Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials
2014; Elsevier BV; Volume: 114; Issue: 3 Linguagem: Inglês
10.1093/bja/aeu414
ISSN1471-6771
AutoresV. Martinez, Leah Guichard, Dominique Fletcher,
Tópico(s)Veterinary Pharmacology and Anesthesia
ResumoThe role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of −6.9 (95% confidence interval −11.3 to −2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was −0.9 (−7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery. The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of −6.9 (95% confidence interval −11.3 to −2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was −0.9 (−7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery. Editor's key points•Adjunctive analgesics offer the possibility of reducing opioid-related side-effects.•Results of small trials conducted in a specific study population may not be generalizable.•Small trials are unlikely to identify adverse effects of medications.•Tramadol can reduce opioid requirements after surgery, but this may not be clinically important. •Adjunctive analgesics offer the possibility of reducing opioid-related side-effects.•Results of small trials conducted in a specific study population may not be generalizable.•Small trials are unlikely to identify adverse effects of medications.•Tramadol can reduce opioid requirements after surgery, but this may not be clinically important. Multimodal analgesic regimens use combinations of different analgesic drugs, methods to reduce pain after operation, or both while decreasing morphine use and its associated adverse effects.1Kehlet H Dahl JB The value of 'multimodal' or 'balanced analgesia' in postoperative pain treatment.Anesth Analg. 1993; 77: 1048-1056Crossref PubMed Scopus (1118) Google Scholar This approach is recommended by national guidelines and publications.2Institute of Medicine (US). Committee on Advancing Pain Research, Care, and Education Board on Health Sciences Policy Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Press, Washington, DC2011Google Scholar, 3Fletcher D Aubrun F Long texts for the formalized recommendation of experts on management of postoperative pain.Ann Fr Anesth Reanim. 2009; 28: 1-2Crossref PubMed Scopus (19) Google Scholar Non-opioid analgesics are generally used for this purpose after major surgery. Tramadol is a unique analgesic with two modes of action.4Grond S Sablotzki A Clinical pharmacology of tramadol.Clin Pharmacokinet. 2004; 43: 879-923Crossref PubMed Scopus (912) Google Scholar It activates the opioid and non-opioid systems involved in pain inhibition. The non-opioid effect of tramadol is mediated through α-2-agonistic and serotoninergic activities.5Desmeules JA Piguet V Collart L Dayer P Contribution of monoaminergic modulation to the analgesic effect of tramadol.Br J Clin Pharmacol. 1996; 41: 7-12Crossref PubMed Scopus (236) Google Scholar Tramadol is also a weak opioid, acting on μ-receptors. Tramadol, administered parenterally or orally, has proven to be an effective and well-tolerated analgesic for the management of moderate to severe acute postoperative pain in adults.6Scott LJ Perry CM Tramadol: a review of its use in perioperative pain.Drugs. 2000; 60: 139-176Crossref PubMed Scopus (533) Google Scholar However, the value of tramadol–morphine combinations remains uncertain. The first randomized controlled trial (RCT) investigating the efficacy of tramadol in combination with potent opioids in 1995 reported negative results,7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar but several additional trials have since reported conflicting results,8Antila H Manner T Kuurila K Salantera S Kujala R Aantaa R Ketoprofen and tramadol for analgesia during early recovery after tonsillectomy in children.Paediatr Anaesth. 2006; 16: 548-553Crossref PubMed Scopus (32) Google Scholar, 9But AK Erdil F Yucel A Gedik E Durmus M Ersoy MO The effects of single-dose tramadol on post-operative pain and morphine requirements after coronary artery bypass surgery.Acta Anaesthesiol Scand. 2007; 51: 601-606Crossref PubMed Scopus (19) Google Scholar, 10Kocabas S Karaman S Uysallar E Firat V The use of tramadol and morphine for pain relief after abdominal hysterectomy.Clin Exp Obstet Gynecol. 