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Evidence Service
Implantable pain therapies: Intrathecal (IT) infusions
Plain language summary
Treatments for persistent pain can involve many therapies including; medication, physiotherapy,
psychological therapy and nerve blocks. In some patients these may not work or cause unpleasant
side effects. For this small group of patients, drugs can be given by intrathecal infusion. A pump is
placed under the skin usually around the stomach region. Tubes from the pump trickle out the drug
into the space around the spinal cord. This may give the patient pain relief.
This review looked at whether IT infusions are helpful for persistent pain that is not due to cancer.
The review did not find enough evidence to confirm that IT infusions are helpful for pain. There are
also possible harms such as; side effects (e.g. nausea, dizziness, sleepiness, headache, addiction) and
complications such as pump malfunction, misplacement and infection.
Report number
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Evidence Service
Implantable pain therapies: Intrathecal (IT) infusions
Evidence summary
Overview
This evidence review is an update of a previous review requested by the Transport Accident Commission (TAC) and
[1]
WorkSafe Victoria (WSV) conducted in September 2008. The current report has identified further evidence for the
effectiveness of IT opioids and IT ketorolac, a non-steroidal anti-inflammatory drug (NSAID). No new evidence for the
effectiveness of IT baclofen and IT ziconotide was identified since the previous report.
At present, the evidence available for the effectiveness of intrathecal (IT) infusions in patients with persistent, noncancer pain is insufficient (IT opioids, baclofen, ziconotide, and ketorolac).
Definition
For a small proportion of patients with non-cancer pain who do not experience sufficient pain relief or have intolerable
side effects with conventional treatments, intrathecal (IT) infusions may be an effective treatment. A pump is implanted
under the skin usually in the abdominal region. Tubes from the implanted pump are programmed to trickle out the drug
at a certain rate into the space around the spinal cord (intrathecal or IT) which may provide the patient with sufficient
pain relief.
The following evidence review identified a total of fifteen studies (three evidence-based guidelines, three health
technology assessments, eight systematic reviews and one randomised clinical trial) of IT infusions for persistent pain
that met the selection criteria.
[2]
ANALGESICS (OPIOIDS):
The most recent high quality systematic review (SR) was found to be well
conducted. The included studies in the SR, which were case series (low level
evidence), provided limited evidence to determine whether IT opioids are effective
for chronic, persistent non-cancer pain.
ANTI-SPASMODICS
(BACLOFEN):
CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):
OTHER MEDICATIONS
(KETOROLAC):
A small cross-over RCT did not find a statistically significant difference in treatment
effect following IT ketorolac or placebo with established, simultaneous IT morphine,
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[3, 4]
[5]
[6]
although a trend for reduced pain intensity and unpleasantness was present following
IT ketorolac. Overall, this led us to conclude that there is insufficient evidence of
effectiveness of IT ketorolac on persistent pain.
What is the efficacy and effectiveness of this intervention on persistent pain in these
conditions?
ANALGESICS (OPIOIDS):
ANTI-SPASMODICS
(BACLOFEN):
CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):
OTHER MEDICATIONS
(KETOROLAC):
What is the effect of this intervention on function, quality of life, return to work,
medication use and use of the healthcare system?
ANALGESICS (OPIOIDS):
ANTI-SPASMODICS
(BACLOFEN):
CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):
OTHER MEDICATIONS
(KETOROLAC):
When the pump cannot be implanted 2.5 cm or less from the surface of the skin
When body size is not sufficient to accept pump bulk and weight
[7]
[7]
[7, 8]
[9]
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[8]
[7]
[8]
[9]
The Australian and New Zealand College of Anesthetists caution the use of IT therapy in patients where
[10]
psychological factors are considered to be a major pain modifying factor.
Device-related adverse events were only reported for IT opioids, however the same device is utilised for all other IT
drugs. Adverse events include pump and catheter malfunctions and malpositioning, surgical complications and
postsurgical complications.
[6]
The following drug-related adverse events were reported with IT ketorolac including mild sedation (n=2, lasting < 2
hours), mild dizziness (n=1, lasting < 30 minutes, and a hot sensation in the back, headache, urinary retention, and hives
(n=1, lasting< 4 hours). Following saline infusion in the RCT, mild sedation (n=2, lasting < 1 hour, mild nausea (n=2,
lasting < 1 hour), and mild headache (n=1, lasting < 2 hours) were reported.
The only serious adverse event reported following IT administration of opioids was hallucinations.
[2]
As no evidence was available for IT baclofen or IT ziconotide, drug-related adverse events remain unknown.
Glossary of Findings
Insufficient
Limited evidence of
effectiveness
There is some evidence of effectiveness but not enough to be sure. More high
quality studies are needed before conclusions can be drawn.
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Evidence Service
Implantable pain therapies: Intrathecal infusions
Evidence Review
July 2011
Loretta Piccenna, Emma Donoghue
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CONTENTS
ACKNOWLEDGEMENTS ..................................................................................................................................... 6
BACKGROUND .................................................................................................................................................. 7
QUESTIONS ..................................................................................................................................................... 10
METHODS ....................................................................................................................................................... 10
RESULTS .......................................................................................................................................................... 11
1. ANALGESICS (OPIOIDS) ..................................................................................................................................... 11
2. ANTI-SPASMODICS (BACLOFEN)........................................................................................................................ 15
3. CALCIUM CHANNEL BLOCKERS (ZICONOTIDE) ................................................................................................... 15
4. OTHER MEDICATIONS (KETOROLAC) ................................................................................................................. 15
DISCUSSION & CONCLUSION........................................................................................................................... 18
DISCLAIMER .................................................................................................................................................... 19
CONFLICT OF INTEREST ................................................................................................................................... 19
REFERENCES.................................................................................................................................................... 20
ACKNOWLEDGEMENTS
The authors would like to thank several colleagues for their assistance in preparation of this
document.
Dr Lisa Sherry for editing of the Plain Language Statement.
Anne Parkhill for her literature searching services.
Ornella Clavisi from the National Trauma Research Institute for proofreading and document editing.
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BACKGROUND
Implantable pain therapies (IPTs) have been used to treat patients for a variety of pain disorders.
They include a range of neurostimulation procedures and intrathecal (IT) infusions of analgesic, local
anaesthetic, antispasmodic and other pharmacological agents. In order to develop and update
policies for the use of IPTs in patients with persistent pain, the Health Services Group of the
Transport Accident Commission and WorkSafe Victoria (TAC/WSV) requested an update of the
Evidence Reviews of IPTs published in September 2008[1]. In light of the complexity of the research
questions and the multiple sources of information available, the previous review developed two
separate reports; one for implantable IT infusions and another for neurostimulation. This approach
was continued for this update.
The focus of this review is to evaluate the effectiveness and safety of implantable IT infusions on
patients with persistent pain following transport-related or workplace injuries. The effect of IT
infusions on pain due to systemic inflammatory conditions, vascular insufficiency, haematological
disorders or cancer is outside the scope of this review.
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Within these categories medications can be administered on their own or combined with other
medications or other implantable therapies, either from the same category or a different category.
In Australia only baclofen is licensed for long term IT use for spasticity. All other IT infusion
medications are prescribed/administered off label under the TGAs Access to Unapproved
Therapeutic Goods scheme.[10]
Background information relating to the different drug categories used for IT infusion is provided
below.
1. Analgesics (opioids)
Opioids are medications usually used for pain relief. Common opioids are morphine, oxycodone and
codeine.
