Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The Effectiveness of Tramadol in Acute Pain Management Reviewers Principal Investigators: Melissa Fields, Sonya Murray Research Information Specialist: Mai Dwairy: Date first draft completed 08/06/2005. Important Note: • The purpose of this evidence-based review is to summarise information on the effectiveness of the analgesic tramadol and to provide best practice advice in acute pain management. • It is not intended to replace clinical judgement, or be used as a clinical protocol. • A reasonable attempt has been made to find and review papers relevant to the focus of this report; however it does not claim to be exhaustive. • This document has been prepared by staff of the Evidence Based Healthcare Advisory Group, ACC. The content does not necessarily represent the official view of ACC or represent ACC policy. • This report is based upon information supplied up to July 2005. Accident Compensation Corporation Page 1 Table of Contents Executive Summary.............................................................................................................. 4 Background....................................................................................................................... 4 Objectives ......................................................................................................................... 4 Search Strategy.................................................................................................................. 4 Selection Criteria .............................................................................................................. 4 Data Collection and Analysis............................................................................................ 4 Main Results ..................................................................................................................... 5 Reviewer’s Conclusions .................................................................................................... 6 Background........................................................................................................................... 7 Objectives ......................................................................................................................... 7 Methodology......................................................................................................................... 7 Types of Studies................................................................................................................ 8 Types of Participants ........................................................................................................ 8 Types of Interventions ...................................................................................................... 8 Types of Outcome Measures............................................................................................. 8 Criteria for Selecting Studies for Review .......................................................................... 8 Search Strategy.................................................................................................................. 7 Review Methodology ...................................................................................................... 10 Description of Studies..................................................................................................... 10 Results ................................................................................................................................ 11 1. Effectiveness ............................................................................................................... 11 2. Safety and Harm.......................................................................................................... 15 Adverse Events............................................................................................................ 15 3. Cost-effectiveness ....................................................................................................... 15 Discussion .......................................................................................................................... 15 Methodological Quality .............................................................................................. 16 Conditions under Investigation .................................................................................. 17 Tramadol versus Placebo ............................................................................................ 17 Adverse Events............................................................................................................ 18 Current Guidelines ..................................................................................................... 19 Prescribing Decisions by the General Practictioner………………………………… 19 Contraindications ....................................................................................................... 21 Cost-effectiveness ........................................................................................................... 22 Limitations of this Review .............................................................................................. 22 Conclusions ........................................................................................................................ 23 Implications for Practice ............................................................................................. 23 Implications for Research ........................................................................................... 23 Implications for Purchasing and Policy Decisions...................................................... 24 Acknowledgements............................................................................................................. 25 APPENDIX 1: Tramadol versus Placebo......................................................................... 27 Table 1: Tramadol versus Placebo .................................................................................. 27 APPENDIX 2: Tramadol versus Paracetamol.................................................................. 30 Table 2: Tramadol versus Paracetamol ........................................................................... 30 APPENDIX 3: Tramadol versus Opioid Analgesics ........................................................ 32 Table 3: Tramadol +/- Paracetamol versus Codeine +/- Paracetamol.............................. 32 Table 4: Tramadol versus Morphine............................................................................... 35 Accident Compensation Corporation Page 2 Table 5: Tramadol versus Meperidine (= Pethidine) ...................................................... 46 Table 6: Tramadol versus Oxycodone ............................................................................ 48 Table 7: Tramadol versus Other Opioid ......................................................................... 50 APPENDIX 4: Tramadol versus NSAIDs ........................................................................ 53 Table 8: Tramadol versus Bromfenac.............................................................................. 53 Table 9: Tramadol versus Diclofenac.............................................................................. 55 Table 10: Tramadol versus Lornoxicam ......................................................................... 57 Table 11: Tramadol versus Ketorolac ............................................................................. 59 Table 12: Tramadol versus Dipyrone.............................................................................. 61 Table 13: Tramadol versus Other NSAID ....................................................................... 63 APPENDIX 5: Tramadol versus Other............................................................................ 65 Table 14: Tramadol versus Bupivacaine ......................................................................... 65 Table 15: Tramadol versus Other ................................................................................... 68 APPENDIX 6: Meta-analyses and systematic reviews..................................................... 73 Table 16: Meta-analyses and systematic reviews ............................................................ 73 APPENDIX 7: Characteristics of Papers Excluded from the Analysis of Clinical Effectiveness of Tramadol............................................................................................... 78 APPENDIX 8: Scottish Intercollegiate Guidelines Network revised grading system ......... 81 APPENDIX 9: NZ Centre for Adverse Reactions Monitoring ............................................ 82 APPENDIX 10: Search Strategy .......................................................................................... 85 APPENDIX 11:Characteristcs of Studies included………………………………………… 87 References........................................................................................................................... 88 Accident Compensation Corporation Page 3 Executive Summary Background Tramadol Hydrochloride (Generic name; Tramadol, brand name; “Ultram®”Tramal® and Zytram®) is commonly used in pain relief, particularly when other pain relief strategies have been tried and failed. Tramal® and Zytram® are used in New Zealand. Tramadol is a centrally acting opioid-like drug, and acts by binding to the µ opiate receptors, where it is a pure agonist like morphine. Its second mechanism of action is to weakly increae both serotonin and noradrenaline spinal cord concentrations by re-uptake inhibition2. ACC currently does not have purchasing criteria to guide the purchasing of Tramadol in the community. Objectives The purpose of this review is to examine the evidence in order to determine the clinical and cost effectiveness of tramadol in the management of acute pain, so that ACC can develop purchasing guidance criteria. Search Strategy A number of medical databases were searched using the key terms “tramadol”, “pain” and “cost-effectiveness.” Evidence based medicine sites were also searched and District Health Board (DHB) guidelines were also referenced in this review. Selection Criteria Randomised controlled trials, systematic reviews or meta-analyses which examine the effectiveness of tramadol in acute pain management were included. Any studies which examined the cost-effectiveness of tramadol were also included. Exclusion criteria: Children < 18 years, cancer pain, labour pain, pain lasting ≥3 months, papers written in a language other than English. Papers were excluded if they assessed post-operative shivering, use of tramadol as a local anaesthetic and the use of tramadol solely as pre-operative analgesia. Papers were also excluded if they were only available as an abstract, including conference proceedings. Data Collection and Analysis Databases were searched and titles skimmed to determine the relevance of papers to the subject under review. Details of potentially relevant papers were downloaded into Endnote, abstracts read and the papers were retrieved if the abstracts were relevant to the topic under review. Once papers had been retrieved they were skimmed to determine whether or not they met the inclusion criteria, and if so, they were critically appraised using the SIGN criteria 1 (see Appendix 8). Accident Compensation Corporation Page 4 Main Results There were 62 studies looking at the effectiveness of tramadol (+/- paracetamol) in acute pain management that fit the criteria for inclusion in this study. Of these, there were six studies which were appraised as 1++, 28 as 1+, and 28 studies were assigned 1- using the SIGN appraisal system (Appendix 8). The shortest trial was one hour, whereas the longest study trial was seven days. Fifty four trials were carried out in a hospital, four were dental trials, one was set in a university (most likely a university hospital) and one was set in a “research institute.” Two trials did not specify where they were set. Fifty nine trials did not mention follow up medication after the study, whereas, three trials did. In one trail [16] tramadol was not prescribed after the trial due to side effects being worse with tramadol compared with codeine. In the trial by Dejonckheere et al; [12] which compared tramadol and paracetamol, morphine was used to treat residual pain after the trial period and in the trial by Thienthong et al; [10] which compared tramadol to placebo, morphine was used if tramadol was not successful. The main findings of this review were: 1) Tramadol appears to be more effective than placebo. 2) There appears to be no significant difference between the effectiveness of tramadol (+/paracetamol) vs codeine (+/- Paracetamol). 3) Of the 16 trials comparing tramadol to morphine, at least five trials showed morphine to be superior to tramadol in some aspect of improvement in analgesia. In no trial presented in this review was tramadol superior to morphine, suggesting that morphine is superior is some respects, but it cannot be claimed that they are equal. More vomiting and nausea was presented with tramadol compared to morphine, however, morphine was shown to confer greater respiratory depression. 4) There is no evidence to suggest that tramadol is more or less effective than pethidine or oxycodone for relieving acute pain. The incidence of adverse reactions was higher for tramadol compared to oxycodone. 5) The NSAIDs, bromfenan and lornoxicam proved to be more effective than tramadol in two randomised controlled trials. However, more evidence is required to support these findings. There also, was not enough evidence to show that diclofenac, ketoraloc, dipyrone and other NSAIDs were more or less effective than tramadol. However, tramadol does not have the potentially hazardous risk of gastric bleeding that affects NSAIDs. 6) There was no significant difference in effectiveness and side effects between using bupivacaine and tramadol. 7) Meta analysis studies showed that pain relief provided by tramadol/paracetamol (APAP) was superior and more effective than the administration of tramadol and paracetamol alone. Accident Compensation Corporation Page 5 8) Tramadol is not associated with clinically relevant respiratory depression or drowsiness unlike morphine, pethidine, or oxycodone. Compared to other opioids, tramadol has a lower incidence of constipation. There is also reduced risk of long term addiction with tramadol compared to the opiates. 9) Tramadol has serotonergic adverse effects such as diarrhoea, sweating, fever or confusion. You are at a greater risk of developing serotonin syndrome by using tramadol. 10) Post abdominal pain was mainly treated with tramadol intravenously, whereas pain releif for post dental pain was administered more via the oral route. Both modes of administration are equally effective. Reviewer’s Conclusions The available studies show that tramadol appaears to be as effective as codeine but less effective than morphine. Tramadol is not associated with respiratory depression and the risk of long term addiction is reduced compared to opiates. Compared to other opioids, tramadol has a lower incidence of constipation. Common side effects include nausea, vomiting, drowsiness dizziness, headache and dry mouth. Prescribing tramadol depends on the status of the individual; it is usually prescribed if it is equally effective to an alternative medication, but safer for the patient. (Second best line of treatment). DHB’s have specific criteria for prescribing Tramadol. Accident Compensation Corporation Page 6 Background Oral tramadol is a commonly used pain relief drug (analgesic) and although tramadol has been available in Germany since the late 1970’s, it has only been on the New Zealand market since 1997. Tramadol is a centrally acting opioid-like drug, and acts by binding to the µ opiate receptors and inhibits adrenaline and serotonin re-uptake. 2 Once ingested, oral tramadol is rapidly absorbed and is metabolised in the liver via cytochromes P450 (CYP) 2D6 and 3A to several metabolites.2 CYP2D6 produces the only active metabolite M1, which has a higher affinity than tramadol for mu opioid receptors and contributes significantly to the analgesic action. Pain relief begins within one hour and starts to peak within two hours. Thirty percent of Tramadol and its metabolites are excreted unchanged primarily in the urine, and have half lives of approximately 7 hours in healthy adults.2 Tramadol is indicated for the relief of moderate to severe pain in adults at a recommended dosage of 50-100mg every four to six hours,3 the maximum recommended daily dose is 400mg Its adverse event profile is typical of other opioids. Common adverse events are nausea, vomiting, headache, drowsiness, dizziness, somnolence, dry mouth and constipation. Tramadol has been favoured over true opioids due to a belief that it is less addictive and because of its relatively good adverse event profile. It is also devoid of many of the classic effects of opioid agonists being less likely to cause respiratory depression36 euphoria, constipation180 or tolerance181. The aim of this review is to provide ACC with an analysis of the clinical and costeffectiveness of oral tramadol as an analgesic for acute pain management. ACC would like to know why tramadol is prescribed in the acute setting in the first place as this may explain why people conitinue on this medication for chronic pain. ACC currently funds tramadol for chronic use if it is prescribed. Also, with the increasing costs associated with tramadol use, combined with the increasing use of tramadol for long term management, ACC would like to know the criteria behind prescribing and how tramadol compares with other analgesics. Objectives To review the clinical evidence to determine: 1) Whether oral tramadol is effective and safe in the management of acute pain. 2) Whether tramadol is cost-effective in the acute setting. 3) The reasons why tramadol was prescribed in the acute setting. Accident Compensation Corporation Page 7 Methodology Types of Studies Randomised controlled trials, systematic reviews, meta-analyses and guidelines. Types of Participants Human adults (18 years or older) with acute non-cancer, non-labour pain. Types of Interventions Any form (oral, IV or IM) of tramadol, either alone or in combination with paracetamol (acetaminophen). Types of Outcome Measures Pain relief, reduced pain intensity, measures of physical and social functioning, and patient or investigator assessment. Criteria for Selecting Studies for Review Randomised controlled trials, systematic reviews or meta-analyses which examine the effectiveness of tramadol in acute pain management were included. Any studies which examined the cost-effectiveness of tramadol were also included. Exclusion criteria: Children < 18 years, cancer pain, labour pain, pain lasting ≥3 months, papers written in a language other than English. Papers were excluded if they assessed the use of tramadol as a local anaesthetic and the use of tramadol solely as pre-operative analgesia. Papers were also excluded if they were only available as an abstract, including conference proceedings. Literature Search Strategy A search strategy was devised and undertaken in the end of Aug 2004 and run again in July 2005 utilizing the following medical databases: • Ovid MEDLINE 1966- 27 Aug 2004 • Ovid MEDLINE daily update Aug 2004 • CINAHL 1982-Aug 2004 • EMBASE 1988- 1 Sep 2004 • All EBM Reviews - Cochrane DSR, ACP Journal Club, DARE, and CCTR Aug 2004 • PsycInfo Aug 2004 Key words and terms used were: Results were limited to “human” and had to have been written in English language. The search strategy was devised that included the following key terms “analgesics; acute pain; tramadol; tramal; ultracet”. A filter was applied to limit the search to randomised Accident Compensation Corporation Page 8 controlled trials, clinical trials and meta-analyses. Hand searching of reference lists of articles already obtained was also undertaken, including the reference lists of the excluded articles. *Detailed literature searches are reported in Appendix number 10. A further search was undertaken to investigate cost effectiveness of tramadol. The same databases listed above were searched using the terms: “tramadol” or “tramal”, “Costbenefit analysis” or “costs and cost analysis” or “economic$ or cost$ or pric$. For these searches, the results were not restricted to randomised controlled trials, clinical trials or meta-analyses, but were limited to human subjects and English language. A further search was undertaken by using the following EBM websites. Evidence Based Medicine websites searched: • • • • • • • • • • • • • • • • • The Oxford Pain site www.jr2.ox.ac.uk/bandolier/ Centre for Reviews and Dissemination www.york.ac.uk/inst/crd/welcome.htm The National Institute for Clinical Excellence www.nice.org.uk National Guideline Clearing House www.guideline.gov/resources/discussion_list.aspx New Zealand Guidelines Group www.nzgg.org.nz New Zealand Health Technology Assessment Clearing House http://nzhta.chmeds.ac.nz/ eGuidelines www.eguidelines.co.uk/ Guidelines International Network www.g-i-n.net/ Scottish Intercollegiate Guidelines Network www.sign.ac.uk/ Evidence – Based Clinical Practice Guideline. The Alberta Medical Association http://www.albertadoctors.org/ American Academy of Orthopedic Surgeons http://www4.aaos.org/aaossearch/bulletin_search.htm A very small database of high quality guidelines across a range of topics http://www.ihs.ox.ac.uk/library/Libraryprimarycare.htm BMJ Publishing Group “ Clinical Evidence” http://www.clinicalevidence.com/ceweb/conditions/index.jsp NeLH Guidelines Finder - database with details of UK national guidelines http://rms.nelh.nhs.uk/guidelinesfinder/ http://omni.ac.uk/ Healthfinder http://www.healthfinder.gov/ Health Services Management Centre Library Catalogue http://www.hsmc.bham.ac.uk/ National Guideline Clearinghouse (U.S.). http://www.guideline.gov/ Accident Compensation Corporation Page 9 Review Methodology All studies that applied to the above criteria were obtained and appraised by the principal investigator using the Scottish Intercollegiate Guidelines Network (SIGN) grading system1 (see Appendix 8) to determine the levels of evidence. The type of study and study quality were determined by reviewing the methodology of each study. Each of the following aspects of each study were analysed: condition for which tramadol was being investigated, inclusion and exclusion criteria for participants, sample size, blinding, randomisation, withdrawal rates, amount of follow-up, outcome measurements, and potential bias in the study. Evidence tables were created which summarised this information as well as the outcomes and level of evidence. Any relevant guidelines or parts of guidelines relevant to the objectives were summarised in text. Description of Studies Sixty-two studies were found to fit the criteria required for this study. However, 112 were excluded for reasons outlined in Appendix 7. Of the 62 studies, 28 compared tramadol effectiveness to opioid analgesics including, morphine, pethidine, oxycodone and other opioids. Twelve studies compared the effectiveness of tramadol to NSAIDs, including diclofenac, lornoxicam, ketorolac, dipyrone and other NSAIDS. Two studies compared paracetamol and tramadol. Eleven “other drugs” were also evaluated compared to tramadol. Four studies were compared directly against placebo and five systematic Meta analysis studies were included in the analysis. Six studies were appraised as 1++, 28 were as 1+ and 28 studies were assigned 1-. Most studies were post operative, that is, tramadol was prescribed in the hospital setting after an operation. The exception was two stmulated pain studies, three colic studies and one right lower quadrant pain indicative of appendicitis. Study periods ranged from one hour to 7 days. Accident Compensation Corporation Page 10 Results 1. Effectiveness Tramadol versus Placebo (See Table 1). Four level one studies compared the effectiveness of tramadol to placebo in acute pain management. Three out of the four studies reported tramadol to be significantly better at relieving pain compared to placebo. Outcome measures varied between studies and included pain visual analogue (PVA) scores, time to discontinuation due to insufficient pain relief, total pain relief measure (PAR) and sum of pain intensity differences (PID). One study showed a 25% reduction in pain compared to placebo when administered 1mg/kg of tramadol. One level 1++ study showed total pain relief for tramadol and tramadol + APAP (Paracetamol) to be superior to placebo (p<0.001) [8]. In another study it was reported that the mean time to first additional analgesic administration was longer in patients who received tramadol 100mg (4.5±3.1 hr) and 200mg (6.6±3.4hr) than those who received placebo (2.8±2hr) (p<0.05 vs control) [9]. One exception to the placebo effect was a study where oral tramadol (100mg) was administered as a slow release formula given 1 hour prior to surgery to 50 women undergoing radical mastectomy and a repeat dose was given 12 hours later. It was discovered that at this dosage, tramadol failed to produce adequate analgesia for this type of situation. A placebo effect was reported in most studies. Tramadol versus Paracetamol (See Table 2). Two studies compared the effectiveness of tramadol and paracetamol. The first study demonstrated that the decrease in pain scores was significantly higher following the administration of tramadol (1.5mg/kg) than propacetamol (an injectable prodrug of paracetamol) p=0.03)[12]. The second study showed that supplementary analgesics were required by 23% of those taking oral tramadol 100mg every 6 hours versus 42% of those taking paracetamol (1g every 6 hours). [13]. Tramadol (prescribed with or without Paracetamol) versus Codeine (prescribed with or without Paracetamol (See Table 3). Four level one studies compared the effectiveness of tramadol in combination with and without paracetamol versus codeine prescribed in combination with or without paracetamol. All four involved a codeine plus paracetamol combination drug and failed to find any statistically significant differences between tramadol and the codeine plus paracetamol combination in terms of pain relief [14-17]. Accident Compensation Corporation Page 11 Tramadol versus Morphine (See Table 4). Of the 16 studies that examined the difference in analgesic effect between morphine and tramadol, eight of the trials were considered to have small sample sizes that ranged from 12 patients to 44 patients. At least five trials showed morphine to be superior to tramadol in some aspect of improvement in analgesia and in no trial presented in this review was tramadol shown to be superior to morphine. This suggests that morphine is superior in some respects, but it cannot be claimed (with the evidence presented) that they are equally effective in pain relief. Five of the trials showed vomiting and nausea to be more prevalent when using tramadol. Morphine showed greater respiratory depression than tramadol. The studies that should be highlighted are those which use doeses in current clinical use. In most cases, this equates to the use of tramadol at 1mg/kg to a maximum of 400mg daily, or morphine at 0.1mg/kg to a maximum of 40mg daily. These studies are described below: The study by Houmes et al (1992) compared analgesic efficiency between IV doses of 50mg tramadol or 5mg morphine involving a trial of 150 patients. Morphine displayed significantly better pain intensity scores in the first two hours after analgesia than tramadol. Adverse events were reported in 32% of the tramadol group and 44% of the morphine group. Another study by Unlugenc et al (2003) showed a more effective analgesic effect for Morphine (IV 0.1mg/kg) in the first 24 hours compared to the intervention group (IV Tramadol at 1mg/kg) (n=90) and with more or less equal but minimial and insignificant adverse short term effects. Vickers et al (1995) trialed 523 patients with either 100mg of tramadol or 5mg of morphine. The responder rates reported were 72.6% for tramadol and 81.2% for morphine. The mean time to analgesia was 17 minutes for tramadol and 19 minutes for the morphine group. There was no significant difference between adverse effects, which mainly consisted of mild nausea, dry mouth, vomiting, dyspepsia and hiccups. The trial by Gong et al (2003) involved 59 patients scheduled for elective hysterectomy. Morphine (10mg IV) showed slightly more of an analgesic effect from tramadol (100mg IV) but also slightly more adverse effects. Tramadol versus Pethidine and Oxycodone (See Table 5 and Table 6). There is no evidence to suggest that tramadol is more or less effective than pethidine or oxycodone for relieving acute pain. However, the incidence of adverse reactions was higher for tramadol compared to oxycodone in the two studies analysed. In one trial, the incidence of vomiting was 4 fold higher in the tramadol group (p=0.27) [37] and the second trial reported the incidence of nausea being slightly greater in the tramadol group (44%) vs (28%) in the oxycodone group [38]. Accident Compensation Corporation Page 12 Tramadol combinations versus other