2005; 32: 45-48PubMed Google Scholar, 11Ozbakis Akkurt BC Inanoglu K Turhanoglu S Asfuroglu Z Effects of dexmedetomidine and tramadol administered before induction of anesthesia on postoperative pain. (Anesteziinduksiyonu oncesiuygulanan tramadol veya deksmedetomidin'in postoperatif agri uzerine etkileri).Anestezi Dergis. 2008; 16: 183-187Google Scholar, 12Spacek A Goraj E Neiger FX Jarosz J Kress HG Superior postoperative analgesic efficacy of a continuous infusion of tramadol and dipyrone (metamizol) versus tramadol alone.Acute Pain. 2003; 5: 3-9Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 13Stiller CO Lundblad H Weidenhielm L et al.The addition of tramadol to morphine via patient-controlled analgesia does not lead to better post-operative pain relief after total knee arthroplasty.Acta Anaesthesiol Scand. 2007; 51: 322-330Crossref PubMed Scopus (27) Google Scholar, 14Stratigopoulou P Vasileiou I Stefaniotou A Melissopoulou T Lampadariou A Tsinari K Comparison of morphine versus morphine plus bolus tramadol for postoperative analgesia in morbidly obese patients.Eur J Anaesthesiol. 2012; 29 (14AP8): 14AP2Crossref Google Scholar, 15Thienthong S Taesiri W Utsahapanich S Krisanaprakornkit W Thaninsurat N Klaichanad C Two doses of oral sustained-release tramadol do not reduce pain or morphine consumption after modified radical mastectomy: a randomized, double-blind, placebo-controlled trial.J Med Assoc Thai. 2004; 87: 24-32PubMed Google Scholar, 16Unlugenc H Ozalevli M Gunes Y Guler T Isik G Pre-emptive analgesic efficacy of tramadol compared with morphine after major abdominal surgery.Br J Anaesth. 2003; 91: 209-213Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 17Webb AR Leong S Myles PS Burn SJ The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial.Anesth Analg. 2002; 95: 1713-1718Crossref PubMed Scopus (54) Google Scholar, 18Wilder-Smith CH Hill L Dyer RA Torr G Coetzee E Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination.Anesth Analg. 2003; 97: 526-533Crossref PubMed Scopus (78) Google Scholar including one study suggesting tramadol and morphine could be infra-additive.19Marcou TA Marque S Mazoit JX Benhamou D The median effective dose of tramadol and morphine for postoperative patients: a study of interactions.Anesth Analg. 2005; 100: 469-474Crossref PubMed Scopus (55) Google Scholar However, other authors reported that the monoaminergic modulation induced by tramadol made this drug valuable for combination with morphine.17Webb AR Leong S Myles PS Burn SJ The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial.Anesth Analg. 2002; 95: 1713-1718Crossref PubMed Scopus (54) Google Scholar It is currently unclear to what extent perioperative tramadol decreases postoperative opioid consumption, opioid-related side-effects, and pain intensity. We thus undertook a systematic review of RCTs comparing the efficacy and safety of tramadol vs placebo or active controls for the treatment of post-surgical pain. This systematic review was performed in accordance with the criteria of the PRISMA statement and the current recommendations of the Cochrane Collaboration.20Higgins J Green S Guide to the contents of a Cochrane protocol and review.in: Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011Available from www.cochrane-handbook.orgGoogle Scholar, 21Liberati A Altman DG Tetzlaff J et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.Br Med J. 2009; 339: b2700Crossref PubMed Scopus (11166) Google Scholar The protocol was registered with PROSPERO, under number CDR 42013006285, on November 13, 2013. We attempted to identify all relevant studies, regardless of language or publication status (published, unpublished). We searched for RCTs indexed in the following databases: CENTRAL, PUBMED, and EMBASE. We applied the highly sensitive search strategy of the Cochrane Collaboration, to identify trials.22Lefebvre C Manheimer E Glanville J Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011Available from www.cochrane-handbook.orgDate: 2008Google Scholar This search strategy combined free text words and controlled vocabulary MeSH terms, with no limitation on the search period. Full details of the search strategy are provided in the Appendix. The search equation for PUBMED was adapted for each database. The date of the last search was June 1, 2014. We searched the Cochrane database of systematic reviews and the DARE