The mechanism of action of opioids is through the attachment to proteins called opioid receptors,
which are abundantly present in the central nervous system. Studies have found a large number of
side effects associated with the use of opioids as well as complications when used in IT pumps. Some
of these have severe consequences, however it is difficult to know from the information available
how likely these problems are to occur.
Opioids used for IT treatment include morphine, hydromorphone, fentanyl, buprenorphine and
sufentanil. These drugs have not been approved by the Australian Therapeutic Goods Administration
(TGA) for IT use.
2. Anti-spasmodics (baclofen)
Baclofen is a GABA- receptor agonist and is a medication that acts through the central nervous
system to relax muscles. GABA (or gamma-aminobutyric acid) is the main inhibitory
neurotransmitter used in the nervous system that regulates neuronal signalling.
The mechanism of action for baclofen is by binding to pre-synaptic GABA- receptors, which in turn
inhibits the release of neurotransmitter (GABA) onto neurons of the spinal cord that causes the
sensation of pain. Post-synaptic binding of baclofen to GABA- receptors, results in a reduction in
neuronal excitability which is thought to contribute to spasticity.
Baclofen can be administered through an IT pump for the treatment of severe pain and disability,
secondary to spasticity.
Baclofen is only approved by the TGA for IT use for spasticity. Lioresal Intrathecal (baclofen
injection) is indicated in patients with severe chronic spasticity of spinal origin (associated with
injury, multiple sclerosis, or other spinal cord diseases) or of cerebral origin that are unresponsive to
orally administered antispasmodics (including oral baclofen) and/or who experience unacceptable
side effects at effective oral doses.
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QUESTIONS
This Evidence Review sought to find the most up-to-date, high quality source of evidence to answer
the following questions regarding IT drug infusions in persistent pain due to work-related or
transport accident injuries:
What is the efficacy and effectiveness of this intervention on persistent pain in these
conditions?
What is the effect of this intervention on function (physical, psychological, social), quality of
life, return to work, medication use and use of the healthcare system?
METHODS
Methods are outlined briefly below. More detailed information about the methodology used to
produce this report is available in Appendices 1 and 2. All appendices are located in the Technical
Report accompanying this document.
A comprehensive search of Medline, Embase and the Cochrane Library, was undertaken in March
2011 to identify relevant synthesised research (i.e. evidence-based guidelines (EBGs), systematic
reviews (SRs), health technology assessments (HTAs)), and any relevant randomised controlled trials
(RCTs) and controlled clinical trials (CCTs). Inclusion and exclusion criteria were established a priori.
A comprehensive search of the internet, relevant websites and electronic health databases was also
undertaken (see Appendix 2, Tables A2.2-A2.4 for search details). Reference lists of included studies
were also scanned to identify relevant references.
Studies identified by the searches were screened for inclusion using specific selection criteria (see
Appendix 2, Table A2.1). Synthesised evidence (EBGs, SRs and HTAs) that met the selection criteria
was reviewed to identify the most up-to-date and comprehensive source. This evidence was then
critically appraised to determine whether it was of high quality. This process was repeated for
additional sources of evidence, until the most recent, comprehensive and high quality source of
evidence was identified. Final source documents were compared to other evidence sources for
consistency of findings and included studies. The available synthesised evidence was mapped (see
Table 2), and the algorithm in Table 1 was followed to determine the next steps necessary to answer
the clinical questions.
Table 1. Further action required to answer clinical questions
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No
Yes
No
Yes
No
Undertake new SR
Undertake new SR
No
No further action
Update existing SR
Data on characteristics of all included studies were extracted and summarised (see Appendix 4). The
most recent, relevant, high quality systematic review was used to address the questions posed
above.
RESULTS
An initial search of electronic databases yielded 4141 articles. After reviewing the title, abstract or
full text, one EBG,[12] two HTAs,[13, 14] nine SRs[2, 5, 13-19] and three RCTs,[6, 20, 21] were found that met the
selection criteria. Internet searches yielded two additional EBGs,[4, 22] one HTA[3] and one additional
SR.[23] In the process of critically appraising these studies, two SRs and two RCTs were excluded.
In total 15 studies (three EBGs, three HTAs, eight SRs and one RCT) of IT infusions for persistent pain
(published between 1996 and 2011) met our selection criteria (see Table 2 for number of studies
and Appendix 2 Table A2.1 for selection criteria). A list and summary of included studies can be
found in Appendices 3 and 4, respectively.
Table 2. Evidence map of included studies by study-type
Synthesised Studies
Primary studies
TOTAL
Drug category
EBGs*
Opioids
2 EBGs
9 SRs
11
Baclofen
1 EBG
2 SR/HTA
Ziconotide
1 SR
Other medications
1 EBG
1 RCT
*columns may not add up to totals as some systematic review (SRs) and primary studies (RCTs) identified
evaluated IT infusions in more than one drug category.
1. ANALGESICS (opioids)
Evidence identified
Searches yielded a total of 11 studies of IT opioids for the treatment of persistent pain published
between 1996 and 2011. The number of studies by study design is illustrated in Table 2 above. A
summary of these studies can be found in Appendix 4, Table 4.1.
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The effectiveness of IT opioids on persistent pain has been assessed in numerous synthesised
studies. Three SRs were recently identified as potentially relevant.[2, 15, 23] One of these SRs[15]
included a study[24] that combined results for cancer and non-cancer pain patients. Our review was
limited to patients with persistent pain not due to cancer and so this SR was excluded from the
analysis.
Two of the most up-to-date SRs were critically appraised (see Appendix 5). It was decided that
Noble, M et al[2] would be used as the primary reference as it contained a larger number of studies
which were more recent and also assessed long-term functional outcomes including quality of life
(QoL) and functional levels which were questions needing to be answered for the evidence review.
Table 3. Key information from most recent, comprehensive, high quality systematic review (Noble,
M et al, 2010) - OPIOIDS
Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, et al. Long-term opioid management for
chronic noncancer pain. Cochrane Database Syst Rev. [Meta-Analysis Review]. 2010(1):CD006605.
Study design
Systematic review
Scope
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Not reported
Conclusion/
Recommendation
Recommendation category
Insufficient evidence
This SR was well conducted and considered to have a low risk of bias (see
Appendix 5 for quality appraisal)
Our comments/summary
Although this SR was well conducted it included nine observational studies that
assessed IT opioids for persistent pain. The authors conclude that there is only
weak evidence of therapeutic effectiveness of IT opioids for persistent pain,
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Findings
Due to a lack of high quality primary studies (i.e. RCTs), there is insufficient evidence to determine
the effectiveness of IT opioids for the treatment of persistent pain.
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2. ANTI-SPASMODICS (baclofen)
Evidence identified
Searches yielded one EBG, one HTA and one SR for IT baclofen for the treatment of persistent pain
(published between 1996 and 2011). The HTA[4] and SR[3] were critically appraised (see Appendix 4)
and it was discovered that both reviews were non-systematic literature reviews, a study type
excluded in the selection criteria of this evidence review (see Appendix 5) and hence they were
excluded. The number of included studies by study design is illustrated in Table 2. A summary of
these studies can be found in Appendix 4, Table 4.1.
The EBG was appraised and found to be well conducted with a low risk of bias. However, it did not
identify any controlled studies that met the inclusion/exclusion criteria for this report.
In summary, there is insufficient evidence to know whether IT baclofen is useful.
pain intensity and unpleasantness between ketorolac and placebo. There was also no difference in
the incidence of adverse events between groups.
These results however, are limited by small sample size and the amount and timing of ketorolac
dosing. Furthermore it is unclear whether the results were subject to carryover effects between the
treatment phases as a wash out period was not reported. The generalisability of the results is also
unclear as the authors state That the paper was more fundamental than practical, since there no
longer exists a preservative free solution of ketorolac for spinal administration (personal
correspondence).