opioids (Table 7). Oral tramadol versus oral hydrocodone was reported in two studies [39, 40]. One study reported oral hydrocodone/paracetamol combination (5mg/500mg) as being more effective at reducing pain intensity in comparison to 100mg of oral tramadol for patients treated with acute muscular pain [39]. A second study showed that a combination of 37.5mg tramadol and 325mg acetaminophen tablets, were statistically superior to placebo on pain relief scales (p≤0.024). However, the mean time to onset of pain relief took longer for the tramadol/paracetamol combination (34 mins) compared to 10mg hydrocodone bitartrate combined with 650mg paracetamol (23.4 mins). Tramadol versus NSAIDs (See Table 8, 9, 10, 11, 12, 13 and 14). The NSAIDs, bromfenac and lornoxicam proved to be more effective than tramadol in three randomised controlled trials. However, more evidence is required to support these findings. One level one study showed that pain relief was significantly higher with bromfenac at 25 and 50mg doses compared to tramadol at 100mg (p<0.05) [43]. Another study reported that 75% and 79% of those taking bromfenac 25mg and 50mg respectively, rated their treatment as good to excellent compared to 33% of the tramadol group [42]. One study reported that lornoxicam had greater analgesic efficacy than tramadol in patients with moderate baseline pain. Eighty two per cent of patients described lornoxicam treatment as good, very good or excellent compared to 49% of patients treated with tramadol [48]. There was insufficient evidence to show whether diclofenac, ketoraloc, dipyrone or flurbiprofen was more or less effective than tramadol. Four studies looked at the effectiveness of tramadol versus bupivacaine. All studies reported no significant difference between both treatments; both of which provided adequate analgesia [54-57]. Among the NSAIDs that are used in New Zealand, diclofenac (Voltaren) is widely regarded as the most efficacious, but its acceptance is limited by risk of gastric bleeding which can on occasions be life-threatening, and the risk is thought to be higher with diclofenac than other NSAIDs. When it is used for moderate to severe pain, average daily doses of 150200mg are usually recomended. The trial carried out by Pagliara et al (1997) involved 120 patients and compared Tramadol 100mg twice per day to Diclofenac 100mg twice per day. Even at these lower than recommend daily doses of tramadol, it was more effective than the full dose of diclofenac. Tramadol versus other analgesics (See Table 15). One study compared the effectiveness of tramadol for pain relief against neostigmine, tenoxicam and bupivacaine for 40 patients who underwent post operative pain who had undergone day case knee surgery. No significant difference was recorded among the study groups with regards to pain scores [58]. Another trial analysed the analgesic action of tramadol versus nisidin for patients undergoing abdominal surgery. The analgesic action of tramadol was shown to be more Accident Compensation Corporation Page 13 effective than that of nisidin after the first dose and during the three days of observation [60]. Dipyrone was reported to be significantly more effective than tramadol in reducing pain intensity in a trial by Stankov et al., 1994. One hundred and four patients suffering from severe or excruciating colic pain reported reduced pain intensity differences (PID) at 20, 30 and 50 minutes after drug administration [61]. A similar study was carried out by Schmeider et al (1993) who compared the effectiveness of tramadol versus metamizole and butylscopolamine for the treatment of severe colic pain. Metamizole was significantly more effective in reducing pain than tramadol and butyscopolamine [62]. However, higher analgesia was achieved by tramadol versus metamizole for another trial that involved 10 healthy volunteers who were subject to constant painful stimuli. No side effects were reported after taking differing doses of metamizole [64]. Meta analysis Studies (See Table 16). Meta analyses showed that pain relief provided by tramadol/APAP was superior and more effective than the administration of tramadol and APAP alone. Three level one trials compared pain relief by tramadol and APAP alone and in combination. Two of the trials looked at pain relief after dental procedures and concluded that pain relief provided by tramadol/APAP was superior to that of tramadol or APAP alone [65,67]. The third study looked at pain relief after dental, gynaecological or orthopaedic patients with moderate to severe pain and also reported more effective pain relief with a combination of tramadol and APAP [68]. Accident Compensation Corporation Page 14 2. Safety and Harm Adverse Events Of the 62 studies included in this review, 57 mention side effects. Of these 57 studies, three reported that no side effects were observed. Nausea and vomiting were the most common side effects when using tramadol. Twenty one studies reported nausea side effects only, 14 noted vomiting only and 22 reported nausea and vomiting as a common side effect of using tramadol. Less common side effects included headaches, dizziness, drowsiness, dysphagia and pruritis. In one study, more women experienced nausea and vomiting (48%) after the administration of tramadol (10mg IV every 2min) in comparison to morphine administration (1mg/IV every 2min). Each of the following adverse reactions was reported in only one case study after the administration of tramadol: itching, dry mouth, hiccups, dyspepsia, sedation, emesis, somnolence and sweating. Constipation was not reported in any study analysed. Tramadol should be used with caution if patients are currently on Selective Serotonin Reuptake Inhibitors (SSRI’s) and they are not recommended in general in conjunction with opioids (personal communication Martin Kennedy, Taranaki District Health Board). This is because SSRI’s increase the risk of seizures with tramadol and increase the risk of serotonin syndrome. When many of the papers described the incidence of patient withdrawal because of lack of efficacy or adverse events from tramadol, it was usually very small and no worse than drugs with which it was compared. 3. Cost-effectiveness One paper was found relating to the cost-effectiveness of tramadol. This paper examined 4 the cost of tramadol compared to morphine in post-operative pain. The main finding was that tramadol was much cheaper than morphine due to its legal status (it is not a controlled drug) and its low potential to cause constipation. The authors of this paper concluded that tramadol could be 19% cheaper than morphine, mainly due to savings in nurse time. The current purchase price of 400mg of tramadol (the recommended maximum daily dose) is NZ$3.191 for either immediate or slow release (excluding GST). This is much more expensive than 240mg codeine (recommended maximum daily dose) which is NZ$0.80ca (excluding GST). The purchase price of 1g of paracetamol (the recommended daily dose for adults) is $NZD 0.15ca (excluding GST). At present ACC makes around 1000 payments for tramadol per month, at an average cost of $96 per payment per month (including GST, mark ups and dispensing fees). This equates to an annual cost to ACC of around $1million [183]. 1 New Ethicals Catalogue May 2005 Accident Compensation Corporation Page 15 Discussion This report is an evidence based review of the effectiveness of oral tramadol in acute pain management. It includes an extensive literature review of this topic and reports on Level 1 evidence to examine the effectiveness of tramadol in comparison to placebo, paracetamol, opioid analgesics, NSAIDS and bupivacaine. Tramadol was investigated because it is known to be associated with less adverse effects such as respiratory depression which is commonly caused by morphine and other analgesics. In post-surgical procedures such as thoracestomy it is important to avoid respiratory depression when surgery has already hindered breathing. Therefore there have been many trials comparing analgesics to tramadol. Another reason why these trials are conducted is that it maybe more cost effective to use tramadol compared to morphine in the acute setting. Bandolier (2005) assessed a series of systemataic reviews and found that tramadol is an effective analgesic in post operative pain. A single 100mg oral dose of tramadol is equivalent to 1000mg of paracetamol. Bandolier state that the “NNT” (Number Needed to Treat which is the numer of patients who need to be treated to prevent one bad outcome) is 4.6 for at least 50% pain releif over 4-6 hours in patients with moderate to severe pain compared with placebo. NNTs were generally lower in post surgical pain than in dental extractionmodels. (www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/AP003.html) Bandolier (2005) also claim that at doses of 50 and 100mg incidence of adverse effects (headache, nausea, vomiting, dizziness, somnolence) was similar to comparator drugs. In dental trials there was increased incidence of vomiting, nausea, dizziness, and somnolence. (www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/AP003.html). Methodological Quality Of the 62 studies relating to the effectiveness of tramadol which were analysed for this review, six studies were appraised as 1++, 28 were as 1+ and 28 studies were assigned 1(see Appendix 8). These levels of incidence took into account aspects of the methodological quality such as study design, sample size, inclusion criteria etc. The fact that all the studies were Level 1 indicates the high quality of studies undertaken in this area. Accident Compensation Corporation Page 16 Conditions under Investigation The conditions under investigation varied widely. In some situations the conditions were very specific such as dental extraction, gynaecological surgery, hip and knee replacement, retinal surgery, elective hysterectomy or radical mastectomy. In other situations the inclusion criteria was broader and included muscoskeletal pain or those with “moderate or severe pain after surgery.” The focus of this study is acute pain management; therefore the specific type of pain under investigation was not thought to be of importance as long as it met the criteria of acute pain management. The criteria for acute pain, was moderate to severe pain reported within three months but not greater than this time frame. Tramadol versus Placebo There is strong evidence to suggest that tramadol is more effective than placebo at relieving acute pain. The majority of studies analysed in this study reported a placebo effect. Tramadol consistently resulted in a significantly better outcome than placebo, regardless of the outcome measured. Tramadol versus Paracetamol. Two studies definitively reported tramadol as being more effective compared to paracetamol for relieving acute pain. Tramadol (prescribed with or without Paracetamol) versus Codeine (prescribed with or without Paracetamol) (See Table 3). There is insufficient evidence to show that tramadol prescribed with or without paracetamol is superior in acute pain relief compared to codeine in combination with or without paracetamol. Considering codeine is much cheaper than tramadol [2], codeine maybe a less expensive option for relieving acute pain given that it has the same analgesic effect as tramadol. No significant difference was detected between groups regarding adverse effects. Tramadol versus Morphine Of the 16 studies analysed, at least five trials showed morphine to be superior to tramadol in some aspect of improvement in analgesia and in no trial presented in this review was tramadol shown to be superior to morphine. This suggests that morphine is superior in some respects, but it cannot be claimed that they are equally effective in pain relief based on the trials presented. Five of the trials showed vomiting and nausea to be more prevalent when using tramadol. Morphine showed greater respiratory depression than tramadol. Accident Compensation Corporation Page 17 Tramadol versus Pethidine and Oxycodone The findings show no evidence to suggest that tramadol is more or less effective than pethidine or oxycodone for relieving acute pain. From the two oxycodone studies analysed, tramadol reported a higher incidence of adverse reactions in comparison to oxycodone. Tramadol versus NSAIDS The NSAIDs bromfenac and lornoxicam proved to be more effective compared to tramadol for the relief of acute pain in three randomised trials. More evidence is required to support the findings from these trials. The bromfenac studies all dealt with patients who had undergone oral surgery. One lornoxicam study involved patients who had undergone hysterectomy while the other study involved patients who had moderate to unbearable pain following arthroscopic reconstruction. Tramadol versus other analgesics As there was only one study found that compared tramadol to either, neostigmine, tenoixicam, bupivacine, nisidine, dipyrone, metamizole and butylscopalmine, there is insufficient evidence to show that tramadol is any better or worse at relieving acute pain than these drugs. Tramadol alone versus Tramadol± Paracetamol Meta analysis studies showed that pain relief provided by tramadol/APAP was superior and more effective than the administration of tramadol and APAP alone. Adverse Events In New Zealand, the Centre for Adverse Reactions Monitoring (CARM) is New Zealand's national monitoring centre for adverse reactions.5 It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. As of 31 December 2004, there had been 75 reports comprising 170 adverse reactions to tramadol in New Zealand (see Appendix 2). It is unknown how many doses of tramadol have been prescribed to date, so therefore not possible to calculate the rate of adverse events in New Zealand. A review article of the general tolerability of tramadol published in 1995 found that the primarily documented adverse events were nausea, dizziness, drowsiness, tiredness/fatigue, sweating, dry mouth and vomiting.6 The overall incidence of these was between 1% and 6%, although the rates reported in different studies varied greatly. For example, the incidence of nausea was found to vary between 2.3% in uncontrolled clinical trials to 21.4% in controlled studies. Accident Compensation Corporation Page 18 Current Guidelines Only one guideline was found that was relevant to this report [45]. This guideline advised caution when prescribing tramadol to patients at risk for seizures and /or who are also taking drugs that can precipitate seizures such as selective serotonin re-uptake inhibitor [SSRI] antidepressants, tricyclic antidepressants or to patients with a prior or active history of chemical dependency. These issues are consistent with the contraindications highlighted below. Three DHB’s reported their current guidelines for Tramadol use. In all cases the following guidelines were specified: • Tramadol was to be used if the patient was opioid dependent or where there is a clinical rationale as to why tramadol maybe a more suitable agent. For example, tramadol does not inflict respiratory depression unlike morphine. • Tramadol is not to be used in combination with SSRIs or any other drug contra indicated. It is not recommended that tramadol be taken in conjunction with other opioids. • Once tramadol was used to manage pain, the analgesic that replaced it was either paracetamol or codeine. However, this depends on the severity of the pain. • Tramadol is not licensed in New Zealand for paediatric use. Northland DHB supplied their tramadol IV Policy. Tramdol was not prescribed if the patient was younger than 12 years old, had pain intensity level of 7/10 or greater. The prescription of tramadol was discussed if the pulse and blood pressure was not in the normal range and if the respiratory rate was not over a level 8. Caution was also taken if the patient was over 65 years of age. Waikato District Healthboard’s tramadol policy is very similar to the other DHBs, claiming that they prescribe on a case by case basis, with prescribing monitored by the medical, nursing and clinical pharmacist teams. Prescribing decisions by the General Practictioner (GP). General practitioners make decisions about prescribing based on a number of factors. A recent BMJ article [182] claimed that while GPs vary in the degree to which any one factor determines what they prescribe, they usually make decisions about the choice of drugs based on: • perceived effectiveness (from literature they read from journals, best practice reviews and the pharmaceutical industry sources) • safety (both short-term and long-term safety or risks) • specialist endorsement ( by specialist working on local clinical settings such as Emergency Departments and Pain Clinics) Other more “patient focused” factors include: Accident Compensation Corporation Page 19 • convenience for patient‐ medications that are reliable by both parenteral (intra‐muscular or intra‐venous) and oral routes are preferred • cost (mainly cost to the patient). Gps make prescribing decisions which weigh up these various factors, and compares the result with that for a drug used for a comparable condition (Personal communication-Dr. Phil White). For example, • is the particular medication likely to be more or less effective than alternatives? • if it is perceived to be equally effective, but possibly safer (that is, less likelihood of distressing short-term side effects or fewer long-term risks), then it is likely to be viewed favourably) • if it is also recommended by colleagues (either directly, as in advice given at meetings, or indirectly, by specialist prescribing in other comparable situations), then it is likely to be “trialled” Decisions are also influenced by familiarity with the patient. Analgesics used for moderate to strong pain are usually opiates (such as morphine, pethidine, codeine or codeine variants), and have well accepted and significant limitations of • risk of addiction • distressing adverse short-term effects, such as dizziness or vomiting, or constipation • unpredictable efficacy when used in oral form GPs also consider both short-term risk (of both minor but also more serious adverse events), but also long-term risks, if this is known. Gps are aware of drug seekers often using acute or long-term pain to try and influence GPs to prescribe opiates. They have a strong aversion to prescribing drugs with significant addictive potential, including Codeine, and will welcome alternatives which are perceived to have fairly comparable efficacy without this potential. New Ethicals implies that tramadol does not produce addiction. The risk of CNS and respiratory depression is another significant consideration for prescribing by GPs, given that patients do not like feeling “drugged” unless there is a very good reasons, and many want to be able to continue driving or using machinery (Personal communication – Dr. Phil White). Opiates are known to have significant risks of these adverse effects. Patients are also generally reluctant to use opiates because of the perception of the risks of drowsiness and addiction, unless all other avenues have been exhausted. Accident Compensation Corporation Page 20 Contraindications The Medsafe Data Sheet7 for Tramal (brand name for tramadol hydrochloride) lists the following contraindications: • individuals with known hypersensitivity to tramadol or any of its excipients • individuals with acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs • patients who are receiving MAO inhibitors or who have taken them within the last 14 days. 7 The Data Sheet also offers the following warning and precautions: • The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions • Tramadol is not recommended in patients with severe renal impairment (creatinine clearance <10mL/min) • Tramadol is not recommended as a substitute in opioid dependent patients as it cannot suppress opioid withdrawal symptoms • In patients with a tendency to drug abuse or dependence, treatment with tramadol should only be carried out for short periods under strict medical supervision • The risk of seizure may be increased when doses of tramadol exceed the recommended upper daily dose limit • Tramadol may increase the seizure risk in patients taking other medication that lowers the seizure threshold. • Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances • When tramadol treatment of pain is required long-term, careful and regular monitoring should be carried out to establish whether and to what extent ongoing treatment is necessary • Tramadol should not be used during pregnancy • Tramadol is not recommended during breast-feeding Interactions with other drugs:7 • Use with CNS depressants - tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquillisers or sedative hypnotics • Drugs which reduce the seizure threshold – tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics and other seizure threshold lowering drugs to cause convulsions. • Use with other serotonergic agents – the presence of another drug that increases serotonin by any mechanism should alert the treating physician to the possibility of an interaction • Use with MAO inhibitors – tramadol should not be used in patients who are taking MAO inhibitors or who have taken them within the last 14 days, as tramadol inhibits the uptake of noradrenaline and serotonin Accident Compensation Corporation Page 21 Cost-effectiveness There appears to be insufficient evidence in the literature to determine whether tramadol is cost-effective compared to other pain relief drugs. The single study found for review has very little relevance to the objectives of this review. The use of nursing time as a cost is not transferable to the likely clinical situation considered by ACC which is likely to be in outpatients. Also, the legal status of the drugs used is not under consideration. Limitations of this Review This report excluded studies which were published in languages other than English. The authors acknowledge that this may exclude some valuable information relating to the clinical effectiveness of tramadol, especially as much of the early work undertaken on tramadol was done in Germany in the 1970’s. The omission of these studies was unavoidable; however, as the resources to translate the journal articles into English were not available to the authors of this report. This report also excluded conference proceedings and studies which have only been published in abstract form. Sufficient information may not be available from study abstracts to extract adequate methodological detail to be able to evaluate the level of evidence. Furthermore, all study findings may not be reported in the study abstract, nor may there be sufficient details of safety and harm. There were no studies which compared tramadol to codeine alone. This is viewed as a limitation as the addition of paracetamol may bias the results of the trial, and a conclusion cannot be reached as to the efficacy of codeine alone versus tramadol. The authors acknowledge that publication bias may exist, in that studies may not have been published which found a neutral outcome or an outcome that did not serve the purpose of the funding body. Furthermore, other studies may have been conducted that found a contradictory result which have not yet been published. It should be noted that many of the studies quoted compared tramadol with drugs that are either not available in New Zealand, are not available in general practice settings, or may not be recommended. These drugs include lornoxicam, ketorolac, dipyrone, flurbiprofen, bupivacaine, neostigmine, nisidin, bromfenac or metamizole. Pethidine is used less frequently in New Zealand general practice, because of a perception that its analgesic effect when used orally is unreliable, and that adverse reactions such as vomiting are too common (Personal communication- Dr. Phil White). The types of studies selected tended to focus on post operative pain, particularly dental pain or post surgical pain which may not be reflective of the target population for ACC funding tramadol. However, in the acute setting these types of studies were only available and the authors assume that the analgesic efficacy between different drugs may not be too dissimilar between clinical settings where there is a definable physical cause for the pain, for example, operative procedure versus acute trauma. Accident Compensation Corporation Page 22 Conclusions Implications for Practice Tramadol is a safe and effective analgesic for the management of acute pain, however, it has not been shown to be more or less effective than codeine (prescribed with or without paracetamol) and has not been shown to be more effective than morphine. This suggests the analgesic properties of tramadol are similar to that of codeine but less than morphine. Tramadol appears effective to use if the patient was opioid dependent or where there is a clinical rationale as to why tramadol maybe a more suitable agent compared with another analgesic, for example, the patient maybe more prone to constipation and constipation tends to feature more prominently with opioids other than tramadol. This current practice is already being practiced by three DHB’s. Tramadol has an adverse event profile which is similar to other analgesics and commonly includes nausea, vomiting, drowsiness, dizziness, headache and dry mouth. There was reasonable evidence to suggest that nausea and vomiting are greater with tramadol than morphine. Tramadol is not associated with clinically relevant respiratory depression unlike morphine, pethidine, or oxycodone. Implications for Research Research is required into the cost-effectiveness of tramadol. Only one study is available which provided limited information regarding the cost-effectiveness of tramadol. In order to prove cost effectiveness one would need to show either increased efficacy, better tolerability or another tangible benefit of using tramadol over a comparator drug. Cost data needs to include consultation fees and prescription charges that may be associated with managing pain associated with injuries. More in-depth studies which compare the efficacy of tramadol compared to NSAIDS would be useful to confirm the case studies analysed in this report. Also, a randomised controlled trial comparing tramadol to codeine alone would provide useful comparative information regarding effectiveness and side effects profiles. More research also needs to be carried out with patients who are poor metabolisers, that is, those where the effectiveness of codeine based analgesics and possibly other weak opioids is limited and tramadol is a good alternative. However, there has been little research regarding the efficacy of tramadol with this set of patients. Accident Compensation Corporation Page 23 Implications for Purchasing and Policy Decisions In terms of acute pain, tramadol (with or without paracetamol) appears to be no more effective than codeine plus paracetamol. Yet, tramadol is more expensive than codeine. Tramadol should only be prescribed if other analgesics cannot be prescribed and tramadol is the second best line of treatment. Three DHB’s have set criteria which describe tramadol prescription criteria which are: Tramadol should be used as a second line agent when: • An opioid dependent paitent needs stronger pain relief • NSAIDS are contraindicated • Patient has respiratory depression • Side effects need to be reduced such as constipation and in some cases, vomiting. Tramadol should not be used when: • In conjunction with SSRIs • Any drug contraindicated • Paediatric use • If pulse and blood pressure are not in the normal range • Respiratory rate is not over a Level 8. Depending on the severity of pain and situation, tramadol was usually replaced with paracetamol or codeine once tramadol was used to manage pain. Caution was also taken if the patient was over 65 years of age. In the post operative setting tramadol is funded by DHB’s. ACC funds outside of this setting if tramadol is prescribed. The majority of cases in this review are post-operative. Accident Compensation Corporation Page 24 Acknowledgements The authors would like to acknowledge the input by internal and external reviewers of this report. Internal: Sunita Goyle, Pharmaceutical Advisor. James Chal. Manager, Research and Information Services. External: Dr. Phil White- General Practitioner, Director, Healthcare New Zealand. Evan Begg and Jane Vella-Brincat, Department of Clinical Pharmacology, Canterbury District Health Board. Marty Kennedy – Clinical Pharmacist- Tairawhiti District Health- Taranaki Accident Compensation Corporation Page 25 Accident Compensation Corporation Tramadol in Acute Pain Page 26 APPENDIX 1: Tramadol versus Placebo Table 1: Tramadol versus Placebo Study Methods Participants Intervention Outcomes Comments and level of evidence Mahadevan, M and L Graff 20008 Double-blind randomised controlled trial. Intervention Group: Tramadol 1mg/kg Randomised using random numbers generated from random numbers tables. There was a significant reduction in mean VAS of 14.2mm (95% CI 5.6-22.8) in the Intervention Group and 6.5mm (95% CI 1.611.4) in the Control Group. This translated to a 25% reduction in pain in the intervention group and 13% reduction in the control group. Not stated whether the difference between groups was significant or not. Level 1- [Source of funding not stated] 66 patients with right lower quadrant (RLQ) pain for less than 1 week, suggestive of acute appendicitis. Mean age 28 years Age range 12-68 years 47% female Control Group: Placebo (normal saline made up to equal volume). 