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Preoperative Oral Dextromethorphan Does Not ReducePain or Analgesic Consumption in ChildrenAfter Adenotonsillectomy John B. Rose, MD, Romulo Cuy, MD, David E. Cohen, MD, and Mark S. Schreiner, MD Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia and The University ofPennsylvania School of Medicine, Philadelphia, Pennsylvania obtained by phone interview, and parental satisfaction controlled, prospective study, we evaluated the analge- was scored (yes/no) regarding their child’s postopera- sic efficacy of dextromethorphan 0.5 mg/kg or tive analgesia. Morphine 0.025 mg/kg IV was adminis- 1.0 mg/kg PO 1 h before adenotonsillectomy in 57 chil- tered to children with CHEOPS score Ͼ6, who verbal- dren 6 –12 yr of age. Anesthetic management was stan- ized pain, or who were crying in any consecutive 5-min dardized. Morphine 0.075 mg/kg IV and acetamino- observation periods in the PACU. Total morphine con- phen 25–35 mg/kg PR were administered after sumption was recorded. The study groups were com- anesthetic induction but before the start of surgery. A parable with respect to demographic variables. We 4-point behavioral score (1 ϭ asleep, 2 ϭ awake and were unable to detect any differences between study calm, 3 ϭ awake and crying, 4 ϭ thrashing) was re- groups with respect to postoperative morphine con- corded on admission to and discharge from the postan- sumption, CHEOPS, behavior scores, VAS, or parental esthesia care unit (PACU). In the PACU, pain was as- satisfaction. Implications: Premedication with dextro-
sessed with Children’s Hospital of Eastern Ontario Pain methorphan 0.5 or 1.0 mg/kg PO does not improve Scale (CHEOPS) and recorded every 15 min until the postoperative analgesia in school-aged children who patient was transferred to the day surgery unit (DSU).
receive preemptive morphine 0.075 mg/kg IV and acet- In the DSU, patients rated their pain using a 10-cm base- aminophen 25–35 mg/kg PR during nitrous oxide and line 0 –10 visual analog pain scale (VAS) every 30 min desflurane anesthesia for adenotonsillectomy.
until they were discharged home. A 24-h VAS was Adenotonsillectomy is one of the most common parentalsatisfactionwithpostoperativepainmanage- surgical procedures performed in children. Post- ment during the first 24 h after adenotonsillectomy in operative pain and discomfort often accompany 6- to 12-yr-old children. We hypothesized that there this procedure; therefore, improved methods for pro- was no difference in morphine consumption, pain viding postoperative analgesia are desirable. Dextro- scores, behavior scores, or parental satisfaction with methorphan, a readily available nonopioid antitussive postoperative analgesia in children who received pla- in clinical use for many years, is an N-methyl-d- cebo versus dextromethorphan 0.5 or 1.0 mg/kg PO aspartic acid (NMDA) receptor antagonist (1,2). Re- cently, dextromethorphan 45 mg PO administered60 min before surgery was shown to reduce postop-erative pain after tonsillectomy in adults (3). In the present study, we aimed to determine whether the After institutional review board approval and in- administration of dextromethorphan 0.5 or 1.0 mg/kg formed, written parental consent, 60 children (6 –12 yr PO 60 min prior to surgery improved analgesia, re- old), ASA physical status I or II scheduled for adeno- duced opioid consumption, and resulted in greater tonsillectomy were enrolled in this investigation. Ahospital pharmacist randomized participants to one ofthree study groups with the aid of a computer- Accepted for publication December 16, 1998.
generated random number table. The pharmacist also Address correspondence and reprint requests to John B. Rose, maintained the randomization table. All investigators MD, Department of Anesthesiology and Critical Care Medicine, The and patients were blinded to the study group assign- Children’s Hospital of Philadelphia, 34th & Civic Center Blvd.,Philadelphia, PA 19104. Address e-mail to [email protected].
ment. Subjects received either dextromethorphan 1999 by the International Anesthesia Research Society0003-2999/99/$5.00 0.5 mg/kg, dextromethorphan 1.0 mg/kg, or placebo.
The parents were asked to provide this information over All study medications were prepared by a pharmacist the telephone on the first postoperative day. They were and administered orally 60 min before the expected also asked to state whether they were satisfied or dissat- start of surgery. Approximately 30 min before the isfied with their child’s postoperative analgesia.