Table 5. Key information from most recent, comprehensive, high quality primary study (Eisenach
2010) OTHER MEDICATIONS (IT ketorolac)
Eisenach, J.C., et al., Role of spinal cyclooxygenase in human postoperative and chronic pain.
Anesthesiology, 2010. 112(5): p. 1225-33.
Study design
Scope
Patient/population: n=12
Conditions indicated for use: Patients with chronic pain, already receiving IT
morphine for at least 6 weeks
Intervention: IT morphine (mean 9.8mg; range 1.3 50mg/day) with IT
ketorolac (2.0mg)
Comparator: Saline + IT morphine (mean 9.8mg; range 1.3 50mg/day)
Outcomes assessed: Pain intensity (pain score and 30% or 50% pain relief),
unpleasantness and adverse events
Not reported
Which patient
groups/conditions is use of
IT drug infusion
contraindicated?
Pregnant women
Following IT ketorolac adverse events included mild sedation lasting < 2 hours
(n = 2), mild dizziness lasting < 2 hours (n = 1), hot sensation in the back,
headache, urinary retention and hives (n = 1) 4 days after injection, lasting < 4
hours. Following IT saline adverse events included mild sedation lasting < 1 hr
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(n = 2), mild nausea lasting < 1 hr (n = 2), mild headache lasting < 2 hr (n = 1).
Two serious adverse events occurred. One patient experienced a numb left leg
for less than 2 h after intrathecal injection of saline, and, as noted, this subjects
pump contained bupivacaine. One patient committed suicide 6 months after
study.
Conclusion/
Recommendation
Recommendation category
Insufficient evidence
The overall risk of bias was low-moderate with the authors not reporting on the
allocation concealment, degree of error in group results and longer term
treatment.
Our comments/summary
The authors were contacted regarding key methodological aspects which were
not reported in paper. This included whether the groups were treated the
same, if outcome measures were assessed independently and if the outcome
assessors were blind to the intervention group. The authors stated that all of
these were met.
Patients were studied twice (cross-over study), hence they received placebo
and ketorolac but at two alternative visits. A cross-over period of at least 1
week but no greater than 3 months was reported, suggesting some assurance
of no direct placebo-ketorolac interactions which would modify the result (true
effect size). However, it is unknown if the initial pain intensity and symptoms
returned to test the efficacy of the second drug treatment, either saline or
ketorolac.
The study does not report the origin or type of pain patients enrolled in the RCT
experienced, i.e. neuropathic or CRPS etc. This might have an impact on the
response to pain reduction.
Although the sample size for the RCT was only 12 patients, the authors of the
study had justified this size well before conducting the study.
Overall the study revealed no greater pain relief with IT ketorolac and IT
morphine in comparison to IT morphine and saline (control).
Findings
Based on the findings of one cross-over trial there is insufficient evidence to determine whether IT
ketorolac is effective in reducing chronic pain.
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DISCLAIMER
The information in this report is a summary of that available and is primarily designed to give readers a starting
point to consider currently available research evidence. Whilst appreciable care has been taken in the
preparation of the materials included in this publication, the authors and the National Trauma Research
Institute do not warrant the accuracy of this document and deny any representation, implied or expressed,
concerning the efficacy, appropriateness or suitability of any treatment or product. In view of the possibility of
human error or advances of medical knowledge the authors and the National Trauma Research Institute
cannot and do not warrant that the information contained in these pages is in every aspect accurate or
complete. Accordingly, they are not and will not be held responsible or liable for any errors or omissions that
may be found in this publication. You are therefore encouraged to consult other sources in order to confirm
the information contained in this publication and, in the event that medical treatment is required, to take
professional expert advice from a legally qualified and appropriately experienced medical practitioner.
CONFLICT OF INTEREST
The TAC/WSV Evidence Service is provided by the National Trauma Research Institute. The NTRI does not
accept funding from pharmaceutical or biotechnology companies or other commercial entities with potential
vested interest in the outcomes of systematic reviews.
The TAC/WSV Health Services Group has engaged the NTRI for their objectivity and independence and
recognise that any materials developed must be free of influence from parties with vested interests. The
Evidence Service has full editorial control.
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REFERENCES
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Reid, J., et al., Implantable Pain Therapies: Intrathecal Infusions Evidence Review, T.A.C.W.
Victoria, Editor. 2008: Melbourne. p. 1-85.
Noble, M., et al., Long-term opioid management for chronic noncancer pain. Cochrane
Database of Systematic Reviews, 2010(1): p. CD006605.
Jadad, A., et al., Management of Chronic Central Neuropathic Pain Following Traumatic
Spinal Cord Injury. 2001, Agency for Healthcare Research and Quality (US): Rockville, MD.
Interventional Pain Management. 2005 [cited 2011 21 April]; Available from:
http://www.acc.co.nz/for-providers/clinical-best-practice/interventional-painmanagement/interventions/intervention-index/index.htm.
Turner, J.A., J.M. Sears, and J.D. Loeser, Programmable intrathecal opioid delivery systems
for chronic noncancer pain: a systematic review of effectiveness and complications. Clinical
Journal of Pain, 2007. 23(2): p. 180-195.
Eisenach, J.C., et al., Role of spinal cyclooxygenase in human postoperative and chronic pain.
Anesthesiology, 2010. 112(5): p. 1225-33.
Medtronic, I. Intrathecal Drug Delivery for Chronic Pain. 2010 [cited 2011 21 April]; Available
from: http://professional.medtronic.com/therapies/intrathecal-drug-delivery-for-chronicpain/index.htm.
Novartis. LIORESAL INTRATHECAL (baclofen). 2010 [cited 2011 21 April]; Available from:
www.novartis.com.au/DownloadFile.aspx?t=p&f=lrsi.pdf&dateid.
Pharmaceuticals., E. Prialt (ziconotide intrathecal infusion) Product Information. 2006 [cited
2011 21 April]; Available from: www.prialt.com/downloads/product_information.pdf.
Guidelines for patient assessment and implantation of intrathecal catheters, ports and
pumps for intrathecal therapy. 2005, Australian and New Zealand College of Anaesthetists:
Melbourne. p. 1-5.
Guidelines for longterm intrathecal infusions (analgesics / adjuvants / antispasmodics). 2007,
Australian and New Zealand College of Anaesthetists: Melbourne. p. 1-5.
Sanders, S.H., R.N. Harden, and P.J. Vicente, Evidence-based clinical practice guidelines for
interdisciplinary rehabilitation of chronic nonmalignant pain syndrome patients. Pain
Practice, 2005. 5(4): p. 303-315.
Intrathecal opioid therapy for chronic nonmalignant pain. 2006, Hayes Inc.: Lansdale, PA.
Williams, J.E., G. Louw, and G. Towlerton, Intrathecal pumps for giving opioids in chronic
pain: a systematic review. Health Technology Assessment. 2000: Wincester, England.
Patel, V.B., et al., Systematic review of intrathecal infusion systems for long-term
management of chronic non-cancer pain. Pain Physician, 2009. 12(2): p. 345-60.
Wallace, M.S., R.L. Rauck, and T. Deer, Ziconotide combination intrathecal therapy: rationale
and evidence. Clinical Journal of Pain, 2010. 26(7): p. 635-44.
Rauck, R.L., et al., Intrathecal ziconotide for neuropathic pain: a review. Pain Practice, 2009.
9(5): p. 327-37.