33 Intervention Group 33 Control Group Siddik-Sayyid et al 19999 Randomised controlled trial. [Source of funding not stated] Investigator blinded (?double-blinded) If VAS ≥ 2, or upon patients request, additional analgesics were provided. Patients were initially treated with a suppository of 100mg diclofenac. If no relief was observed within 30min, 1.0mg/kg mereidine im One patient was excluded from each group due to having an incomplete record or absconding before study completion. This would have brought the sample size up to the required 68. 60 full-term pregnant women undergoing elective caesarean section. ASA physical status I or II Intervention Group 1: 100mg tramadol made up to 10mL with 0.9% NaCl Intervention Group 2: 200mg tramadol made up to 10mL with 0.9% NaCl Mean age 32 years 20 Intervention Group 1 20 Intervention Group 2 20 Control Group Control Group: 10mL saline Exclusion criteria: • Obesity (weight >115kg) • Short stature (<152cm) Accident Compensation Corporation The reliability of the 30 minute findings were measured against 60 minute repeat findings which showed substantial agreement. Tramadol or saline administered at skin closure via the epidural catheter. D R A F T R E P O R T The mean time to first analgesic administration was longer in patients who received tramadol 100mg (4.5±3.1 hr) and 200mg (6.6±3.4 hr) than those who received placebo (2.8±2 hr) (p<0.05 vs control). The sample size did not reach the calculated power required (needed 68 patients for 80% power to detect a 10% difference). There were significantly more females in the intervention than control group (p=0.048). Level 1Small sample size. Not stated if patients were blinded or not. No difference was observed between patients receiving 100mg and 200mg tramadol concerning all parameters studied. The mean VAS values taken at 1, Page 27 was administered. • • • • Thienthong, S et al 200410 Double-blind randomised controlled trial. [Study funded by the Faculty of Medicine, Khan Kaen University. Tramadol provided by Sanofi-Synthelabo Company, Thailand] If analgesia was inadequate, IV morphine via PCA was administered as 1mg bolus with a 5 minute lockout time. The PCA was used continuously in the surgical ward for 24 hours. Fricke, J et al 200411 Double-blind randomised controlled trial. [Funded by OrthoMcNeil Pharmaceutical Inc.] Computer generated randomisation schedule used. All tablets appeared identical. Rescue analgesia was permitted, but patients 50 women undergoing modified radical mastectomy. ASA I or II. 25 Intervention Group 25 Control Group Mean age 47.2 years Age range 18-75 years Weight range 40-75kg Exclusion Criteria: • Inability to use PCA or VAS • Allergy to tramadol • Substance abuse 456 patients with moderate to severe pain within 5 hours after extraction of ≥2 third molars. Age range 18-49 years Mean age 21.8 years 89% white 64% female 69% reported moderate pain. Accident Compensation Corporation 2, 4, 8, 12 and 24 hr postoperatively was lower in the tramadol groups than in the control group (p<0.05). Diabetes Pregnancy induced hypertension or chronic hypertension Heart disease Multiple gestation Intervention Group: Oral tramadol 100mg (slow release formula) given 1 hour before surgery, and a repeat dose given 12 hours later. Control Group: Oral placebo tablet given 1 hour before surgery, and a repeat dose given 12 hours later. Intervention Group 1: Oral tramadol 100mg (2 x 50mg Tablets) Intervention Group 2: Oral tramadol 75mg + acetaminophen (APAP) 650mg (2 x 37.5/325mg Tablets) Control Group: Placebo (2 x oral Tablets) D R A F T R E P O R T Adverse side-effects such as respiratory depression, vomiting and pruritus were not observed. The proportion of patients with a VAS >30 at each measurement period were not significantly different between the groups, except for the mVAS at 24 hours where the proportion in the tramadol group were higher than placebo (48% vs 20%, p=0.04). Level 1+ 100mg tramadol not enough for severe pain. The median morphine consumption in both groups at 2, 4, 12 and 24 hours were comparable. No serious adverse events were observed, however patients in the tramadol group reported nausea and vomiting more than the placebo group (56% vs 24%, p=0.02). Tramadol + APAP was superior to tramadol (p<0.001) and placebo (p<0.001) on all efficacy measures: total pain relief (PAR) over 6 hours (7.4, 2.5 and 1.5 for tramadol + APAP, tramadol and placebo respectively on a scale of 0-24), sum of pain intensity differences (PIDs) (3.1, 0.6 and 0.1 respectively on a scale of –6 to 42). Median times to onset of meaningful PAR were 37.6 and Level 1++ Good sample size, blinding and randomisation. 97% of patients completed the study without a treatmentlimiting adverse event or premature use of Page 28 were encouraged to wait at least 1hr after taking the study medication and to wait until pain returned to baseline level before using rescue analgesia. 152 Intervention Group 1 152 Intervention Group 2 152 Control Group 126.5mins respectively for the tramadol + APAP group (p<0.001 for each compared to tramadol and placebo). Inclusion Criteria: • Score of 2 or 3 on a 4point Likert scale for pain intensity • Score of ≥50mm on 100mm VAS. rescue medication. Significantly more patients in the tramadol (82%) and placebo (89%) groups requested rescue analgesia prior to study completion, compared to patients in the tramadol + APAP group (50%, p<0.001). Exclusion Criteria: • Pregnancy or lactation • Serious medical condition • Contraindication to study medication • Previous tramadol or tramadol + APAP failure • Use of investigational drug or device in previous 30 days • NSAID use in previous 3 days • Analgesic use in previous 24 hours. 47% of patients rated tramadol + APAP as excellent, very good or good overall, compared to 17% in the tramadol group (p<0.001) and 5% in placebo group (p<0.001). The most common adverse events with active treatment were nausea, dizziness and vomiting. These events occurred more frequently in the tramadol group that in the tramadol + APAP group. Nausea was the only adverse event that reached statistical significance (33% tramadol + APAP vs 46% tramadol, p=0.019). Most adverse events were mild to moderate in severity. No serious adverse events were seen. Tramadol + APAP compared to placebo: NNT 3.8 (2.9-5.5) NNH (any events) 6.9 (3.9-29.1) Accident Compensation Corporation D R A F T R E P O R T Page 29 APPENDIX 2: Tramadol versus Paracetamol Table 2: Tramadol versus Paracetamol Study Methods Participants Intervention Outcomes Comments and level of evidence Dejonckheere, M et al 200112 Double-blind randomised controlled trial. Residual pain was treated with IV PCA morphine. Intervention Group: Tramadol 1.5mg per kg IV Mean age 45.5 years. 87.5% female. Control Group: Propacetamol (an injectable prodrug of paracetamol) 2g. After surgery, pain intensity significantly decreased over time in both treatment groups. Patient satisfaction was similar in both groups throughout the study. Level 1+ [Trial drugs supplied by Searle Continental Pharma Inc.] 80 patients post thyroidectomy. ASA class I, II or III. 40 Intervention Group 40 Control Group Groups were similar at the start of the trial. Exclusion criteria: • Patients on chronic opiates, clonidine or MAOI therapy • Abnormal liver function tests • Chronic alcohol abuse • Patients unable to understand the principle of PCA. Rawal, N et al 200113 [Source of funding not stated] Double-blind randomised controlled trial. Randomisation was achieved via random number tables. Rescue medication consisted of oral dextropropoxyphene Accident Compensation Corporation 109 ASA I and II patients scheduled to undergo ambulatory hand surgery with IV regional anaesthesia. Mean age 44.2 years 46.8% female 34 Group 1 The decrease in VAS pain scores was significantly higher following tramadol (p=0.03) than propacetamol. More patients complained of nausea and vomiting (p=0.01) during the first 2 hours following injection of tramadol, but no difference overall. Morphine consumption was comparable between both groups (p=0.71). VAS scores did not fall below 3 despite the use of supplemental morphine. Intervention Group 1: Oral tramadol 100mg every 6 hours. Intervention Group 2: Metamizol 1g every 6 hours. Control Group: Paracetamol 1g every 6 D R A F T R E P O R T Supplementary analgesics were required by 23% of intervention group 1, 31% of intervention group 2, and 42% of the control group. Not stated whether this was significant or not. The incidence of side effects was greatest with tramadol, especially post-operative nausea and Level 1The authors stated that “Tramadol was the most effective analgesic, as evidenced by low pain scores, least rescue medication, and fewest number of Page 30 100mg on demand. 37 Group 2 38 Group 3 hours. Exclusion criteria: • >70 years • Alcoholism • Drug dependence • Psychiatric disease • Pregnancy • Lactation • Severe allergic, hepatic, renal, cardiovascular or pulmonary disease. If the study drug was ineffective (VAS>3), a second dose could be taken after 1 hour. If second dose was inadequate, the patients were instructed to take rescue medication. vomiting. Seven patients (17.5%) withdrew from the study because of the severity of nausea and dizziness associated with the use of tramadol. 39% of Group 1 patients experienced nausea on day one compared to 13% in group 2 and 8% in the control group (p<0.05). 59% of patients in group 2 were satisfied with the study drug, compared to 47% in group 1 (p<0.05). About 40% of all patients experienced inadequate analgesia, and required rescue medication. Accident Compensation Corporation D R A F T R E P O R T patients with sleep disturbance.” Tramadol only produced significantly lower pain scores on day one and compared to paracetamol. The amount of rescue medication taken was not significantly different between groups. Sleep disturbance was not outlined in the Tables or text, other than in the abstract. Page 31 APPENDIX 3: Tramadol versus Opioid Analgesics Table 3: Tramadol +/- Paracetamol versus Codeine +/- Paracetamol Study Methods Participants Intervention Outcomes Comments and level of evidence Smith, AB et al 200414 Double-blind randomised controlled trial. 305 patients with moderate or severe post-surgical pain. Multicentre. 153 Orthopaedic patients 152 Abdominal patients Tramadol + APAP was superior to placebo for total pain relief, sum of pain intensity differences, and sum of pain relief and pain intensity differences (p≤0.015). Level 1++ [Funded by OrthoMcNeil Pharmaceutical, Raritan, New Jersey] Intervention Group: Tramadol 37.5mg + acetaminophen (APAP) 325mg 29.5% female Mean age 47.3 years Age range 18-79 years Control Group 2: Placebo 98 Intervention Group 109 Control Group 1 98 Control Group 2 Exclusion criteria: • Use of analgesic within 3 hours of study medication or concomitant use of sedatives (other than during surgery) • Administration of longacting nerve blocks or epidural anaesthesia • Use of tramadol within 30 days of the study • Inability to tolerate tramadol HCl or previously failed treatment with tramadol HCl • Contraindication to opioids or paracetamol Accident Compensation Corporation Control Group 1: Codeine 30mg + APAP 300mg Initially all patients were given 2 tablets of study medication, then 1-2 Tablets every 4-6 hours as needed for pain for 6 days. D R A F T R E P O R T Mean dose of tramadol + APAP was 4.4 Tablets. There were no significant differences between Tramadol + APAP and codeine + APAP (p≥0.281). Discontinuation due to adverse events occurred in 8.2% of tramadol + APAP, 10% of codeine + APAP, and 3% of placebo patients. Except for constipation (4.1% tramadol + APAP vs 10.1% codeine + APAP) and vomiting (9.2% tramadol + APAP vs 14.7% codeine + APAP) adverse events were similar for both active treatments. No p-values were noted for the adverse events. Page 32 • • Pluim, M et al 199915 Open randomised controlled trial. [Source of funding not stated] Morbid obesity History of abnormal hepatic and/or renal function • Chronic alcohol abuse or substance abuse, or unsTable medical disease • Indication of major psychiatric disorder or treatment with antipsychotic medication • Use of an investigational drug or device within 30 days of study entry. 38 patients undergoing elective surgery. Mean age 42.5 years Age range 20-74 years 60% female. Intervention Group: Rectal tramadol suppositories, 100mg 6 hourly qds. Control Group: Acetaminophen/codeine suppositories 1000/20mg qds. 19 Intervention Group 19 Control Group Inclusion Criteria: • ASA I or II • Patients not expected to require opiates postoperatively • Body weight 50-125kg There was no difference in pain scores between the two groups. The incidence of nausea and vomiting was significantly higher in the tramadol group (84%) than control group (31%). Level 1Small sample size. No blinding. The Relative Risk (RR) of experiencing an episode of nausea under treatment with tramadol was 2.7 (1.3-5.3, p<0.001) compared to APAP/codeine. Exclusion Criteria: • Known allergies to the study medication • Recent use of MAO inhibitors Accident Compensation Corporation D R A F T R E P O R T Page 33 • Jeffrey, HM et al 199916 Double-blind randomised controlled trial [Source of funding not stated] >75 years One patient was lost to follow up from each group. 65 patients who had undergone elective intracranial surgery. Mean age 52.4years Age range 48-56 years 60% female 22 Intervention Group 1 25 Intervention Group 2 18 Control Group Intervention Group 1: IM Tramadol 50mg Intervention Group 2: IM Tramadol 75mg Control Group: IM Codeine 60mg Exclusion Criteria: • Body weight <50kg or >100kg • Age <18 years Moore, P et al 199817 [Funded by R.W. Johnson Pharmaceutical Research Institute] Double-blind randomised controlled trial. 2-centre. 6 hour study. 197 healthy subjects with moderate or severe pain following surgical extraction of at least one third molar. Intervention Group 1: Tramadol 100mg 58% female Age range 18-68 years Control Group 1: Codeine 60mg 48 Intervention Group 1 49 Intervention Group 2 32 Control Group 1 41 Control Group 2 27 Control Group 3 Control Group 2: Aspirin 650mg + Codeine 60mg Exclusion Criteria: Accident Compensation Corporation Intervention Group 2: Tramadol 50mg Control Group 3: Placebo D R A F T R E P O R T Patients receiving codeine had significantly lower pain scores over the first 48 hours after surgery (p<0.0001) than either tramadol group. Although there was no difference in VAS scores between the 3 groups at 24 hours, the codeine group had significantly lower scores at 48 hours (p<0.0001). Intervention group 2 had significantly higher scores for both sedation and nausea & vomiting (p<0.0001). No significant differences in the number of analgesic injections required in recovery, or in pain, nausea & vomiting, and sedation scores between the 3 groups on discharge. Aspirin + Codeine were found to be statistically superior to placebo for all measures of efficacy. Tramadol 100mg was statistically superior to placebo for TOTPAR, SPID and time to remedication, whereas tramadol 50mg was statistically superior to placebo only for remedication time. Codeine was not found to be statistically superior to placebo for any efficacy measure. Level 1+ Level 1+ Gastrointestinal side effects (nausea, dysphagia, vomiting) were reported more frequently Page 34 • • • • • with tramadol 100mg, aspirin + codeine, and codeine 60mg than with placebo. History of significant diseases Pregnancy Patients with known hypersensitivity to tramadol, codeine, or other opiates, aspirin or NSAIDs. History of seizure disorder History of suspected abuse of narcotics or alcohol. Table 4: Tramadol versus Morphine Study Methods Participants Intervention Outcomes Comments and level of evidence Wiebalck, A et al 200018 Double-blind randomised controlled trial. 20 patients with extremely severe post-operative pain. VAS ≥ 8/10 during the first hour of recovery. Intervention Group: Intravenous tramadol 1mg per kg Both tramadol and morphine reduced pain intensity to VAS ≤ 1 within a median of 135 mins. Median dosages were 292.5mg for tramadol (160-461mg) and 27mg for morphine (2045.1mg). Tramadol patients experienced significantly fewer side effects. Level 1- [not drug company funded] Exclusion criteria: • Insufficient spontaneous respiration • Sedated patients who were unable to communicate • ASA class V patients • Pregnancy • Patients < 18 years • Patients with known drug or alcohol abuse • Patients being treated for chronic pain. Accident Compensation Corporation Control Group: Intravenous morphine 0.1mg per kg Drug given after standardised anaesthesia. Dosages were halved when pain intensity reached a VAS of 5. Drug administration was repeated every 30 mins until VAS ≤ 1. D R A F T R E P O R T Small sample size (as this was a pilot study). Minor side effects were observed in both groups at a similar incidence. Page 35 10 Tramadol 10 Morphine 15% female Mean age 44.3 years Bloch, MB et al 200219 Double-blind randomised controlled trial. [Tramadol was supplied by Grunenthal GmbH, Aachen, Germany] All patients received PCA morphine, and rescue morphine as necessary post-operatively. IV morphine boluses delivered 1.5mg increments with a lockout period of 8 mins. Vergnion, M et al 200120 Double-blind randomised controlled trial. [Source of funding not stated] To observe blinding of the emergency physician Accident Compensation Corporation Two morphine patients had to be excluded from the efficacy analysis – one for extreme sedation and the other because of severe respiratory depression. 89 patients with postthoracotomy pain. Mean age 45 years. 29 Intervention Group 30 Control Group 1 30 Control Group 2 Exclusion criteria: • Contraindications to the placement of an epidural catheter or to the use of any of the study medications. • Use of any analgesic during the 36 hours before surgery. 101 patients with posttraumatic musculoskeletal pain requiring rapid analgesia with opioids. Intervention Group: Continuous IV tramadol in 150mg bolus followed by infusion, total 450mg/24hr. Control Group 1: Epidural morphine 2mg then 0.2mg/hr Control Group 2: PCA morphine only. Intervention Group: 100mg Tramadol IV initially. A further 50mg could be added after 10 min if needed, and a D R A F T R E P O R T No significant differences in pain scores and PCA morphine used between tramadol and epidural morphine. Level 1+ Small sample size. Pain scores at rest and on coughing were lower in the intervention group and control group 1 than in control group 2 at various time points over the first 12 hours. The intervention group and control group 1 used significantly less hourly PCA morphine than control group 2 at specific time points in the first 10 hours. Few adverse events required treatment. One patient in the intervention group experienced pruritis and two in control group 1 reported nausea. Analgesia was similar in both groups. The 95% CI for the difference between the decrease in pain intensity observed with tramadol or morphine was –0.26 Level 1Mean age, age range and gender not mentioned. Page 36 administering the study medication, 50mL infusion sets with morphine or tramadol were prepared each day by the hospital pharmacy according to a computer-generated random assignment schedule. Houmes, R-J M et al 199221 Double-blind randomised controlled trial. [Tramadol supplied by Grunenthal GmbH, Stolberg, Germany] Drugs were administered by persons other than those responsible for data collection and clinical assessments. If analgesia was still inadequate after 3 doses, treatment failure was diagnosed, rescue medication was given (morphine 0.1mg/kg IM) and the last pain score recorded was used for the remaining observation times (up to 6 hours). Accident Compensation Corporation 53 Intervention Group 48 Control Group further 50mg thereafter, to a maximum of 200mg. Exclusion criteria: • Patients with severe head injury, multiple trauma, or a Glasgow Coma Scale Score <12. • Age <18 years • Weight >100kg • Alcohol intoxication • Recent history of drug abuse • Pregnancy • Known contraindications to tramadol or morphine. Control Group: 5mg Morphine IV (body weight ≤70kg) or 10mg Morphine IV (body weight >70kg). This could be increased to 15 or 20mg if necessary after 10 minutes. 150 female patients after gynaecological surgery (abdominal, vaginal or both) with moderate or severe pain. Intervention Group: 50mg IV tramadol x3 if needed Mean age 36 years Age range 20-58 years 100 Intervention Group 50 Control Group Exclusion criteria: • Pregnant • Lactating • Chronic drug use • Consumption of monoamine oxidase inhibitors • Allergic to opioids Control Group: 5mg IV morphine x3 if needed Minimum interval between first and second dose was 20 mins, and 30 mins between second and third doses. D R A F T to 0.30. Neither sedation scores or physiologic data differed between groups. 67% of patients in the intervention group and 76% of the control group were satisfied or very satisfied with the treatment (p=0.38). Nausea and vomiting were reported with similar frequency. Nine patients (17%) treated with tramadol and 7 patients treated with morphine (15%) experienced at least one episode of nausea. No serious side effects were reported. Both drugs produced acceptable analgesia, and there were no clinically significant adverse events. Morphine displayed significantly better pain intensity difference scores in the first two hours after analgesia than tramadol. Level 1+ In 13.3% of the morphine group and 0% of tramadol group, transcutaneous pulse oxygen saturation decreased to <86%. In 50% of these patients, the decrease occurred only after the first 5mg of morphine. Adverse events were reported in 32% of the tramadol group and 44% of the morphine group. Drowsiness was the only event R E P O R T Page 37 with a statistically significant difference between the 2 study groups. • Unlugenc, H et al 200322 Double-blind randomised controlled trial. [Source of funding not stated] Patients could use a PCA device giving bolus doses of morphine 0.025mg/kg with a lock out time of 20 minutes and no background infusion or maximal dose. Participation in other drug studies • History of seizure disorders. 90 ASA I or II grade patients undergoing elective major abdominal surgery with general anaesthetic. 54.4% female Mean age 47.7 years Age range 21-58 years Intervention Group: IV tramadol (1mg/kg) Control Group 1: IV morphine (0.1mg/kg) Control Group 2: Saline 2mL 30 in each group Exclusion criteria: • Inability to use PCA device • Long term use of opioid medications • History of chronic pain Post-operative pain after abdominal surgery was treated successfully in all 3 groups. Level 1+ There were no significant differences between groups in mean pain, discomfort and sedation at any study period. Cumulative morphine consumption was significantly lower in the morphine group at 12 and 24 hours after starting PCA than the saline group (p<0.017). In the tramadol group it was lower only after 24 hours (p<0.017). Compared with the saline group, patients given pre-emptive morphine consumed 28% less morphine and those given preemptive morphine consumed 17% less morphine in the first 24 hours (p<0.017). There were no significant differences in morphine consumption between tramadol and morphine groups. 10 patients (3 in tramadol group, 3 in morphine group and 4 in saline group, no significant difference) complained of pain during the first 2 hours despite the PCA therapy and these were Accident Compensation Corporation D R A F T R E P O R T Page 38 treated with IV single dose of meperidine (0.4mg/kg). Grace, D and JPH Fee 199423 Double-blind randomised controlled trial. [Funded by the Department of Health and Social Services for Northern Ireland] Computer-generated random numbers used for group allocation 12 ASA grade I and II patients aged 18-80 years, weighing 50-100kg admitted for elective knee replacement under extradural anaesthesia and light general anaesthesia. Mean age 67 years 50% female 3 Intervention Group 1 3 Intervention Group 2 6 Control Group Hopkins, D et al 199824 Double-blind randomised controlled trial. [Source of funding not stated] Study period was 72 hours after surgery. Accident Compensation Corporation Exclusion Criteria: • Women of childbearing age • Patients with hepatic or renal impairment • Patients taking monoamine oxidase inhibitors • Those in whom regional anaesthesia was contraindicated. 40 patients scheduled for elective major orthopaedic surgery. ASA I or II Intervention Group 1: Tramadol 50mg bolus injection followed by infusion (5mg/hr for 12 hours then 2.5mg for a further 12 hours). Intervention Group 2: Tramadol 100mg bolus injection followed by infusion (10mg/hr for 12 hours then 5mg for a further 12 hours). Control Group: Morphine sulphate 2mg by bolus injection followed by infusion (0.2mg/hr for 12 hours then 0.1mg for a further 12 hours). Intervention Group: Subcutaneous PCA tramadol Control Group: Subcutaneous PCA D R A F T R E P O R T 6 patients in tramadol group, 8 in morphine group and 6 in saline group experienced nausea (no significant difference between groups). VAS pain scores were markedly poorer (p<0.05) and PCA consumption was significantly greater (p<0.01) in the two tramadol groups when compared with the morphine group. There were no significant differences in pain scores between the tramadol groups. Although not statistically significant the time to first PCA analgesia demand was much shorter in patients who received tramadol. There were no statistically significant differences in the incidence of adverse events between the groups and VAS for nausea were similar in all treatment groups. Both drugs provided effective analgesia. The mean consumption in the first 24 hours was 792±90mg tramadol and 42±4mg morphine. Thereafter, consumption of both Level 1Very small sample size due to study discontinuation. A study of 60 patients was originally planned. The study was discontinued after recruitment of 12 patients, as analgesia was deemed inadequate in those receiving tramadol extradurally. Level 1Small sample size. More men received tramadol and more Page 39 Mean age 49 years 52.5% female. morphine drugs declined markedly. Graphically the consumption curves were very similar and virtually superimposable when a 20:1 conversion factor was applied. 20 Intervention Group 20 Control Group Exclusion Criteria: • Age outside 17-70 years • Morbid obesity • Hypotension or uncontrolled hypertension • Bradycardia, arrhythmia, short block and other conduction disturbances. • Significant lung pathology • Renal and liver dysfunction • Substance abuse disorders • Known sensitivity to morphine or tramadol • Inability to operate the PCA device. Tramadol appeared to cause more nausea and vomiting than morphine. In the tramadol group, 65% of patients complained of at least one episode of post-operative nausea and vomiting compared to 40% in morphine group. Pruritus was experienced by 35% of patients given morphine compared with 25% given tramadol. The onset of analgesia appeared faster with tramadol leading to lower, although no statistically significant, pain scores in the first few hours post-operatively. Eroclay, H and L Yuceyar 200325 Randomised controlled trial. 44 patients scheduled for thoracotomy. [Source of funding not stated] 24 hour study period. ASA I-III patients Intervention Group: Tramadol 10mg/mL via PCA throughout 24 hours. Morphine 0.3mg/kg given interpleurally 20mins before a standard general anaesthetic. 19 Intervention Group 21 Control Group 20mg as IV bolus with 10mins lockout time. Mean age 54.7 years 15% female Control Group: Morphine 1mg/kg in 0.9% NaCl via PCA throughout 24 hours. Premedication consisted of midazolam 5mg given IM Accident Compensation Corporation 2 patients in the women received morphine, although there was a similar number of men and women in the trial. D R A F T R E P O R T Mean cumulative morphine and tramadol consumption were 48.13±30.23 and 493.5±191.5mg respectively. No significant difference in quality of analgesia between groups. Level 1Small sample size. 5 patients (26.3%) in the tramadol group and 7 (33%) in the morphine group had nausea, and 3 morphine patients vomited. Page 40 1hr before start of anaesthesia. Baraka, A et al 199326 Double-blind randomised controlled trial. [Source of funding not stated] Patients monitored for 24 hours. intervention group had to be re-operated. 1 patient in the control group refused to co-operate. 20 patients undergoing elective major abdominal surgery. ASA II and III patients 2mg as IV bolus with 10mis lockout time. Sedation was less with tramadol, but not statistically significant. Intervention Group: Epidural tramadol 100mg diluted in 10mL normal saline. In both groups, the mean hourly VAS pain scores ranged from 0.2±0.6 to 1.4±2.5 throughout the period of observations (no significant differences between the groups). Control Group: Epidural morphine 4mg in 10mL normal saline. Mean age 59 years 25% female 10 Intervention Group 10 Control Group Silvasti, M et al 200027 Double-blind randomised controlled trial. [Source of funding not stated] The loading dose of pain relief was administered when post-operative pain occurred. In addition, all patients received 500mg paracetamol rectally, 3 times per day. Accident Compensation Corporation 53 women scheduled to undergo microvascular breast reconstruction under standard general anaesthsia. 