meta-register. We also searched the proceedings of the two major annual meetings of two major anaesthesiology societies; the ASA and the European Society of Anaesthesiology, over the last 5 yr (from June 2008 to December 2013). In addition to the preplanned literature search, we also searched for randomized trials that had already been completed in the clinicaltrials.gov (http://www.clinicaltrial.gov) and international clinical trials registry platform (http://apps.who.int/trialsearch) databases. We then searched the reference lists of the relevant review articles and selected articles, for the identification of additional, potentially relevant trials. Authors were contacted, as necessary, to obtain additional information if the published reports were incomplete or to collect data for unpublished studies. We included all RCTs, with no restriction as to date of publication, language, or number of participants. The study populations included were (i) adults and children (able to perform an auto-evaluation of pain), (ii) undergoing all types of surgery, and (iii) receiving rescue morphine over a period of at least 24 h, regardless of the route of administration (p.o., i.v., subcutaneous, or patient-controlled analgesia) and the opioid used (e.g. meperidine, alfentanil, fentanyl, hydromorphone, oxycodone). The interventions considered were the addition of tramadol to the regimen, whatever the route of administration (parenteral or p.o.), the timing (pre-, post-incision), and the mode of administration (single bolus, continuous, or repetitive). Comparisons were made with placebo or any other non-opioid analgesic drug. Studies were excluded if: (i) analgesia techniques or the drugs used were not equivalent or comparable between groups during the intervention, and (ii) the duration of the study was limited to the stay in the postoperative anaesthesia care unit (PACU). The primary outcomes were cumulative morphine consumption in the 24 h after surgery, expressed in milligrams of morphine equivalent, and pain at rest at 24 h, expressed on a visual analogue scale (VAS: 0: no pain to 100: worst possible pain). Intensity scores reported on a numerical rating scale (NRS: 0: no pain to 10: worst possible pain) were converted to the equivalent values for a 0-to-100 VAS scale. The following outcomes were considered as secondary outcomes: morphine titration in the PACU; pain at rest at other time points (PACU, 4 h, 12 h); opioid-related adverse effects, such as nausea, vomiting, sedation, dizziness, dry mouth, or any other adverse effect reported at 24 h. If another shorter or longer time interval was reported, we used the time interval closest to the defined time of 24 h. The original papers often did not distinguish between nausea and vomiting23Visser K Hassink EA Bonsel GJ Moen J Kalkman CJ Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane–nitrous oxide: postoperative nausea with vomiting and economic analysis.Anesthesiology. 2001; 95: 616-626Crossref PubMed Scopus (204) Google Scholar and reported both outcomes together. We therefore used the classification defined in the article by Apfel and colleagues24Apfel CC Turan A Souza K Pergolizzi J Hornuss C Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis.Pain. 2013; 154: 677-689Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar to determine the incidence of nausea. When an adverse effect was assessed with a score, we considered only the presence of the adverse effect, regardless of its severity. Two authors (L.G. and D.F.) independently screened titles, abstracts, and full texts according to the inclusion criteria. Any disagreement between these two authors was settled by discussion with the third author (V.M.), until a consensus was reached. The reasons for exclusion were noted, for each publication, at the full-text review stage. One author (V.M.) designed a standard data extraction form in Excel, and the other authors (L.G. and D.F.) amended and validated the design of this form before its use for data extraction. Data were extracted by one author (L.G.) and were cross-checked by the other authors (V.M. and D.F.). The authors of the study were contacted (by V.M.) and asked to provide missing data or to add to the data when possible. If necessary, means and measures of dispersion were approximated from figures