Group, W.C.B.E.B.P., Intrathecal fentanyl for chronic nonmalignant pain. 2005, WorkSafe BC:
Richmond, BC.
Noble, M., et al., Long-term opioid therapy for chronic noncancer pain: a systematic review
and meta-analysis of efficacy and safety. Journal of Pain & Symptom Management, 2008.
35(2): p. 214-228.
Wallace, M.S., et al., Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain:
A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Neuromodulation, 2006. 9(2):
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TransportAccidentCommission&WorkSafeVictoria
EvidenceService
Implantablepaintherapies:Intrathecalinfusions
TechnicalReport:Appendices15
July2011
LorettaPiccenna,EmmaDonoghue
Reportnumber:0611002R7.3
Accompanyingdocumentstothisreport
Title
Implantablepaintherapies:Intrathecal(IT)
infusionsFullReport
Implantablepaintherapies:Intrathecal(IT)
infusionsEvidenceSummary
Implantablepaintherapies:Intrathecal(IT)
infusionsPlainLanguageSummary
Reportnumber
ResearchReportNo.0611002R7
ResearchReportNo.0611002R7.1
ResearchReportNo.0611002R7.2
Reportnumber:0611002R7.3
INTRODUCTION
ThistechnicalreportisacompaniondocumenttoImplantablePaintherapies:Intrathecalinfusions
EvidenceReview.Itcontainsdetailedinformationaboutthemethodsusedinthedevelopmentof
theEvidenceReview,summariesofthestudiesincludedinthereview,andqualityappraisalresults
forthemostrecentand/ormostrelevantincludedstudies.
CONTENTS
APPENDIX1:REVIEWPROCESS...............................................................................................................3
APPENDIX2:METHODS..........................................................................................................................4
APPENDIX3:LISTOFINCLUDEDSTUDIES.............................................................................................17
APPENDIX4:SUMMARYOFINCLUDEDSTUDIES..................................................................................18
APPENDIX5:APPRAISALTABLES...........................................................................................................27
Reportnumber:0611002R7.3
IntrathecalinfusionsTechnicalReport
Page2of62
APPENDIX1:REVIEWPROCESS
Atwostagedapproachwasundertaken.
STAGE1
Identifyevidenceavailableforeachintervention
Runsearchinhealthdatabases,websitesandontheinternet,limittoEBGs,HTAs,SRs,RCTsandcontrolled
clinicaltrials(CCTs)
Applyinclusionandexclusioncriteria
Criticallyappraisesynthesisedresearch
Startwithmostrecentreview,applystandardappraisalcriteria
If found to be of high quality, cross check to ensure references from all other synthesised research are
includedandcheckforconsistencyoffindings
Ifnothighquality,appraisenextmostrecentandrepeatprocess
If there are inconsistent findingsacross the existing reviews, investigate the possibility of synthesis of this
informationorwhetheranewsystematicreviewisrequired
DecideonactionsforStage2
Mapavailableevidence(asperTableA1.1)
Identify whether sufficient high level evidence exists to answer questions or identify what further action
needstobetaken(seealgorithminTableA1.2).
STAGE2
Addressfurtheractionsidentified.
TableA1.1.Mapofavailableevidence
Medication
Analgesics(opioidsmorphine,fentanyletc.)
Antispasmodics(baclofen)
Calciumchannelblockers(ziconotide)
Othermedications(includingketorolacandmidazolam)
SynthesisedStudies
EBGs
SRs&HTAs
Primarystudies
TOTAL
TableA1.2.Furtheractionrequiredtoanswerclinicalquestions
Isthereanysynthesisedresearchavailable?(e.g.EBGs,HTAs,SRs)
Yes
No
Isthisgoodqualityresearch?
AreRCTsavailable?
Yes
No
Yes
No
UndertakenewSR
UndertakenewSR
Considerlookingfor
lowerlevelsofevidence
Isitcurrent(within2years)?
Yes
No
Nofurtheraction
UpdateexistingSR
Reportnumber:0611002R7.3
IntrathecalinfusionsTechnicalReport
Page3of62
APPENDIX2:METHODS
TAC/WSVstaffassistedinthedevelopmentofsearchtermsandinclusionandexclusion.
Inclusionandexclusioncriteria
Inclusionandexclusioncriteriawereestablishedapriori(TableA2.1).Referencesforprimaryscreeningwere
conductedbyonereviewer.Tenpercentofthereferenceswerescreenedbybothreviewersindependentlyto
checkforconsistencyofinclusion/exclusiondecisions,andresultswerefoundtobe100%inagreement.
TableA2.1InclusionandExclusioncriteria
Patient/
population
Inclusion:Anyindividualwithpersistentpain(asdefinedinthestudy)
Allages
Allgenders
Exclusion:
Intervention/
indicator
Acutepain(e.g.postoperativepain,womeninlabour)
Nonpersistentpain(e.g.dysmenorrhoea)
Persistentpainduetosystemicinflammatoryconditions,vascularinsufficiency,haematological
disordersorcancer
Inclusion:Pharmacologicalagentsadministeredatanystageofthemanagementofpersistentpainthrough
intrathecalinfusions(i.e.firstline,secondline,whenallelsefailsorasanadjuncttotherapy)
Analgesics(e.g.opioidsmorphine)
Antispasmodics(e.g.baclofen)
Localanaesthetics
Otherpainmodifyingagentsused(e.g.clonidine,ziconotide)
Exclusion:Drugsadministeredbyroutesotherthanintrathecalinfusion(i.e.epidural,intravenousetc.)
Comparison/
control
Outcomes
Inclusion:Placebo,standardtreatmentoranotherimplantablepaintherapy
Exclusion:Nil
Inclusion:Any(e.g.painmeasuresscales,scoresetc.,physicalfunctionmobility,disability,psychological
depression,socialfunctioning/roles,activitiesofdailyliving,qualityoflife(QOL),returntowork,medication
useandhealthcareutilisation)
Exclusion:Nil
Setting
Inclusion:Anyhealthcaresetting(e.g.acute,subacute,rehabilitation,community)
Exclusion:Nil
StudyDesign
Inclusion:Evidencebasedguidelines(EBGs),systematicreviews(SRs),healthtechnologyassessments(HTAs),
randomisedcontrolledtrials(RCTs)andcontrolledclinicaltrials(CCTs)
Exclusion:Nonevidencebasedguidelines(EBGs),nonsystematicreviews(SRs),cohortstudies,casecontrol
studies,caseseries,editorials,lettersorcommentaries
Publication
details
Inclusion:StudiesinEnglishandconductedonhumans
Timeperiod
Inclusion:Anypublicationdate
Exclusion:StudiesinlanguagesotherthanEnglishand/orconductedonanimals
Exclusion:Nil
Reportnumber:0611002R7.3
IntrathecalinfusionsTechnicalReport
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Searchmethods
Searcheswereconductedinelectronichealthdatabases,relevantwebsitesandtheinternetandwererepeatedfrom
thoseperformedintheinitial2008evaluation.
Searchstrategiesinelectronicdatabases
It is difficult to ensure a comprehensive, uptodate systematic search given the vast number of analgesic drugs
available,thevarietyofgenerictermsusedindifferentcountriesandthechangeinbrandnamesovertime.Hencedrug
termswerenotincluded,howeverallrelevantstudiesshouldbeidentifiedbycombiningtermsrelatedtochronicpain
withtermsrelatedtotheapplicableroutesofadministrationforintrathecalinfusions.Notermshavebeenincludedfor
comparisonoroutcomestoenableabroadersearch.
