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Anesth Analg 2001;93:1288-1292
© 2001 International Anesthesia Research Society

OBSTETRIC ANESTHESIA

A Comparison of Tramadol, Amitriptyline, and Meperidine for Postepidural Anesthetic Shivering in Parturients

Yu-Chuan Tsai, MD*, and Koung-Shing Chu, MD{dagger}

*Department of Anesthesiology, College of Medicine, National Cheng Kung University; and {dagger}Pain Clinic, Kuo General Hospital, Tainan, Taiwan

Address correspondence and reprint requests to Yu-Chuan Tsai, MD, Department of Anesthesiology, National Cheng Kung University Hospital, 138 Sheng-Li Rd., Tainan 704, Taiwan. Address e-mail to yctsai{at}mail.ncku.edu.tw


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Tramadol is effective for treating shivering during epidural anesthesia in parturients. In addition to its low affinity to opioid receptors, tramadol exerts a modulatory effect on central monoaminergic pathways. In this respect, there are parallels between the mechanisms of the action of tramadol and antidepressants such as amitriptyline. Meperidine is often recommended for the treatment of postanesthetic shivering. This prospective, double-blinded, and randomized clinical study was performed to compare the antishivering effects and accompanying side effects among tramadol, meperidine, and amitriptyline for the treatment of postepidural anesthetic shivering. Forty-five parturients who shivered during cesarean delivery under epidural anesthesia and requested antishivering treatment were randomly allocated to one of three groups for IV treatment: Group T (n = 15) received tramadol 0.5 mg/kg, Group M (n = 15) received meperidine 0.5 mg/kg, and Group A (n = 15) received amitriptyline 15 or 20 mg. The response rate (shivering ceased after treatment in 15 min) was 87% and 93% for Groups T and M, respectively, compared with 13% in Group A (P < 0.01). The time that elapsed from treatment to the time shivering ceased was 5.1 ± 3.6 min (mean ± SD) for Group T and 4.2 ± 2.3 min for Group M. There was a significantly more frequent incidence (33%) of somnolence in Group M when compared with Groups T (7%) and A (0%) (P < 0.01). However, no significant differences were shown for pruritus, nausea, vomiting, or Apgar scores of newborns. We concluded that both tramadol and meperidine show a significantly faster response rate in the treatment of postepidural anesthetic shivering when compared with amitriptyline in the dosage used; tramadol had a decreased incidence of somnolence when compared with meperidine.

IMPLICATIONS: This study was performed to compare the antishivering and side effects among tramadol, amitriptyline, and meperidine for the treatment of postepidural anesthetic shivering in parturients. Both tramadol and meperidine show a significantly faster response rate in the treatment of shivering when compared with amitriptyline. Tramadol had a less frequent incidence of somnolence than meperidine.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Shivering is very uncomfortable for patients and may interfere with monitoring of electrocardiogram, blood pressure, and pulse oxygen saturation. It increases oxygen consumption, lactic acidosis, and carbon dioxide production; thus, it may cause distress to patients with a low cardiac pulmonary reserve.

Tramadol hydrochloride, a centrally-acting analgesic drug, is effective in the treatment of shivering after epidural anesthesia (EA) in parturients (1). In addition to a µ-opioid agonist effect, it exerts a modulatory effect on central monoaminergic pathways, inhibiting the neuronal uptake of noradrenaline and serotonin (2–5). In this respect, there are parallels between the mechanisms of action of tramadol and antidepressants such as amitriptyline, which are believed to potentiate the effects of biogenic amines (6–8). Meperidine, a combined µ- and {kappa}-receptor agonist, is frequently recommended for the treatment of postanesthetic shivering (9–12). Much evidence has suggested that the antishivering effects of meperidine are mediated by {kappa}-receptor activity (10,13,14).

This prospective, double-blinded, and randomized clinical study was performed to compare the anti- shivering effects and the accompanying side effects among tramadol, meperidine, and amitriptyline for the treatment of post-EA shivering in parturients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from the human investigation committee of Kuo General Hospital, 115 obstetric patients (ASA physical status I or II, aged 18 to 40 yr) scheduled for cesarean delivery under EA with no prior medication were included in this study. Excluded were parturients with hyperthyroidism, cardiopulmonary disease, and known history of alcohol or substance abuse. Shivering was graded with a scale similar to that validated by Crossley and Mahajan (15): 0 = no shivering, 1= piloerection or peripheral vasoconstriction but no visible shivering, 2 = muscular activity in only one muscle group, 3 = muscular activity in more than one muscle group but not generalized shivering, 4 = shivering involving the whole body. Only parturients who developed Grade 3 or 4 shivering for at least 3 min were included. Body temperature (tympanic temperature) was monitored with an ear thermometer (Thermoscan IRT 3020; Braun, Kronberg, Germany) at the start of EA and treatment for shivering. The temperature of the operating room was maintained at 21°C–23°C, with a room humidity of approximately 60%. Standard monitoring was used.