generated with dedicated software (ref: http://www.datathief.org/). We extracted information about the general characteristics of the study (first author, number of arms, country), participants (characteristics of the populations, population randomized and analysed, type of surgery), experimental intervention (administration route, timing of administration, and doses), and outcomes. Dichotomous outcomes were extracted as the presence or absence of an effect. For continuous data, we extracted means and standard deviations (sds). If not reported, the sds were obtained from confidence intervals (CIs) or P-values for the differences between the means of two groups.22Lefebvre C Manheimer E Glanville J Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011Available from www.cochrane-handbook.orgDate: 2008Google Scholar, 25Higgins JP White IR Wood AM Imputation methods for missing outcome data in meta-analysis of clinical trials.Clin Trials. 2008; 5: 225-239Crossref PubMed Scopus (230) Google Scholar If medians with ranges were reported, we obtained the mean and sd as described by Hozo and colleagues.26Hozo SP Djulbegovic B Hozo I Estimating the mean and variance from the median, range, and the size of a sample.BMC Med Res Methodol. 2005; 5: 13Crossref PubMed Scopus (5499) Google Scholar If only means were reported, we contacted the authors. If no response could be obtained, we took the respective median sds of each group. We used the Cochrane Collaboration tool to evaluate the risk of bias in the randomized studies selected. We documented the methods used for the generation of allocation sequences, allocation concealment, the blinding of investigators and participants, the blinding of outcome assessors, and for dealing with incomplete outcome data. Each item was classified as having a low, unclear, or high risk of bias. The overall risk of bias corresponds to the lowest risk of bias documented. Pain intensity scores were assumed to have been obtained at rest, unless otherwise stated. Pain scores reported within 2 h of our time points were included in the analysis. Doses of opioids other than morphine were converted to morphine equivalents with standard conversion factors (1 mg of i.v. morphine was considered to be equivalent to 7.5 mg of i.v. meperidine or 1 mg of i.v. nalbuphine).27Sparks DA, Fanciullo GJ. Opioids. In: Lynch ME, Craig KD, Peng PWH, eds. Clinical Pain Management: A Practical Guide, 2011: 128-34.Google Scholar Nausea and vomiting were analysed separately. We calculated risk ratios (RRs) with 95% CI for dichotomous data and mean differences (MD) with 95% CI for continuous data. We expected there to be heterogeneity (because of the diverse populations included), and we therefore used the Dersimonian and Lairs random effects meta-analysis modules. We assessed heterogeneity with the I2 statistic (I2>50% indicates substantial heterogeneity). Sources of heterogeneity were investigated by the analysis of prespecified subgroups. The subgroups included were defined as follows: high/low doses were defined for each intervention (low <1 defined daily dose, high ≥1 defined daily dose), type of administration (single bolus or multiple doses), timing of administration (pre/post-surgical incision). The World Health Organization defined daily dose for tramadol as 300 mg 24 h−1, regardless of the route of administration (http://www.whocc.no/atc_ddd_index/). Finally, we evaluated publication bias by assessing funnel plot asymmetry. All statistical analyses were performed with Review Manager (RevMan version 5.2.5; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The systematic literature search identified 1477 relevant publications. After a review of titles and abstracts, 54 studies were selected as potentially eligible for inclusion in this systematic review. After reading the full-text articles, we selected 14 RCTs (published between 1995 and 2013) including a total of 713 patients in the meta-analysis (Fig. 1). None of the trials in the clinicaltrial.gov register satisfied our eligibility criteria. Two trials of potential interest were identified in the ESA symposium, but with too little information for their inclusion. We requested additional information from the authors, but this information was not forthcoming. All of the studies included were carried out at single sites. The median target sample size was 60 (16–120) [median (min–max)] patients. The participants were adults or children with an ASA physical status of class I or II. The studies investigated patients undergoing surgery in various specialities: gynaecology,10Kocabas S Karaman S Uysallar E Firat V The use of tramadol and morphine for pain relief after abdominal hysterectomy.Clin Exp Obstet Gynecol. 