Internetsearchestoidentifyrelevantwebsites
The reviewers were aware of websites of guideline clearinghouses, guideline developers, centres of evidencebased
practiceandAustraliangovernmenthealthservicesknowntocontainevidencebasedresources.Additionalwebsitesof
specificrelevance(e.g.accidentcompensationgroups)weresoughtviaaninternetsearchusingtheGoogleAdvanced
Search function. The term evidence was combined with the terms accident, injury, trauma, road, transport,
traffic,work,employmentandsafety.
Fourteen websites relevant to Implantable Pain Therapies were identified. These, and the 31 generic websites
previouslyidentifiedbythereviewteam(9professionalorganisations,9guidelineservices,12Australiangovernment
websitesand1centreofevidencebasedpractice)weresearchedforrelevantguidelines.Thesearchesareoutlinedin
detailinTableA2.4.
WebsitesearchestoidentifyrelevantEBGs
Websitesweresearchedusinganylistsofguidelines,publicationsorotherresourcesidentifiedonthesiteandscanned
for relevant documents for both neurostimulation and intrathecal infusion. Where an internal search engine was
availablewebsitesweresearchedusingappropriatesearchstringsrelatingtopainandthemethodofdrugdelivery.
Internetsearchestoidentifyrelevantreferences
An internet search strategy was conducted using the Google Advanced Search function. The search strings were
limitedtodocumentsinEnglishandwereusedtoidentifyguidelinesforbothinterventions
painAND(evidenceORguideline)AND(intrathecalORintraspinalORspinalORsubarachnoidORsubduralOR
stimulationORelectrodeORimplantable)
painAND(evidenceORsystematicORreview)AND(intrathecalORintraspinalORspinalORsubarachnoidOR
subduralORstimulationORelectrodeORimplantable)
ThesearchesareoutlinedindetailinTableA2.4.
Thefirst100Googlesearchresultswerescreenedandyieldednonewstudies.AsGooglesearchresultsarepresented
inorderofrelevance,wedidnotscreenfurther.
Searchesofreferencelists
ThereferencelistsofEBGsandSRswerealsocheckedtoidentifyanyotherpotentiallyrelevantEBGs,SRsorCCTsthat
hadnotbeenidentifiedinourelectronicsearches.
Databasesaccessed
TableA2.2Databasesaccessed
Reportnumber:0611002R7.3
Page5of62
EvidenceSource
Period
DateofSearch
#hits
OvidMEDLINE(R)1948to
17th March2011
267
MarchWeek22011
PreMedline(Ovid) OvidMEDLINE(R) InProcess& 17th March2011
0
OtherNonIndexedCitations
March16,2011
AllEBM(Ovid)*
Various
17th March2011
21
th
CINAHL(Ovid)
1982MayWeek12008
17 March2011
733
th
EMBASE
EMBASE1996to2011Week
17 March2011
553
10
*includingTheCochraneDatabaseofSystematicReviews,DARE,CENTRAL,NHSEED,HTAandACPJournalClub
Medline(Ovid)
TableA2.3Majormedicaldatabasesearchstrategies
pain.ti,ab.
21
intrathecal*.ti,ab.
expPain/
22
intraspinal*.ti,ab.
or/12
23
intraspinal*.ti,ab.
persist*.ti,ab.
24
subarachnoid.ti,ab.
chronic.ti,ab.
25
subarachnoid.ti,ab.
longterm.ti,ab.
26
subdural*.ti,ab.
longterm.ti,ab.
27
subdural*.ti,ab.
refractory.ti,ab.
28
or/1427
intractable.ti,ab.
29
infus*.ti,ab.
10
or/49
30
pump*.ti,ab.
11
3and10
31
device*.ti,ab.
12
Pain,Intractable/
32
30or31
13
or/1112
33
29and32
14
InfusionPumps,Implantable/
34
spinal*.ti,ab.
15
Drugdeliverysystems/
35
infus*.ti,ab.
16
idds.ti,ab.
36
and/3435
17
iip*.ti,ab.
37
or/28,33,36
18
synchromed.ti,ab.
38
and/13,37
19
medtronic.ti,ab.
39
limit38to(englishlanguageandhumans)
20
intrathecal*.ti,ab.
40
limit39toed="20080520 20110331"
*SearchundertakeninMedline,adaptedforuseinotherdatabases
Reportnumber:0611002R7.3
Page6of62
TableA2.4WebsitesearchestoidentifyrelevantEBGs
Search1:Identificationofrelevantguidelinesforintrathecalimplantabletherapiesusingspecificguidelinerelatedwebsites
GuidelineServices
Results
Search
NationalHealthandMedicalResearchCouncil
(NHMRC)
Acutepainmanagement:scientificevidence.2010
Webpagereviewedby:HealthGuidelines
http://www.nhmrc.gov.au/publications/synopses/cp104syn.htm
NationalInstituteforHealthandClinicalExcellence Spinalcordstimulationforchronicpainofneuropathicorischaemicorigin
UK(NICE)
http://guidance.nice.org.uk/TA159
Stereotacticradiosurgeryfortrigeminalneuralgiausingthegammaknife
http://guidance.nice.org.uk/IPG85
Webpagereviewedby:publishedclinicalguidelines,
publishedinterventionalprocedures
Additionalsearchbyterms:chronicpain,intrathecal
infusion,neurostimulation
Webpagereviewedby:Guidelines
NewZealandGuidelineGroup(NZGG)
N/A
Additionalsearchbyterms:pain,intrathecalinfusion,
neurostimulation
Webpagereviewedby:guidelinesbysubject
ScottishIntercollegiateGuidelinesNetwork(SIGN)
N/A
JoannaBriggsInstitute
N/A
GuidelinesInternationalNetwork
Reportnumber:0611002R7.3
Additionalsearchbyterms:chronicpain,intrathecal
infusion,neurostimulation
Webpagereviewedby:chronicpain,intrathecal
infusion,neurostimulation
EFNSguidelinesonneurostimulationtherapyforneuropathic
pain.EuropeanFederationofNeurologicalSocieties.
NGC:005909http://www.guideline.gov/content.aspx?id=11372
Comprehensiveevidencebasedguidelinesforinterventional
techniquesinthemanagementofchronicspinalpain.American
SocietyofInterventionalPainPhysicians.NGC:007428
Webpagereviewedby:painANDspinal,chronicpain,
intrathecal,neurostimulation
IntrathecalinfusionsTechnicalReport
Page7of62
Spinalimplants:DR8pediclescrewsystem(TechnologyReview)
Spinalcordstimulationforchronicpainofneuropathicor
ischaemicorigin(TA159)
Khankinetictreatment(KKT)(TechnologyReview)
Lumbosacraalradiculairsyndroom(M55)
EpiduraleRckenmarkstimulationzurTherapiechronischer
Schmerzen.S3LL(DGAI/DGK/DGNC/DGN/DGSS)
Durerealombarajoasa.Ghidpentrumediculdefamilie
Percutaneousintradiscallaserablationinthelumbarspine
(IPG357)
GuidelinesAdvisoryCommittee
NationalGuidelineClearinghouseUS(NGC)
Internationalguidelinelibraryupdate
N/A
Webpagereviewedby:GACEndorsedGuidelines
Spinalcordstimulationforchronicpainofneuropathic
orischaemicorigin.2008Oct.NGC:006752
NationalInstituteforHealthandClinicalExcellence
(NICE)NationalGovernmentAgency[NonU.S.].
Searchedby:
DiagnosisandTreatmentofLow
BackPain:AJointClinicalPracticeGuidelinefromthe
AmericanCollegeofPhysiciansandtheAmericanPain
Society.What'sNew?What'sDifferent?
