Department of Anesthesia, British Columbia Womens 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
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Abstract |
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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 1.214.1); for intrathecal morphine 0.2 mg, 7.9 (2.327.1)]. 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 1.38.2); for intrathecal morphine 0.2 mg, 3.7 (1.49.5)]. Women receiving dextromethorphan had a lower incidence of nausea and vomiting [odds ratio 2.6 (1.16.3)].
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: 6538
Keywords: analgesic techniques, subarachnoid; analgesics opioid, morphine
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Introduction |
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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 1030 mg orally three to six times daily. The antitussive effect of a single dose of dextromethorphan 30 mg lasts 46 h, and 60 mg 68 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 23 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.
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Methods |
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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% 1.21.6 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 litre1 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 510 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 () 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.
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Results |
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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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Discussion |
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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 3090 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 3080% 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.
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