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PAIN MEDICINE

The Addition of a Tramadol Infusion to Morphine Patient-Controlled Analgesia After Abdominal Surgery: A Double-Blinded, Placebo-Controlled Randomized Trial

Ashley R. Webb, MB BS, FANZCA^*, Samuel Leong, MB BS, FANZCA^*, Paul S. Myles, MB BS, MPH, MD, FFARCSI, FANZCA, and Sara J. Burn, BA RN^*

*Department of Anaesthesia, Frankston Hospital, Frankston; and Department of Anaesthesia and Pain Management, Alfred Hospital, Prahran, Victoria, Australia

Address correspondence and reprint requests to Dr. Ashley R. Webb, Department of Anaesthesia, Frankston Hospital, Hastings Road, Frankston, Victoria, 3199 Australia. Address e-mail to awebb{at}phcn.vic.gov.au

	Abstract

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In this double-blinded, randomized controlled trial, we tested whether the addition of tramadol to morphine for patient-controlled analgesia (PCA) resulted in improved analgesia efficacy and smaller morphine requirements compared with morphine PCA alone after abdominal surgery in adults. Sixty-nine patients were randomly allocated into two groups, each receiving morphine 1 mg/mL via PCA after surgery. The tramadol group received an intraoperative initial loading dose of tramadol (1 mg/kg) and a postoperative infusion of tramadol at 0.2 mg · kg^-1 · h^-1. The control group received an intraoperative equivalent volume of normal saline and a postoperative saline infusion. Postoperatively, tramadol was associated with improved subjective analgesic efficacy (P = 0.031) and there was significantly less PCA morphine use in the tramadol group (P = 0.023). No differences between the groups were found with regard to nausea, antiemetic use, sedation, or quality of recovery (all P > 0.05). We conclude that a tramadol infusion combined with PCA morphine improves analgesia and reduces morphine requirements after abdominal surgery compared with morphine PCA alone.

IMPLICATIONS: In this study, we determined whether adding a second pain-killing drug, tramadol, could improve pain relief after major surgery in patients receiving morphine patient-controlled analgesia. We found that patients receiving tramadol had significantly better opinions of their pain relief and used significantly less morphine with no increase in side effects.

	Introduction

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Tramadol is a unique analgesic with multiple sites of action (1–3). It is classified as an atypical centrally acting analgesic, and has opioid and non-opioid properties. Its action on µ-opioid receptors is weak, and naloxone antagonizes only 30% of its analgesic activity (1); -2 adrenoceptor antagonists such as yohimbine significantly reverse tramadol analgesia (2). Therefore, much of its antinociceptive actions are likely to be via inhibition of reuptake of neurotransmitters, such as norepinephrine and serotonin in the central nervous system (3). Whereas there are data comparing the efficacy of morphine to tramadol in several surgical populations (4–6), there is no information on the addition of tramadol to morphine.

If analgesia from tramadol is predominantly caused by its weak opioid activity, its actions may be dominated by a more potent µ-opioid agonist such as morphine, with no expected improvement in analgesia for patients receiving the drug combination. Furthermore, partial opioid agonists may potentially inhibit the analgesia provided by full agonists such as morphine. However, if the non-opioid actions of tramadol on central neurotransmitters are significant, an additive or synergistic effect is possible. The research question we wanted to address was whether there was an interaction between morphine and tramadol on analgesic outcome.

	Patients and Methods

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Adult patients scheduled for elective abdominal surgery were recruited to this double-blinded randomized controlled trial. The study was approved by the institutional ethics committee, and informed consent was obtained from all patients. Patients were ASA physical status I–III, aged 20–80 yr, and weighed 43–110 kg. All patients underwent laparotomy and were managed by a variety of surgeons and anesthesiologists. All patients received patient-controlled analgesia (PCA) for at least 48 h postoperatively, and most patients (81%) had an upper abdominal incision. Exclusion criteria were unsuitability for PCA, chronic opiate usage, allergy to opiates or tramadol, epilepsy, pregnancy, psychiatric disorders involving the use of monoamine oxidase inhibitor or selective serotonin reuptake inhibitor drugs, sleep apnea, or severe hepatic or renal impairment.

General anesthesia, including intraoperative opiate administration, was determined by the anesthesiologist. Although the majority of patients received only intraoperative morphine, a few received fentanyl or meperidine. The meperidine dosage was converted to morphine equivalents in a ratio of 10:1, and fentanyl in a ratio of 100:1 (7). The anesthetic technique was at the discretion of the anesthesiologist but supplementary postoperative analgesia was not permitted until the 48-h data collection period was completed. This included the use of local anesthetic wound infiltration or nerve blocks, acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), ketamine, or clonidine.