2005; 32: 45-48PubMed Google Scholar, 15Thienthong S Taesiri W Utsahapanich S Krisanaprakornkit W Thaninsurat N Klaichanad C Two doses of oral sustained-release tramadol do not reduce pain or morphine consumption after modified radical mastectomy: a randomized, double-blind, placebo-controlled trial.J Med Assoc Thai. 2004; 87: 24-32PubMed Google Scholar, 28Guler A Celebioglu B Sahin A Beksac S Comparison of preemptive administration of lornoxicam and tramadol on postoperative analgesia.: Preemptif olarak kullanilan lornoksikam ve tramadolun postoperatif analjeziye katkilarinin karsilastirilmasi.Anestezi Dergizi. 2013; 21: 43-48Google Scholar abdominal surgery,12Spacek A Goraj E Neiger FX Jarosz J Kress HG Superior postoperative analgesic efficacy of a continuous infusion of tramadol and dipyrone (metamizol) versus tramadol alone.Acute Pain. 2003; 5: 3-9Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 14Stratigopoulou P Vasileiou I Stefaniotou A Melissopoulou T Lampadariou A Tsinari K Comparison of morphine versus morphine plus bolus tramadol for postoperative analgesia in morbidly obese patients.Eur J Anaesthesiol. 2012; 29 (14AP8): 14AP2Crossref Google Scholar, 16Unlugenc H Ozalevli M Gunes Y Guler T Isik G Pre-emptive analgesic efficacy of tramadol compared with morphine after major abdominal surgery.Br J Anaesth. 2003; 91: 209-213Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 17Webb AR Leong S Myles PS Burn SJ The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial.Anesth Analg. 2002; 95: 1713-1718Crossref PubMed Scopus (54) Google Scholar Caesarean section,18Wilder-Smith CH Hill L Dyer RA Torr G Coetzee E Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination.Anesth Analg. 2003; 97: 526-533Crossref PubMed Scopus (78) Google Scholar, 29Elhakim M Abd El-Megid W Metry A El-hennawy A El-Queseny K Analgesic and antacid properties of i.m. tramadol given before Caesarean section under general anaesthesia.Br J Anaesth. 2005; 95: 811-815Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar cardiac surgery,9But AK Erdil F Yucel A Gedik E Durmus M Ersoy MO The effects of single-dose tramadol on post-operative pain and morphine requirements after coronary artery bypass surgery.Acta Anaesthesiol Scand. 2007; 51: 601-606Crossref PubMed Scopus (19) Google Scholar orthopaedic surgery,7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar tonsillectomy,8Antila H Manner T Kuurila K Salantera S Kujala R Aantaa R Ketoprofen and tramadol for analgesia during early recovery after tonsillectomy in children.Paediatr Anaesth. 2006; 16: 548-553Crossref PubMed Scopus (32) Google Scholar and various types of major surgery.11Ozbakis Akkurt BC Inanoglu K Turhanoglu S Asfuroglu Z Effects of dexmedetomidine and tramadol administered before induction of anesthesia on postoperative pain. (Anesteziinduksiyonu oncesiuygulanan tramadol veya deksmedetomidin'in postoperatif agri uzerine etkileri).Anestezi Dergis. 2008; 16: 183-187Google Scholar General anaesthesia was used in 11 trials,8Antila H Manner T Kuurila K Salantera S Kujala R Aantaa R Ketoprofen and tramadol for analgesia during early recovery after tonsillectomy in children.Paediatr Anaesth. 2006; 16: 548-553Crossref PubMed Scopus (32) Google Scholar spinal anaesthesia in two trials,7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 18Wilder-Smith CH Hill L Dyer RA Torr G Coetzee E Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination.Anesth Analg. 2003; 97: 526-533Crossref PubMed Scopus (78) Google Scholar and the type of anaesthesia was not reported in one trial.14Stratigopoulou P Vasileiou I Stefaniotou A Melissopoulou T Lampadariou A Tsinari K Comparison of morphine versus morphine plus bolus tramadol for postoperative analgesia in morbidly obese patients.Eur J Anaesthesiol. 