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Canadian Journal of Anesthesia 50:48-51 (2003)
© Canadian Anesthesiologists' Society, 2003
Regional Anesthesia and Pain

Tramadol 2.5 mg·kg-1 appears to be the optimal intraoperative loading dose before patient-controlled analgesia

[Une dose de 2,5 mg·kg-1 de tramadol semble la dose d’attaque peropératoire optimale avant l’analgésie auto-contrôlée]

Wei-Wu Pang, MD*, Hurng-Sheng Wu, MD{dagger} and Chien-Chiung Tung, MD{ddagger}

* From the Department of Anesthesia,
{dagger} Show-Chwan Memorial Hospital Changhua The Department Of Surgery,
{ddagger} Show-Chwan Memorial Hospital Changhua National Defense Medical Center Tri-service General Hospital Taipei The Department Of Anesthesia Chen-Ching Hospital Wu-Fong Taichung Taiwan R.O.C.

Address correspondence to: Dr. Wei-Wu Pang, 7630 Pissarro Dr. Apt #108, Orlando, Florida 32819, USA. Phone: 407-351-8246; Fax: 407-351-8246; E-mail: sungfangrong{at}aol.com


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Purpose: We previously established that a 5 mg•kg-1 intraoperative dose can reduce the nausea/vomiting associated with tramadol patient-controlled analgesia (PCA). This study was conducted to identify the most appropriate initial dose to improve the quality of tramadol PCA.

Methods: During general anesthesia, 60 patients undergoing knee arthroplasty were randomly allocated to receive 1.25 mg•kg-1 (Group I), 2.5 mg•kg-1 (Group II), 3.75 mg•kg-1 (Group III), or 5 mg•kg-1 (Group IV) tramadol. The emergence condition was recorded. The titration of additional tramadol 20 mg + metoclopramide 1 mg doses by PCA every five minutes was performed in the postanesthesia care unit (PACU) until the visual analogue scale (VAS) score was # 3. An investigator blinded to study group recorded the VAS and side effects every ten minutes.

Results: In the PACU, significantly more tramadol (8.4 ± 3.1 vs 4.3 ± 2.1, 2.5 ± 1.8, and 0.4 ± 0.3, P < 0.05), and a higher incidence (15/15 vs 5/15, 3/15, and 2/15, P < 0.05) of PCA use was observed in Group I compared to Groups II–IV. VAS was significantly higher in Group I than in Groups II–IV at zero and ten minutes (P < 0.05). Unexpected delayed emergence anesthesia (> 30 min) was observed in Group III (n = 1) and in Group IV (n = 2). Sedation was more important in Groups III and IV than in Groups I and II (P < 0.05).

Conclusion: When considering efficacy and side-effect profile, 2.5 mg•kg-1 of tramadol is the optimal intraoperative dose of this drug to provide effective postoperative analgesia with minimal sedation.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
VARIOUS attempts have been made to improve pain relief after major surgery. The most commonly used drug for iv patient controlled analgesia (PCA) is morphine, an opioid that has several adverse effects.

Tramadol is a centrally acting analgesic with a mostly non-opioid mode of action.1,2 It is effective for the relief of acute and chronic pain.3,4 The adverse effect profile of tramadol, especially sedation and respiratory depression, is that of a weak opioid at effective analgesic doses.5 With low abuse and addiction potential,6 tramadol is not a controlled substance in many countries.

However, tramadol PCA is hampered by its major side effects, nausea and vomiting.4,7 We reported previously that by administering a 5 mg•kg-1 tramadol loading dose during surgery, the nausea/vomiting associated with tramadol PCA in the postanesthesia care unit (PACU) can be significantly reduced.8 This is a follow-up study to determine the optimal intraoperative loading dose when tramadol PCA is used for postoperative pain control.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Following approval by the Hospital’s Research Committee and after receiving patient informed consent, 60 adult patients ASA physical status I and II undergoing elective total knee replacement were enrolled into this prospective, randomized, double-blind study. All patients were instructed on the use of the PCA device and on pain assessment using the visual analogue score (VAS; 0 cm = no pain, 10 cm = the most excruciating pain) during the preoperative interview and again in the PACU. The exclusion criteria included: 1) difficulty in communication or inability to use PCA; 2) allergy to the study drug; 3) history of severe hepatic, cardiopulmonary or renal disease; 4) history of substance abuse; 5) obesity with body weight > 120% of the ideal body weight; 6) history of previous postoperative nausea and vomiting (PONV).

