesia 1996; 51: 871–3[ISI][Medline]

7 Yang T, Breen TW, Archer D, Fick G. Comparison of 0.25 mg and 0.1 mg intrathecal morphine for analgesia after Cesarean section. Can J Anaesth 1999; 46: 856–60[Abstract]

8 Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose–response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999; 90: 437–44[ISI][Medline]

9 Weinbroum AA, Rudick V, Paret G, Ben-Abraham R. The role of dextromethorphan in pain control. Can J Anaesth 2000; 47: 585–96[Abstract/Free Full Text]

10 Bem JL, Peck R. Dextromethorphan. An overview of safety issues. Drug Saf 1992; 7: 190–9[ISI][Medline]

11 Aylward M, Maddock J, Davies DE, Protheroe DA, Leideman T. Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects. Eur J Respir Dis 1984; 65: 283–91[ISI][Medline]

12 Silvasti M, Karttunen P, Tukiainen H, Kokkonen P, Hanninen U, Nykanen S. Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J Clin Pharmacol Ther Toxicol 1987; 25: 493–7[Medline]

13 Kawamata T, Omote K, Kawamata M, Namiki A. Premedication with oral dextromethorphan reduces postoperative pain after tonsillectomy. Anesth Analg 1998; 86: 594–7[Abstract]

14 Wu CT, Yu JC, Yeh CC, et al. Preincisional dextromethorphan treatment decreases postoperative pain and opioid requirement after laparoscopic cholecystectomy. Anesth Analg 1999; 88: 1331–4[Abstract/Free Full Text]

15 Wong CS, Wu CT, Yu JC, Yeh CC, Lee MMS, Tao PL. Preincisional dextromethorphan decreases postoperative pain and opioid requirement after modified radical mastectomy. Can J Anaesth 1999; 46: 1122–6[Abstract]

16 Henderson DJ, Withington BS, Wilson JA, Morrison LMM. Perioperative dextromethorphan reduces postoperative pain after hysterectomy. Anesth Analg 1999; 89: 399–402[Abstract/Free Full Text]

17 Weinbroum AA. Dextromethorphan reduces immediate and late postoperative analgesic requirements and improves patients’ subjective scorings after epidural lidocaine and general anesthesia. Anesth Anal 2002; 94: 1547–52[Abstract/Free Full Text]

18 McConaghy PM, McSorley P, McCaughey W, Campbell WI. Dextromethorphan and pain after total abdominal hysterectomy. Br J Anaesth 1998; 81: 731–6[Abstract/Free Full Text]

19 Weinbroum AA, Gorodezky A, Niv D, Ben-Abraham R, Rudick V, Szold A. Dextromethorphan attenuation of postoperative pain and primary and secondary thermal hyperalgesia. Can J Anaesth 2001; 48: 167–74[Abstract/Free Full Text]

20 Wadhwa A, Clarke D, Goodchild CS, Young D. Large-dose oral dextromethorphan as an adjunct to patient-controlled analgesia with morphine after knee surgery. Anesth Analg 2001; 92: 448–54[Abstract/Free Full Text]

21 Ilkjaer S, Bach LF, Nielsen PA, Wernberg M, Dahl JB. Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain 2000; 86: 19–24[CrossRef][ISI][Medline]

22 Ilkjaer S, Nielsen PA, Bach LF, Wernberg M, Dahl JB. The effect of dextromethorphan, alone or in combination with ibuprofen, on postoperative pain after minor gynaecological surgery. Acta Anaesthesiol Scand 2000; 44: 873–7[CrossRef][ISI][Medline]

23 Helmy SAK, Bali A. The effect of the preemptive use of the NMDA receptor antagonist dextromethorphan on postoperative analgesic requirements. Anesth Analg 2001; 92: 739–44[Abstract/Free Full Text]

24 Pan P, Moore C, Fragneto R, Ross V. Does oral dextromethorphan increase the analgesic efficacy of intrathecal fentanyl for labor analgesia? 31st Annual Meeting of Society of Obstetric Anesthesia and Perinatology (SOAP), Denver, 1999. Abstract 54

25 Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–9[CrossRef][ISI][Medline]

26 Price DD, Mao J, Frenk H, Mayer DJ. The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 1994; 59: 165–74[CrossRef][ISI][Medline]

27 Ilkjaer S, Dirks J, Brennum J, Wernberg M, Dahl JB. Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans. Br J Anaesth 1997; 79: 600–5[Abstract/Free Full Text]

28 Kauppila T, Gronroos M, Pertovaara A. An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist. Pharmacol Biochem Behav 1995; 52: 641–4[CrossRef][ISI][Medline]

29 Kinnman E, Nygards EB, Hansson P. Effects of dextromethorphan in clinical doses on capsaicin-induced ongoing pain and mechanical hypersensitivity. J Pain Symptom Manage 1997; 14: 195–201[CrossRef][ISI][Medline]

30 Plesan A, Hedman U, Xu XJ, Wiesenfield-Hallin Z. Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg 1998; 86: 825–9[Abstract]

31 Plesan A, Sollevi A, Segerdahl M. The N-methyl-D-aspartate-receptor antagonist dextromethorphan lacks analgesic effect in a human experimental ischemic pain model. Acta Anaesthesiol Scand 2000; 44: 924–8[CrossRef][ISI][Medline]

32 Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61: 276–310[ISI][Medline]

33 Bromage PR, Camporesi EM, Durant PAC, Nielsen CH. Rostral spread of epidural morphine. Anesthesiology 1982; 56: 431–6[ISI][Medline]

34 Bailey PL, Rhondeau S, Schafer PG, et al. Dose–response pharmacology of intrathecal morphine in human volunteers. Anesthesiology 1993; 79: 49–59[ISI][Medline]

35 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[ISI][Medline]

36 Swart M, Sewell J, Thomas D. Intrathecal morphine for caesarean section: an assessment of pain relief, satisfaction and side-effects. Anaesthesia 1997; 52: 364–81[CrossRef][ISI][Medline]

37 Eisenach JC, Grice SC, Dewan DM. Patient-controlled analgesia following Cesarean section: a comparison with epidural and intramuscular narcotics. Anesthesiology 1988; 68: 444–8[ISI][Medline]

38 Russell D, Duncan LA, Frame WT, Higgins SPJ, Asbury AJ, Millar K. Patient-controlled analgesia with morphine and droperidol following caesarean section under spinal anaesthesia. Acta Anaesthesiol Scand 1996; 40: 600–5[ISI][Medline]

39 Cardoso MMSC, Carvalho JCA, Amaro AR, Prado AA, Cappelli EL. Small doses of intrathecal morphine combined with systemic diclofenac for postoperative pain control after cesarean delivery. Anesth Analg 1998; 86: 538–41[Abstract]

40 Gerancher JC, Floyd H, Eisenach J. Determination of an effective dose of intrathecal morphine for pain relief after cesarean delivery. Anesth Anal 1999; 88: 346–51[Abstract/Free Full Text]

41 Pavy TJG, Gambling DR, Merrick PM, Douglas MJ. Rectal indomethacin potentiates spinal morphine analgesia after Caesarean delivery. Anaesth Intensive Care 1995; 23: 555–9[ISI][Medline]

42 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[CrossRef][ISI][Medline]