2012; 29 (14AP8): 14AP2Crossref Google Scholar Most of the RCTs (n =12) investigated tramadol administered i.v.7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar One RCT explored oral administration7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar and one used i.m. administration.13Stiller CO Lundblad H Weidenhielm L et al.The addition of tramadol to morphine via patient-controlled analgesia does not lead to better post-operative pain relief after total knee arthroplasty.Acta Anaesthesiol Scand. 2007; 51: 322-330Crossref PubMed Scopus (27) Google Scholar In most studies, the comparison was with placebo (n =13).7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 8Antila H Manner T Kuurila K Salantera S Kujala R Aantaa R Ketoprofen and tramadol for analgesia during early recovery after tonsillectomy in children.Paediatr Anaesth. 2006; 16: 548-553Crossref PubMed Scopus (32) Google Scholar, 9But AK Erdil F Yucel A Gedik E Durmus M Ersoy MO The effects of single-dose tramadol on post-operative pain and morphine requirements after coronary artery bypass surgery.Acta Anaesthesiol Scand. 2007; 51: 601-606Crossref PubMed Scopus (19) Google Scholar, 10Kocabas S Karaman S Uysallar E Firat V The use of tramadol and morphine for pain relief after abdominal hysterectomy.Clin Exp Obstet Gynecol. 2005; 32: 45-48PubMed Google Scholar, 11Ozbakis Akkurt BC Inanoglu K Turhanoglu S Asfuroglu Z Effects of dexmedetomidine and tramadol administered before induction of anesthesia on postoperative pain. (Anesteziinduksiyonu oncesiuygulanan tramadol veya deksmedetomidin'in postoperatif agri uzerine etkileri).Anestezi Dergis. 2008; 16: 183-187Google Scholar, 12Spacek A Goraj E Neiger FX Jarosz J Kress HG Superior postoperative analgesic efficacy of a continuous infusion of tramadol and dipyrone (metamizol) versus tramadol alone.Acute Pain. 2003; 5: 3-9Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 13Stiller CO Lundblad H Weidenhielm L et al.The addition of tramadol to morphine via patient-controlled analgesia does not lead to better post-operative pain relief after total knee arthroplasty.Acta Anaesthesiol Scand. 2007; 51: 322-330Crossref PubMed Scopus (27) Google Scholar, 14Stratigopoulou P Vasileiou I Stefaniotou A Melissopoulou T Lampadariou A Tsinari K Comparison of morphine versus morphine plus bolus tramadol for postoperative analgesia in morbidly obese patients.Eur J Anaesthesiol. 2012; 29 (14AP8): 14AP2Crossref Google Scholar, 15Thienthong S Taesiri W Utsahapanich S Krisanaprakornkit W Thaninsurat N Klaichanad C Two doses of oral sustained-release tramadol do not reduce pain or morphine consumption after modified radical mastectomy: a randomized, double-blind, placebo-controlled trial.J Med Assoc Thai. 2004; 87: 24-32PubMed Google Scholar, 16Unlugenc H Ozalevli M Gunes Y Guler T Isik G Pre-emptive analgesic efficacy of tramadol compared with morphine after major abdominal surgery.Br J Anaesth. 2003; 91: 209-213Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 17Webb AR Leong S Myles PS Burn SJ The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial.Anesth Analg. 2002; 95: 1713-1718Crossref PubMed Scopus (54) Google Scholar, 18Wilder-Smith CH Hill L Dyer RA Torr G Coetzee E Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination.Anesth Analg. 2003; 97: 526-533Crossref PubMed Scopus (78) Google Scholar In one trial, the control was a histamine receptor subtype 2 antagonist.29Elhakim M Abd El-Megid W Metry A El-hennawy A El-Queseny K Analgesic and antacid properties of i.m. tramadol given before Caesarean section under general anaesthesia.Br J Anaesth. 2005; 95: 811-815Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar One trial compared two doses of tramadol.7Stubhaug A Grimstad J Breivik H Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.Pain. 1995; 62: 111-118Abstract Full Text PDF PubMed Scopus (100) Google Scholar Tramadol were given before (n =6)8Antila H Manner T Kuurila K Salantera S Kujala R Aantaa R Ketoprofen and tramadol for analgesia during early recovery after tonsillectomy in children.Paediatr Anaesth. 2006; 16: 548-553Crossref PubMed Scopus (32) Google Scholar, 11Ozbakis Akkurt BC Inanoglu K Turhanoglu S Asfuroglu Z Effects of dexmedetomidine and tramadol administered before induction of anesthesia on postoperative pain. (Anesteziinduksiyonu oncesiuygulanan tramadol veya deksmedetomidin'in po
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