Download The Effectiveness of Tramadol in Acute Pain Management

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.
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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
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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
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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).
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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.
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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.
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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.
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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
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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/
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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.
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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].
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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].
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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
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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].
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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
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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.
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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.
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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.
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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:
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•
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.
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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
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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.
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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.
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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.
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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
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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)
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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.
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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)
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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
•
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•
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.
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•
•
•
•
•
•
•
•
•
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
•
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•
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
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•
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
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•
•
•
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
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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.
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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.
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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
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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
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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
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RASH MACULO-PAPULAR
RASH PRURITIC
RASH VESICULAR
URTICARIA
2
3
1
1
Special Senses
PHOTOPHOBIA
1
Urinary
URINARY RETENTION
3
TOTAL
1
3
170
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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)
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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$.ab.
or/52-56
selection criteria.ab.
data extraction.ab.
58 or 59
(review or review literature).pt.
60 and 61
comment.pt.
letter.pt.
editorial.pt.
animal/
human/
66 not (66 and 67)
or/63-65,68
42 or 51 or 57 or 62
70 not 69
35 or 71
11 and 72
Accident Compensation Corporation
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Search strategy used for the following databases.
Date: 27/8/04
Database: CDSR, ACP Journal Club, DARE, CCTR, CINAHL, Ovid MEDLINE(R) InProcess, Other Non-Indexed Citations, Ovid MEDLINE(R), Ovid MEDLINE(R) Daily
Update, PsycINFO
Search Strategy:
-------------------------------------------------------------------------------1 exp Analgesics, Opioid/ or exp Pain Measurement/ or exp Pain, Postoperative/ or exp
Analgesics/ or exp Pain/ or acute pain.mp. or exp Pain Clinics/ or exp Analgesia/
2 tramadol.mp. or exp TRAMADOL/
3 tramal.mp.
4 ultracet.mp.
5 or/2-4
6 1 and 5
7 limit 6 to (human and english language) [Limit not valid in: CDSR,ACP Journal
Club,DARE,CCTR,CINAHL,Ovid MEDLINE(R) In-Process & Other Non-Indexed
Citations; records were retained]
8 exp clinical trials/
9 Clinical trial.pt.
10 (clinic$ 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/
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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$.ab.
or/77-81 (13892)
selection criteria.ab.
data extraction.ab.
83 or 84
(review or review literature).pt.
85 and 86
comment.pt.
letter.pt.
editorial.pt.
animal/
human/
91 not (91 and 92)
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94
95
96
97
98
99
100
101
102
103
or/88-90,93
67 or 76 or 82 or 87
95 not 94
19 or 31 or 37 or 60 or 96
7 and 97
chronic pain.mp.
acute pain.mp.
99 not (99 and 100)
98 not 101
remove duplicates from 102
Database: CDSR, ACP Journal Club, DARE, CCTR, CINAHL, Ovid MEDLINE(R) In-Process, Other NonIndexed Citations, Ovid MEDLINE(R), Ovid MEDLINE(R) Daily Update, PsycINFO
Search Strategy (27-8-04):
-------------------------------------------------------------------------------1 exp Analgesics, Opioid/ or exp Pain Measurement/ or exp Pain, Postoperative/ or exp Analgesics/ or exp
Pain/ or acute pain.mp. or exp Pain Clinics/ or exp Analgesia/ (551652)
2 tramadol.mp. or exp TRAMADOL/ (1749)
3 tramal.mp. (108)
4 ultracet.mp. (5)
5 or/2-4 (1758)
6 1 and 5 (1347)
7 limit 6 to (human and english language) [Limit not valid in: CDSR,ACP Journal
Club,DARE,CCTR,CINAHL,Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations; records were
retained] (954)
8 exp clinical trials/ (220665)
9 Clinical trial.pt. (632537)
10 (clinic$ 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)
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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.
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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
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