The Effectiveness of Tramadol in Acute Pain Management - ACC

114 Pages·2006·0.47 MB·English

The Effectiveness of Tramadol in Acute Pain Management

Principal Investigators:
Reviewers
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 cost-
effectiveness 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”, “Cost-
benefit 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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