(2)painAND(stimulationORelectrodeORimplantable)
(1)painAND(intrathecal*ORintrathecal*OR
intraspinal*ORintraspinal*ORspinal*OR
subarachnoidORsubarachnoidORsubdural*ORsub
dural*)
Bestpractices&practiceguidelines.2008.NGC:007125
InternationalChiropractorsAssociationMedical
SpecialtySociety.
Reportnumber:0611002R7.3
IntrathecalinfusionsTechnicalReport
Page8of62
Chronicpain.2008.NGC:007160
AmericanCollegeofOccupationalandEnvironmental
MedicineMedicalSpecialtySociety.
Pain(chronic).2003(revised2008May19).NGC:006564
WorkLossDataInstitutePublicForProfitOrganization.
EFNSguidelinesonneurostimulationtherapyfor
neuropathicpain.2007Sep.NGC:005909
EuropeanFederationofNeurologicalSocietiesMedical
SpecialtySociety.
Diagnosisandtreatmentofdegenerativelumbarspinal
stenosis.2002(revised2007Jan).NGC:005896
NorthAmericanSpineSocietyMedicalSpecialty
Society.
EFNSguidelinesonpharmacologicaltreatmentof
neuropathicpain.2006Nov.NGC:005495
EuropeanFederationofNeurologicalSocietiesMedical
SpecialtySociety.
Practiceguidelinesforchronicpainmanagement.An
updatedreportbytheAmericanSocietyof
AnesthesiologistsTaskForceonChronicPain
ManagementandtheAmericanSocietyofRegional
AnesthesiaandPainMedicine.1997Apr(revised2010
Apr).NGC:007951
Reportnumber:0611002R7.3
IntrathecalinfusionsTechnicalReport
Page9of62
AmericanSocietyofAnesthesiologists Medical
SpecialtySociety.
Assessment:efficacyoftranscutaneouselectricnerve
stimulationinthetreatmentofpaininneurologic
disorders(anevidencebasedreview).Reportofthe
TherapeuticsandTechnologyAssessment
SubcommitteeoftheAmericanAcademyofNeurology.
2010Jan.NGC:007678
AmericanAcademyofNeurologyMedicalSpecialty
Society.
TRIPDatabase
www.tripdatabase.com
Searchedby:
searchedon15/3/2011144resultstotal144
RelevantpublicationsdownloadedtoEndnotelibrary
(1)painAND(intrathecal*ORintrathecal*OR
intraspinal*ORintraspinal*ORspinal*OR
subarachnoidORsubarachnoidORsubdural*ORsub
dural*)Limitedby:Guidelines)from:2008to:2011
searchedon19/5/20081986resultstotal89
(2)painAND(stimulationORelectrodeORimplantable)
Limitedby:Guidelinesfrom:2008to:2011
AustralianGovernmentWebsitescontainingGuidelines
AustralianGovernmentDepartmentofHealth&
Ageing
www.health.gov.au
AustralianInstituteofHealthandWelfare
www.aihw.gov.au
N/A
N/A
Reportnumber:0611002R7.3
ScannedlistofTopicsforPain
Webpagereviewedby:Publicationssearchedwithin
forguidelinesusesGoogletosearch
IntrathecalinfusionsTechnicalReport
Page10of62
HealthInsite
ACTHealth
N/A
Webpagereviewedby:Healthtopicschronicpain
noguidelineslocatesSRsfromtheCochraneLibrary
www.health.act.gov.au
NoEBGs
www.healthinsite.gov.au
N/A
NSWHealth
www.health.nsw.gov.au
OnlycontainsasmalllistofPaediatricGuidelines
N/A
NTDepartmentofHealthandCommunityServices
www.nt.gov.au/health
NoEBGs
N/A
QueenslandHealth
www.health.qld.gov.au
NoEBGs
N/A
SADepartmentofHealthandHumanServices
www.health.sa.gov.au
+guideline+pain
N/A
TasmanianDepartmentofHealthandHuman
Services
www.dhhs.tas.gov.au
VictorianDepartmentofHumanServices
www.dhs.vic.gov.au
guidelineANDpain
N/A
guidelineANDpain
N/A
VictorianGovernmentHealthInformation
www.health.vic.gov.au
Listoftopics:Pain,ChronicPain
N/A
WADepartmentofHealth
Reportnumber:0611002R7.3
www.health.wa.gov.au
guidelineANDintrathecalANDpain
N/A
neurostimulation
IntrathecalinfusionsTechnicalReport
Page11of62
CentresofEvidenceBasedPracticeWebsites
WACentreforEvidencebasedNursingand
Midwifery
N/A
Webpagereviewedby:ResourcesReports,
GuidelinesandArticle(notrelevant)
www.tac.vic.gov.au/
SearchforGuidance,Guideline
http://wacebnm.curtin.edu.au
OtherAccidentCommissions
TransportAccidentCommission
N/A
AustralianTransportSafetyBureau
http://www.atsb.gov.au/
SearchforGuideline
N/A
RoadSafetyVictoria(TAC)
www.tacsafety.com.au/
SearchforGuideline
WorkSafeVictoria
http://www.workcover.vic.gov.au/
SearchforintrathecalANDpain,neurostimulation
Evidencereviews
ImplantablePainTherapyPolicy
MicrosoftWordNeurostimulation20100430.doc
NoGuidelinesinpublicationscontainsguidance
materialsbutnotevidencebased(includedforinterest)
TrafficInjuryResearchFoundation
http://www.trafficinjuryresearch.com/index.cfm
NoGuidelinescontainstrafficreports
MotorAccidentsAuthorityNSW
http://www.maa.nsw.gov.au/
IntrathecalANDpain,neurostimulation
N/A
WorkSafeBritishColumbia
Reportnumber:0611002R7.3
http://www.worksafebc.com/
IntrathecalFentanylUseInPatientsWithChronicNonmalignant
Pain
ChronicPainTreatments:WhatistheEvidence?
Theeffectivenessofspinalcordstimulatorintreatingcomplex
IntrathecalANDpain,neurostimulation
IntrathecalinfusionsTechnicalReport
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regionalpain...