Anesthesia was induced with iv fentanyl 100 µg, thiopental 4 mg•kg-1, and succinylcholine 1 mg•kg-1 and maintained with isoflurane in N2O 60% and oxygen 40%. Vecuronium was used for muscle relaxation. No local anesthetics, anti-emetics or non-steroidal anti-inflammatory drugs (NSAIDs) were administered 24 hr before or during surgery. At the beginning of wound closure (about 40 min before the end of the procedure), patients were randomly divided into four equal groups using a computerized randomization table. Patients in Group I received tramadol (Tramtor®, Patron Chemical & Pharmaceutical Co., Taiwan) 1.25 mg•kg-1; Group II received 2.5 mg•kg-1; Group III received 3.75 mg•kg-1; and Group IV received 5 mg•kg-1. The drugs were prepared by a pharmacist in identically appearing syringes and the anesthesiologists administering the drug were blind to drug dose. After drug administration, the isoflurane inspiratory concentration was adjusted to maintain blood pressure and heart rate within appropriate limits. When the last skin suture was inserted, isoflurane was turned off, 100% oxygen given and the trachea extubated. Any unusual condition during emergence was recorded.

On arrival in the PACU, patients were connected to a PCA pump (Pain Management Provider, Abbott Laboratories, North Chicago, USA). A baseline pain assessment was done with VAS. When VAS was more than 4, PCA at the dose of 1 mL (containing 20 mg tramadol + 1 mg metoclopramide) every five minutes was administered until VAS # 3. An investigator blinded to the study grouping carried out pain control (VAS) and side effect assessments that were recorded every ten minutes in the PACU for one hour. The addition of 1 mg metoclopramide to each 20 mg tramadol was based on a previous study in which we found that nausea and vomiting were significantly reduced with this combination throughout the 48-hr PCA period.9 The investigator did not specifically ask about nausea; rather, those patients who reported nausea themselves or presented with the symptoms of nausea and/or vomiting were counted. Patients who had nausea for more than ten minutes and vomited twice or more, were categorized as having severe PONV and were treated with iv ondansetron 4 mg. The degree of sedation was scaled as: grade 0 = awake and alert; grade 1 = drowsy or eyes closed but can be aroused using only a verbal command; grade 3 = somnolence, arousable only by strong physical stimulation; grade 4 = unarousable sleep. Grade 3 and 4 sedation were treated with close observation, oxygenation and intubation if necessary. Data on PCA demand, delivery, and total consumption as well as blood pressure, heart rate, respiratory rate, and side effects were recorded. The patient was discharged to the ward at one hour if stable.

Analysis of variance (ANOVA) was used for demographic data analysis and PCA delivery. Results are reported as mean ± standard deviation. When differences between groups were statistically significant, the ANOVA was followed-up with the least significant difference test. The Chi-square test was used for categorical data. Chi-squared or Fisher’s exact test were used for the incidence of side effects. The Kruskal-Wallis test and post-hoc Dunn test were used to analyze pain scores among the four groups. A P value of 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Demographics were similar among groups (Table IGo).


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  		TABLE I Demographic data
 
In the PACU, in order to achieve a VAS # 3, more tramadol was required in Group I than in groups II, III, and IV (8.4 ± 3.1 vs 4.3 ± 2.1, 2.5 ± 1.8, and 0.4 ± 0.3, P < 0.05). The incidence of PCA use in the PACU was also more frequent in Group I than in Groups II, III, and IV (15/15 vs 5/15, 3/15, and 2/15, P < 0.05; Table IIGo).


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  		TABLE II Total volume of drugs delivered and incidence of PCA use in the postanesthesia care unit
 
The pain score by VAS at each assessment is presented in the Figure. Group I had higher VAS scores than Groups II, III, and IV at zero and ten minutes (P < 0.05).

The incidence of side effects in the operating room and PACU is shown in Table IIIGo. Delayed emergence from general anesthesia was observed in one patient (lasted 35 min) in Group III and two patients (lasted 35 min and 60 min respectively) in Group IV. The incidence of grade 2 sedation was greater in Groups III and IV than in Groups I and II (P < 0.05). There was no statistical difference during the entire PACU observation period among the groups in terms of other side effects such as nausea, vomiting, dizziness, pruritus, dry mouth, etc. None of the patients had shivering, seizures, or respiratory depression. All patients had stable vital signs.


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  		TABLE III Incidence of side effects in operating room and postanesthesia care unit
 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
This study suggests that a 2.5 mg•kg-1 intraoperative loading dose of tramadol is optimal. When tramadol was given at doses >= 3.75 mg•kg-1, a greater incidence of sedation was observed in the PACU. In addition, three patients manifested unexpected delayed emergence from general anesthesia lasting longer than 30 min. Conversely, if a 1.25 mg•kg-1 intraoperative loading dose was given, inadequate pain control occurred necessitating the administration of additional analgesics in the PACU. Either under dosing such as in Group I or over dosing in Groups III and IV is undesirable since it does not offer satisfactory care in the PACU.