25 Intervention Group 28 Control Group Intervention Group: Tramadol 10mg IV loading dose delivered every 2 minutes until the patient was pain free or fell asleep, up to a maximum of 100mg. Then tramadol via PCA 450µg/kg bolus with a 5 minute lockout time. Inclusion Criteria: • ASA I-III • Women who had Control Group: Morphine 1mg IV loading dose delivered 100% female Mean age 50.5 years D R A F T R E P O R T Level 1Small sample size. Mean PaO2 was decreased postoperatively in the morphine group while no change was observed in the tramadol group. One patient in the tramadol group had itching compared with two patients in the morphine group. 2 patients in the tramadol group had nausea and vomiting compared with 4 patients in the morphine group. There were no significant differences between groups in terms of side effects. There was no significant difference between the groups in overall satisfaction of the analgesic medication on the VAS and verbal rate scales for pain. More women in the tramadol group (48%) than the morphine group (4%) had nausea and vomiting during administration of the loading dose (p<0.05) and were given droperidol. More patients in the tramadol group (7) than in the morphine Level 1Many protocol violations. For example, because of prolonged nausea and vomiting 7/25 (28%) of the tramadol group and 3/28 (11%) of the morphine group did not want to use the PCA pump so pain relief was given by oxycodone IM (not Page 41 undergone a mastectomy for breast cancer performed some years earlier. Ng, K et al 199828 [Boehringer Mannhein, Hong Kong, supplied tramadol for this study] Double-blind randomised controlled trial. (Patients and nurses who were responsible for postoperative care and observation were blinded). 38 ASA I-III patients undergoing lower abdominal operations. Morphine was given to all patients intraoperatively. 19 Intervention Group 19 Control Group Rescue medication was available as required: metaclopramide 10mg IV and pethidine 0.4mg/kg IM every 4 hours. Exclusion Criteria: • < 18 years • ASA ≥ IV • Not mentally fir for the operation of PCA • Known allergy to morphine or tramadol • History of substance or alcohol abuse • Pregnant or lactating Vickers, M and D Paravicini 199529 Double-blind randomised controlled trial. [Source of funding not stated] Multi-centre (26 Hospitals) 24 hour study. A computer generated random assignment schedule and a doubledummy technique was Accident Compensation Corporation Mean age 58.5 years 55.3% female every 2 minutes until the patient was pain free or fell asleep, up to a maximum of 10mg. Then morphine via PCA 45µg/kg bolus with a 5 minute lockout time. group (3) wanted to discontinue the PCA therapy before the end of the study due to nausea (not significant). Intervention Group: PCA tramadol 10mg in 0.9% NaCl, 5 min lockout time. There were no between-group differences in the pain, sedation or vomit scores. Control Group: PCA morphine 1mg in 0.9% NaCl, 5 min lockout time. 523 ASA I-III patients with post-operative pain following intra-abdominal surgery. Mean age 52 years. Age range 19-97 years. 66.9% female. 263 Intervention Group 260 Morphine Group significant). 60 patients were enrolled, but 7 were re-operated within the same day so were withdrawn from the study. Level 1Small sample size. The nausea scores were significantly higher in the intervention group in the initial 20 hours and between 32 and 36 hours (p<0.01 for 0-4 hours, and 8-12 hours, p<0.05 for 4-8 hours, 12-16 and 16-20 hours). The incidence of dizziness was also significantly higher in the tramadol group. No patients were excluded from the study because of inadequate analgesia necessitating changes in the PCA regime. Intervention Group: An initial dose of 100mg tramadol was given. If necessary, repeat doses of tramadol 50mg could be given on demand over the first 90mins. Further doses of up to 400mg tramadol could be given after 90mins up to 24 hours after the first dose D R A F T R E P O R T Overall, the responder rate after 90mins was 76.9%. 402 patients were classified as responders and 121 as non-responders. Responder rates were 72.6% with tramadol and 81.2% with morphine (not statistically significant). The mean time to meaningful Level 1++ Good sample size, good blinding, randomisation and reporting of results. Retrospective calculations showed that equivalence between treatments Page 42 used. An anti-emetic was allowed. Exclusion Criteria: • Known or suspected pregnancy • Prone to drug abuse • Contraindication to use of opioids of study medication. Control Group: An initial dose of 5mg morphine was given. If necessary, repeat doses of morphine 5mg could be given on demand over the first 90mins. Further doses of up to 40mg morphine could be given after 90mins up to 24 hours after the first dose of study medication. analgesia (no or slight pain) was 17min in tramadol group and 19min in morphine group. was established with 84% power. A high incidence of gastrointestinal adverse events were observed in both groups mostly consisting of mild nausea, dry mouth, vomiting, dyspepsia and hiccups. There were no statistically significant differences between the two groups. IV administration started as soon as the patient reported pain. Yaddanapudi, LN et al 200030 Randomised controlled trial. [Source of funding not stated] Observer anaesthetist was blinded. 24 hour observation period. 30 ASA I or II patients undergoing thoracic or lumbar laminectomy for prolapsed intervertebral disk. 36.7% female Mean age 45.5 years Intervention Group: Epidural tramadol 50mg in 10mL saline. Control Group: Epidural morphine 3mg in 10mL saline. 15 Intervention Group 15 Control Group Exclusion Criteria: • Patients with respiratory dysfunction • Patients with motor deficit above T10 level • Opioid addiction • Those scheduled to Accident Compensation Corporation D R A F T The summed pain intensity difference scores (SPID) were similar in both the groups, as were the number of supplementary analgesic doses required. Level 1Small sample size. Patient blinding was not mentioned. The time to first supplementary dose was significantly shorter in the tramadol group compared to the morphine group (p<0.05). Mean time was 310mins in the tramadol group and 670mins in the morphine group. No patients in either group suffered respiratory depression. No-one required rescue medication. R E P O R T Page 43 undergo laminectomy of ≥3 vertebrae. Zimmermann, A et al 200231 Double-blind randomised controlled trial. [Source of funding not stated] 24 hour study. Envelope concealment used. 40 patients undergoing cardiac surgery (coronary artery bypass grafting and/or valve replacement surgery). Mean age 66.5 years 25% female 19 Intervention Group 21 Control Group Gong, Z et al 200332 [Source of funding not stated] Randomised controlled trial. 24 hour study 50mg pethidine IM Accident Compensation Corporation Exclusion Criteria: • Known allergy to morphine, tramadol or droperidol • Patients currently taking any psychotropic drugs (including carbamazepine) • Epilepsy • Parkinson’s disease or other extrapyramidal diseases • Patients with acutely deteriorating or persistent moderate to severe renal failure • Any contraindication to PCA 59 patients scheduled for elective hysterectomy or hysteromyomectomy. Age range 25-57 years Mean age 42.7 years Control Group: Morphine 1mg/mL + droperidol 0.1mg/mL PCA The incidence of pruritis and nausea and vomiting was similar in the two groups. There were no statistically significant differences between groups for dose or duration of PCA use or in recorded pain scores. There was no difference in the amount of rescue medication used between groups. A lockout time of 6mins with a maximum 1 hour limit of 8-10mL was charted. The duration of PCA use with the tramadol group was also longer than the morphine group (31 hr vs 27hr, not significant). Intervention Group: Tramadol 10mg/mL + doperidol 0.1mg/mL PCA Level 1Small sample size. There was a statistically significant difference (p=0.01) between the two groups in terms of QoRS (Quality of Recovery Score) with the tramadol group scoring 11.6 compared to 13.3 in the morphine group. Both groups had a very low incidence of nausea. One patient in the tramadol group had to be taken off the trial because of insufficient analgesia obtained in the prescribed dose range. Intervention Group: Tramadol 100mg IV via PCA up to a maximum of 400mg/day. Control Group: D R A F T R E P O R T There was no significant difference between tramadol and morphine by TOTPAR values (15.9 and 16.4 respectively) and SPID values (9.2 and 9.0, p>0.05). Level 1+ Blinding not mentioned. Page 44 permitted as rescue medication. Morphine 10mg IV via PCA up to a maximum of 40mg/day. 100% female 29 Intervention Group 30 Control Group Exclusion Criteria: • Patients with bleeding and coagulation diseases • Inclusion in drug trial in previous 3 months Likar, R et al 199533 [Source of funding not stated] Double-blind randomised controlled trial. 86 patients undergoing arthroscopic surgery. 2 centres. Mean age 34.6 years 26.7% female Minimal time interval between consecutive PCA injections was 5mins (lockout time). Intervention Group: Intra-articular Tramadol 10mg injection Control Group: Intra-articular morphine 1mg injection. 45 Intervention Group 41 Control Group Inclusion Criteria: • ASA I to III • Age 18-70 years • Weight 50-90kg Patients’ global impression score suggested the pain was relieved (to none or mild pain) in approximately 72% and 86% of patients treated with tramadol and morphine respectively. Tramadol caused fewer adverse events than morphine (16.7% and 26.7% of patients respectively). There was no significant difference between groups with respect to vomiting. Both analgesics provided effective post-operative analgesia. Level 1+ Patients who received morphine recorded lower scores for pain on VAS and consumed less supplemental analgesia than patients treated with tramadol. Morphine was significantly more effective than tramadol only at 2hrs post surgery (p=0.025). The analgesic effects of morphine were maximal between 3 and 6 hours. Exclusion Criteria: • Severe cardiovascular or respiratory tract disease, neurological disorders, impaired Accident Compensation Corporation The cumulative dose of study drug in the morphine group were significantly less than in the tramadol group at 1, 4, 8, 16, 20 and 24 hours from the start of PCA (p<0.01). D R A F T One patient who received tramadol experienced vomiting R E P O R T Page 45 • while 2 patients who received morphine experienced vomiting and another patient had nausea (not significantly different). renal or hepatic function or post operative muscle tremor Patients who had been receiving long-term treatment with analgesics or benzodiazepines prior to surgery. Table 5: Tramadol versus Meperidine (= Pethidine) Study Methods Participants Intervention Outcomes Comments and level of evidence Tarradell, R et al 199634 Double-blind randomised controlled trial. 48 patients undergoing total hip or knee replacement. [Tramadol supplied by Andromaco, Spain. Grunenthal, Germany, undertook plasma determination of the drugs] ASA II or III For the first 30mins, meperidine produced lower pain intensity scores than tramadol or saline (p<0.05). At this time, 14/16 patients on saline, 8/16 on meperidine and 11/16 on tramadol were rescued (difference between meperidine and tramadol not significant). Level 1- Rescue medication 75mg diclofenac and morphine was available as required 30 minutes after the study drug was administered. Intervention Group: 100mg tramadol IV, single dose 16 Intervention Group 16 Control Group 1 16 Control Group 2 Mean age 65.9 years 62.5% female Control Group 1: 100mg meperidine IV, single dose Control Group 2: Saline IV, single dose Small sample size. Onset for meperidine analgesia was 10 minutes, and >30 minutes for tramadol. Both opioids produced similar degrees of analgesia in patients who were not rescued. The incidence of nausea and vomiting was higher in the tramadol group than the other groups (p=0.02). Meperidine induced sedation and respiratory depression (p<0.05). Accident Compensation Corporation D R A F T R E P O R T Page 46 Eray, O et al 200235 [Source of funding not stated] Vickers, MD et al 199236 Double-blind randomised controlled trial. 47 patients with suspected renal colic. After 30 minutes, additional doses of meperidine 50mg were given intravenously as a rescue medication in an open fashion. Mean age 40 years. 27.7% female. Randomised controlled trial [Analgesia delivery Accident Compensation Corporation Intervention Group: Initial dose of tramadol 50mg IV over 1 minute Control Group: Initial dose of meperidine 50mg IV over 1 minute. 23 Intervention Group 24 Control Group Exclusion Criteria: • Patients known to be pregnant • Known cardiac or pulmonary disease • Suspected renal infection. • Creatinine concentration >1.2mg/L • Age <18 years Inclusion Criteria: Patients who were diagnosed clinically with acute renal colic by the emergency medicine physician. Diagnosis of renal colic made by a typical presentation of the acute onset of flank pain associated with both haematuria and the presence of a renal calculus in the renal pelvis or ureters shown by a renal ultrasound scan. 30 patients who had just undergone elective gynaecological surgery, ASA class 1 or 2. VAS pain scores after 15 and 30 minutes decreased in both tramadol and meperidine groups (p<0.05). Level 1Small sample size. Pain relief was better in the meperidine group at the 15 and 30 minute evaluations than tramadol (p<0.05). 11 patients (48%) initially receiving meperidine needed rescue medication compared to 16 patients (67%) in the tramadol group (not significant). Both drugs were well tolerated. One patient in each group complained of nausea. No other side effects were encountered. Intervention Group: Tramadol by PCA. 20mg as 1mL solution. D R A F T R E P O R T Mean 24hour consumption of tramadol and pethidine was 642mg and 606mg respectively giving a potency estimate of Level 1Small sample size. Page 47 system supplied by Abbott Laboratories Ltd] Control Group: Pethidine by PCA. 20mg as 1mL solution. Mean age 38 years Age range 23-53 years 100% female 20 Tramadol group 10 Pethidine group tramadol relative to pethidine of 0.94 (0.72-1.17). The mean pain score for pethidine was higher than for tramadol for both pain at rest and pain on movement, although not statistically significant. Tramadol patients claimed to be less sedated, but this difference only approached statistical significance (p=0.07) in this number of patients. Nausea was the most common side-effect, and affected both groups equally. Table 6: Tramadol versus Oxycodone Study Methods Participants Intervention Outcomes Comments and level of evidence Kaufmann, J et al 200437 Double-blind randomised controlled trial. 35 ASA I-III patients undergoing retinal surgery. All patients had access to IV opioid rescue medication. Age range 18-85 years Mean age 67.5 years 37% female Premedication with oral midazolam 7.5mg was given 1hr before surgery. 19 Intervention Group 16 Control Group The AUC for quality of analgesia was significantly higher in the control group (p=0.0023). Patients rated quality of analgesia was significantly higher in the control group than tramadol group at 8 hours (p=0.048), 16 hours (p=0.009) and 24 hours (p=0.001) post-operatively. Level 1+ [Funded in part by a grant from Mundipharma GmbH, Limburg, Germany] Intervention Group: Placebo Tablet after surgery then another placebo Tablet 12 hours later. Simultaneously 100mg tramadol combined with 1g metamizol administered IV every 4 hours until 24 hours post-operatively. On arrival to the recovery room, patients were randomly allocated to 2 groups utilising computerbased randomisation. Accident Compensation Corporation Exclusion Criteria: • Any contraindications to oxycodone, tramadol or metamizol • Patients with alcoholism, psychiatric Control Group: Controlled-release oxycodone (CRO) 10mg after surgery. 12 hours after the initial dose, D R A F T R E P O R T There was no significant difference in AUC for pain scores between the groups (p=0.205). The control group experienced significantly less nausea than the intervention group (p=0.012). Small sample size. The power analysis indicated that 16 subjects per group would allow the detection of 25% difference in overall quality of analgesia (power=80%, α=0.05). Page 48 disease, history of opioid dependency or communicative difficulties. Silvasti, M et al 199938 Double-blind randomised controlled trial. 52 patients undergoing maxillofacial surgery. [Source of funding not stated] All patients were given Diclofenac sodium 1mg/kg IM and dexamethasone 8mg twice a day. Inclusion Criteria: • ASA I and II • Ages 12-54 years Mean age 29.5 years 63% female 27 Intervention Group 25 Control Group Accident Compensation Corporation another 10mg administered. Simultaneously with the initial CRO dose, and every 4 hours up to 24 hours post-operatively, given IV isotonic saline infusion. Intervention Group: Tramadol given in 10mg increments in the immediate recovery period until pain control was judged to be satisfactory by the patient. The patients were then given tramadol via PCA 0.3mg/kg, lockout time 5mins. Control Group: Oxycodone given in 1mg increments in the immediate recovery period until pain control was judged to be satisfactory by the patient. The patients were then given oxycodone via PCA 0.03mg/kg, lockout time 5mins. D R A F T R E P O R T Six patients in the intervention group compared to none in the control group interrupted the study before finishing the study protocol (p=0.022). The incidence of vomiting was 4 fold higher in the tramadol group (p=0.27). There was no statistically significant influence of VAS scores on dropouts. All 6 patients experienced nausea, 5 patients >1 episode. No significant differences were observed between the groups in VAS scores for pain. Level 1+ Small sample size. No respiratory depression was identified. The incidence of nausea was slightly greater in the tramadol group than in the oxycodone group (44% vs 28%, not significant). There was no significant difference in the incidence of other minor adverse events. No serious side effects occurred in either group. Page 49 Table 7: Tramadol versus Other Opioid Study Methods Participants Intervention Outcomes Comments and level of evidence Turturro, MA et al 199839 Double-blind randomised controlled trial 68 adult Emergency Department patients with acute musculoskeletal pain caused by minor trauma (specifically fracture, sprain/strain, contusion or tendon rupture). Intervention Group: Oral tramadol 100mg Mean pain scores did not differ at baseline, but were significantly lower in the control group at 30mins through to 180mins. At 30mins, intervention group 62.7±19.1, control 50.7±18.5, p=0.03. At 180mins, intervention group 51.2±29.1, control, 23.4±21.5, p<0.01. Level 1+ [Funded by the Emergency Medicine Association of Pittsburgh] Age range 18-70 years Control Group: Oral hydrocodone/ acetaminophen combination (5mg/500mg) 33 Intervention Group 35 Control Group Fricke, JR et al 200240 Double blind randomised controlled trial [Source of funding not stated] Accident Compensation Corporation Exclusion criteria: • Analgesia use within prior 4 hours • Known pregnancy/ lactation • Acute intoxication • Suspected substance abuse • Hypersensitivity to tramadol, APAP, or hydrocodone. • On MAO inhibitors, SSRI’s, cabamazepine, quinidine, tricyclic compounds • Back pain • Require parenteral analgesia 200 adults with at least moderate pain (score ≥ 50 on a 100mm VAS) after extraction of ≥ 2 impacted third molars. Small sample size. Demographics of study population not described. There were 6 dropouts (3 in each group) as a result of reported inadequate analgesia, and these patients were then given rescue medication. The discharge diagnoses and prevalence of side effects did not differ significantly between groups. Side effects were uncommon, but did occur in 6 patients in the intervention group and 4 in the control group. Intervention Group 1: 37.5mg tramadol + 325mg acetaminophen Tablets x1 D R A F T R E P O R T Intervention group 2 and 3 were statistically superior to placebo on the primary measures of TOTPAR (total pain relief), SPID (sum of pain intensity Level 1+ Page 50 Intervention Group 2: 37.5mg tramadol + 325mg acetaminophen Tablets x2 56.5% female Age range 16-38 years Mean age 21.4 years 50 Intervention Group 1 50 Intervention Group 2 50 Intervention Group 3 50 Control Group Inclusion Criteria: • 16-75 years • Experiencing moderate or severe pain within 5 hours after surgical removal of ≥2 impacted 3rd molars. • Could tolerate oral medication • Able to provide reliable pain assessments Intervention Group 3: 10mg hydrocodone bitartrate/ 650mg acetaminophen Tablets x1 Control Group: Placebo D R A F T All active treatments were statistically superior to placebo in terms of onset of pain relief (p≤0.001), duration of pain relief (p≤0.024), time to remedication (p<0.001) and patient overall assessment of medication (p<0.001). A statistically significant dose response with tramadol was seen (2 Tablets > 1 Tablet> placebo) for TOTPAR, SPID and SPRID (all p≤0.018). The median time to onset of pain relief was about 34 mins with group 2, and 23.4 mins in group 3. Time to remedication was not significantly different between groups 2 and 3. Exclusion Criteria: • UnsTable medical disease or significant abnormal renal function and/or hepatic function that could compromise metabolism or excretion of study medication • Significant psychiatric disorder • History of substance abuse • History of hypersensitivity or contraindication to Accident Compensation Corporation differences), and SPRID (sum of pain relief and pain intensity differences) (p≤0.024), as well as on hourly PAR (pain relief), PID (pain intensity difference), and PRID (combined PAR and PID) over 6 hours (p≤0.045). The overall incidence of adverse events was lower with tramadol (0% treatment related AE’s) than with group 3 (4%) or placebo (10%). The incidence of nausea (18% tramadol, 36% group 3) and vomiting (12% tramadol, 30% group 3) was about 50% lower in group 2 than group 3. Adverse Events (AE’s) were R E P O R T Page 51 • • • • Vercauteren, M et al 199941 Double-blind randomised controlled trial. [Source of funding not stated] reported by 84 (42%) of patients. Fewer patients experienced treatment-emergent AE’s in group 1 (34%) and group 2 (30%) compared to group 3 (56%) and control (48%). No deaths or serious AE’s occurred during the study, and no patients withdrew due to an AE. tramadol, paracetamol, or hydrocodone Women who were pregnant or lactating Failure to respond to previous tramadol therapy or discontinuation of such therapy due to adverse events Use of tramadol within the previous 21 days Use of any long acting NSAID within previous 3 days. 185 patients completed the study (92.5%) with similar numbers in each treatment group. 66 patients undergoing elective caesarean section. Mean age 31.1 years Age range 25-40 years 100% female Intervention Group: Extradural injection of tramadol 10mg/mL PCA Control Group 1: Extradural injection of sufentanil 2µg/mL PCA 22 Intervention Group 22 Control Group 1 22 Control Group 2 PCA regimen was discontinued in 5 patients. Control Group 2: Extradural injection of a combination of tramadol 10mg/mL and sufentanil 2µg/mL PCA At 6 hours, pain was significantly less in the combination group compared with patients receiving tramadol alone. The 24 hour dose requirements for sufentanil and tramadol when used alone were 123.5±10.3µg and 652±42mg respectively. Combining both drugs decreases the consumption and number of demands for tramadol only (22%, p<0.05 vs 18% for sufentanil, NS). In the tramadol group, more failures and significantly more side effects, mainly nausea and vomiting, were noticed. Level 1Many patients discontinued during the study for various reasons. Exclusion criteria not outlined. The combination group had twice as much analgesia than the other two groups. In both tramadol containing Accident Compensation Corporation D R A F T R E P O R T Page 52 groups, the PCA was removed on request of patients because of inefficacy (after 6hrs in 2 patients in the tramadol group) or side effects (after 18hours in 2 patients in the combination group). APPENDIX 4: Tramadol versus NSAIDs Table 8: Tramadol versus Bromfenac Study Methods Participants Intervention Outcomes Comments and level of evidence Mehlisch, D.R 199842 Double-blind randomised controlled trial. Intervention Group: Tramadol 100mg 8 hour study. Both doses of bromfenac were superior to tramadol and placebo in terms of hourly and peak pain relief and pain intensity difference (PID). Level 1+ [Funded by WyethAyerst Research, Radnor, Pennsylvania] 128 patients with moderate or severe pain after oral surgery to remove one or more impacted third molars. 60.9% female Mean age 25 years. Age range 18-50 years. Control Group 2: Bromfenac sodium 50mg Computer generated randomisation schedule used. Control Group 1: Bromfenac sodium 25mg Control Group 3: Placebo 30 Intervention Group 32 Control Group 1 33 Control Group 2 33 Control Group 3 The 3 hour and 8 hour TOTPAR and SPID results for both doses of bromfenac also were significantly superior to those for tramadol and placebo. Tramadol was not statistically superior to placebo. Exclusion Criteria: • <18 years • Pregnancy • Active peptic ulcers • Gastrointestinal disease associated with Accident Compensation Corporation 100mg of tramadol was probably not enough. D R A F T Both doses of bromfenac were superior to tramadol and placebo as measured by patient global assessment, time to meaningful pain relief and duration of pain relief. 75% and 79% of those taking bromfenac 25mg and R E P O R T Page 53 • Desjardins, P et al 199843 Double-blind randomised, controlled trial. [Funded by WyethAyerst Research Division of Wyeth Laboratories Inc] Multicentre. Patients were stratified according to the severity of their baseline pain. All medication was identical in appearance and administered as 2 capsules with a glass of water. Rescue analgesia was permitted, but patients were encouraged to refrain for at least 1hr after the test dose. Accident Compensation Corporation 50mg respectively rated their treatment as good to excellent, compared to 33% of the tramadol group and 21% of the placebo group. clinically significant blood loss within the last 2 years History of sensitivity to NSAIDs, tramadol, or narcotic analgesics. 130 outpatients with moderate or severe pain after oral surgery (removal of one or more impacted 3rd molars). Intervention Group: Tramadol 100mg Mean age 23.5 years Age range 17-41 years 62% female Control Group 2: Bromfenac 50mg Control Group 1: Bromfenac 25mg Control Group 3: Placebo 32 Intervention Group 32 Control Group 1 33 Control Group 2 33 Control Group 3 Exclusion Criteria: • <18 years • History of epilepsy • History of peptic ulcer or disease or any clinically significant condition that would affect the absorption, metabolism or elimination of the study medications. • History of D R A F T Bromfenac was well tolerated and was equivalent to placebo with respect to treatment emergent study events. Overall, significantly more adverse events were reported from the tramadol group than all control groups. Bromfenac at 25 and 50mg doses were superior to tramadol 100mg and placebo. Pain relief was significantly higher than with tramadol 100mg (p<0.05) and placebo 30mins after dose administration and the difference remained significant for 6-8 hours. Level 1+ Good sample size. Good randomisation method and concealment of treatment groups. 100mg tramadol was probably not enough. Patients who received bromfenac reported more favourable global responses to therapy than did those who received tramadol 100mg or placebo (p<0.05). The responses to tramadol 100mg were not distinguishable from placebo for any of the efficacy variables. Fewer patients remedicated with a rescue analgesic in the bromfenac groups than the tramadol and placebo groups (p<0.05). R E P O R T Page 54 • • • hypersensitivity to NSAIDs or tramadol Required concomitant use of any drug that would make it difficult to quantify analgesia Pregnant or lactating women Patients who abused alcohol or other drugs Adverse events were infrequent, however significantly more patients in the tramadol group (7 patients) than in bromfenac 50mg group (1 patient) reported events (p<0.05). Table 9: Tramadol versus Diclofenac Study Methods Participants Intervention Outcomes Comments and level of evidence Pagliara, L et al 199744 Multicentre open-label RCT. Random assignment to either treatment. Intervention Group: Tramadol 100mg twice per day. The analgesic activity of tramadol was higher than that of diclofenac, both after first dose (between treatment at the 5th and 6th hours, p<0.05), and during repeated therapy (between treatment on day 2 and at the end of treatment). Level 1+ [Source of funding not stated] 120 patients with moderate to strong musculoskeletal pain caused by trauma, involving joints and/or ligaments. Both drugs given at 12 hour intervals for 5-7 days. 25.8% female Control Group: Diclofenac 100mg twice per day. VAS ≥ 7/10 at admission to the trial. Patients could take a 3rd dose if needed. Mean age 42 years. Age range 18-90 years. 