On arrival to the operating room, patients were randomly allocated to one of two groups, the result of which was known only by the postanesthesia care unit (PACU) staff member who prepared the study medications as follows: 1) in the tramadol group, an IV initial loading dose of tramadol 1 mg/kg was given at the end of surgery. This was diluted to a final volume of 3 mL with normal saline to maintain blinding of the anesthesiologist administering it. In the PACU, a tramadol infusion was commenced at a rate of 1 mL/h and continued for 48 h. The infusion was prepared such that the delivery of tramadol was 0.2 mg · kg^-1 · h^-1. 2) In the control group, normal saline was administered at an equivalent volume to that of the tramadol group, with a normal saline infusion commenced in the PACU at a rate of 1 mL/h and continued for 48 h.

Our institutional morphine pain protocol was used in the PACU if required to produce patient comfort, defined as a 0–10 pain verbal rating score (VRS) 3. Patients 70 yr of age could receive 2-mg IV morphine boluses while in the PACU at 5-min intervals. The dose was reduced to 1 mg for patients >70 yr of age. A morphine PCA, programmed to deliver a 1.0-mg bolus with a 5-min lockout time, was commenced once patients were comfortable.

The primary end-point of the study was subjective analgesic efficacy (8), in which patients were asked, "How effective was your medication in relieving your pain over the last 24 h?" with responses: 1 = excellent, 2 = good, 3 = satisfactory, 4 = poor, and 5 = very poor. We also collected pain scores (VRS), a 5-point sedation score, a 5-point sleep quality, and a 3-point nausea score (Appendix 1). Overall quality of recovery (QoR) was measured by the 9-item QoR score (9).

Patient pain scores at rest and on movement were assessed at 4-h intervals for 48 h. At 24 and 48 h after commencement of the infusion, assessment was made of PCA morphine usage, subjective assessment of analgesia efficacy, nausea score, antiemetic usage, sleep quality, and QoR.

Any patient with inadequate analgesia during the 48-h assessment period had the PCA morphine bolus increased to 2.0 mg. The study protocol permitted a background infusion of 1–2 mg/h if pain relief remained inadequate. If the pain VRS remained 4 despite these measures, patients were withdrawn and alternative analgesia was provided. Where appropriate, this included the use of morphine-ketamine infusions, NSAIDs, and acetaminophen. Such events were recorded. The study protocol defined treatment regimens for nausea and vomiting (IV metoclopramide, or ondansetron if this was ineffective) and pruritus (IV promethazine).

An estimate of sample size was based on identifying a clinically significant benefit, and this was defined as a 30% improvement in subjective analgesic efficacy. A study of 30 patients per group provided 80% power with a type I error of 0.05. To account for patient withdrawals and protocol violations, a further 9 patients were recruited and randomized until each study group had at least 30 subjects with a complete dataset. Available data from withdrawn patients were included in the analysis provided there had been no violations of the study protocol. Normally distributed data were analyzed by using general linear models and presented as mean (SD). Patient age, ASA physical status, duration of surgery, and extent of surgery (using number of dermatomes involved) were included as covariates in the analysis of subjective analgesic efficacy and PCA morphine consumption. Log transformation was performed for skewed data to equalize the group variances.

Other non-normally distributed data were analyzed by using the Mann-Whitney U-test and presented as median (range). Proportions were analyzed by using ² and were presented as number (%). All statistical analyses were performed by using SPSS for Windows version 9.0 (SPSS Inc., Chicago, IL). A P value < 0.05 was considered significant.

	Results

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Patient characteristics, duration and extent of surgery, and intraoperative opiate usage are shown in Table 1. There was no significant imbalance between the two groups.

	Discussion

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This trial supports the hypothesis that a small-dose tramadol infusion is a useful adjunct to morphine PCA in patients recovering from abdominal surgery. Patients in the tramadol group had less PCA morphine consumption at both the 24- and 48-hour assessment times, and reported significantly better opinions of the efficacy of their analgesic medication. There was no evidence of increased side effects in patients receiving tramadol.

The morphine-sparing effect of tramadol was greater on the second postoperative day. Mean morphine consumption decreased 52% on the second day in the tramadol group and 21% in the saline group. The modest morphine-sparing effect during the first 24 hours compared with the second requires some explanation. The intraoperative tramadol initial loading dose of 1 mg/kg was modest compared with other studies of tramadol in abdominal surgery in which 3–5 mg/kg was used (10,11). The smaller initial loading dose was used in this study in accordance with the Australian product information sheet. Because this data sheet also recommends a maximal daily dose of 400 mg, the conservative infusion rate of 0.2 mg · kg^-1 · h^-1 was used.