induction of general anesthesia, all children received The primary outcome variables were the number of an oral preanesthetic medication consisting of mida- patients who required morphine rescue in the PACU zolam 0.5 mg/kg (maximal dose 15 mg) and atropine and the total dose of morphine required postopera- 0.02 mg/kg. General anesthesia was induced in all tively. Secondary outcome variables included the be- children with sevoflurane and nitrous oxide in oxy- havior scores in the PACU, the maximal and discharge gen. After anesthetic induction, an IV catheter was CHEOPS scores while in the PACU, the maximal and inserted, and vecuronium 0.1 mg/kg IV was admin- discharge VAS scores in the DSU, and the VAS score istered to facilitate endotracheal intubation. Morphine at home 24 h after surgery. The following data were 0.075 mg/kg IV and acetaminophen 25–35 mg/kg PR also recorded for each patient: age, weight, gender, were given before incision. Local anesthetic infiltra- anesthesia time, surgery time, PACU length of stay, tion of the tonsillar beds was not performed in any and DSU length of stay. Differences among groups patients enrolled in this study. Patients also received were compared using an analysis of variance for in- dexamethasone 0.5 mg/kg IV (maximal dose 10 mg) terval data, the Kruskal-Wallis test for nonparametric and ondansetron 0.05 mg/kg IV (maximal dose 4 mg) data, and ␹2 analysis for nominal data. P Ͻ 0.05 was to reduce postoperative swelling and vomiting, as is our standard practice. General anesthesia was main- The sample size calculation was based on the pri- tained with desflurane and nitrous oxide in oxygen.
mary end point of total morphine dose. We expected At the conclusion of surgery, children were awakened that children undergoing adenotonsillectomy would in the operating room, and their tracheas were extu- receive a total morphine dose of 0.16 Ϯ 0.05 mg/kg IV bated before transfer to the postanesthesia care unit before discharge from the PACU (6). The primary method of analysis was an analysis of variance. Using Pain scores used included the Children’s Hospital of a computer software package, we determined that a Eastern Ontario Pain Scale (CHEOPS) and a 0–10 visual sample size of 16 patients per group would permit us analog pain scale (VAS) consisting of a 10-cm baseline to detect a 25% reduction in morphine consumption with 0 ϭ no pain and 10 ϭ worst imaginable pain (4,5).
compared with placebo with an 80% power while All postoperative behavioral and pain scores were ob- controlling for a type I error of 5% (7). A final sample tained by one of two research nurses. Interrater reliabil- size of 20 patients per study group was determined to ity was not assessed. These same nurses conducted all allow for possible participant attrition.
postoperative phone calls. In the PACU, patients wereassessed using a behavioral scale (1 ϭ asleep, 2 ϭ awakeand calm, 3 ϭ awake and crying, or 4 ϭ thrashing) on admission and at discharge, and the CHEOPS every15 min until discharge from the PACU. Additional an- Of the 60 participants, 3 were excluded from data algesia—morphine 0.025 mg/kg IV (maximal dose analysis because of protocol violations. One patient 0.2 mg/kg IV)—was provided to patients with a was excluded for refusal to take the study medication CHEOPS score Ͼ6, who verbalized that they had throat (dextromethorphan 0.5 mg/kg study group). Another pain, or who were crying during two consecutive 5-min patient was excluded for omission of the midazolam observation periods. PACU nurses recorded all doses of premedication (dextromethorphan 1 mg/kg study morphine. Patients were discharged from the PACU group). The third patient who was excluded from data after a minimal 1-h observation period and were admit- analysis required a second operative procedure in the ted to the day surgery unit (DSU) to complete their immediate postoperative period to control bleeding recovery. In the DSU, patients were asked to rate their from the tonsillar fossa (placebo group).
pain on a 0–10 VAS on admission and every 30 min until The study groups were comparable with respect to discharge while awake. Codeine 0.5 mg/kg PO was age, weight, gender, time of study drug administra- provided to patients with a VAS score Ͼ6 in the DSU, tion, intraoperative morphine dose, intraoperative who verbalized that they had throat pain, or who were acetaminophen dose, duration of surgery, and dura- crying during two consecutive 5-min observation peri- tion of anesthesia (Table 1). All patients were dis- ods. After discharge from the DSU, parents were pro- charged from the PACU 1 h after admission. One vided with a prescription for oral codeine 0.5 mg/kg and patient in the placebo group vomited six times in the acetaminophen 10–15 mg/kg and with instructions to DSU, required rescue antiemetic therapy with ondan- administer the analgesics every 4 h for pain. The parents setron and trimethobenzamide hydrochloride, and of all patients were instructed to assess pain at rest 24 h had a delayed discharge time of 6 h 15 min. All other after surgery with the same VAS form used in the DSU.