AccidentCompensationCorporation
http://www.acc.co.nz/index.htm
IntrathecalANDpainANDguideline
ACC2404Traumaticbraininjuryguidelines
(2.488MB)
Evidencetables:Infusion:IntrathecalOpioids
(295KB)
ConsideredJudgementForm:IntrathecalInfusionofBaclofen
(61KB)
ConsideredJudgementForm:InfusionIntrathecalBaclofen
(42KB)
Evidencetables:Infusion:IntrathecalBaclofen
(74KB)
EvidenceBasedReview:ContinuousIntrathecalBaclofenforSpasticity
Management
(98KB)
Intrathecalbaclofen
Evidencetables:NeuromodulationDeepbrainstimulation
(75KB)
PainTreatmentTopics
http://paintopics.org/guidelines_reports/index.php
(IntrathecalORneurostimulation)Guideline
PainTreatmentGuidelinesDescriptions
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TheGeorgeInstitute
http://www.thegeorgeinstitute.org/iih/research/criticalcare&
trauma/criticalcare&trauma_home.cfm
IntrathecalANDpain,neurostimulation
http://www.tac.vic.gov.au/upload/Neurostimulationfullreport.pdf
http://www.tac.vic.gov.au/upload/Intrathecalinfusionfullreport.pdf
InjuryResearchandPreventionUnit
http://www.injuryresearch.bc.ca/
Intrathecal,neurostimulation
N/A
TheBrainTraumaFoundation
http://tbiguidelines.org/glHome.aspx
Guidelines
InhospitalSevereTBIGuidelines
SurgicalManagementofTBI
SaferRoads
http://www.saferroads.org.uk/
NoGuidelines
RailAccidentInvestigationBranch
http://www.raib.gov.uk/about_us/index.cfm
NoGuidelines
OsloSportsTraumaResearchCentre
http://www.klokeavskade.no/en/
NoGuidelines
OregonEvidenceBasedPracticeCentre
http://www.ohsu.edu/epc/pastProjects/index.htm
Intrathecalpain,neurostimulation
N/A
InjuryPreventionNetworkofAotearoaNew
Zealand
http://www.ipnanz.org.nz/
TraumaCentreatJusticeResourceCentre
http://www.traumacenter.org/
Publications
N/A
Publications
N/A
TheDANAFoundation
http://www.dana.org/
IntrathecalpainGuideline,neurostimulationguideline
N/A
Reportnumber:0611002R7.3
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EuropeanAssociationforInjuryPreventionand
SafetyPromotion
http://www.eurosafe.eu.com/
NewZealandInjuryPreventionstrategy
http://www.nzips.govt.nz/resources/publications.php
GuidelineANDpain
N/A
Resources/Publications/
N/A
NHSHealthatWork
http://www.nhsplus.nhs.uk/web/public/default.aspx?PageID=330
TACGuidelinesonly
TheCanadianAssociationofRoadSafety
Professionals
http://www.carsp.ca/index.php?0=page_content&1=59&2=134
Resources/Publications
N/A
Search2:IdentificationofrelevantstudiesforintrathecalimplantabletherapiesusingGoogle
Findwebpagesthathaveall thesewords
painAND(evidenceORguideline)AND(intrathecalORintraspinalORspinalORsubarachnoidORsubduralORstimulationORelectrodeOR
implantable)
Limits
English,PastYear
Results21/5/2008completedsearch
About2,410,000results
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Appraisal
Appraisalwasundertakeninsteps.
Themostrecentreview(EBG,SRorHTA)wasassessedforqualityusingstandardappraisalcriteria.
Iffoundtobeofhighquality,itwascrosscheckedagainsttheotheravailablereviewstocompare
scope(populationandoutcomesaddressed)andconsistencyoffindings
If found not to be of high quality, the next most recent was appraised and the above process
repeated.
Quality
Evidencebasedguidelinesandsystematicreviewswereappraisedusingstandardcriteriabyasinglereviewer
in consultation with colleagues as required. RCTs were also appraised using standard criteria by a single
reviewerinconsultationwithcolleaguesasrequired.DetailsofqualityappraisalsareincludedinAppendix5.
Systematicreviews
SRs were appraised using standard criteria applied by a single reviewer in consultation with colleagues as
required.Dataoncharacteristicsofthestudieswereextractedandsummarised.
DataExtraction
Dataoncharacteristicsofthestudieswereextractedandsummarised.
Consistencyoffindings
Whereacurrent,goodqualityreviewisavailable,thefindingsarecomparedwithothersourcesof
synthesised evidence that have been identified to determine whether any inconsistencies exist in
theinformationprovided.
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APPENDIX3:LISTOFINCLUDEDSTUDIES
1.
Eisenach,J,Curry,R,Rauck,R,Pan,P,andYaksh,T.RoleofSpinalCyclooxygenaseinHuman
PostoperativeandChronicPain.Anesthesiology.May2010.112(5):12251233.
2.
NobleM,TreadwellJR,TregearSJ,CoatesVH,WiffenPJ,AkafomoC,SchoellesKM.Longtermopioid
managementforchronicnoncancerpain.CochraneDatabaseofSystematicReviews2010,Issue1.Art.
No.:CD006605.DOI:10.1002/14651858.CD006605.pub2.
3.
Patel,V,Manchikanti,L,Singh,V,Schultz,D,Hayek,SandSmith,H.SystematicReviewofIntrathecal
InfusionSystemsforLongTermManagementofChronicNonCancerPain.PainPhysician.2009.12:345
360.
4.
Rauck,R,Wallace,M,Burton,A,Kapural,L,andNorth,J.IntrathecalZiconotideforNeuropathicPain:A
Review.PainPractice.2009.9(5):303327337.
5.
TeasellRW,MehtaS,AubutJA,FoulonB,WolfeDL,HsiehJT,Townson,AF,Short,CtheSpinalCordInjury
RehabilitationEvidenceResearchTeam.ASystematicReviewofPharmacologicalTreatmentsofPain
AfterSpinalCordInjury.Archivesofphysicalmedicineandrehabilitation.May2010.91(5):81631.
6.
Wallace,M,Rauck,RandDeer,T.ZiconotideCombinationIntrathecalTherapy:RationaleandEvidence.
ClinicalJournalofPain.September2010.26(7):635644
7.
Jadad,A.,etal.,ManagementofChronicCentralNeuropathicPainFollowingTraumaticSpinalCordInjury.
2001,AgencyforHealthcareResearchandQuality(US):Rockville,MD.
8.
InterventionalPainManagement.2005[cited201121April];Availablefrom:http://www.acc.co.nz/for
providers/clinicalbestpractice/interventionalpainmanagement/interventions/intervention
index/index.htm.
9.
Turner,J.A.,J.M.Sears,andJ.D.Loeser,Programmableintrathecalopioiddeliverysystemsforchronic
noncancerpain:asystematicreviewofeffectivenessandcomplications.ClinicalJournalofPain,2007.
23(2):p.180195.
10. Sanders,S.H.,R.N.Harden,andP.J.Vicente,Evidencebasedclinicalpracticeguidelinesfor
interdisciplinaryrehabilitationofchronicnonmalignantpainsyndromepatients.PainPractice,2005.5(4):
p.303315.
11. Williams,J.E.,G.Louw,andG.Towlerton,Intrathecalpumpsforgivingopioidsinchronicpain:a
systematicreview.HealthTechnologyAssessment.2000:Wincester,England.
12. Intrathecalopioidtherapyforchronicnonmalignantpain.2006,HayesInc.:Lansdale,PA.
13. Group,W.C.B.E.B.P.,Intrathecalfentanylforchronicnonmalignantpain.2005,WorkSafeBC:Richmond,
BC.
14. Noble,M.,etal.,Longtermopioidtherapyforchronicnoncancerpain:asystematicreviewandmeta
analysisofefficacyandsafety.JournalofPain&SymptomManagement,2008.35(2):p.214228.
15. AssessmentandManagementofChronicPain.2007[cited2011April];Availablefrom:
http://www.icsi.org/guidelines_and_more/gl_os_prot/musculo
skeletal/pain__chronic__assessment_and_management_of_14399/pain__chronic__assessment_and_ma
nagement_of_14400.html
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APPENDIX4:SUMMARYOFINCLUDEDSTUDIES
TableA4.1summaryofincludedstudies
st
1 author,year,title
Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
Conclusion/Recommendation
Recommendation
category
Othercomments
EBG
Intraspinaltherapycanprovideanexcellenttherapeutic
effectfornonmalignantandcancerpain.However,itshould
bereservedonlyforpatientswhohavefailedother
conservativeapproachesforthetreatmentofpain,and
shouldbeusedcautiously.Beforestartingintrathecal
treatmentinapatientwithchronicpain,theexpectations
andplansshouldbediscussedindetail.Thebestcandidates
arepatientswhorespondwelltooralopioidsbutwhocannot
toleratethesideeffects(e.g.,sedation,nausea,constipation).