Various attempts have been made to improve postoperative pain relief by non-opioids to avoid adverse effects such as respiratory depression. Tramadol is an analgesic with a mostly non-opioid mode of action.1 With iv administration it has an onset time of less than three minutes.1,4 Its plasma half-life is six hours longer than that of morphine (two hours).1,3,4 It would be an attractive alternative if its associated nausea and vomiting could be reduced. Since it is known that intraoperative loading reduces nausea/vomiting in the PACU,5 the aim of this study was to determine the best possible loading dose.

We did not use doses greater than 5 mg•kg-1 in the design of this study, based on the report by Spiller et al.10 In a prospective multi-centre evaluation of tramadol, they reported 87 cases of tramadol intoxication in which 500 mg tramadol was the lowest dose associated with seizure, tachycardia, hypertension or agitation while 800 mg was the lowest dose associated with coma and respiratory depression.10 The toxic reaction was brief and self-limited, severe cardiovascular toxicity, such as hypotension or arrhythmias, was not seen and general supportive therapy appeared to be sufficient in managing these cases of overdose.10 With a 5 mg•kg-1 loading dose, not exceeding 500 mg, we did not observe any serious adverse events. Conversely, intraoperative loading doses less than 1.25 mg•kg-1 appear of little benefit because of lack of analgesia in the PACU. We believe the two patients who had mild nausea in Group I may have been pain related, since nausea subsided as more tramadol was given.

Interestingly, when the initial dose was >= 3.75 mg•kg-1, three patients manifested unexpected delayed emergence from general anesthesia (greater than 30 min). It seemed that tramadol was synergistic with general anesthetic agents and prolonged emergence similar to other analgesics. However, Coetzee et al.11 observed that tramadol causes a dose-dependent activation of the electroencephalogram, a finding in apparent conflict with our clinical observations.

In clinical practice, for those patients who receive general or regional anesthesia, we believe tramadol intraoperative loading and tramadol PCA are another option for postoperative pain control in addition to morphine, nerve blocks, or NSAIDs. However, 1 mg metoclopramide should be added to each 20 mg tramadol.9


   Conclusion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
An intraoperative dose of 2.5 mg•kg-1 tramadol was superior in analgesic efficacy to 1.25 mg•kg-1 and equivalent to 3.75 mg•kg-1 and 5 mg•kg-1 for postoperative pain relief after knee arthroplasty. Significant sedating side effects apear with doses greater than 2.5 mg•kg-1. Therefore, 2.5 mg•kg-1 appears to be the optimal intraoperative loading dose before tramadol PCA.



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  		FIGURE Pain scores by visual analogue score (VAS) at each assessment time. Group I = tramadol 1.25 mg•kg-1; Group II = tramadol 2.5 mg•kg-1; Group III = tramadol 3.75 mg•kg-1; Group IV = tramadol 5 mg•kg-1; 0 = arrival in postanesthesia care unit. *P < 0.05 Group I vs Groups II, III, and IV (at zero, ten minutes).

 

   Acknowledgments
 
The authors would like to express thanks to Shu-Hui Yang, chief CRNA for data collection and all other CRNA members who collaborated this work.


   Footnotes
 
This study was financially self-supported and was carried out at the Department of Anesthesia, Show-Chwan Memorial Hospital, Changhua, Taiwan, R.O.C. Part of this article was presented as the abstract poster for the ASA 2000 Annual Meeting, Oct. 16, 2000 San Francisco, California, USA.

Revision received October 18, 2002. Accepted for publication July 15, 2002.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
1 Raffa RB, Nayak RK, Liao S, Minn FL. The mechanism(s) of action and pharmacokinetics of tramodol hydrochloride. Rev Contemp Pharmacother 1995; 6: 485–97.

2 Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000; 60: 139–76.[Medline]

3 Katz WA. Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs 1996; 52(Suppl 3): 39–47.

4 Vickers MD. The efficacy of tramadol hydrochloride in the treatment of postoperative pain. Rev Contemp Pharmacother 1995; 6: 499–506.

5 Vickers MD, O’ Flaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47: 291–6.[Medline]

6 Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 1991; 27: 7–17.[Medline]

7 Pang WW, Mok MS, Lin CH, Yang TF, Huang MH. Comparison of patient-controlled analgesia (PCA) with tramadol or morphine. Can J Anesth 1999; 46: 1030–5.[Abstract/Free Full Text]

8 Pang WW, Mok MS, Huang S, Hung CP, Huang MH. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anesth 2000; 47: 968–73.[Abstract/Free Full Text]

9 Pang WW, Wu HS, Lin CH, Chang DP, Huang MH. Metoclopramide decreases emesis but increases sedation in tramadol patient-controlled analgesia. Can J Anesth 2002; 1029–33.

10 Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997; 35: 361–4.[Medline]

11 Coetzee JF, Maritz JS, Du Toit JC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996; 76: 415–8.[Abstract/Free Full Text]




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