7 patients discontinued because of moderate to severe adverse reactions (4 in tramadol group and 3 from diclofenac group). The analgesic effect of both drugs was confirmed by the significant reduction in pain compared to baseline (p<0.01). Final assessments of efficacy and safety were all significant in favour of tramadol. Patients and assessors were not blinded to treatment. Note that 200mg per day of both drugs were used. This is the maximum daily dose of diclofenac, but not tramadol (max daily dose 400mg). Both drugs were well tolerated. Another 6 patients had moderate to mild reactions (4 tramadol, 2 diclofenac). Accident Compensation Corporation D R A F T R E P O R T Page 55 Courtney, MJ and D Cabraal 200145 Randomised controlled trial. [Source of funding not stated] Single-blind (surgeon and research team members) Computer-generated random numbers used to randomise participants. Exclusion criteria: patients known to be intolerant to the test drugs. Also those receiving monoamine oxidase inhibitors, pregnant or breast-feeding women, and non-co-operative patients. 49 patients undergoing bipolar electroauctery tonsillectomy. Mean age 18 years 67.3% female 24 Intervention Group 25 Control Group Exclusion criteria: • <11 years • Elective tonsillectomy for reasons other than recurrent or chronic tonsillitis. • Asthma • Pregnancy • Breast-feeding • Epilepsy • Relevant drug allergies • Any additional procedure excluding adeniodectomy Wilder-Smith, CH et al 200346 Double-blind randomised controlled trial. 120 patients who had elective caesarean surgery. [Funded in part by Grunenthal GmbH, Computerised randomisation list used. Age range 27-32 years Mean age 30 years Accident Compensation Corporation Intervention Group: Oral tramadol hydrochloride for 14 days. 100mg taken in the morning, 50mg in the afternoon and 50mg in the evening. Control Group: Oral diclofenac sodium for 14 days. 50mg taken in the morning, afternoon and evening. Pain scores for the 14 days were not significantly different between the oral tramadol and oral diclofenac groups. There were no significant differences in the incidence of post-operative heamorrhage and hospital readmission for uncontrolled pain. No significant difference between the two groups in the duration of use of the trial drug or control. Level 1Small sample size. The study required 25 patients in each group to detect a large effect of 0.8 SD between the group means, with power of 80% and α2 = 0.05. The incidence of vomiting was higher in the tramadol group vs diclofenac group. 49/64 patients completed and returned their data collection forms. Of the 15 who dropped out, 8 were from the tramadol group and 7 from diclofenac group (p=0.77). Intervention Group 1: Tramadol 100mg + placebo (0.9% NaCl) Intervention Group 2: D R A F T R E P O R T The median time to first rescue was 197 mins (Interquartile range 70-1000min) with tramadol and diclofenac (group 3), 113 mins (35-270 mins) with Level 1+ Page 56 Aachen, Germany] Morphine 10mg IV was administered on demand up to every 4 hours as analgesic rescue. No other analgesics were allowed in the first 24 hours following surgery. 100% female Sodium diclofenac 75mg + placebo 30 in each group. Exclusion criteria: • Known allergy to diclofenac or tramadol • ASA status > III • History of peptic ulcer disease or gastrointestinal bleeding • Opioid use in the last month • Inability or unwillingness to consent • Preeclampsia or eclampsia • Significant pulmonary disease Intervention Group 3: Tramadol 100mg + sodium diclofenac 75mg Control Group: Placebo + placebo The study drugs were injected separately into the left and right buttock. diclofenac and placebo (group 2), and 48 min (25-90 mins) with tramadol and placebo (group 1). For the control group this was 55 mins (30-100min). There was a statistically significant difference between group 3 and all other groups (p<0.05). Pain intensity decreased markedly over time in all groups, and time and drug effects were significant. Side effects were similarly minimal with all treatments. Table 10: Tramadol versus Lornoxicam Study Methods Participants Intervention Outcomes Comments and level of evidence Ilias, W and M Jansen 199647 Double-blind randomised controlled trial 78 females aged 20-65 years with moderate to intolerable post-operative pain following hysterectomy. Intervention Group: Single-dose IV injection of tramadol 50mg A reduction in pain intensity was achieved in all groups except the placebo group. Level 1- Control Group 1: Single-dose IV injection of lornoxicam 4mg The overall subjective assessment, pain relief was rated as ‘good’ or ‘very good’ by 61.1% control group 1, 40% control group 2 and 40% intervention group. 95% of placebo patients reported poor pain relief. [Funded by Forschungsforderungsford der Gewerblichen Wirtschaft Osterreichs] Accident Compensation Corporation Mean age 45.5 years Age range 20-65 years 100% Caucasian 20 Intervention Group 18 Control Group 1 20 Control Group 2 Control Group 2: Single-dose IV injection of lornoxicam 8mg D R A F T R E P O R T Small number of participants in each group. Concomitant medication was permitted with the exception of cytotoxic drugs and centrally acting drugs. Page 57 20 Control Group 3 Exclusion Criteria: • Complications during surgery • 25% greater than normal duration of surgery • History of asthma or hypersensitivity to NSAIDs • Blood dyscrasias or clotting disorders • Malignancy • Gastrointestinal disease or any significant internal disease Staunstrup, H et al 199948 Double-blind randomised controlled trial. [Funded by Forschungsforderungsfond der Gewerblichen Wirtschaft Osterreichs] Accident Compensation Corporation 73 patients with moderate to unbearable pain following arthroscopic reconstruction of the anterior cruciate ligament using the patella-bonetendon technique. Control Group 3: Placebo Additional doses of study medication could be administered during the 24 hour study period, if requested, up to a maximum daily dose of 32mg lornoxicam or 400mg tramadol. 9 placebo patients (45%) reported intolerable pain following surgery, compared with 2 (11.1%) of control group 1, 5 (25%) of control group 2 and 3 (15%) of the intervention group. The median number of doses of study medication was 4 in all treatment groups. Lornoxicam was well tolerated at both doses and was associated with a lower incidence of adverse events than tramadol (35% tramadol patients reported at least one adverse event compared to 15% lornoxicam patients). Intervention Group: Single dose Tramadol 100mg IM Control Group: Single-dose Lornoxicam 16mg IM All adverse events were mild to moderate in intensity and most were transient. Patients who received lornoxicam experienced significantly greater total pain relief than patients receiving tramadol over the following 8 hours. 35 Intervention Group 38 Control Group Lornoxicam had greater analgesic efficacy than tramadol in patients with moderate baseline pain but was of equivalent efficacy in those with severe/unbearable baseline pain. Exclusion Criteria: • <18 years or >65 years • <50kg or >100kg Fewer patients in the lornoxicam group required rescue medication (58% versus 77%). Mean age 26.7 years 45.2% female D R A F T R E P O R T Level 1+ Good sample size. All injuries (except 3) occurred ≥2 months previously. Page 58 • • • • • • • • • • • Patients’ global impression of efficacy showed lornoxicam to be superior to tramadol with 82% and 49% of patients respectively rating the treatment as good, very good or excellent. Pregnant Systemic disorders that may affect the pharmacokinetics of the test drugs Esophageal varices Gastric or duodenao ulcers Participated in a drug trial within the last 3 months Complications associated with surgery History of drug or alcohol abuse Hypersensitivity to NSAIDs Blood disorders or anticoagulant treatment Respiratory insufficiency Heart disease Following multiple dose administration of lornoxicam or tramadol for 3 days, efficacy profiles remained similar. Adverse events were reported by 50% of all patients and were mainly mild to moderate in severity. Significantly fewer patients reported one or more adverse events with lornoxicam than with tramadol (14 vs 24, p=0.012). Table 11: Tramadol versus Ketorolac Study Methods Participants Intervention Outcomes Comments and level of evidence Zackova, M et al 200149 Randomised controlled trial. [Source of funding not stated] Intervention Group: Tramadol 100mg IV at the time of skin closure and repeated after 8 and 16 hours after surgery. Very good post-operative analgesia was recorded in all 3 groups. No significant differences in pain scores were measured between the groups. Level 1+ Meperidine 50mg was permitted as rescue analgesia. 51 ASA I and II patients undergoing elective major maxillofacial surgery. 41% female Mean age 34.3 years Age range 18-65 years. Exclusion Criteria: Accident Compensation Corporation Control Group 1: Ketorolac 30mg IV at the time of skin closure and D R A F T R E P O R T Only a small number of patients required opioid administration to achieve adequate analgesia Page 59 • • Serious cardiac, respiratory, renal or liver disease. History of chronic use of analgesics or oral anticoagulants. repeated after 8 and 16 hours after surgery. Control Group 2: Tramadol 100mg IV during surgery, then 30mg ketorolac 8 and 16 hours after surgery. (17.6% of the ketorolac group, 5.9% of the tramadol group, and none of the combination group). No significant differences between the groups. Patients were considered to have excellent analgesia in 64.8% of the tramadol group and 58.8% of the ketorolac group. Vomiting was recorded in 41.2% of the tramadol group, 11.2% of the ketorolac group and 35.5% of the combination group. Mais, V et al 199750 [Source of funding not stated] Randomised controlled trial. Multicentre (4 university institutes of obstetrics and gynaecology). 3 day study duration. Randomisation list utilised, not known to the investigator. 66 women aged 30-65 years undergoing laparotomic or vaginal hysterectomy with post-operative pain classified as strong/unbearable. Mean age 49 years 100% female 34 Intervention Group 32 Control Group Exclusion Criteria: • Abnormal hepatic or renal function • Patients undergoing plastic surgery, emergency surgery or re-operations during Accident Compensation Corporation Intervention Group: Tramadol 100mg in 2mL given as required up to a maximum of 4 ampoules per day. Control Group: Ketorolac 30mg in 1mL given as required up to a maximum of 3 ampoules per day. Given by IM injection for 3 days post-operatively. Ampoules given at least 2 hours apart. D R A F T R E P O R T No adverse events were noted with regard to hypo/hypertension, arrhythmias and respiratory depression. Both drugs achieved rapid and constant control of pain after the first injection (73.5% within 1 hour with tramadol, 65.6% with ketorolac, not significantly different) and for the next 2 days. Level 1- Night-time pain and the quality of sleep improved likewise, and the safety profile was good for both drugs. During the first day the pain free interval was longer for patients given tramadol than those taking ketorolac between 2nd/3rd and 3rd/4th ampoule with tramadol 6.3±0.7 and 3.5 hours, with ketrolac 5.1±0.5 and 1.5. During Page 60 • • • the same hospital stay Hypersensitivity or contraindications to the test drugs Receiving concomitant therapy with analgesics or anti-inflammatory drugs Pregnant or breastfeeding. the 3 days of the trial the number of ampoules used did not differ significantly between the 2 groups. 6 patients discontinued the trial, 2 in the tramadol group and 4 in the ketorolac group. One patient in the tramadol group and 3 in the ketorolac group complained of lack of effect and a supplementary analgesic was required. Table 12: Tramadol versus Dipyrone Study Methods Participants Intervention Outcomes Torres, L et al 200151 Comments and level of evidence Double-blind randomised controlled trial. 130 women undergoing elective abdominal hysterectomy. Intervention Group: Tramadol. 100mg loading dose IV over 15mins, followed by continuous infusion 12.5mg tramadol/hour and demand doses of 16.5mg up to a maximum of 6 bolus injections in 24 hours. The mean number of boluses in the dipyrone group was 3.8 and 3.5 in the tramadol group (not significantly different). The percentage of patients requiring rescue medication was not significantly different (26.9% dipyrone and 26.8% tramadol). Other analgesic efficacy parameters such as pain intensity differences, sum of pain intensity differences, pain relief assessed by the patient, or patient requiring the maximum number of doses on demand were not different between the treatment groups. Level 1+ [Source of funding not stated] Multicentre study. 24 hour study period. Rescue medication = IV morphine. Randomisation scheme drawn up using a Table of random numbers. 67 Intervention Group 63 Control Group Inclusion Criteria: • Age 18-60 years • ASA I or II • Duration of surgical operation between 45180 minutes. • Mental status sufficient to be able to understand PCA Exclusion Criteria: • Patients with known hypersensitivity to study medications Accident Compensation Corporation Control Group: Dipyrone. 2g loading dose IV over 15mins, followed by continuous infusion 166mg dupyrone/hour and demand doses of 333mg up to a maximum of 6 bolus injections in 24 hours. D R A F T R E P O R T No demographic information provided. A significantly higher percentage of gastrointestinal effects were found in patients given tramadol Page 61 • • • • Stankov, G et al 199552 Double-blind, randomised controlled trial. [Source of funding not stated] Multicentre (5 centres in Germany). Randomisation list utilised variable block size and a ratio of 1:1 per investigational centre. 48 hour study, 4 hour observation period. Disorder contraindicating administration of dipyrone or NSAIDs Pregnancy Severe underlying disease History of drug or alcohol abuse 100 patients with acute post-operative pain who underwent elective major abdominal surgery. Mean age 49 years. 53% female In all cases, the minimum interval allowed between bolus injections was 30 minutes. Intervention Group: 100mg tramadol IV single dose Control Group: 2.5g dipyrone IV single dose 49 Intervention Group 51 Control Group 12 patients (5 in the intervention group and 7 in the control group) were excluded. D R A F T Patients and investigators reported similar tolerability for both study arms. At 24 hours, 100% dipyrone and 94% of tramadol patients had mild or no pain according to observers. Dipyrone was significantly more effective than tramadol in reducing pain in the acute postoperative phase for the primary endpoint, Sum of Pain Intensity Differences (SPID) on a VAS as well as for the secondary endpoint, SPID on the Tursky pain adjective scale, total pain relief (TOTPAR) and mood as part of the MPAC. Level 1+ Good sample size and randomisation. Short observation period (4hrs). All individual SPID values between 15mins and 4 hours showed significant differences between the treatment groups in favour of dipyrone. Exclusion Criteria: • <strong post-operative pain • tumour surgery • Pregnant or breastfeeding women • Patients with altered sensation or mobility • Allergy or intolerance to dipyrone, tramadol or other related drugs • Severe renal, hepatic or systemic haemolytic Accident Compensation Corporation (42.1%) than in patients given dipyrone (20.2%) (p<0.05). During the 4hr evaluation period, only 1 patient (in dipyrone group) needed rescue medication. Dipyrone was also significantly more effective than tramadol for the global efficacy as assessed by the patients and investigators at the end of the observation period. R E P O R T Page 62 • • • • • disorder Concomitant medication which might have potentially interacted with the study drugs, eg. NSAIDs, MAO inhibitors Immunodeficiency Acute pulmonary oedema Bronchial asthma Narcotic drug abuse Both drugs were well tolerated. Mild to moderate adverse events were reported in 12 patients in the dipyrone and 16 in the tramadol group. None of the adverse events were thought to be related to the study drug. There were no serious adverse events. Table 13: Tramadol versus Other NSAID Study Methods Participants Intervention Outcomes Comments and level of evidence Doroschak, A et al 199953 Double-blind randomised controlled trial. 49 dental patients that fulfilled the criteria below. Sealed envelope and identical looking medication used for randomisation and to maintain blinded status. 12 Intervention Group 12 Control Group 1 13 Control Group 2 12 Control Group 3 The placebo group demonstrated a 50% reduction in pain by 24 hours (p<0.01). Patients treated with flurbiprofen + tramadol reported less pain than those taking placebo at 6 and 24 hours (p<0.01 for both times). The tramadol and flurbiprofen groups were no different to placebo. Level 1- [Source of funding not stated] Intervention Group: Tramadol 100mg loading dose and then 100mg every 6 hours. Paracetamol (APAP) 650mg was provided as escape medication. Accident Compensation Corporation Inclusion Criteria: • Patient reports spontaneous pain ≥30 (on 100 point VAS) • Patient elects root canal therapy for pain originating from a vital/ nonvital tooth • Patient presents with an ASA class I or II medical history • Patient reads and Control Group 1: Flurbiprofen 100mg loading dose then 50mg every 6 hours Control Group 2: Flurbiprofen 100mg + tramadol 100mg loading dose and then 100mg tramadol + 50mg flurbiprofen every 6 hours Control Group 3: One Placebo Tablet initially then one every 6 D R A F T R E P O R T The flurbiprofen group reported signs of dyspepsia (25%) and one case of headache. Those in the tramadol group had similar sideeffect profiles to other opioids (sedation, nausea, emesis and euphoria). 25% of the tramadol group reported combined gastrointestinal and central nervous system symptoms. The Small sample size. The sample size was chosen based on calculations using a 20% treatment effect, variance at 20mm on 100mm VAS, and 85% power with a 2-sided test and α=0.05. Demographic data was not given. Patients took all medication and questionnaires home with them to take and complete. Page 63 understands questionnaires and gave informed consent hours. combination group also had GI and CNS symptom complaints. Differences between the groups with regard to side effects were not significant. Exclusion Criteria: • <18 years or >65 years • Analgesic ingestion within last 4 hours • History of allergy to NSAIDs, aspirin, tramadol or local anaesthetics • History of ulcers, active asthma, decreased renal or hepatic function, hemorrhagic disorders or poorly controlled diabetes mellitus • Currently taking opioids, MAO inhibitors, tricyclic antidepressants, carbamazepine, diuretics, or anticoagulants • Reported history of opioid addiction or abuse • Pregnant or lactating Accident Compensation Corporation D R A F T R E P O R T The result of the combined medication resulting in significant improvements at 6 and 24 hours is probably due to the doubling of analgesic dose compared to the individual analgesic groups. Page 64 APPENDIX 5: Tramadol versus Other Table 14: Tramadol versus Bupivacaine Study Methods Participants Intervention Outcomes Comments and level of evidence Subash, P and M Zachariah, 199854 Double-blind randomised controlled trial. 105 patients who had undergone elective surgery that could be performed under lumbar epidural anaesthesia alone. Intervention Group: 0.5% bupivacaine + 50mg tramadol injection The mean durations of complete analgesia were 5.0 hours in the intervention group, 5.1 in control group 1 and 4.3 in control group 2 (not statistically significant). Level 1+ [Source of funding not stated] Mean age 40.3 years 26.7% female Control Group 1: 0.5% bupivacaine + 50mg pethidine injection Control Group 2: 0.5% bupivacaine injection. 40 Intervention Group 32 Control Group 1 33 Control Group 2 Exclusion Criteria: • ASA >2 • Age <20 years or >70 years • Weight <40 kg or >75kg Darwish, A and Z Hassan 199955 Randomised controlled trial. [Source of funding not stated] Accident Compensation Corporation 90 patients undergoing day case laparoscopic surgery (including laparoscopic drilling of polycystic ovaries, Intervention Group: IV tramadol slowly in a dose of 2mg/kg after the end of the procedure. D R A F T R E P O R T Good sample size and blinding. There were no significant differences between groups in the first two hours. At 4 hours post surgery, the mean pain scores were significantly better in control group 1 (2.76) and the intervention group (2.50) compared to control group 2 (4.67). There was no significant difference between the intervention group and control group 1 (p>0.05). 12.5% of the tramadol group and 6.3% of the pethidine group had nausea and vomiting (not significantly different). The incidence of side effects showed no significant differences between the groups (p>0.05). Both analgesics provided adequate analgesia. A statistically significant reduction in pain scores up to 4hrs postoperatively in tramadol and Level 1Demographics were not stated, other than to say that they were Page 65 diathermycoagulation of endometriosis, ovarian cystectomy and moderate adhesiolysis). 30 Intervention Group 30 Control Group 1 30 Control Group 2 Inclusion Criteria: • ASA I or II • Aged 18-35 years • Weight 60-100kg Control Group 1: Intraperitonel infusion of bupivacaine 20mL, 0.25% through the laparoscopic cannula and another 5mL which was injected around the incision sites. bupivacaine groups compared to placebo (p<0.05). Control Group 2: Placebo. Saline 20mL intraperitonelly and 5mL at the incision sites, then 2mL IV injection. Generalised abdominal pain was experienced by 90% of control group 2, compared to 53.3% of control group 1 and 66.7% of the intervention group. Exclusion Criteria: • Tubal operations • Women who experienced pain immediately prior to the procedure. Aribogan, A et al 200356 Randomised controlled trial. [Source of funding not stated] Rescue medication permitted: epidural bolus dose of 5mL study medication with a lockout time of 30mins. 51 patients undergoing major urological surgeries with abdominal surgical incision. Mean age 54.3 years 5.9% female 17 Intervention Group 17 Control Group 1 17 Control Group 2 Exclusion Criteria: • History of chronic pain • Presence of contraindication to epidural catheter placement • Contraindication to Accident Compensation Corporation Time to analgesia was prolonged and there was less need for rescue analgesia (fentanyl) and earlier discharge in the tramadol and bupivacaine groups. comparable. Limited information was given about randomisation and blinding. This was a pilot study. Minimum pain scores were significantly lower in control group 1 than control 2 and the intervention group. Intervention Group: Loading dose of 20mg tramadol with a continuous infusion of 1mg/mL tramadol at a rate of 8mL/hr. Adequate analgesia was provided in all patients. The haemodynamic values and sedation scores were not significantly different between groups. Control Group 1: Loading dose of 20mL bupivacaine 0.125% and a continuous infusion of 8mL/hr. The demand on epidural bolus dose requirement was the lowest in control group 2 (p<0.05). VAS values were significantly lower in control group 2 than in the other groups at every measurement (p<0.05). Control Group 2: Loading dose of 20mg tramadol with 20mL bupivacaine 0.125% and supplemental infusion of 1mg/mL tramadol in D R A F T R E P O R T Level 1Small numbers in each group. Blinding not mentioned. The VAS values for pain intensity for the intervention group (6.79) was significantly higher than the two control groups (4.41 and Page 66 • • • • PCA History of drug abuse ASA > 3 Age <18 or >80 years History of allergy to local anaesthetics. Delilkan, AE and R Vijayan 199357 Randomised controlled trial. 58 patients undergoing elective abdominal surgery. [Funded by Grunenthal (Germany) and Duopharme (Malaysia)] Blinded observer. ASA grades I and II The drugs were administered by the blinded observer when requested by the patient. If satisfactory analgesia was not achieved at 15mins, the second dose was given epidurally. If pain relief was not achieved with the second dose, the patient was removed form the trial and rescue medication was given parenterally. Mean age 41.3 years Age range 18-60 years 86.2% female Accident Compensation Corporation 20mL bupivacaine 0.125% combination at a rate of 8mL/hr. Intervention Group 1: Epidural tramadol 50mg in 10mL volume Intervention Group 2: Epidural tramadol 100mg in 10mL volume 20 Intervention Group 1 18 Intervention Group 2 20 Control Group Exclusion criteria: • Pregnant or lactating women • Patient’s with bleeding diathesis or were on anticoagulant therapy • Taking MAO inhibitors • Clinical history of drug abuse • Mentally defective • Taking drugs acting on CNS Control Group: Epidural bupivacaine 0.25% in 10mL volume. The study drugs were administered at the patients’ request with each patient being allowed 4 doses in the first 24 hours following surgery. D R A F T R E P O R T 1.22) at the first measurement just after surgery (p<0.05). The incidence of side effects in the 3 groups was low. Nausea was the most common side effect (11.8% of total). Most patients had adequate pain relief on epidural administration of the trial drug. Pain scores were significantly less (p<0.05) at 3, 12 and 24 hour in patients receiving tramadol 50mg or control. Level 1Not stated whether or not the patients were blinded to the group they were in. The mean interval between doses for intervention groups 1 and 2 was 7.40hr and 9.36 hr respectively. The mean interval for the control group was 5.98 hrs. The mean interval in intervention group 2 was significantly longer than in the control group (p<0.05). The incidence of nausea and vomiting in intervention group 2 was significantly higher than in the control group (p<0.05). Nausea and vomiting was reported by 26.3% of group 1, 50% group 2 and 15% of the control group. Page 67 Table 15: Tramadol versus Other Study Methods Participants Intervention Outcomes Comments and level of evidence Kayacan, N et al 200258 Double-blind randomised controlled trial. 40 patients with postoperative pain who underwent day case knee surgery. Intervention Group 1: 100 mg tramadol There were no significant differences among the study groups regarding pain scores, haemodynamic changes, the first analgesic requirement time, and complications. All patients had adequate post-operative analgesia without any severe complications. Level 1- [Source of funding not stated] ASA I or II. Intervention Group 3: 20mg tenoxicam Mean age 42 years. 65% female. Control Group: 20mL 0.5% bupivacaine 10 Group 1 10 Group 2 10 Group 3 10 Control Group Hoogewijs, J et al 200059 Randomised controlled trial. [Source of funding not stated] Single blind (patient only). Exclusion criteria: • <18 years • >60 years • Use of analgesic within the last 24 hours before the operation. • Relevant drug allergy. • Need for surgical debridement or synovectomy for post operative intra-articular drainage. 131 patients admitted to the emergency department with a single peripheral trauma, defined as a traumatic injury of the soft tissue and/or bony structures of the limbs. Mean age 45 years Accident Compensation Corporation Intervention Group 2: 0.5mg neostigmine All prepared in 20mL normal saline and injected into the knee joint at the end of surgery 10 minutes before tourniquet release. Intervention Group: Tramadol 1mg/kg IV Control Group 1: Propacetamol (prodrug of paracetamol) 20mg/kg IV Control Group 2: D R A F T R E P O R T The highest incidence of nausea was observed in the tramadol group. Hypotension was only noted in the tramadol group. Pain scores in all groups decreased with time. No significant differences were found between groups at any particular time point. Small sample size and number in each group. Analgesic therapy in the recovery room was managed with 25mg bolus doses of meperidine when the patients had VAS scores above 3 points. It was not stated how many people needed this or when. Level 1+ Single blind only. Good sample size. VAS scores were significantly lower (p<0.02) than baseline scores 30mins after injection of all treatments except for control group Page 68 75% female 30 Intervention Group 31 Control Group 1 36 Control Group 2 34 Control Group 3 Canepa, G et al 199360 Randomised controlled trial. [Source of funding not stated] Single-blind (patient only). Utilised a randomisation list which was prepared prior to study commencement. Exclusion Criteria: • <18 years • Pregnant or lactating • Psychiatric disease or mental illness • Undergoing chronic pain treatment • Concomitant pain treatment prior to admission • Allergic to the study drugs 60 patients undergoing surgical operations on the abdomen involving opening of the peritoneum. 48.3% female Age range 20-70 years Mean age 49.5 years. 