patients met discharge criteria and were discharged Table 1. Demographic Variables, Operative Times, and Intraoperative Analgesics
from the DSU 2 h after admission to the DSU, which is and acetaminophen 25–35 mg/kg PR to determine the minimal required observation period at our insti- whether the addition of dextromethorphan improved analgesia and reduced analgesic consumption after ad- The three groups were similar with regard to the enotonsillectomy in children. We thought that it was number of patients who required morphine in the PACU unethical to withhold our standard care to determine (n ϭ 13, 14, and 14, respectively; P ϭ 0.91), the mean dose whether dextromethorphan by itself reduced pain and of morphine administered to these patients in the PACU analgesic consumption in children. Dextromethorphan (44 Ϯ 7, 49 Ϯ 7, and 41 Ϯ 7 ␮g/kg, respectively; P ϭ potentiates morphine-induced antinociception in labora- 0.75), the maximal and discharge CHEOPS scores, and tory animals (8), and we hoped to demonstrate a similar behavioral scores in the PACU (Table 2). There were no benefit in a clinical setting. Pain assessment in children is differences among the groups with respect to the mean also more difficult than pain assessment in adults. Al- dose of codeine administered in the DSU (0.74 Ϯ 0.24, though we used observational and subjective pain scores 0.69 Ϯ 0.13, 0.74 Ϯ 0.3 mg/kg, respectively; P ϭ 0.72), the as well as behavior scores to determine whether dextro- maximal and discharge VAS scores in the DSU, VAS methorphan reduced postoperative pain in children, score 24 h postoperatively, and parental satisfaction with other factors, such as fear, anxiety, and parental separa- tion, which are not modified by NMDA receptor antag-onism, may contribute to these scores. In the study in-volving adult subjects, pain was assessed daily for 7 days postoperatively. We evaluated pain only during the first A single dose of dextromethorphan 0.5 or 1.0 mg/kg 24 h postoperatively. Although Kawamata et al. (3) ob- PO administered 60 min before adenotonsillectomy served the analgesic benefit of dextromethorphan as had no discernable effect on the postoperative mor- soon as the patients were awake and alert postopera- phine requirements, pain scores, and behavior scores tively, it may be necessary to evaluate postoperative pain of 6- to 12-yr-old children. Parental satisfaction with in children for a period longer than 24 h to determine postoperative analgesia during the first 24 h after sur- whether preoperative oral dextromethorphan reduces gery was similarly unaffected. Our findings are not postoperative pain. Finally, there is some evidence in consistent with an earlier report that dextromethor- adult volunteers to justify the doses of dextromethor- phan 45 mg PO reduced pain and analgesic require- phan (30 and 45 mg PO) used by Kawamata et al. (9).
ments after tonsillectomy in adults (3).
However, there are no similar studies in pediatric vol- Kawamata et al. (3) recognized that dextromethor- unteers. We chose dextromethorphan 0.5 and 1.0 mg/kg phan has no direct antinociceptive effects and attributed PO based on these adult studies and on the recom- the reduction in posttonsillectomy pain and analgesic mended doses for antitussive therapy in children (10). It use they observed to dextromethorphan’s ability to pre- is possible that the doses we used were too small to vent the development of central sensitization. Aside produce an analgesic benefit in children.
from our studying preadolescent children, several differ- NMDA receptor antagonism inhibits windup or ences in study design between our study and the study central hypersensitivity of dorsal horn neurons in re- of Kawamata et al. (3) may account for the differing sponse to noxious stimulation (11). Dextromethor- results. First, the adults in the above-mentioned study phan, an NMDA receptor antagonist, has been shown received no other analgesics intraoperatively and were to reduce secondary hyperalgesia but to have no effect given only the nonsteroidal antiinflammatory drugs on primary hyperalgesia in healthy adult male volun- loxoprofen and diclofenac for postoperative pain. We teers (9,12). In one study, dextromethorphan 30 or administered dextromethorphan before surgery in com- 45 mg PO reduced secondary hyperalgesia but had no bination with intraoperative morphine 0.075 mg/kg IV effect on primary hyperalgesia in response to electric Table 2. Patients Who Required MSO Rescue in the PACU, Morphine Administered, CHEOPS and Behavioral Scores in
the PACU, VAS in the DSU and at Home, and Parental Satisfaction with Analgesia Values are median (interquartile range).
PACU ϭ postanesthesia care unit, CHEOPS ϭ Children’s Hospital of Eastern Ontario Pain Scale, VAS ϭ visual analog scale, DSU ϭ day surgery unit.
shocks or 52°C heat pulses (9). More recently, adult In conclusion, dextromethorphan 0.5 and 1.0 mg/kg volunteers who received dextromethorphan 60 or PO administered 1 h before adenotonsillectomy in 6- 120 mg PO versus placebo experienced a reduction in to 12-yr-old children whose general anesthetic was the magnitude of secondary hyperalgesia to pinprick supplemented with morphine 0.075 mg/kg IV and after burn injuries (12). However, dextromethorphan acetaminophen 25–35 mg/kg PR had no effect on did not attenuate primary hyperalgesia, as measured postoperative morphine requirements, pain and be- by pain during heat stimulation, or heat-pain- havior scores, or parental satisfaction with postopera- detection thresholds in undamaged skin (12). Other tive analgesia in the first 24 h after surgery.
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of side effects, including sedation and ataxia, during the 6. Rose JB, Martin TM. Posttonsillectomy vomiting. Ondansetron escalation of dextromethorphan dosing resulted in 5 of or metoclopramide during paediatric tonsillectomy: are two 31 patients dropping out of this study.
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