EA was instituted at the lumbar vertebrae 3-4 or 4-5 interspace, with 2% lidocaine 15 mL combined with epinephrine 1:80,000. The volume of IV fluid and the use of ephedrine for hypotension were determined by attending anesthesiologists. The administration of pre- or intraoperative opioids was not permitted. Patients were supplemented with oxygen 6 L/min by face mask and covered with sheets but not actively warmed during anesthesia. All preloading fluids and drugs were used at room temperature. Of the 115 parturients, 45 who shivered during cesarean delivery under EA and requested antishivering treatment were randomly allocated to one of three groups for IV treatment: Group T (n = 15) received tramadol hydrochloride 0.5 mg/kg, Group M (n = 15) received meperidine 0.5 mg/kg, and Group A (n = 15) received amitriptyline hydrochloride 15 or 20 mg. The dosage of tramadol and meperidine was chosen according to previous studies (1,16).

Parturients did not know which drug was administered. The nursing anesthetists, who were unaware of the parturients’ group and treatments, measured the time elapsed from treatment to the time when shivering ceased. If shivering did not cease after 15 min, the treatment was regarded as ineffective. Treatment efficacy was evaluated subjectively by the parturient as no improvement, partial improvement, or marked improvement. Side effects, such as pruritus, somnolence (mildly sedated but easily aroused or heavily sedated), dizziness, nausea, vomiting, and Apgar scores of the newborns at 1 and 5 min, were recorded. Vital signs were measured before and 15 min after EA, as well as 5 min after treatment.

A study population of 15 patients for each group was determined to have a statistical power >90% at {alpha} = 0.05 (two-tailed) to detect a difference of 60% in the incidence compared with the Amitriptyline group in response to Tramadol and Meperidine groups for post-EA shivering treatment. Statistical analysis was performed with the software GraphPad Prism (GraphPad Software, San Diego, CA). Parametric data were analyzed by using one-way analysis of variance. Nonparametric data were analyzed by using the Kruskal-Wallis test. Category data were analyzed by using the {chi}2 test. A P value of <0.05 was considered statistically significant. Data are presented as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thirty-nine percent of parturients experienced shivering at Grade 3 or 4 and requested treatment. There were no significant differences among the three groups with respect to age, weight, upper sensory spread of EA, or onset of shivering after EA (Table 1). There were also no significant differences among the groups in shivering severity or tympanic temperature, either at the start of EA or at the time of treatment (Table 1).


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  		Table 1. Patient Characteristics
 
The response rate (shivering ceased after treatment in 15 min) was 87% and 93% for Groups T and M, respectively, compared with 13% in Group A (P < 0.01, {chi}2 test, Table 2). Eighty-seven percent of Group A patients showed no changes in shivering 15 min after treatment. The time that elapsed from treatment to the time shivering ceased was 5.1 ± 3.6 min for Group T (n = 13) and 4.2 ± 2.3 min for Group M (n = 14). The number of patients who assessed treatment efficacy as no, partial, and marked improvement was 0, 1, and 14 for Group T; 0, 1, and 14 for Group M; and 13, 0, and 2 for Group A , respectively (P < 0.01, {chi}2 test, Table 2).


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  		Table 2. Response of Postepidural Shivering After Treatment
 
Side effects, such as pruritus, nausea, and vomiting, were not significantly different. However, there was a significantly more frequent incidence of somnolence (33%) in Group M parturients when compared with Group T (7%) and Group A (0%) (P < 0.01, {chi}2 test, Table 2). No parturient in Group T complained of dizziness; however, 20% in Groups A and M developed dizziness (P < 0.01, {chi}2 test, Table 2). There were no significant differences among groups in Apgar scores of newborns at 1 and 5 min (Table 3). In addition, the results of arterial blood pressure, heart rate, respiratory rate, and pulse oxygen saturation were not significantly different before EA, 15 min after EA, and 5 min after treatment among the groups.


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  		Table 3. Apgar Scores of Newborns in Each Group
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study indicate that both tramadol (0.5 mg/kg) and meperidine (0.5 mg/kg) effectively treated post-EA shivering. However, amitriptyline at both 15 and 20 mg did not show significant effects in the treatment of shivering. The incidence of shivering during EA was 39% in this study; this is similar to the results in other series (1,17,18).

The exact mechanism of shivering under EA has not been fully established. The possible mechanisms of shivering during EA in parturients result from central thermoregulation (19,20). Pharmacologic drugs remain the most popular mode for treatment and prevention of shivering. Meperidine is a commonly used medication for controlling postanesthetic shivering and apparently inhibits shivering when compared with amitriptyline; it was comparable to tramadol in this study. Although the mechanism of meperidine’s antishivering effect has yet to be fully elucidated, IV meperidine controlled shivering better than equianalgesic doses of pure µ-opioid agonists such as fentanyl, alfentanil, sufentanil, or morphine (10–12), and the antishivering effects of meperidine were not reversed by small doses, but they were reversed by large-dose naloxone (10,13). Accordingly, the antishivering effect of meperidine may be mediated in part by activation of {kappa}-opioid receptors, but not of µ-opioid receptors. However, meperidine probably acts directly on the thermoregulatory center and not all through the receptor activation.