30 Intervention Group 30 Control Group Exclusion Criteria: • Those who had previously shown intolerance to the study drugs. • Alterations of respiratory, hepatic or renal function Accident Compensation Corporation Piritramide 0.25mg/kg IM 2 where significance (p<0.01) was reached after 60mins. Control Group 3: Diclofenac 1mg/kg IV In Control Group 2, significantly more side effects were noted than in the other groups (p<0.05). Intervention Group: Tramadol 100mg/2mL vial administered parenterally (either IM or IV). 3 vials per day for the first 3 days following surgery. The analgesic action of tramadol was shown to be more effective than that of Nisidin both after the first dose and during the 3 days of observation (p<0.01). Control Group: Nisidin IM 2mL vials parenterally administered. 3 vials per day for the first 3 days following surgery. D R A F T R E P O R T Local and general safety was good in both groups. 3 patients who had IM tramadol suffered adverse events. One patient had moderate nausea, one had moderate nausea and slight dizziness, and the other had moderate nausea and dryness of the throat. In the Nisidin group, one patient complained of slight nausea after first administration. Level 1Only single blind. Some patients in the tramadol group received it IM, and others IV, whereas all control patients received Nisidin IM. Page 69 • Stankov, G et al 199461 Randomised controlled trial. [Source of funding not stated] Multicentre (8 German centres). Observer blind only. There was no possibility of using matching preparations for the three drugs. If no adequate pain relief had been achieved by 20mins after the first injection of the study drug, a second IV injection of study medication was given. Accident Compensation Corporation Those treated with other analgesics in the pre and post-operative period. • Use of MAO inhibitors • Chronic pain before surgery • Those undergoing oncological surgery for palliative reasons • Emergency surgery. 104 patients suffering from severe or excruciating colic pain due to a confirmed calculus in the upper urinary tract. 32% female Mean age 46.4 years Age range 18-83 years. Intervention Group: 100mg IV tramadol Control Group 1: 2.5g IV dipyrone Control Group 2: 20mg IV butylscopolamine 35 Intervention Group 36 Control Group 1 33 Control Group 2 Exclusion Criteria: • Pregnant or nursing women • Patients who had pretreatment with any spasmolytic or analgesic drug in the previous 24 hours. • Known tolerance to study drugs • Any pre-existing conditions or diseases • Any concomitant therapy that might have D R A F T Dipyrone was significantly more effective than tramadol in reducing pain intensity differences (PID) at 20, 30 and 50mins after drug administration, and was significantly more effective than butylscopolamine at 30 and 50mins for PID on a categorical scale. Level 1+ Only 5 patients receiving dipyrone needed rescue medication compared to 13 who were given tramadol and 11 who were given butylscopolamine. Adverse events were observed in 4 patients receiving butylscopolamine and 1 patient each given dipyrone and tramadol. Overall, 66% of patients in the dipyrone group rated efficacy of treatment as excellent or very good at the end of the 2 hour evaluation period compared to 41% of the tramadol group and 42% of the butylscopolamine group. R E P O R T Page 70 Schmieder, G et al 199362 Randomised controlled trial. [Source of funding not stated] Observer blind only. interfered with the mode of action of the study drugs. 74 patients suffering from ‘severe’ or ‘excruciating’ colic pain caused by a calculus in the bile duct. Multicentre (5 German centres) 72% female Mean age 57.5 years If 20mins after the first injection the study drug pain had not been adequate, a second IV injection of ‘rescue’ medication was given. Intervention Group: 100mg IV tramadol Control Group 1: 2.5g IV metamizole Control Group 2: 20mg IV butylscopolamine 25 Intervention Group 25 Control Group 1 24 Control Group 2 Exclusion Criteria: • <18 years • Pre-treatment with analgesics or spasmolytics during the last 24 hours. • Intolerance of the study drugs • Pre-existing diseases such as hepatic prophyria and prostatic adenoma • Pregnant or nursing women • Impaired compliance • Use of MAO inhibitors Metamizole was significantly more effective in reducing pain on VAS (p<0.05) than tramadol and butylscopolamine. Metamizole was also significantly better at reducing the sum of pain intensity differences (SPID) for the 2hr observation period (p<0.005). Level 1+ Observer blind only The mean time until the onset of analgesic action occurred was shortest (p<0.005) for metamizole (10.9±5.8min) compared with tramadol (15.8±11.7min) and butylscopolamine (25.6±24.3min). 3 patients in the metamizole group, 1 in the tramadol group and 8 in the butylscopolamine group needed a second injection of study medication (p=0.022). Two patients in the butylscopolamine group were prematurely withdrawn from the study because of lack of efficacy. In the patients overall assessment of treatment efficacy at the end of the trial, metamizole was rated as the most effective drug (p<0.005). Adverse events were reported in 3 patients each in the metamizole group (burning at the site of injection, mild blood pressure reduction) and the butylscopolamine group (nausea, dry mouth) and in 9 patients in the Accident Compensation Corporation D R A F T R E P O R T Page 71 Hogger, P and P Rohdewald, 199963 Double-blind randomised controlled cross-over study. 12 healthy human volunteers. Intervention: Tramadol 50mg [Medications provided by Georg A. Brenner Arzneimittel GmbH, Alpirsbach, Germany] Acute pain was generated by electrical tooth pulp stimulation. 50% female Mean age 25 years Control 1: 50mg tilidine + 4mg naloxone combination All medication was identical in appearance. Each volunteer had a one week wash-out period between each study drug. Rohdewald, P et al 198864 [Source of funding not stated] Double-blind randomised controlled trial. Cross over study design. Constant painful stimuli were applied by controlled electrical stimulation of tooth pulp. Exclusion Criteria: • Renal, hepatic or other disorders • Other medications used in the last 2 weeks or during study period (excluding contraceptives) 10 healthy volunteers. 40% female. Age range 23-36 years. Control 2: 25mg bromfenac The tilidine/naloxone combination was the most potent medication, followed by bromfenac 75mg which produced an early pain relief. Control 3: 50mg bromfenac Tramadol was least effective than tilidine/naloxone and 25mg and 75mg bromfenac. Control 4: 75mg bromfenac There was no dose-response relationship for bromfenac. Control 5: Placebo Adverse effects were reported in 3 volunteers on tramadol, and 9 on tilidine/naloxone. 25mg and 50mg bromfenac resulted in one subject each reporting an adverse effect. No adverse effects were reported for 75mg bromfenac or placebo. Intervention 1: 50mg tramadol Intervention 2: 100mg tramadol Control 1: 500mg metamizole Control 2: 1000mg metamizole Accident Compensation Corporation tramadol group (nausea, vomiting). Although not statistically significant, bromfenac 75mg and tramadol appeared superior to placebo. D R A F T R E P O R T Pain attenuation started as early as 30mins after bromfenac 75mg, although this was not significantly quicker than the other drugs. Higher analgesia was achieved by the 100mg dose of tramadol compared with all other medications. Significant differences between the curves of 50 and 100mg tramadol were noted at 2hours after drug application. 50mg tramadol and both 500mg and 1000mg doses of metamizole were not significantly different. Level 1Not enough subjects to reach statistical significance. A large placebo effect was seen. Tramadol 50mg is probably not a large enough dosage for this kind of study. Level 1+ Pain relief was limited to 3-4 hours Page 72 All drugs were given as oral solutions. for 100mg tramadol, this being the longest period of pain relief achieved. No side effects were reported after taking either dose of metamizole. 50mg tramadol caused a dry mouth in 2 cases from 40 to 120 minutes until the end of the measurement (240mins). 100mg tramadol evoked sleepiness in 1 volunteer from 40180 mins, dry mouth and weak sleepiness in 2 volunteers starting 40mins after drug intake until 240mins, the 4th volunteer had dryness of mouth, sleepiness and light nausea without vomiting from 1-7 hours following medication. APPENDIX 6: Meta-analyses and systematic reviews Table 16: Meta-analyses and systematic reviews Study Methods Participants Intervention Outcomes Comments and level of evidence Moore, RA and HJ McQuay 199765 Meta-analysis of patient data from RCT’s. Intervention Group 1: Oral tramadol 50mg Tramadol and comparator drugs gave significantly more analgesia than placebo. Level 1++ [funded by Grunenthal GmbH] 18 randomised, doubleblind, parallel group, single-dose trials with 3453 patients. People with moderate or severe pain after surgery or dental extraction. Accident Compensation Corporation Age range 18-70 years. Exclusion criteria: • Mild or no pain. • Those who had taken analgesic drugs within 3 hours of study drug administration. Intervention Group 2: Oral tramadol 75mg Intervention Group 3: Oral tramadol 100mg Intervention Group 4: Oral tramadol 150mg Intervention Group 5: D R A F T R E P O R T In post-surgical pain, NNT’s (and 95% CI’s) for >50% maxTOTPAR were: • Tramadol 50mg 7.1 (4.6-18) • Tramadol 100mg 4.8 (3.4-8.2) • Tramadol 150mg 2.4 Page 73 • • Those needing sedatives during the observation period. Those with known contraindications. 409 Intervention group 1 281 Intervention group 2 468 Intervention group 3 279 Intervention group 4 50 Intervention group 5 695 Control group 1 649 Control group 2 305 Control group 3 316 Control group 4 Scott LJ and CM Perry 200066 Systematic review [Adis Drug evaluation] Patients aged 18 to 84 years with perioperative moderate to severe pain who received tramadol Large (≥45 patients), wellcontrolled trials with appropriate statistical methodology were preferred. Included both inpatients and day surgery patients. Oral tramadol 200mg Control Group 1: Placebo Control Group 2: Codeine 60mg Control Group 3: Aspirin 650mg + codeine 60mg Control Group 4: Acetaminophen 650mg + propoxyphene 100mg Intervention Group: Tramadol Control Group 1: Morphine Control Group 2: Pentazocine Control Group 3: Alfentanil Control Group 4: Ketorolac Control Group 5: Propacetamol Accident Compensation Corporation D R A F T R E P O R T • • (2.0-31) Aspirin 650mg + codeine 60mg 3.6 (2.5-6.3) Acetaminophen 650mg + propoxyphene 100mg 4.0 (3.0-5.7). Different results were found for dental pain. With the exception of tramadol 100mg, NNT’s were lower in postsurgical pain than in dental pain. The most common adverse events associated with tramadol 50 and 100mg (headache, nausea, vomiting, dizziness, somnolence) had similar incidence to the comparator drugs. Oral and parenteral tramadol effectively relieved moderate to severe post-operative pain associated with surgery. Level 1++ Tramadol’s overall analgesic efficacy was similar to that of morphine or alfentanil and superior to pentazocine. Tramadol was generally well tolerated. The most common adverse events (with an incidence of 1.6-6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Tramadol was not associated with clinically relevant respiratory depression (unlike morphine, pethadine, Page 74 Medve, RA et al 200167 [Johnson Pharmaceutical Research Institute] Meta-analysis 3 centres each performed RCT’s, double-blind, parallel-group, active controlled, single dose trials with a placebo control. 1200 patients were enrolled and 400 patients were randomised equally to each site, with 5 groups each site. 1197 patients with moderate to severe pain following extraction of 2 or more third molars. Intervention Group 1: Single dose of tramadol/APAP (75mg/650mg) Mean age 21.4 years Age range 16-46 years 60.2% female Intervention Group 2: Single dose of tramadol 75mg 240 in each group Intervention Group 3: Single dose of APAP 650mg Control Group 1: Single dose of ibuprofen 400mg Control Group 2: Placebo oxycodone and nalbuphine). Pain relief and improved pain intensity were superior to placebo (p≤0.0001) for all treatments. Level 1++ Pain relief provided by tramadol/APAP was superior to that of tramadol or APAP alone or shown by mean TOTPAR8 (12.1 vs 6.7 and 8.6 respectively, p≤0.0001) and SPID8 (4.7 vs 0.9 and 2.7 respectively, p≤0.0001). Estimated onset of pain relief was 17mins (95% CI 15-20 mins) for tramadol/APAP compared with 51 mins (95% CI 40-70 mins) for tramadol, 18 mins (95% CI 16-21 mins) for APAP and 34 mins (95% CI 2844 mins) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (p<0.05) for the tramadol/APAP group than for the tramadol or APAP monotherapy groups. McQuay, H and J Edwards 200368 Meta-analysis. [Source of funding Accident Compensation Corporation Individual data from >1400 adult dental or gynaecologic/ orthopaedic patients with moderate to Intervention Groups: Tramadol 75mg or 112.5mg + acetaminophen 650mg or D R A F T R E P O R T Treatment-emergent adverse events were generally transient, mild to moderate in severity and were comparable in incidence between tramadol/APAP and tramadol groups. The tramadol + APAP combination was more effective than either of its two components administered alone. Level 1+ All trials were supplied for analysis Page 75 not stated] severe pain were taken from 7 randomised, double-blind, placebo-controlled trials of tramadol (75mg or 112.5mg) + acetaminophen (650mg or 975mg) with identical methods. 975mg Control Groups: Placebo 1376 patients with dental pain. 407 patients with gynaecologic pain. Edwards, J et al 200269 [Funded by R.W Johnson Pharmaceutical Research Institute, Raritan, New Jersey] Meta-analysis. 7 unpublished randomised, double-blind, placebo controlled trials were used which had identical methods. A MEDLINE search to April 2000 did not reveal any further trials to include. 8 hour observation period. 1783 adults with moderate or severe post-operative pain. Age range 16-83 years. 1376 patients with dental pain, 407 patients with post-surgical pain. Control Group 1: Tramadol 75mg Control Group 2: Tramadol 112.5mg Dental pain: 339 Placebo 339 Ibuprofen 337 Tramadol 75mg 340 APAP 650mg 340 Tramadol 75mg + APAP 650mg Control Group 3: Acetaminophen 650mg Control Group 4: Acetaminophen 975mg Post-surgical pain: 100 Placebo 98 Tramadol 112.5mg 100 APAP 975mg 101 Tramadol 112.5mg + APAP 975mg Accident Compensation Corporation Intervention Group: Single dose oral tramadol 75mg or 112.5mg + acetaminophen (APAP) 650mg or 975mg. Control Group 5: Ibuprofen 400mg Control Group 6: Placebo D R A F T For dental patients, the combination also had significantly better NNT (≈3) than the components alone (≈812). The adverse effects associated with tramadol + APAP were similar to those associated with the components alone. The most common adverse effects were dizziness, drowsiness, nausea, vomiting and headache. Dental pain: Combination tramadol + APAP had significantly lower (better) NNT’s than tramadol or APAP alone, and comparable efficacy to ibuprofen 400mg. The NNT for at least 50% pain relief with tramadol + APAP was 2.6 (2.3-3.0) compared to placebo over 6 hours and 2.9 (2.5-3.5) over 8 hours. 44% of patients who took the tramadol + APAP combination rated the treatment as Very Good or Excellent, compared to 10% in the placebo group. by The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA. Level 1+ All trials were supplied for analysis by The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA. All trials were unpublished. Well conducted study, all trials used the same methodology. Post-surgical pain: There were not enough people in this group to adequately assess this group. Adverse effects for tramadol + APAP were similar to tramadol alone. Common adverse effects R E P O R T Page 76 were dizziness, drowsiness, nausea and vomiting and headache. Fewer than 10% of patients withdrew from the individual studies for reasons other than early remedication or lack of efficacy. No more than 3 patients withdrew from each study due to adverse events. Accident Compensation Corporation D R A F T R E P O R T Page 77 APPENDIX 7: Characteristics of Papers Excluded from the Analysis of Clinical Effectiveness of Tramadol Study Reason for Exclusion Ekman, E and L Koman 200494 Elbourne, D and RA Wiseman 200395 Engelhardt, T et al 200396 Filippi, R et al 199997 Fu, Y-P et al 199198 Gandhe, U et al 199899 Goldsack, C et al 1996100 Gunduz, M et al 2001101 Gunes, Y et al 2004102 Gurses, E et al 2003103 Gritti, G et al 1998104 Analgesia given preoperatively. Abstract only. Included in Scott and Perry (2000) meta-analysis. Abstract only. Tramadol administered intra-operatively. Also included in Scott and Perry (2000) meta-analysis. Abstract only. Abstract only. Abstract only. Analgesia given intra-operatively. Study medication administered pre-operatively. Analgesia given preoperatively. Analgesia given intra-operatively. Abstract only. All patients received tramadol. Tramadol not covered. Included in Scott and Perry (2000) meta-analysis. Included in Moore and McQuay (1997) meta-analysis. Analgesia given intra-operatively. Included in Scott and Perry (2000) meta-analysis. Level 3 evidence. Included in Scott and Perry (2000) meta-analysis. This study did not examine pain relief. It examined gastric emptying. Duplicate of Delilkan A and R Vijayan 199357 This study did not examine pain relief. It examined post-operative shivering. This was also included in Scott and Perry (2000) meta-analysis. Tramadol not well covered. This study examined labour pain. Study of children. Dosages not explicit. All patients received tramadol. All patients received tramadol. Does not cover tramadol. Study of children. Study of children. All patients in this study received tramadol. Included in Scott and Perry (2000) meta-analysis. Alhashemi, J and A Kaki 200370 Amin, E et al 199071 Bamigbade, T et al 199872 Bourne, M et al73 Broome, IJ et al 199974 Brown, J et al 1992a75 Brown, J et al 1992b76 Brown, P et al 199077 Cafiero, T et al 200478 Cagney, B et al 199879 Chia, Y-Y and K Liu 199780 Chew, S et al 200381 Chrubasik, J et al 198782 Chrubasik, J et al 199283 Cohen, S et al 200484 Colletti, V et al 199885 Collins, M et al 199786 Colonna, U et al 200187 Coetzee J and H van Loggerenberg88 Coulthard, P et al 199689 Crighton, I M et al 199790 Crighton, I M et al 199891 Delilkan, A and R Vijayan 199392 DeWitte, J et al 199893 Accident Compensation Corporation D R A F T R E P O R T Page 78 Jain, S et al 2003105 James, M et al 1996106 Keskin, H et al 2003105 Kumara, R and M Zacharias 2002107 Kupers, R et al 1995108 Lanzetta, A et al 1998109 Lauretti, G et al 1997110 Lehmann, K et al 1990111 Lehmann, K 1994112 Lehmann, K 1997113 Lempa, M and L Kohler 1999114 Likar, et al 1999115 Liukkonen, K et al 2002116 Lone, N and S Qazi 2004117 McQuay, H and R Moore 1998118 Magrini, M et al 1998119 Manji, M et al 1997120 Memis, D et al 2002a121 Memis, D et al 2002b122 Moroz, B et al 1991123 Murphy, D et al 1997124 Naguib, M et al 1998125 Naguib, M et al 2000126 Ng, K et al 1997127 Nikolajsen, L and T Jensen 2001128 Ong, K and J Tan 2004129 Ozcan, S et al 2002130 Ozcengiz, D et al 2001131 Ozer, Z et al 2003a132 Ozer, Z et al 2003b133 Ozkan, S et al 2003134 Ozkocak, I et al 2002135 Ozkose, Z et al 2000136 Oztekin, S et al 2003137 Pang, W-W et al 1999138 Pang, W-W et al 2000a139 Pang, W-W et al 2000b140 Pang, W-W et al 2002141 Pang, W-W et al 2003142 Accident Compensation Corporation This study examined labour pain. Included in Scott and Perry (2000) meta-analysis. This study examined labour pain. Level 3 evidence. Included in Scott and Perry (2000) meta-analysis. Included in Scott and Perry (2000) meta-analysis. Included in Scott and Perry (2000) meta-analysis. Level 3 evidence. Review, not systematic. Not in English. Level 3 evidence. Included in Scott and Perry (2000) meta-analysis. Analgesia given preoperatively. Abstract only. Chapter in a book, refers to a paper already reviewed (Moore, R and H McQuay 199765). Included in Scott and Perry (2000) meta-analysis. Included in Scott and Perry (2000) meta-analysis. This study examined tramadol as a local anaesthetic. This study examined tramadol as a local anaesthetic. Level 3 evidence. This study does no assess analgesic efficacy. Included in Scott and Perry (2000) meta-analysis. Included in Scott and Perry (2000) meta-analysis. All patients received tramadol. Tramadol not covered. Analgesia given preoperatively. Analgesia given preoperatively. Study of children. Study of children. Comment on another study. Study of children. Not in English. Study of children. Does not assess the analgesic efficacy of tramadol. Included in Scott and Perry (2000) meta-analysis. All patients received tramadol. All patients received tramadol. All patients received tramadol. Tramadol administered intra-operatively before tramadol PCA. D R A F T R E P O R T Page 79 Pendeville, P et al 2000143 Peters, A et al 1996144 Phero, J et al 2004145 Pieri, M et al 2002146 Prasertssawat, P et al 1986147 Putland, AJ and A McCluskey148 Radbruch, L et al 1996149 Raff, M 1998150 Robaux, S et al 2004151 Robbins, L 2004152 Rodriguez, M et al 1993153 Roelofse, J and K Payne 1999154 Schecter, W et al 2002155 Schnitzer, T et al 2004156 Sekar, C et al 2004157 Shipton, E 2003158 Shipton, E et al 2003159 Soto, R and E Fu 2003160 Stamer, U et al 1997161 Stamer, U et al 1999162 Stubhaug, A et al 1995163 Sunshine, A et al 1992164 Tarkkila, P et al 1997165 Tarkkila, P et al 1998166 Tuncer, S et al 2003167 Unlugenc, H et al 2002168 Van den Berg, A et al 1998169 Van den Berg, A et al 1999170 Vanhelleputte, P et al 2003171 Verchere, E et al 2002172 Viegas, O at al 1993173 Viitanen, H and P Annila 2001174 Walder, B et al 2001175 Ward, M et al 1997176 Webb, AR et al 2002177 Wilder-Smith, CH et al 1998178 Wordliczek, J et al 2002179 Accident Compensation Corporation Study of children. Included in Scott and Perry (2000) meta-analysis. Review, not systematic. Level 3 evidence. Labour pain. Pre-operative analgesia versus ketorolac. Also included in Scott and Perry (2000) meta-analysis. Review, not systematic. Included in Scott and Perry (2000) meta-analysis. Analgesia given pre-operatively. Brief description of the study, methodology and results inadequate to extract necessary detail. Included in Scott and Perry (2000) meta-analysis. Study of children. Review, not systematic. Tramadol not well covered. Analgesia given preoperatively. Review, not systematic. Analgesia given preoperatively. Tramadol not well covered. Included in Scott and Perry (2000) meta-analysis. Study medication administered pre-operatively as well as post-operatively. Included in Moore and McQuay (1997) meta-analysis. Included in Moore and McQuay (1997) meta-analysis. This study does not assess analgesic efficacy. This study does not assess analgesic efficacy. Both groups given tramadol. All patients received tramadol. Study of children. This study does not assess analgesic efficacy, and includes children as well as adults. Analgesia given pre-operatively. Analgesia given intra-operatively. This study examined labour pain. Study of children. This systematic review only included one study of tramadol (20 patients). Level 2 evidence. All patients given morphine, some also given tramadol. Pre-operative analgesia, tramadol given to all patients post-surgery. All patients received tramadol. D R A F T R E P O R T Page 80 APPENDIX 8 Scottish Intercollegiate Guidelines Network Revised Grading System Levels of evidence 1++ High quality meta analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1 - Meta analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of case-control or cohort studies High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2 - Case control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4 Expert opinion Grades of recommendation At least one meta analysis, systematic review, or RCT rated as 1++, and directly A applicable to the target population; or A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results A body of evidence including studies rated as 2++, directly applicable to the target B population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ A body of evidence including studies rated as 2+, directly applicable to the target C population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++ Evidence level 3 or 4; or D Extrapolated evidence from studies rated as 2+ Good practice points best practice based on the clinical experience of the guideline 4 Recommended development group Accident Compensation Corporation D R A F T R E P O R T Page 81 APPENDIX 9 NZ Centre for Adverse Reactions Monitoring Causal Reactions to Tramadol, Compiled as of 31 December 2003 TRAMADOL (75 reports comprising 170 adverse reactions) Alimentary ANOREXIA CONSTIPATION DYSPEPSIA DYSPHAGIA GLOSSITIS MELAENA MOUTH DRY NAUSEA VOMITING 17 Application Site ISR ABCESS ISR PAIN 2 Cardiovascular BRADYCARDIA CHEST PAIN DIZZINESS HYPERTENSION HYPOTENSION TACHYCARDIA 21 Endocrine/Metabolic ANKLE OEDEMA HYPOGLYCAEMIA HYPONATRAEMIA OEDEMA DEPENDENT SIADH THIRST 6 Haematological HAEMATOMA 1 Liver HEPATIC ENZYMES INCREASED JAUNDICE 3 Nervous System BRADYKINESIA COMA CONVULSIONS CONVULSIONS GRAND MAL FAINTNESS FORMICATION HEADACHE 24 2 1 1 1 1 1 1 6 3 1 1 2 2 6 3 3 5 1 1 1 1 1 1 1 2 1 Accident Compensation Corporation 1 1 2 3 3 1 1 D R A F T R E P O R T Page 82 HYPERTONIA MUSCLE WEAKNESS SEROTONIN SYNDROME SOMNAMBULISM TREMOR VERTIGO 1 1 1 1 6 2 Others 21 DRUG WITHDRAWAL SYNDROME FALL FEELING OF WARMTH FLUSHING HYPERREFLEXIA OEDEMA PERIORBITAL PAIN LIMB PALLOR SWEATING INCREASED THERAPEUTIC RESPONSE INADEQUATE 1 1 1 3 1 1 1 1 10 1 Psychiatric Changes 41 AGITATION ANXIETY ASTHENIA CONCENTRATION IMPAIRED CONFUSION DELIRIUM DEMENTIA DEPERSONALIZATION DEPRESSION DEPRESSION AGGRAVATED DRUG DEPENDENCE (NARCOTIC) DRUG INTERACTION HALLUCINATION ILLUSION MALAISE SOMNOLENCE SUICIDAL TENDENCY WITHDRAWAL SYNDROME 3 2 1 1 4 2 2 2 1 1 1 9 2 1 1 3 1 4 Respiratory BRONCHOSPASM AGGRAVATED DYSPHONIA DYSPNOEA HYPERVENTILATION HYPOXIA RESPIRATORY DEPRESSION 9 1 1 3 1 1 2 Skin and Appendages ANGIOEDEMA DERMATITIS LICHENOID PRURITUS RASH 21 Accident Compensation Corporation 1 1 8 4 D R A F T R E P O R T Page 83 RASH MACULO-PAPULAR RASH PRURITIC RASH VESICULAR URTICARIA 2 3 1 1 Special Senses PHOTOPHOBIA 1 Urinary URINARY RETENTION 3 TOTAL 1 3 170 Accident Compensation Corporation D R A F T R E P O R T Page 84 APPENDIX 10 Search Strategy Search Strategy used for Embase. Date: 1/9/04 Database: EMBASE <1988 to 2004 Week 35> Search Strategy: -------------------------------------------------------------------------------1 exp PAIN RECEPTOR/ or exp PAIN PARAMETERS/ or exp LABOR PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME TYPE II/ or exp MYOFASCIAL PAIN/ or exp INJECTION PAIN/ or exp BONE PAIN/ or exp ANKLE PAIN/ or exp INTRACTABLE PAIN/ or exp HEEL PAIN/ or exp SHOULDER PAIN/ or exp NECK PAIN/ or exp LOW BACK PAIN/ or exp POSTTRAUMATIC PAIN/ or exp KNEE PAIN/ or exp GENITAL PAIN/ or exp TOOTH PAIN/ or exp LIVER PAIN/ or exp EYE PAIN/ or exp PELVIS PAIN SYNDROME/ or exp FACE PAIN/ or exp THORAX PAIN/ or exp RADICULAR PAIN/ or exp LEG PAIN/ or exp STOMACH PAIN/ or exp ABDOMINAL PAIN/ or exp FOOT PAIN/ or exp LIMB PAIN/ or exp PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME TYPE I/ or exp URETHRAL PAIN/ or exp POSTPARTUM PAIN/ or exp PHANTOM PAIN/ or exp VISCERAL PAIN/ or exp EPIGASTRIC PAIN/ or exp PSYCHOGENIC PAIN/ or exp FLANK PAIN/ or exp SUBSTERNAL PAIN/ or exp "HEADACHE AND FACIAL PAIN"/ or exp POSTOPERATIVE PAIN/ or exp DEAFFERENTATION PAIN/ or exp PAIN THRESHOLD/ or exp SPINAL PAIN/ or ! exp PLEURAL PAIN/ or exp RETROSTERNAL PAIN/ or exp KIDNEY PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME/ (197661) 2 chronic pain/ 3 acute pain/ 4 2 not (2 and 3) 5 1 not 4 6 tramadol.mp. or exp TRAMADOL/ 7 tramal/ 8 ultracet.af. 9 or/6-8 10 5 and 9 11 limit 10 to (human and english language) 12 Clinical trial/ 13 Randomized controlled trial/ 14 Randomization/ 15 Single blind procedure/ 16 Double blind procedure/ 17 Crossover procedure/ 18 Placebo/ 19 Randomi?ed controlled trial$.tw. 20 Rct.tw. 21 Random allocation.tw. 22 Randomly allocated.tw. 23 Allocated randomly.tw. 24 (allocated adj2 random).tw. 25 Single blind$.tw. 26 Double blind$.tw. 27 ((treble or triple) adj blind$).tw. 28 Placebo$.tw. (66964) Accident Compensation Corporation D R A F T R E P O R T Page 85 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 Prospective study/ or/12-29 Case study/ Case report.tw. Abstract report/ or letter/ or/31-33 30 not 34 Meta-Analysis/ meta analy$.tw. metaanaly$.tw. meta analysis.pt. (systematic adj (review$1 or overview$1)).tw. (5080) exp Review Literature/ or/36-41 cochrane.ab. embase.ab. (psychlit or psyclit).ab. (psychinfo or psycinfo).ab. (cinahl or cinhal).ab. science citation index.ab. bids.ab. cancerlit.ab. or/43-50 reference list$.ab. bibliograph$.ab. hand-search$.ab. relevant journals.ab. manual search$.ab. or/52-56 selection criteria.ab. data extraction.ab. 58 or 59 (review or review literature).pt. 60 and 61 comment.pt. letter.pt. editorial.pt. animal/ human/ 66 not (66 and 67) or/63-65,68 42 or 51 or 57 or 62 70 not 69 35 or 71 11 and 72 Accident Compensation Corporation D R A F T R E P O R T Page 86 Search strategy used for the following databases. Date: 27/8/04 Database: CDSR, ACP Journal Club, DARE, CCTR, CINAHL, Ovid MEDLINE(R) InProcess, Other Non-Indexed Citations, Ovid MEDLINE(R), Ovid MEDLINE(R) Daily Update, PsycINFO Search Strategy: -------------------------------------------------------------------------------1 exp Analgesics, Opioid/ or exp Pain Measurement/ or exp Pain, Postoperative/ or exp Analgesics/ or exp Pain/ or acute pain.mp. or exp Pain Clinics/ or exp Analgesia/ 2 tramadol.mp. or exp TRAMADOL/ 3 tramal.mp. 4 ultracet.mp. 5 or/2-4 6 1 and 5 7 limit 6 to (human and english language) [Limit not valid in: CDSR,ACP Journal Club,DARE,CCTR,CINAHL,Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations; records were retained] 8 exp clinical trials/ 9 Clinical trial.pt. 10 (clinic$ adj trial$1).tw. 11 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$3 or mask$3)).tw. 12 Randomi?ed control$ trial$.tw. 13 Random assignment/ 14 Random$ allocat$.tw. 15 Placebo$.tw. 16 Placebos/ 17 Quantitative studies/ 18 Allocat$ random$.tw. 19 or/8-18 20 Meta analysis/ 21 Meta analys$.tw. 22 Metaanaly$.tw. 23 exp Literature review/ 24 (systematic adj (review or overview)).tw. 25 or/20-24 26 Commentary.pt. 27 Letter.pt. 28 Editorial.pt. 29 Animals/ 30 or/26-29 31 25 not 30 32 guideline.pt. 33 practice guideline.pt. 34 exp guidelines/ 35 health planning guidelines/ 36 guideline$.ti. 37 or/32-36 38 Randomized controlled trials/ 39 Randomized controlled trial.pt. 40 Random allocation/ 41 Double blind method/ Accident Compensation Corporation D R A F T R E P O R T Page 87 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 Single blind method/ Clinical trial.pt. exp clinical trials/ or/38-44 (clinic$ adj trial$1).tw. ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. Placebos/ Placebo$.tw. Randomly allocated.tw. (allocated adj2 random).tw. or/46-51 45 or 52 Case report.tw. Letter.pt. Historical article.pt. Review of reported cases.pt. Review, multicase.pt. or/54-58 53 not 59 Meta-Analysis/ meta analy$.tw. metaanaly$.tw. meta analysis.pt. (systematic adj (review$1 or overview$1)).tw. exp Review Literature/ or/61-66 cochrane.ab. embase.ab. (psychlit or psyclit).ab. (psychinfo or psycinfo).ab. (cinahl or cinhal).ab. science citation index.ab. bids.ab. cancerlit.ab. or/68-75 reference list$.ab. bibliograph$.ab. hand-search$.ab. relevant journals.ab. manual search$.ab. or/77-81 (13892) selection criteria.ab. data extraction.ab. 83 or 84 (review or review literature).pt. 85 and 86 comment.pt. letter.pt. editorial.pt. animal/ human/ 91 not (91 and 92) Accident Compensation Corporation D R A F T R E P O R T Page 88 94 95 96 97 98 99 100 101 102 103 or/88-90,93 67 or 76 or 82 or 87 95 not 94 19 or 31 or 37 or 60 or 96 7 and 97 chronic pain.mp. acute pain.mp. 99 not (99 and 100) 98 not 101 remove duplicates from 102 Database: CDSR, ACP Journal Club, DARE, CCTR, CINAHL, Ovid MEDLINE(R) In-Process, Other NonIndexed Citations, Ovid MEDLINE(R), Ovid MEDLINE(R) Daily Update, PsycINFO Search Strategy (27-8-04): -------------------------------------------------------------------------------1 exp Analgesics, Opioid/ or exp Pain Measurement/ or exp Pain, Postoperative/ or exp Analgesics/ or exp Pain/ or acute pain.mp. or exp Pain Clinics/ or exp Analgesia/ (551652) 2 tramadol.mp. or exp TRAMADOL/ (1749) 3 tramal.mp. (108) 4 ultracet.mp. (5) 5 or/2-4 (1758) 6 1 and 5 (1347) 7 limit 6 to (human and english language) [Limit not valid in: CDSR,ACP Journal Club,DARE,CCTR,CINAHL,Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations; records were retained] (954) 8 exp clinical trials/ (220665) 9 Clinical trial.pt. (632537) 10 (clinic$ adj trial$1).tw. (119163) 11 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$3 or mask$3)).tw. (176764) 12 Randomi? ed control$ trial$.tw. (41634) 13 Random assignment/ (7815) 14 Random$ allocat$.tw. (20347) 15 Placebo$.tw. (187701) 16 Placebos/ (41338) 17 Quantitative studies/ (1884) 18 Allocat$ random$.tw. (4297) 19 or/8-18 (870037) 20 Meta analysis/ (11610) 21 Meta analys$.tw. (23248) 22 Metaanaly$.tw. (733) 23 exp Literature review/ (17413) 24 (systematic adj (review or overview)).tw. (11924) 25 or/20-24 (52554) 26 Commentary.pt. (35918) 27 Letter.pt. (545049) 28 Editorial.pt. (219406) 29 Animals/ (3681617) 30 or/26-29 (4417691) 31 25 not 30 (48257) 32 guideline.pt. (12442) 33 practice guideline.pt. (8296) 34 exp guidelines/ (41572) 35 health planning guidelines/ (1791) 36 guideline$.ti. (31654) 37 or/32-36 (72699) 38 Randomized controlled trials/ (57560) 39 Randomized controlled trial.pt. (366707) 40 Random allocation/ (71409) 41 Double blind method/ (141026) Accident Compensation Corporation D R A F T R E P O R T Page 89 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 Single blind method/ (13176) Clinical trial.pt. (632537) exp clinical trials/ (220665) or/38-44 (760736) (clinic$ adj trial$1).tw. (119163) ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. (176764) Placebos/ (41338) Placebo$.tw. (187701) Randomly allocated.tw. (17136) (allocated adj2 random).tw. (1447) or/46-51 (379497) 45 or 52 (883504) Case report.tw. (117192) Letter.pt. (545049) Historical article.pt. (210676) Review of reported cases.pt. (50388) Review, multicase.pt. (8548) or/54-58 (914568) 53 not 59 (861960) Meta-Analysis/ (11610) meta analy$.tw. (24280) metaanaly$.tw. (733) meta analysis.pt. (9886) (systematic adj (review$1 or overview$1)).tw. (13871) exp Review Literature/ (2109) or/61-66 (42944) cochrane.ab. (9282) embase.ab. (6134) (psychlit or psyclit).ab. (1429) (psychinfo or psycinfo).ab. (1115570) (cinahl or cinhal).ab. (7108) science citation index.ab. (888) bids.ab. (430) cancerlit.ab. (429) or/68-75 (1129813) reference list$.ab. (4059) bibliograph$.ab. (8212) hand-search$.ab. (1902) relevant journals.ab. (400) manual search$.ab. (845) or/77-81 (13892) selection criteria.ab. (11864) data extraction.ab. (4962) 83 or 84 (15499) (review or review literature).pt. (1093960) 85 and 86 (5663) comment.pt. (264403) letter.pt. (545049) editorial.pt. (219406) animal/ (3683869) human/ (8831420) 91 not (91 and 92) (2825683) or/88-90,93 (3599138) 67 or 76 or 82 or 87 (1166134) 95 not 94 (1163272) 19 or 31 or 37 or 60 or 96 (2086793) 7 and 97 (662) chronic pain.mp. (16550) acute pain.mp. (3070) 99 not (99 and 100) (15957) 98 not 101 (627) remove duplicates from 102 (400) Accident Compensation Corporation D R A F T R E P O R T Page 90 Database: EMBASE <1988 to 2004 Week 35> Search Strategy: -------------------------------------------------------------------------------1 exp PAIN RECEPTOR/ or exp PAIN PARAMETERS/ or exp LABOR PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME TYPE II/ or exp MYOFASCIAL PAIN/ or exp INJECTION PAIN/ or exp BONE PAIN/ or exp ANKLE PAIN/ or exp INTRACTABLE PAIN/ or exp HEEL PAIN/ or exp SHOULDER PAIN/ or exp NECK PAIN/ or exp LOW BACK PAIN/ or exp POSTTRAUMATIC PAIN/ or exp KNEE PAIN/ or exp GENITAL PAIN/ or exp TOOTH PAIN/ or exp LIVER PAIN/ or exp EYE PAIN/ or exp PELVIS PAIN SYNDROME/ or exp FACE PAIN/ or exp THORAX PAIN/ or exp RADICULAR PAIN/ or exp LEG PAIN/ or exp STOMACH PAIN/ or exp ABDOMINAL PAIN/ or exp FOOT PAIN/ or exp LIMB PAIN/ or exp PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME TYPE I/ or exp URETHRAL PAIN/ or exp POSTPARTUM PAIN/ or exp PHANTOM PAIN/ or exp VISCERAL PAIN/ or exp EPIGASTRIC PAIN/ or exp PSYCHOGENIC PAIN/ or exp FLANK PAIN/ or exp SUBSTERNAL PAIN/ or exp "HEADACHE AND FACIAL PAIN"/ or exp POSTOPERATIVE PAIN/ or exp DEAFFERENTATION PAIN/ or exp PAIN THRESHOLD/ or exp SPINAL PAIN/ or ! exp PLEURAL PAIN/ or exp RETROSTERNAL PAIN/ or exp KIDNEY PAIN/ or exp COMPLEX REGIONAL PAIN SYNDROME/ (197661) 2 chronic pain/ (8752) 3 acute pain/ (38387) 4 2 not (2 and 3) (7709) 5 1 not 4 (189952) 6 tramadol.mp. or exp TRAMADOL/ (3033) 7 tramal/ (3003) 8 ultracet.af. (13) 9 or/6-8 (3034) 10 5 and 9 (1737) 11 limit 10 to (human and english language) (1015) 12 Clinical trial/ (304639) 13 Randomized controlled trial/ (87295) 14 Randomization/ (11879) 15 Single blind procedure/ (4859) 16 Double blind procedure/ (48204) 17 Crossover procedure/ (15215) 18 Placebo/ (46099) 19 Randomi?ed controlled trial$.tw. (14098) 20 Rct.tw. (913) 21 Random allocation.tw. (397) 22 Randomly allocated.tw. (6249) 23 Allocated randomly.tw. (1052) 24 (allocated adj2 random).tw. (365) 25 Single blind$.tw. (4431) 26 Double blind$.tw. (51199) 27 ((treble or triple) adj blind$).tw. (80) 28 Placebo$.tw. (66964) 29 Prospective study/ (39799) 30 or/12-29 (395503) 31 Case study/ (1734) 32 Case report.tw. (67277) 33 Abstract report/ or letter/ (281584) 34 or/31-33 (349407) 35 30 not 34 (382631) 36 Meta-Analysis/ (18927) 37 meta analy$.tw. (9963) 38 metaanaly$.tw. (663) 39 meta analysis.pt. (0) 40 (systematic adj (review$1 or overview$1)).tw. (5080) 41 exp Review Literature/ (5346) 42 or/36-41 (31575) 43 cochrane.ab. (1644) 44 embase.ab. (1448) 45 (psychlit or psyclit).ab. (311) Accident Compensation Corporation D R A F T R E P O R T Page 91 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 (psychinfo or psycinfo).ab. (323) (cinahl or cinhal).ab. (389) science citation index.ab. (286) bids.ab. (131) cancerlit.ab. (193) or/43-50 (3420) reference list$.ab. (991) bibliograph$.ab. (3311) hand-search$.ab. (528) relevant journals.ab. (72) manual search$.ab. (492) or/52-56 (4927) selection criteria.ab. (2904) data extraction.ab. (2504) 58 or 59 (5336) (review or review literature).pt. (515891) 60 and 61 (2011) comment.pt. (0) letter.pt. (270434) editorial.pt. (128091) animal/ (7054) human/ (3895330) 66 not (66 and 67) (5706) or/63-65,68 (404102) 42 or 51 or 57 or 62 (37279) 70 not 69 (34289) 35 or 71 (398251) 11 and 72 (477) Accident Compensation Corporation D R A F T R E P O R T Page 92 APPENDIX 11-CHARACTERISTICS OF STUDIES INCLUDED SUMMARY OF STUDIES INCLUDED IN TRAMADOL ACUTE REPORT. A SUMMARY OF TYPE OF TRIALS AND FINDINGS. Authors Drug study Route of administration Situation for pain relief Effectiveness of Tramadol Treatment Hospital setting? Length of treatment Treatment after trial? Gong Z Tramadol vs Morphine Injection Abdominal hysterecto my Morphine in the first 24 hours compared to the intervention group (n=90) and with more or less equal but minimial and insignificant adverse short term effects. 100mg ampule Tramadol versus 10mg ampule Morphine Yes - post op 24 hours Not mentioned Canepa Tramadol versusNisid in Parenterally Abdominal Surgery Tramadol superior Yes 3 days Not mentioned More adverse events reported in the Tramadol group Vickers Tramadol versus Morphine IV Abdominal Surgery Higher % responder rates for Morphine versus Tramadol 100mg/2mL Tramadol, 3 vials per day first 3 days, 1M2mL 3 vials per day first 3 day s 100mg tramadol vs 5mg morphine repeats doses after 90min Yes-post op 24 hours Not mentioned High level of gastrointestinal adverse events. Accident Compensation Corporation D R A F T R E P O R T Page 93 Notes - Side Effects Delikan Tramadol versus bupivacain e epidural Abdominal Surgery Tramadol 100mg most effective Unlugene Tramadol versus Morphine IV Abdominal Surgery First 24 hours Morphine is better. After that NSD Likar Tramadol vs Morphine Intra-Articularly Arthroscopi c Surgery Staunstru p Tramadol vs Lornixicam Oral Yaddanap udi Tramadol versus Morphine Epidural Silvasti Tramadol versus Morphine IV Arthroscopi c reconstructi on-knee Back surgery (Laminecto my) Breast reconstructi on Zimmerm ann Tram/drope ridol vs Morphine + droperidol IV Cardiac Surgery Accident Compensation Corporation 50mg tramadol, 100mg tramadol 10ml bupivacaine 0.25% 1mg kg-1 Tramadol vs morphine 0.1mg kg -1 Yes 24 hours Not mentioned Higher incidence of vomiting and nausea with group 2. Yes 24 hours Not mentioned Morphine superior to Tramadol 2 hrs after surgery Tramadol 10 mg/ 1mg Morphine Yes -post op 12 hours Not mentioned Tramadol offered after induction of anaesthesia offered equivalent post op pain releif. Further trials recommended to confirm this study. Lornixicam superior 16mg Lornixicom vs 100mg Tramadol 3mg Morphine versus 50mg tramadol Yes 8 hours Not mentioned Yes-post op 24 hours Not mentioned Tramadol (10mg) vs Morphine (1mg). Yes - post op 24 hours Not mentioned morphine 1mg/ml+ 0.1mg/mL vs Tramadol 10mg/ml + 0.1 mg/mLdop Yes 24 hours Not mentioned NSD NSD Nausea and vomiting greater in Tramadol. NSD D R A F T R E P O R T Page 94 Tramadol reported more side effects cf to Lornixicam. Respiratory depression not observed with either groups. Both groups low incidence of nausea. SaddickSayyid Tramadol vs placebo IV Caesarean Tramadol superior to placebo 100mg/200mg tramadol Yes 24 hours Not mentioned Vercauter en Tramadol vs other opioid Oral Caesarean Combination of tramadol and sufenail superior to either alone 123.5ug Sufentanil + 652mg Tramadol Yes 24 hour dose Not mentioned WilderSmith Tramadol vs Diclofenac. IV Caesarean Tramadol/Dicl ofenac superior to Tramadol or Diclofenac alone. 100mg Tram vs 75mg diclofenac Yes 17 hours Not mentioned Houmes Tramadol vs morphine IV Gynacologi cal Morphine better in first 2 hours. Yes 6 hours Not mentioned Torres Tramadol vs Dipyrone IV Hysterecto my nsd Yes 24 hours Not mentioned Ilias Tramadol vs Lornixicam IV Hysterecto my nsd 50mg Tramadol versus 5mg of Morphine 500mg Tramadol vs 8g dipyrone 4mg and 8mg Lornoxicam vs 50mg Tramadol Yes 24 hours Not mentioned Mais Tramadol vs Ketorolac IV Hysterecto my nsd 100mg tramin 2ml 2 Xper day versus 30mg/1mL 3 amps per day. Yes 3 days Not mentioned Accident Compensation Corporation D R A F T R E P O R T Page 95 In the tramadol groups,. There were more side effects, -nausea and vomiting plus, high dose requirements. Side effects similar in all groups. Tramdol produced more nausea and side effects. 8mg Lornixicam as effective as 50mg Tramadol. Loroxicam has a more favourable profile. Similar side effects Jeffrey Codeine versus Tramadol IM Intracranial Surgery Codeine superior to tramadol- 50mg Tramadol vs 60mg codeine IM Yes 48 hours Tramadol not prescribed Side effects worse with Tramadol Eray Tramadol vs Meperidine IV Renal Colic Pain NSD 50mg IV over 1 min vs 50mg IV over 1 min Yes 30 mins initially meperidine the rescue medication after 30 mins NSD between side effects for each group Schmeide r Metamizole vs tramadol vs butylscopol amine IV Acute Colic Pain Metamizole more effective than tramadol or butylscopolami ne Yes 2hour observation period Not mentioned Spasmoyltic effect of dipyrone on the smooth muscles may help. Stankov Dipyrone vs tramadol vs buyylscopol amine IV Renal colic dipyrone more effective than other drugs 2.5g metamizole, 100mg tramadol, 20mg butylscopolami ne 2.5g dipyrone, 100mg tramadol, 20mg butylscopolami ne, Yes 50 minutes Not mentioned Spasmoyltic effect of dipyrone on the smooth muscles may help. Moore Tram vs codeine vs asprin Oral Dental-post surgical extraction Tramadol superior to placebo ? 6 hour study Not mentioned Fricke Tram/APAP vs Tramadol Oral Dental Tramadol/APA P superior to Tramadol alone. 75mg tramadol + 650mg APAPvs 50mg Tramadol Post surgical setting 6 hour study Not mentioned Moore Tram vs codeine, vs codeine/AS P vs placebo Oral Dental All better than placebo, Codeine aSP better 100mg Tramadol, 50mg Tramadol, 60mg codeine, ? 6 hour study Not mentioned Accident Compensation Corporation D R A F T R E P O R T Page 96 Side effects worse with Tramadol 650mgasp/cod 60mg Doroscha k Flurbiprofe n /Tramadol vs each alone Oral Endodontic Pain Combined is superior Medve Tramadol/A PAP vs either alone Oral Dental extraction Combination of tramadol/APA P is superior to either alone Moore oral tram vs placebo, codeine and other combinatio n analgesics Oral Dental extraction Traamdol superior to placebo in both surgical and dental pain Grace Tramadol vs morphine IV Knee replacemen t Kayacan Tramadol vs neostigmin e. Tenoxicam and bupivacain Oral Knee surgery Accident Compensation Corporation 100mg flurbiprofen then 50mg every 6h, tramadol 100mg every 6h. Tramadol/APA P (75mg/650mg) , tramadol75mg, iboprofen 400mg 50mg and 100mg Tramadol Dental School 24 hours Not mentioned Research Insitotute 3-4hours Not mentioned Time of onset much faster about 17 minutes University 24 hours Not mentioned Side effects worse with Tramadol in post dental extraction Morphine superior Tram 50mg, 100mg vs morphine sulphate 2mg Yes - post op 24 hous Not mentioned Tramadol maybe better in less severe pain. nsd between any treatment 0.5mg neo vs 100mg tram vs 20mg teno, vs 0.5% bupivicane Yes 24 hours Not mentioned No severe complications reported with any drug D R A F T R E P O R T Page 97 e Subash Tramdol vs bupivacain e, b+pethidine , b+ tramadol Injection Surgery under lumber epidural surgery nsd : Tramadol is as efficient as pethidine Zasckova Tramadol vs Ketorolac Oxycodone versus Tramadol IV Maxillofacia l Surgery NSD IV Maxillofacia l Surgery NSD Turturro Tramadol vs Hydrocodo ne Oral Muscoskele tal Pain Tramadol inferior to Hydrocodone Pagliara Tramadol vs diclofenac sub cutaneous Tramadol vs SCT Morphine Oral Muscoskele tal Tramadol superior Suppositories Orthopaedi c Nsd. More side effects with Tramadol. Silvasti Hopkins Accident Compensation Corporation D R A F T 0.5% bupivacaine, 0.5% bup+50mg peth, 0.5%bup+ 50mg tramadol 100mg iv vs ketorolac 30mg. PCA Tramadol 10mg or Oxycodone 1mg 100mg Tramadol vs 5mg hydrocodone+ 500mg acetaminophe n 200mg/d (both) Yes 24 hours Not mentioned Similar side effects in both groups Yes 24hours Not mentioned Yes -post op 24 hours Not mentioned Similar side effects in both groups. Nausea slightly greater in the Tramadol group. Yes - 180 minutes Not mentioned No difference between side effects. Yes 7 days Not mentioned First 24 hours 792 mg tramadol, 42 mg morphine. Yes post op 72 hours Not mentioned Efficacy and safety in favour of tramadol. Tramadol side effects similar to Morphine. R E P O R T Page 98 Tarradell Meperidine vs Tramaadol IV Orthopaedi c NSD in analgesic properties 100mg tramadol 100mg meperidine Saline Yes -post op 4 hours Bloch Tramadol vs morphine Paracetam ol IV Post Thoracesto my Thyroidecto my NSD 150mg IV Tramadol vs 2mg morphine 1.5mg/kg of Tramadol Yes 24 hours Yes 24 hours Eroclay Tramadol vs Morphine IV Post Thoracesto my NSD 48mg Morphine vs 493 mg Tramadol. Yes -post op 24 hours Not mentioned Pluim Tramadol vs codeine/AP AP Suppositories Post operative Pain NSD 100mg every 6 hours Tramadol vs 1000mgPara/2 0mg codeine Yes 42 hours Not Mentioned Ng Tramadol versus Morphine IV Post Operative Pain 1mg morphine versus 10mg of tramadol Yes-post op 36 hours Not mentioned Baraka Tramadol vs epidural morphine Epidural Post operative Pain NSD apart from side effects which were higher in Tramadol group. NSD 100mg Tramadol vs 4mg Morphine Yes -post op 10 hours Not mentioned Dejonckhe ere IV Accident Compensation Corporation Superior to Propacetamol during the first 6 hours. D R A F T R E P O R T Page 99 Not mentioned Respiratory depression observed and sedation with meperidine not with Tramadol. Not Tramadol just as mentioned effective as Morphine. Residual pain treated with morphine Post Thoractemy patients experience difficulty breathing, that is why tramadol is considered over opioids Tramadol not included in hospital formularly More side effects with Tramadol versus Morphinemainly nausea and dizziness. Rosenthal Tramadol/A PAP vs Codeine/A PAP IV Post Surgical Pain Tramadol/APA P more effective 37.5mg Tram + 325mg APAP Yes 6 days Not mentioned Similar side effects to Morphine. Vergnion Tramadol versus Morphine IV Post traumatic pain 100mg Tramadol vs 5mg Morphine No-pre hospital 6 hours Not mentioned Tramadol is a good alternative to Morphine Thienthon g Tramadol vs placebo Oral Radical Masectomy NSD Nausea an dvomiting worse in tramdol group Tramadol superior to Placebo. Yes -post op 12 hours Tramadol/ metamizol vs Oxycodone Oral/IV Retinal Surgery CRO superior in terms of pain relief and side effects Yes post op 24 hours Morphine used if tramadol not successful Not mentioned 100mg Tramadol no enough for severe pain. Kaufman 100mg tram given 1 hour prior to surgery reeat 12 hours later 10mg CRO every 12 hours vs 100g tramadol+ 1g Metamizol. Mahadeva n Tramadol vs Placebo Oral Tramadol superior to Placebo. 1mg/kg Yes 1 hour 24 hour check up. Weibalk Tramadol vs Morphine IV Right Lower Quadrant Pain (Acute appendicitis ) Severe post op pain NSD 292.5mg tramadol versus 27mg Morphine Yes 135 minutes Not mentioned Rhodewal d Tramadol vs Metamizol. Oral Stimulated Pain 100mg Tramadol most effective 50 and 100mg Tramadol, 500 and 1000mg Metamizole University 240 minutes Not mentioned Courtney Tram HCl vs Oral diclofenac Sodium Oral Tonsillecto my NSD 200mg Tram per day vs 150mg Diclofenac Yes 14 days Not mentioned Accident Compensation Corporation D R A F T R E P O R T Page 100 Control released Oxycodone superior. Tramadol experienced fewer side effects than Morphine patients. Pain releif limited to 3-4 hours with 100mg Tramadol Aribogan Tram vs tramadol + bupivacain e Dipyrone vs Tramadol IV Urological Surgery Combination superior to either alone 1mg/ml tram+ 0.125% bupivacaine Yes 24 hours Not mentioned IV Urological Surgery Dipyrone superior to tramadol in reducing pain. 2.5g dipyrone vs 100mg Tramadol Yes 24 hours Not mentioned Tramadol vs metamizol vs acetaminop hen Tramadol/A PAP vs Hydrocodo ne/APAP Bromfenac Sodium vs Tramadol Oral Hand Surgery (Ambulator y) Tramadol superior to other analgsics 100mg every 6 hours Yes 48 hours Not mentioned Very high analgesic effects with tramadol cf to other drugs Oral Oral Surgery NSD ? Post Dental extraction 8 Hours Not mentioned Oral Oral Surgery Bromfenac superior to Tramadol 37.5mgtram+3 25mgAPAP vs 10mg Cod+ 650mgACAP 25mg or 50mg Bromfenac vs Tramadol 100mg ?-Dental 8 hours Not mentioned Comparable to Hydrocodone but with better tolerability. Single oral doses of Bromofenac were superior to Tramadol, they were longer acting and better tolerated. Desjardins Bromfenac vs Tramadol Oral Oral surgery Bromfenac 25mg or 50mg superior to Tramadol 100mg 25mg or 50mg Bromfenac vs Tramadol 100mg ?-Dental 8 hours Not mentioned Darwish bupivacain e vs tramadol. IV vs intraperioteneal Laparoscop ic Surgery Intraperiteneal bupivacaine superior to IV tramadol 2mg/kg tram vs 20ml of 0.25% bupivacaine Yes 240 mins Not mentioned Stankov Rawal Fricke Mehlisch Accident Compensation Corporation D R A F T R E P O R T Page 101 Side effects similar with both groups and combinations Similar side effects in both groups. Hoogewijs Tramadol vs paracetamo l, vs piritriamide vs diclofenac Tilidine/nal oxone vs tramadol vs bromefenac IM, and IV Peripheral Injury nsd between parac, tramadol and diclofenac. Oral Stimulated Pain Tilidine/Naloxo ne McQuay Tramadol/A PAP vs each alone Oral Metanalysis Combination superior to either alone Edwards Tramadol/A PAP vs each alone Oral Meta analysis Tram +APAP superior in combination Dugan Tramadol versus Morphine IV Post Surgical Pain NSD but a significant saving in cost (nurse time) Smith Tramadol vs Codeine vs Placebo Oral Post Surgical Pain Tram +APAP superior to placebo, NSD between Tram/APAP and Codeine/APAP Hogger Accident Compensation Corporation D R A F T 20mg/kgpara, 0.25mg tramadol, 1mg/kg tramadol, 1mg/kg diclofenac brom20, 50 and 75mg, 50mg tildine+4mg Naloxone, 50mg tram, Yes 1hour Not mentioned Piritramide their were more side effects. Yes -Clinical trial 300 minutes Not mentioned Hardly any side effects with any group. Tram 75mg or 112.5mg +APAP 650mgor975m g Tram 75mg or 112.5mg +APAP 650mgor975m g 2 X 100mg Tram vs 2 X 10mg Morphine Yes -post op pain 8 hours Not mentioned Yes-post op pain 8 hours Not mentioned Yes ? Not mentioned Adverse effects similar. Gynacoogical and post dental pain were researched. Adverse effects similar for combination and individual components. Savings in using Tramdol post surgically versus Morphine 325mg APAP+37.5mg APAP, Codeine 30mg +300mg Codeine Yes 6 days Not mentioned R E P O R T Page 102 Vickers Tramadol versus Pethidine IV gynaecolog ical surgery NSD Tramadol 20mg as a 1 mL solution vs Pethidine 20mg 1 mL solution Yes 24hours Reason for using it in the first place. Mainly used as an alternative to other analgesics because does not cause respiratory depression. Post Thoractemy patients experience difficulty breathing, that is why tramadol is considered over opioids Cheaper than Morphine? To test in a clinical trial due for reduced side effects Settings 54 trials are set in hospitals Four in Dental Clinics Institutes One set in a Univerisity-most likely a hospital One is set in a research institute Length of each trial 1 hour shortest trial- 7 days is the longest trial Follow up treatment The majority of trials only focused on the trial period. Only in three cases were follow up treatments mentioned. Accident Compensation Corporation D R A F T R E P O R T Page 103 Not mentioned NSD between adverse effects References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. SIGN, Grading system for recommendations in evidence-based clinical guidelines-report of a review of the system for grading recommendations in SIGN guidelines: Scottish Intercollegiate Guidelines Network (SIGN). 2000 Lewis, K.S. and N.H. Han, Tramadol: A new centrally acting analgesic. American Journal of Health System Pharmacy, 1997. 54(6): p. 643-652 1079-2082 Charlton, J.E., Tramadol hydrochloride. Prescribers' Journal, 1999. 39(2): p. 109112 Duggan, A.K., The cost of managing post-operative pain - A comparison of tramadol and morphine. British Journal of Medical Economics, 1995. 9(1): p. 59-66 Centre for Adverse Reactions Monitoring (CARM), http://carm.otago.ac.nz/ Accessed April 2004 Cossmann, M. and C. Kohnen, General tolerability and adverse event profile of tramadol hydrochloride. Rev Contemp Pharmacother, 1995. 6: p. 513-31 Medsafe NZ, Tramal Data Sheet. 2002 Mahadevan, M. and L. Graff, Prospective randomized study of analgesic use for ED patients with right lower quadrant abdominal pain. American Journal of Emergency Medicine., 2000. 18(7): p. 753-6 0735-6757 Siddik-Sayyid, S., et al., Epidural tramadol for postoperative pain after Cesarean section. Canadian Journal of Anaesthesia., 1999. 46(8): p. 731-5 0832-610X Thienthong, S., et al., 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. Journal of the Medical Association of Thailand., 2004. 87(1): p. 24-32 0125-2208 Fricke, J.R., Jr., et al., A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Pain, 2004. 109(3): p. 250-7 0304-3959 Dejonckheere, M., et al., Intravenous tramadol compared to propacetamol for postoperative analgesia following thyroidectomy. Acta Anaesthesiologica Belgica., 2001. 52(1): p. 29-33 0001-5164 Rawal, N., et al., Postoperative analgesia at home after ambulatory hand surgery: a controlled comparison of tramadol, metamizol, and paracetamol. Anesthesia & Analgesia., 2001. 92(2): p. 347-51 0003-2999 Smith, A.B., et al., Combination tramadol plus acetaminophen for postsurgical pain. American Journal of Surgery., 2004. 187(4): p. 521-7 0002-9610 Pluim, M.A., et al., Tramadol suppositories are less suitable for post-operative pain relief than rectal acetaminophen/codeine. European Journal of Anaesthesiology., 1999. 16(7): p. 473-8 0265-0215 Jeffrey, H.M., et al., Analgesia after intracranial surgery: a double-blind, prospective comparison of codeine and tramadol. British Journal of Anaesthesia., 1999. 83(2): p. 245-9 0007-0912 Moore, P.A., et al., Tramadol hydrochloride: analgesic efficacy compared with codeine, aspirin with codeine, and placebo after dental extraction. Journal of Clinical Pharmacology., 1998. 38(6): p. 554-60 0091-2700 Wiebalck, A., et al., Efficacy and safety of tramadol and morphine in patients with extremely severe postoperative pain. Acute Pain, 2000. 3(3): p. 112-118 Accident Compensation Corporation D R A F T R E P O R T Page 104 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. Bloch, M.B., et al., Tramadol Infusion for Postthoracotomy Pain Relief: A PlaceboControlled Comparison with Epidural Morphine. Anesthesia & Analgesia, 2002. 94(3): p. 523-528 0003-2999 Vergnion, M., et al., Tramadol, an alternative to morphine for treating posttraumatic pain in the prehospital situation. Anesthesia & Analgesia., 2001. 92(6): p. 1543-6 0003-2999 Houmes, R.J., et al., Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesthesia & Analgesia., 1992. 74(4): p. 510-4 0003-2999 Unlugenc, H., et al., Pre-emptive analgesic efficacy of tramadol compared with morphine after major abdominal surgery. British Journal of Anaesthesia., 2003. 91(2): p. 209-13 0007-0912 Grace, D. and J.P. Fee, Ineffective analgesia after extradural tramadol hydrochloride in patients undergoing total knee replacement. Anaesthesia., 1995. 50(6): p. 555-8 00032409 Hopkins, D., et al., Comparison of tramadol and morphine via subcutaneous PCA following major orthopaedic surgery. Canadian Journal of Anaesthesia., 1998. 45(5 Pt 1): p. 435-42 0832-610X Erolcay, H. and L. Yuceyar, Intravenous patient-controlled analgesia after thoracotomy: a comparison of morphine with tramadol. European Journal of Anaesthesiology., 2003. 20(2): p. 141-6 0265-0215 Baraka, A., et al., A comparison of epidural tramadol and epidural morphine for postoperative analgesia. Canadian Journal of Anaesthesia., 1993. 