An alternate explanation for the significant morphine-sparing effect on the second postoperative day relates to how tramadol is metabolized. During infusions of tramadol, there may have been accumulation of the M1 metabolite of tramadol, O-desmethyl tramadol (3). This metabolite has a higher affinity for opioid receptors than the parent drug and has an elimination half-life of nine hours, which is almost double that of tramadol (3). The formation of M1 was a significant effect of tramadol on experimental pain in humans (12). The best patient assessments of analgesic efficacy were in the tramadol group at 48 hours postoperatively.

Several studies have compared tramadol with morphine after abdominal surgery, but this study is novel in that it is the first to investigate the use of the combination of the two drugs. Studies comparing morphine and tramadol after abdominal surgery have generally found a similar analgesic response (4–6). The increased analgesic efficacy and significant morphine-sparing effect seen in the tramadol group suggests that non-opioid mechanisms of action are acting in synergy with opioid effects. At least some of the analgesic actions of racemic tramadol are mediated via central noradrenergic and/or serotonergic mechanisms. Levo-tramadol mainly inhibits central noradrenaline reuptake, whereas dextro-tramadol inhibits serotonin reuptake and has direct central 5-hydroxytryptamine releasing actions (3,13).

One drawback of this study is that combining a tramadol infusion with morphine PCA is an excessively complex analgesic regimen, given that subjective analgesic efficacy tended to be good in the control group and there were no significant differences in the pain VRS. However, analgesic efficacy was more likely to be rated as excellent in the tramadol group, particularly on the second postoperative day. On each postoperative day, there was an improvement of approximately 0.4 of a point in the 5-point subjective analgesic efficacy scoring system.

Whereas there were statistically significant differences between the two groups with regard to subjective assessment of analgesic efficacy, pain VRS did not differ. The 11-point VRS correlates well with the 100-mm visual analog scale, but both are point estimates that fluctuate in different situations (14). For example, nursing care, movement, anxiety, and the effects of treatment change pain VRS at different times and situations. We consider analgesic efficacy and the incidence of side effects to be the most relevant outcomes in any analgesia studies, because efficacy and pain intensity do not always correlate (8,15). Despite similar pain VRS, patients in the tramadol group may have rated their treatment more effective because of affective and cognitive changes leading to a greater sense of well-being. It may be speculated that tramadol may alter some of the emotional responses to pain because most antidepressants work via central noradrenergic or serotonergic mechanisms, and tramadol has an effect on these neurotransmitters at analgesic plasma concentrations (16).

Patients in this study had a small incidence of nausea and no differences in antiemetic usage. Some previous studies comparing morphine and tramadol for postoperative analgesia have found increased side effects with patients receiving tramadol, particularly nausea and vomiting (17,18). These studies administered tramadol via bolus doses, whereas in this study, it was given by continuous infusion. This method of delivery at a rate of 0.2 mg · kg^-1 · h^-1 was well tolerated.

There is evidence of potential benefits from combining non-opioid with opioid analgesics as part of a multimodal approach to pain relief (19). Whereas data have been available to support combining NSAIDs and paracetamol to morphine after surgery, there have been no data on tramadol until now. It is possible to use a variety of drugs after surgery to improve analgesia and reduce side effects. Tramadol has significantly less effect on bowel transit time than morphine (20), but this study did not investigate whether there was earlier return of bowel function in the tramadol group.

Although the number of withdrawn patients was too small to analyze, it was interesting to note that the two patients withdrawn because of respiratory depression both came from the control group. One had undiagnosed sleep apnea syndrome. The other received a morphine background infusion having had poor analgesia with PCA alone. PCA background infusions are known to increase side effects without substantially improving analgesia, although their use remains frequent for difficult postoperative pain problems at many institutions (21).

In summary, we have demonstrated clinical benefit in using tramadol as an adjunctive drug to morphine PCA after abdominal surgery. Reduced morphine requirements, increased analgesic effi- cacy, and a relative lack of side effects were the main advantages of the technique used. Further studies should be done to determine whether larger tramadol initial loading doses and postoperative infusion rates provide greater benefits, particularly in the first 24 hours after surgery. A longer follow-up study may provide data on the potential for this technique to allow earlier return of postoperative bowel function and home discharge.

	Appendix 1. Patient Scoring System

Top Abstract Introduction Patients and Methods Results Discussion Appendix 1. Patient Scoring... References

 

	Acknowledgments

	References

Top Abstract Introduction Patients and Methods Results Discussion Appendix 1. Patient Scoring... References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Webb, A. R. Articles by Burn, S. J. Search for Related Content PubMed PubMed Citation Articles by Webb, A. R. Articles by Burn, S. J. Related Collections Pain