Disadvantages of meperidine treatment are the side effects of sedation and respiratory depression, which may be induced with previously administered opioids or anesthetics. In this study, the incidence of somnolence in the group that received meperidine (33%) was more frequent than in those who received tramadol (7%) or amitriptyline (0%). Pruritus, nausea, and vomiting were also important potential side effects but did not occur frequently with the dosage we used. Because both tramadol and meperidine have similar shivering-quenching effects, whereas tramadol has a decreased incidence of central depressive effects, tramadol should be considered superior to meperidine for the treatment of shivering in parturients.

Tramadol is effective in the treatment of postanesthetic shivering (9). In the study of Chan et al. (1), IV tramadol (0.25 mg/kg) effectively controlled shivering during cesarean delivery under regional anesthesia with minimal side effects; however, increasing the tramadol dose to 0.5 mg/kg did not increase its therapeutic effect. Tramadol’s distinct features in the treatment of shivering reside in its weak sedative and smaller respiratory depressive properties than morphine (21), particularly in parturients and patients with poor cardiorespiratory reserves (9). Tramadol inhibits the neuronal reuptake of norepinephrine and 5-hydroxytrypamine, facilitates 5-hydroxytrypamine release, and activates µ-opioid receptors (3–5). Each of these actions is likely to influence thermoregulatory control. However, tramadol had only slight thermoregulatory effects (22). Thus, it is unlikely to provoke hypothermia or to facilitate fever. The main opioid effect of tramadol is mediated via the µ receptor, with minimal effect at {delta}- or {kappa}-binding sites (5). Tramadol and its enantiomers are bound with only weak affinity to cloned human µ-opioid receptors expressed in neuroblastoma cell line HN9.10, and they are bound with even less affinity for human {delta}- or {kappa}-opioid receptors. The O-desmethyl metabolite (M1) of tramadol and its enantiomers are bound with higher affinity than the parent compounds at µ-opioid receptors with less affinity for {delta}- or {kappa}-opioid receptors, although still with a much lower affinity than morphine (23).

The potent antinociceptive effects of tramadol were significantly decreased by yohimbine and idazoxan (both {alpha}2-adrenoceptor antagonists) (24). In this respect, tramadol is similar to clonidine, a partial {alpha}2-adrenoceptor agonist that is also useful in the treatment of postoperative shivering (25). Delaunay et al. (26) showed that clonidine reduced the thermoregulatory thresholds for both vasoconstriction and shivering. This suggests that it acts by impairing central thermoregulatory control. However, clonidine is associated with side effects such as bradycardia, hypotension, and sedation (27). Tramadol may induce its antishivering effects via the additive or synergistic action of both {kappa}-opioid receptor and {alpha}2-adrenergic agonist mechanisms. The interaction of {kappa}-opioid and {alpha}2-adrenoceptor mechanisms working in a complementary or synergistic manner to produce antishivering effects seems a possible explanation.

As an inhibitor of the reuptake of serotonin and norepinephrine in the central nervous system, the mechanism of action of tramadol resembles that of amitriptyline, one of the tricyclic antidepressants that is often suggested in neuropathic pain management. Amitriptyline inhibits the amine pump uptake of neurotransmitters, e.g., norepinephrine and serotonin (6–8). It produces varying degrees of sedation and blocks {alpha}1-adrenergic, H1, and H2 receptors. The antidepressants have many anticholinergic side effects, such as tachycardia, orthostatic hypotension, urinary retention, reduced gut motility, and visual problems, and these limit its use in some situations. Chronic treatment with amitriptyline produces supersensitivity to the nicotinic mechanism, which is involved in the regulation of core temperature in rats (28). Moreover, amitriptyline attenuates the febrile response to a pyrogen in rabbits, but it lacks this effect in afebrile animals (29). In this study, amitriptyline at both 15 and 20 mg had no significant effects in the treatment of shivering during EA in parturients when compared with tramadol or meperidine. This may have resulted from the single and relatively small doses of amitriptyline used when compared with the dose for an antidepressant effect. However, the single and small doses of both meperidine and tramadol induced significant effects in the treatment of shivering. Thus, this may imply that the mechanism of tramadol in the treatment of shivering is not strongly mediated by central monoaminergic pathways.

In conclusion, both tramadol (0.5 mg/kg) and meperidine (0.5 mg/kg) effectively treated patients with post-EA shivering. However, amitriptyline at both 15 and 20 mg did not show significant effects in the treatment of shivering.


   Acknowledgments
 
The authors thank Professor Shan-Tair Wang for statistical assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 5, 2001.




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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