40(4): p. 308-13 0832-610X Silvasti, M., et al., Comparison of intravenous patient-controlled analgesia with tramadol versus morphine after microvascular breast reconstruction. European Journal of Anaesthesiology., 2000. 17(7): p. 448-55 0265-0215 Ng, K.F., et al., Increased nausea and dizziness when using tramadol for post-operative patient-controlled analgesia (PCA) compared with morphine after intraoperative loading with morphine. European Journal of Anaesthesiology., 1998. 15(5): p. 56570 0265-0215 Vickers, M.D. and D. Paravicini, Comparison of tramadol with morphine for postoperative pain following abdominal surgery.[see comment]. European Journal of Anaesthesiology., 1995. 12(3): p. 265-71 0265-0215 Yaddanapudi, L.N., et al., Comparison of efficacy and side effects of epidural tramadol and morphine in patients undergoing laminectomy: a repeated dose study. Neurology India., 2000. 48(4): p. 398-400 0028-3886 Zimmermann, A.R., D. Kibblewhite, and J. Sleigh, Comparison of morphine/droperidol and tramadol/droperidol mixture for patient controlled analgesia (PCA) after cardiac surgery: A prospective, randomised, double-blind study. Acute Pain, 2002. 4(2): p. 65-69 Gong, Z., et al., Comparison of patient-controlled analgesia with tramadol vs morphine in patients undergoing abdominal gynecological surgery. Chinese Medical Sciences Journal, 2003. 18(3): p. 180-184 Likar, R., et al., Randomised, double-blind, comparative study of morphine and tramadol administered intra-articularly for postoperative analgesia following arthroscopic surgery. Clinical Drug Investigation, 1995. 10(1): p. 17-21 Tarradell, R., et al., Respiratory and analgesic effects of meperidine and tramadol in patients undergoing orthopedic surgery. Methods & Findings in Experimental & Clinical Pharmacology., 1996. 18(3): p. 211-8 0379-0355 Accident Compensation Corporation D R A F T R E P O R T Page 105 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. Eray, O., et al., Intravenous single-dose tramadol versus meperidine for pain relief in renal colic. European Journal of Anaesthesiology., 2002. 19(5): p. 368-70 02650215 Vickers, M.D., et al., Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia, 1992. 47: p. 291-296 Kaufmann, J., et al., Controlled-release oxycodone is better tolerated than intravenous tramadol/metamizol for postoperative analgesia after retinal-surgery. Current Eye Research, 2004. 28(4): p. 271-5 0271-3683 Silvasti, M., et al., Efficacy and side effects of tramadol versus oxycodone for patientcontrolled analgesia after maxillofacial surgery. European Journal of Anaesthesiology., 1999. 16(12): p. 834-9 0265-0215 Turturro, M.A., P.M. Paris, and G.L. Larkin, Tramadol versus hydrocodoneacetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Annals of Emergency Medicine., 1998. 32(2): p. 139-43 0265-0215 Fricke, J.R., Jr., et al., A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clinical Therapeutics., 2002. 24(6): p. 953-68 0149-2918 Vercauteren, M.R., et al., Patient-controlled extradural analgesia after caesarean section: A comparison between tramadol, sufentanil and a mixture of both. European Journal of Pain: Ejp, 1999. 3(3): p. 205-210 Mehlisch, D.R., Double-blind, single-dose comparison of bromfenac sodium, tramadol, and placebo after oral surgery. Journal of Clinical Pharmacology., 1998. 38(5): p. 455-62 0091-2700 Desjardins, P.J., et al., Bromfenac, a non-opioid analgesic, compared with tramadol and placebo for the management of postoperative pain. Clinical Drug Investigation, 1998. 15(3): p. 177-185 Pagliara, L., et al., Tramadol compared with dicolfenac in traumatic musculoskeletal pain. Current Therapeutic Research, 1997. 58(8): p. 473-480 Courtney, M.J. and D. Cabraal, Tramadol vs Diclofenac for Posttonsillectomy Analgesia. Archives of Otolaryngology Head & Neck Surgery, 2001. 127(4): p. 385388 0886-4470 Wilder-Smith, C.H., et al., Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination. Anesthesia & Analgesia., 2003. 97(2): p. 526-33 0003-2999 Ilias, W. and M. Jansen, Pain control after hysterectomy: an observer-blind, randomised trial of lornoxicam versus tramadol. British Journal of Clinical Practice., 1996. 50(4): p. 197-202 0007-0947 Staunstrup, H., et al., Efficacy and tolerability of lornoxicam versus tramadol in postoperative pain. Journal of Clinical Pharmacology., 1999. 39(8): p. 834-41 00912700 Zackova, M., et al., Ketorolac vs tramadol in the treatment of postoperative pain during maxillofacial surgery. Minerva Anestesiologica., 2001. 67(9): p. 641-6 0375-9393 Mais, V., et al., Intramuscular tramadol in gynaecological postoperative pain: Multicentre controlled clinical trial against ketorolac. Italian Journal of Gynaecology & Obstetrics, 1997. 9(1): p. 33-39 Torres, L.M., et al., Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study. Regional Anesthesia & Pain Medicine., 2001. 26(2): p. 118-24 1098-7339 Stankov, G., et al., Observer-blind multicentre study with dipyrone versus tramadol in postoperative pain. European Journal of Pain, 1995. 16(1-2): p. 56-63 Accident Compensation Corporation D R A F T R E P O R T Page 106 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. Doroschak, A.M., W.R. Bowles, and K.M. Hargreaves, Evaluation of the combination of flurbiprofen and tramadol for management of endodontic pain. Journal of Endodontics., 1999. 25(10): p. 660-3 0099-2399 Subash, P.N. and M. Zachariah, Comparison of epidural analgesia with plain bupivacaine, bupivacaine with pethidine and bupivacaine with tramadol. Journal of Anaesthesiology Clinical Pharmacology, 1998. 14(3): p. 221-225 Darwish, A.M. and Z. Hassan, Intraperitoneal bupivacaine vs. tramadol for pain relief following day case laparoscopic surgery. Gynaecological Endoscopy, 1999. 8(3): p. 169-173 Aribogan, A., et al., Patient-controlled epidural analgesia after major urologic surgeries. A comparison of tramadol with or without bupivacaine. Urologia Internationalis., 2003. 71(2): p. 168-75 0042-1138 Delilkan, A.E. and R. Vijayan, Epidural tramadol for postoperative pain relief. Anaesthesia., 1993. 48(4): p. 328-31 0003-2409 Kayacan, N., et al., The effect of intra-articular neostigmine, tramadol, tenoxicam and bupivacaine on postoperative pain. Ambulatory Surgery., 2002. 10(1): p. 29-32 09666532 Hoogewijs, J., et al., A prospective, open, single blind, randomized study comparing four analgesics in the treatment of peripheral injury in the emergency department. European Journal of Emergency Medicine., 2000. 7(2): p. 119-23 0969-9546 Canepa, G., et al., Post-operative analgesia with tramadol: a controlled study compared with an analgesic combination. International Journal of Clinical Pharmacology Research., 1993. 13(1): p. 43-51 0251-1649 Stankov, G., et al., Double-blind study with dipyrone versus tramadol and butylscopolamine in acute renal colic pain. World Journal of Urology., 1994. 12(3): p. 155-61 0724-4983 Schmieder, G., et al., Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain. Arzneimittel-Forschung., 1993. 43(11): p. 1216-21 0004-4172 Hogger, P. and P. Rohdewald, Comparison of tilidine/naloxone, tramadol and bromfenac in experimental pain: a double-blind randomized crossover study in healthy human volunteers. International Journal of Clinical Pharmacology & Therapeutics., 1999. 37(8): p. 377-85 0946-1965 Rohdewald, P., H.W. Granitzki, and E. Neddermann, Comparison of the analgesic efficacy of metamizole and tramadol in experimental pain. Pharmacology., 1988. 37(4): p. 209-17 0031-7012 Moore, R.A. and H.J. McQuay, Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain, 1997. 69: p. 287-294 Scott, L.J. and C.M. Perry, Tramadol: a review of its use in perioperative pain. [Review] [136 refs]. Drugs., 2000. 60(1): p. 139-76 0012-6667 Medve, R.A., J. Wang, and R. Karim, Tramadol and acetaminophen tablets for dental pain. Anesthesia Progress., 2001. 48(3): p. 79-81 0003-3006 McQuay, H. and J. Edwards, Meta-analysis of single dose oral tramadol plus acetaminophen in acute postoperative pain. European Journal of Anaesthesiology Supplement, 2003. 28: p. 19-22 0952-1941 Edwards, J.E., H.J. McQuay, and R.A. Moore, Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.[see comment]. Journal of Pain & Symptom Management., 2002. 23(2): p. 121-30 0885-3924 Accident Compensation Corporation D R A F T R E P O R T Page 107 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. Alhashemi, J.A. and A.M. Kaki, Effect of intrathecal tramadol administration on postoperative pain after transurethral resection of prostate. British Journal of Anaesthesia., 2003. 91(4): p. 536-40 0007-0912 Amin, E., O. Tawfik, and K. Elborolossy, Tramadol hydrochloride in postoperative analgesia. A double blind comparison against butorphanol tartrate and nalbuphine. Pain, 1990. 186(S5): p. 55-8 Bamigbade, T.A., et al., Pain control in day surgery: Tramadol vs standard analgesia. British Journal of Anaesthesia, 1998. 80(4): p. 558-559 Bourne, M.H., et al., Combination tramadol and acetaminophen tablets (Ultracet) for the treatment of orthopedic postsurgical pain: a multicenter, randomized, double-blind, placebo-controlled study. Journal of Pain, 2003. 4(2 suppl 1): p. 88 Broome, I.J., et al., The use of tramadol following day-case oral surgery. Anaesthesia., 1999. 54(3): p. 289-92 0003-2409 Brown, J., et al., Tramadol HCE: Dose response in pain following caesarean section. Clinical Pharmacology & Therapeutics, 1992. 51: p. 121-126 Brown, J., et al. Analgesic oral efficacy of tramadol HCl in pain from oral surgery. in American Society for Clinical Pharmacology and Therapeutics. 1992. Orlando, Florida.121 Brown, P., D.R. Mehlisch, and F. Minn, Tramadol hydrochloride: Efficacy compared to codeine sulfate, acetaminophen with dextropropoxyphene and placebo in dentalextraction pain. European Journal of Pharmacology, 1990. 183(4) Cafiero, T., et al., Analgesic transition after remifentanil-based anesthesia in neurosurgery. A comparison of sufentanil and tramadol. Minerva Anestesiologica., 2004. 70(1-2): p. 45-52 0375-9393 Cagney, B., et al., Tramadol or fentanyl analgesia for ambulatory knee arthroscopy. European Journal of Anaesthesiology., 1999. 16(3): p. 182-5 0265-0215 Chia, Y.Y. and K. Liu, Prospective and randomized trial of intravenous tenoxicam versus fentanyl and tramadol for analgesia in outpatient extracorporeal lithotripsy. Acta Anaesthesiologica Sinica., 1998. 36(1): p. 17-22 0529-5769 Chew, S.T., P.C. Ip-Yam, and C.F. Kong, Recovery following tonsillectomy a comparison between tramadol and morphine for analgesia. Singapore Medical Journal., 2003. 44(6): p. 296-8 0037-5675 Chrubasik, J., et al., Analgesic potency of epidural tramadol after abdominal surgery. Pain, 1987. Suppl 4: p. S 154 Chrubasik, J., et al., Intravenous tramadol for post-operative pain--comparison of intermittent dose regimens with and without maintenance infusion. European Journal of Anaesthesiology., 1992. 9(1): p. 23-8 0265-0215 Cohen, S.P., R. Mullings, and S. Abdi, The pharmacologic treatment of muscle pain. Anesthesiology, 2004. 101(2): p. 495-526 Colletti, V., et al., Intramuscular tramadol versus ketorolac in the treatment of pain following nasal surgery: A controlled multicenter trial. Current Therapeutic Research, 1998. 59(9): p. 608-618 0011-393X Collins, M., et al., The effect of tramadol on dento-alveolar surgical pain. British Journal of Oral & Maxillofacial Surgery., 1997. 35(1): p. 54-8 0266-4356 Colonna, U., M. Paddeu, and G. Manani, Perioperative epidural ropivacaine + morphine vs i.v. tramadol + ketorolac in the treatment of postoperative pain after abdominal surgery. Acta Anaesthesiologica Italica/Anaesthesia & Intensive Care in Italy, 2001. 52(1): p. 7-15 Coetzee, J.F. and H. van Loggerenberg, Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy. British Journal of Anaesthesia., 1998. 81(5): p. 737-41 0007-0912 Accident Compensation Corporation D R A F T R E P O R T Page 108 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. Coulthard, P., A.T. Snowdon, and J.P. Rood, The efficacy and safety of postoperative pain managment with tramadol for day case surgery. Ambulatory Surgery, 1996. 4: p. 25-29 Crighton, I.M., G.J. Hobbs, and I.J. Wrench, Analgesia after day case laparoscopic sterilisation. A comparison of tramadol with paracetamol/dextropropoxyphene and paracetamol/codeine combinations. Anaesthesia., 1997. 52(7): p. 649-52 0003-2409 Crighton, I.M., et al., A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesthesia & Analgesia., 1998. 87(2): p. 445-9 0003-2999 Delilkan, A.E. and R. Vijayan, Forum: Epidural tramadol for postoperative pain relief. Anaesthesia, 1993. 48(4): p. 328-331 0003-2409 De Witte, J., et al., Post-operative effects of tramadol administered at wound closure. European Journal of Anaesthesiology., 1998. 15(2): p. 190-5 Ekman, E.F. and L.A. Koman, Acute pain following musculoskeletal injuries and orthopaedic surgery: Mechanisms and management. Journal of Bone & Joint Surgery American, 2004. 86(6): p. 1316-1327 Elbourne, D. and R.A. Wiseman, Types of intra-muscular opioids for maternal pain relief in labour. Cochrane Database of Systematic, 2003. Reviews.(2)1469-493X Engelhardt, T., et al., Tramadol for pain relief in children undergoing tonsillectomy: A comparison with morphine. Paediatric Anaesthesia, 2003. 13(3): p. 249-252 11555645 Filippi, R., et al., Postoperative pain therapy after lumbar disc surgery. Acta Neurochirurgica., 1999. 141(6): p. 613-8 0001-6268 Fu, Y.P., et al., Epidural tramadol for postoperative pain relief. Ma Tsui Hsueh Tsa Chi Anaesthesiologica Sinica., 1991. 29(3): p. 648-52 0254-1319 Gandhe, U., et al., Intravenous tramadol analgesia using patient controlled analgesia device for post coronary artery bypass graft surgery patients. Journal of Anaesthesiology Clinical Pharmacology, 1998. 14(2): p. 135-141 Goldsack, C., S.M. Scuplack, and M. Smith, A double-blind comparison of codeine and morphine for post-operative analgesia following intracranial surgery. Anaesthesia, 1996. 51: p. 1029-32 Gunduz, M., et al., A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children. Paediatric Anaesthesia., 2001. 11(3): p. 323-6 1155-5645 Gunes, Y., et al., Comparison of caudal vs intravenous tramadol administered either preoperatively or postoperatively for pain relief in boys. Paediatric Anaesthesia., 2004. 14(4): p. 324-8 1155-5645 Gurses, E., et al., The addition of droperidol or clonidine to epidural tramadol shortens onset time and increases duration of postoperative analgesia. Canadian Journal of Anaesthesia., 2003. 50(2): p. 147-52 0832-610X Gritti, G., et al., Multicenter trial comparing tramadol and morphine for pain after abdominal surgery. Drugs Under Experimental & Clinical Research., 1998. 24(1): p. 9-16 0378-6501 Jain, S., et al., Analgesic efficacy of intramuscular opioids versus epidural analgesia in labor. International Journal of Gynaecology & Obstetrics, 2003. 83(1): p. 19-27 0020-7292 James, M.F., S.A. Heijke, and P.C. Gordon, Intravenous tramadol versus epidural morphine for postthoracotomy pain relief: a placebo-controlled double-blind trial. Anesthesia & Analgesia., 1996. 83(1): p. 87-91 0003-2999 Kumara, R. and M. Zacharias, Effectiveness of tramadol as an analgesic in oral surgery. New Zealand Dental Journal., 2002. 98(431): p. 9-11 0028-8047 Accident Compensation Corporation D R A F T R E P O R T Page 109 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. Kupers, R., et al., Efficacy and safety of oral tramadol and pentazocine for postoperative pain following prolapsed intervertebral disc repair. Acta Anaesthesiologica Belgica., 1995. 46(1): p. 31-7 0001-5164 Lanzetta, A., et al., Intramuscular tramadol versus ketorolac in patients with orthopedic and traumatologic postoperative pain: A comparative multicenter trial. Current Therapeutic Research, Clinical & Experimental, 1998. 59(1): p. 39-47 Lauretti, G.R., A.L. Mattos, and I.C. Lima, Tramadol and beta-cyclodextrin piroxicam: effective multimodal balanced analgesia for the intra- and postoperative period. Regional Anesthesia., 1997. 22(3): p. 243-8 0146-521X Lehmann, K.A., et al., Postoperative patient controlled analgesia with Tramadol, analgesic efficacy and minimum effective concentrations. Clinical Journal of Pain, 1990. 6: p. 212-220 Lehmann, K.A., Tramadol for the management of acute pain. [Review] [71 refs]. Drugs, 1994. 47 Suppl 1: p. 19-32 0012-6667 Lehmann, K.A., Tramadol in acute pain. Drugs, 1997. 53(Suppl 2): p. 25-33 Lempa, M. and L. Kohler, Postoperative pain relief in the morbidly obese patient: Feasibility study of a combined dipyrone/tramadol infusion. Acute Pain, 1999. 2(4): p. 172-175 Likar, R., et al., Postoperative patient controlled analgesia using a low-tech PCA system. Acute Pain, 1999. 2(1): p. 17-26 Liukkonen, K., et al., Peroral tramadol premedication increases postoperative nausea and delays home-readiness in day-case knee arthroscopy patients. Scandinavian Journal of Surgery, 2002. 91(4): p. 365-8 1457-4969 Lone, N. and S. Qazi, Clinical Evaluation of Safety of Epidural Tramadol Hydrochloride and Its Analgesic Effectiveness for Postoperative Pain Relief. Pain Medicine March, 2004. 5(1): p. 126-127 1526-2375 McQuay, H.J. and R.A. Moore, Oral tramadol versus placebo, codeine, and combination analgesics, in An Evidence-Based Resource for Pain Relief, H.J. McQuay and R.A. Moore, Editors. 1998, Oxford University Press: Oxford. p. 138-146. Magrini, M., et al., Analgesic activity of tramadol and pentazocine in postoperative pain. International Journal of Clinical Pharmacology Research., 1998. 18(2): p. 8792 0251-1649 Manji, M., et al., Tramadol for post operative analgesia in coronary artery bypass graft surgery. British Journal of Anaesthesia, 1997. 79(SUPPL. 2): p. 44 Memis, D., et al., The prevention of propofol injection pain by tramadol or ondansetron. European Journal of Anaesthesiology., 2002. 19(1): p. 47-51 02650215 Memis, D., et al., The prevention of pain from injection of rocuronium by ondansetron, lidocaine, tramadol, and fentanyl. Anesthesia & Analgesia., 2002. 94(6): p. 1517-20 0003-2999 Moroz, B.T., Y. Ignatov, and V.I. Kalinin, Use of tramadol hydrochloride in therapeutic operative dentistry: Clinical investigation. Current Therapeutic Research, 1991. 49(3): p. 371-375 0011-393X Murphy, D.B., et al., A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia., 1997. 52(12): p. 1224-9 0003-2409 Naguib, M., et al., Perioperative antinociceptive effects of tramadol. A prospective, randomized, double-blind comparison with morphine. Canadian Journal of Anaesthesia., 1998. 45(12): p. 1168-75 0832-610X Naguib, M., M. Attia, and A.H. Samarkandi, Wound closure tramadol administration has a short-lived analgesic effect. Canadian Journal of Anaesthesia., 2000. 47(8): p. 815-8 0832-610X Accident Compensation Corporation D R A F T R E P O R T Page 110 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. Ng, K.F.J., et al., Comparison of tramadol and tramadol/droperidol mixture for patientcontrolled analgesia. Can J Anaesth, 1997. 44(8): p. 810-815 Nikolajsen, L. and T.S. Jensen, Phantom limb pain. British Journal of Anaesthesia, 2001. 87(1): p. 107-116 Ong, K.S. and J.M.L. Tan, Preoperative intravenous tramadol versus ketorolac for preventing postoperative pain after third molar surgery. International Journal of Oral & Maxillofacial Surgery, 2004. 33(3): p. 274-278 Ozcan, S., et al., Comparison of three analgesics for extracorporeal shock wave lithotripsy. Scandinavian Journal of Urology & Nephrology., 2002. 36(4): p. 281-5 0036-5599 Ozcengiz, D., et al., Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatric Anaesthesia., 2001. 11(4): p. 459-64 1155-5645 Ozer, Z., et al., Efficacy of tramadol versus meperidine for pain relief and safe recovery after adenotonsillectomy. European Journal of Anaesthesiology., 2003. 20(11): p. 920-4 0265-0215 Ozer, Z., et al., Bicifadine * is as effective as, and safer than, tramadol in postoperative dental pain. Inpharma Weekly September, 2003. 20(11): p. 8 1173-8324 Ozkan, S., et al., The effect of caudal bupivacaine versus tramadol in post-operative analgesia for paediatric patients. Journal of International Medical Research., 2003. 31(6): p. 497-502 0300-0605 Ozkocak, I., et al., The comparison of preemptive intraperitoneal analgesic effects of tramadol, pethidine and bupivacaine. Anestezi Dergisi, 2002. 10(1): p. 49-52 Ozkose, Z., et al., Relief of posttonsillectomy pain with low-dose tramadol given at induction of anesthesia in children. International Journal of Pediatric Otorhinolaryngology., 2000. 53(3): p. 207-14 0165-5876 Oztekin, S., et al., Comparison of the antiemetic efficacy of tropisetron and droperidol with patient-given tramadol. Journal of International Medical Research., 2003. 31(4): p. 267-71 0300-0605 Pang, W.W., et al., Comparison of patient-controlled analgesia (PCA) with tramadol or morphine. Canadian Journal of Anaesthesia., 1999. 46(11): p. 1030-5 0832-610X Pang, W., et al., Patient-controlled analgesia with tramadol versus tramadol plus lysine acetyl salicylate. Anesthesia & Analgesia., 2000. 91(5): p. 1226-9 0003-2999 Pang, W.W., et al., Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Canadian Journal of Anaesthesia., 2000. 47(10): p. 96873 0832-610X Pang, W.W., et al., Metoclopramide decreases emesis but increases sedation in tramadol patient-controlled analgesia.[see comment]. Canadian Journal of Anaesthesia., 2002. 49(10): p. 1029-33 0832-610X Pang, W.W., H.S. Wu, and C.C. Tung, Tramadol 2.5 mg x kg(-1) appears to be the optimal intraoperative loading dose before patient-controlled analgesia. Canadian Journal of Anaesthesia., 2003. 50(1): p. 48-51 0832-610X Pendeville, P.E., et al., Double-blind randomized study of tramadol vs. paracetamol in analgesia after day-case tonsillectomy in children. European Journal of Anaesthesiology., 2000. 17(9): p. 576-82 0265-0215 Peters, A.A., et al., Pain relief during and following outpatient curettage and hysterosalpingography: a double blind study to compare the efficacy and safety of tramadol versus naproxen. Cobra Research Group. European Journal of Obstetrics, Gynecology, & Reproductive Biology., 1996. 66(1): p. 51-6 Phero, J.C., D.E. Becker, and R.A. Dionne, Contemporary trends in acute pain management. Current Opinion in Otolaryngology & Head & Neck Surgery, 2004. 12(3): p. 209-216 Accident Compensation Corporation D R A F T R E P O R T Page 111 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. Pieri, M., et al., Control of acute pain after major abdominal surgery in 585 patients given tramadol and ketorolac by intravenous infusion. Drugs Under Experimental & Clinical Research., 2002. 28(2-3): p. 113-8 0378-6501 Prasertsawat, P.O., Y. Herabutya, and K. Chaturachinda, Obstetric analgesia: comparison between tramadol, morphine, and pethidine. Current Therapeutic Research Clinical Exp, 1986. 40: p. 1022-28 Putland, A.J. and A. McCluskey, The analgesic efficacy of tramadol versus ketorolac in day-case laparoscopic sterilisation. Anaesthesia., 1999. 54(4): p. 382-5 0003-2409 Radbruch, L., S. Grond, and K.A. Lehmann, A risk-benefit assessment of tramadol in the management of pain. Drug Safety, 1996. 15: p. 8-29 Raff, M., The comparison of continuous intravenous tramadol and morphine sulphate for postoperative analgesia. International Journal of Acute Pain Management, 1998. 1: p. 7-10 Robaux, S., et al., Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improves postoperative analgesia dose-dependently. Anesthesia & Analgesia., 2004. 98(4): p. 1172-7 0003-2999 Robbins, L., Tramadol for Tension-type Headache. [References]. Headache, 2004. 44(2): p. 192-193 0017-8748 Rodriguez, M.J., et al., Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for managing postoperative pain. Current Therapeutic Research, 1993. 54(4): p. 375-383 0011-393X Roelofse, J.A. and K.A. Payne, Oral tramadol: analgesic efficacy in children following multiple dental extractions. European Journal of Anaesthesiology., 1999. 16(7): p. 441-7 0265-0215 Schecter, W.P., et al., Pain control in outpatient surgery. Journal of the American College of Surgeons, 2002. 195(1): p. 95-104 Schnitzer, T.J., et al., A comprehensive review of clinical trials on the efficacy and safety of drugs for the treatment of low back pain. Journal of Pain & Symptom Management, 2004. 28(1): p. 72-95 Sekar, C., et al., Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine Journal: Official Journal of the North American Spine Society., 2004. 4(3): p. 261-4 1529-9430 Shipton, E.A., Tramadol - A multimodal, multipurpose analgesic for the surgeon. South African Journal of Surgery, 2003. 41(4): p. 86-88 Shipton, E.A., J.A. Roelofse, and R.J. Blignaut, An evaluation of analgesic efficacy and clinical acceptability of intravenous tramadol as an adjunct to propofol sedation for third molar surgery. Anesthesia Progress., 2003. 50(3): p. 121-8 0003-3006 Soto, R.G. and E.S. Fu, Acute pain management for patients undergoing thoracotomy. Annals of Thoracic Surgery, 2003. 75(4): p. 1349-1357 Stamer, U.M., et al., Tramadol in the management of post-operative pain: a doubleblind, placebo- and active drug-controlled study. European Journal of Anaesthesiology., 1997. 14(6): p. 646-54 0265-0215 Stamer, U.M., S. Grond, and C. Maier, Responders and non-responders to postoperative pain treatment: the loading dose predicts analgesic needs. European Journal of Anaesthesiology., 1999. 16(2): p. 103-10 0265-0215 Stubhaug, A., J. Grimstad, and H. Breivik, Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison.[see comment]. Pain., 1995. 62(1): p. 111-8 03043959 Sunshine, A., et al., Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clinical Pharmacology & Therapeutics., 1992. 51(6): p. 740-6 0009-9236 Accident Compensation Corporation D R A F T R E P O R T Page 112 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. Tarkkila, P., M. Tuominen, and L. Lindgren, Comparison of respiratory effects of tramadol and oxycodone. Journal of Clinical Anesthesia., 1997. 9(7): p. 582-5 09528180 Tarkkila, P., M. Tuominen, and L. Lindgren, Comparison of respiratory effects of tramadol and pethidine. European Journal of Anaesthesiology., 1998. 15(1): p. 64-8 0265-0215 Tuncer, S., et al., Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial. European Journal of Gynaecological Oncology., 2003. 24(2): p. 181-4 0392-2936 Unlugenc, H., et al., A comparative study on the analgesic effect of tramadol, tramadol plus magnesium, and tramadol plus ketamine for postoperative pain management after major abdominal surgery. Acta Anaesthesiologica Scandinavica September, 2002. 46(8): p. 1025-1030 0001-5172 van den Berg, A.A., et al., Analgesia for adenotonsillectomy in children and young adults: a comparison of tramadol, pethidine and nalbuphine. European Journal of Anaesthesiology., 1999. 16(3): p. 186-94 0265-0215 van den Berg, A.A., et al., The effects of tramadol on postoperative nausea, vomiting and headache after ENT surgery. A placebo-controlled comparison with equipotent doses of nalbuphine and pethidine. Acta Anaesthesiologica Scandinavica., 1999. 43(1): p. 28-33 0001-5172 Vanhelleputte, P., et al., Pain during bone marrow aspiration: prevalence and prevention. Journal of Pain & Symptom Management., 2003. 26(3): p. 860-6 08853924 Verchere, E., et al., Postoperative pain management after supratentorial craniotomy. Journal of Neurosurgical Anesthesiology., 2002. 14(2): p. 96-101 0898-4921 Viegas, O.A., B. Khaw, and S.S. Ratnam, Tramadol in labour pain in primiparous patients. A prospective comparative clinical trial. European Journal of Obstetrics, Gynecology, & Reproductive Biology., 1993. 49(3): p. 131-5 0301-2115 Viitanen, H. and P. Annila, Analgesic efficacy of tramadol 2 mg kg(-1) for paediatric day-case adenoidectomy. British Journal of Anaesthesia., 2001. 86(4): p. 572-5 00070912 Walder, B., et al., Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiologica Scandinavica., 2001. 45(7): p. 795-804 0001-5172 Ward, M.E., J. Radburn, and S. Morant, Evaluation of intravenous tramadol for use in the prehospital situation by ambulance paramedics. Prehospital and Disaster Medicine., 1997. 12(2): p. 87-91 1049-023X Webb, A.R., et al., The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial. Anesthesia & Analgesia., 2002. 95(6): p. 1713-8 0003-2999 Wilder-Smith, C.H., et al., Preoperative adjuvant epidural tramadol: the effect of different doses on postoperative analgesia and pain processing. Acta Anaesthesiologica Scandinavica., 1998. 42(3): p. 299-305 0001-5172 Wordliczek, J., et al., Influence of pre- or intraoperational use of tramadol (preemptive or preventive analgesia) on tramadol requirement in the early postoperative period. Polish Journal of Pharmacology., 2002. 54(6): p. 693-7 1230-6002 Wilder-Smith CH, et al., Oral Tramadol, a µ-opioid agonist and monoamine reuptakeblocker, and morphine for strong cancer-related pain. Annual Oncology 5: p 141-6. Osipova, N.A., et al., Analgesic effect of Tramadol in cancer patients with chronic pain : a comparison with prolonged-action morphine sulphat e. Current Therapy Research 50: p. 812-821. Accident Compensation Corporation D R A F T R E P O R T Page 113 182. 183. Jones, Greenfield and Bradley, Prescribing new drugs; qualitative study of influences on consultants and general practictioners. British Medical Journal, 2001; 323:378. Carter, M. EBH Review:The effectiveness of oral tramadol for chronic, nonmalignant pain. (www.acc.co.nz). Accident Compensation Corporation D R A F T R E P O R T Page 114