Insufficient
evidencetodraw
conclusions
Theconcernswiththis
reviewincludepossible
conflictofinterest,the
searchstrategynotbeing
explicitlydocumented,and
thevalidityofthetrialsnot
beingassessed
EVIDENCEBASEDGUIDELINES
InstituteforClinical
SystemsImprovement
2007
Population:Physiologicallymatureadolescents(between1618years)and
adults.Itcanbeappliedtopaediatricpopulationswherenoted.
Assessmentand
ManagementofChronic
Pain
Intervention:Intrathecalmedicationdeliverysystems
Setting:Notspecified
Comparator:Notspecified
Outcomes:Nonedetailed
Inclusion:Nonespecifiedotherthaninthepatient/populationsection
Exclusion:
Itisnotintendedforthetreatmentofmigraineheadaches,cancerpain,
advancedcancerpain,orinthecontextofpalliativecareorendoflife
management
AccidentCompensation
CorporationofNew
Zealand(ACCNZ)2005
Population:Peopleovertheageof12yearsandwereexperiencing
persistentnoncancerpain.
Interventionalpain
management
Intervention:Continuousspinalinfusionincludingthefollowingsites:
intrathecal,subarachnoid,andneuroaxial
Comparator:Notspecified
Setting:Notspecified
Outcomes:Pain,adverseeffects,function,medicationuse,work
Onlyoneobservationstudywasincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
EBG
Wedonotrecommendintrathecalinfusionofopioidson
theirownforthetreatmentofadultswithpersistentpainof
noncancerorigin.
Insufficient
evidencetodraw
conclusions
Onlyobservationstudieswereincludedinthisguideline
whichprovideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
Inclusion:Thefollowingstudytypeswereconsideredforinclusioninthe
InterventionalPainManagement(IPM)guidance:(1)systematicreviews,
(2)guidelines,(3)healthtechnologyassessments,(4)randomised
controlledtrials/quasirandomisedcontrolledtrials,concurrentcontrol
andcasecontrolstudieswith10ormoresubjects,(5)caseserieswith50
ormoresubjects,(6)cohortstudieswith50ormoresubject.However,
caseseriesandcohortstudieswithfewerthan50subjectswereincludedif
theyreportedonadverseeventsorsafetyconcernsassociatedwiththe
interventioninquestionintheabstract.Evidenceonharmisoftenweaker
thanthatonbenefits,sothesamplesizethresholdforevidenceabout
harmwasthereforelowered.
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Page18of62
st
1 author,year,title
Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
Conclusion/Recommendation
Recommendation
category
Othercomments
EBG
Intervention:Implantableinfusionpumps
Giventhecontinualabsenceofqualityresearchshowing
consistentandclinicallysignificantevidence,thecurrent
guidelinesdonotrecommendusingimplantableinfusion
pumpswithChronicPainSyndromepatients.
Insufficient
evidencetodraw
conclusions
Comparator:Notspecified
Outcomes:Pain,function,mood
Onlyobservationstudieswereincludedinthisguideline
whichprovideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
Althoughthisresearch
articleisaguideline,we
haveappraiseditusing
criteriaforasystematic
review.Thelimitations
includenothavinga
documented
comprehensivesearch
strategyandnot
appraisingtheincluded
studyusingappropriate
appraisalcriteria.
OnlystudiesreportedintheEnglishlanguagewereincluded.Inordertobe
includedintheappraisal,studieswererequiredtoreportonatleastone
painrelatedprimaryoutcome.
Exclusion:Allstudiesonhealthyvolunteers,orinvolvingexperimentally
inducedpain,wereexcluded.Studieswereexcludediftheyreportedon:
painduetomalignancy;acuteresolvingpainsuchaspostoperativepain;
childbirth;dysmenorrhoea;dentalpain;infectionsuchaspostherpetic
neuralgia;systemicinflammatoryconditions;migraine;angina;other
visceralpain;peripheralvasculardisease;orhaematologicaldisorders.
Studiesthatdidnotreportpaincontrolorpainreliefasaprimaryoutcome
wereexcluded.
Casestudiesinvolving<50subjectswereexcluded,unlesstheycontained
informationonadverseeffectsorsafetyintheabstract.Studiesgradedas
lowqualityorscoringlow(ifacaseseries)wereexcludedfromthereview
ofeffectiveness.
Sanders2005
Population:Chronicnonmalignantpainsyndromes
Evidencebasedclinical
practiceguidelinesfor
interdisciplinary
rehabilitationofchronic
nonmalignantpain
syndromepatients.
Setting:Notspecified
Inclusion:Studiesthatwereprospective,controlresearchdesignusing
quantifiable,objectiveoutcomemeasures,includingfunction.
Exclusion:Notspecified
SYSTEMATICREVIEWS/HEALTHTECHNOLOGYASSESSMENTS
Noble2010
Longtermopioid
managementfor
chronicnoncancer
pain
Population:Adultsagedatleast18yearswithpainduetoanycauseother
thancancerlastingforatleastthreemonths
Intervention:
Intrathecalmorphinealoneorwithclonidine,bupivacaineormidazolam
Intrathecalbupivacaine
Intrathecalsufentanilcitrate
Reportnumber:0611002R7.3
SR
Manypatientsdiscontinuelongtermopioidtherapy
(especiallyoralopioids)duetoadverseeventsorinsufficient
painrelief;however,weakevidencesuggeststhatpatients
whoareabletocontinueopioidslongtermexperience
clinicallysignificantpainrelief.Whetherqualityoflifeor
functioningimprovesisinconclusive.Manyminoradverse
events(likenauseaandheadache)occurred,butserious
adverseevents,includingiatrogenicopioidaddiction,were
Positivebutneeds
furtherevidence
oncombination
therapiesandon
longtermquality
oflifeand
functionalstatus
outcomes.
*NoteThissystematic
reviewisnottobe
confusedwithasimilar
onepublishedin2008by
thesameauthors.
However,theinclusion
andexclusioncriteriahave
beenupdatedsothis
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1 author,year,title
Inclusion,Exclusioncriteria(forP.I.C.O)
Intrathecalmethadone
Intrathecalmidazolam
Intrathecaldilaudid
Intrathecalfentanyl
Intrathecalclonidine
Intrathecalbaclofen
Study
design
Conclusion/Recommendation
Recommendation
category
rare.
Othercomments
evidenceisnew.
Comparator:Nocomparatorassessedasthestudiesincludedwerecaseseries
(observational).
Inclusion:
Efficacydataonparticipantsafteratleast6monthsoftreatment;
Inanylanguageandwerefulltextarticles;
Wereprospective;
Enrolledandadministeredtoatleast10participants;
ReporteddataofparticipantswithCNCPlastingforatleast3months;
Previousnonopioidpharmacotherapymusthavefailedbeforebeginning
opioids;
Noreportingofredundantdataonpatientswhowerealsoreportedonin
includedstudiesorstudieswithduplicatedata;
RCTsandprepostcaseserieswereincluded
Exclusion:Notreported
Outcomes: Average change in pain scores, patients with at least 50% pain
relief,qualityoflife(QoL),functionlevels,AEs,discontinuationfromstudydue
toinsufficientpainreliefanddiscontinuationfromstudyduetoAEs.
Teasell2010
ASystematicReview
ofPharmacological
TreatmentsofPain
AfterSpinalCord
Injury
Population:Patientswithmixedpain(neuropathicand
musculoskeletal/spastic)
Intervention:ITmorphineandclonidine,ITbaclofen
Comparator:N/A
Inclusion:
Studieswereonlyincludedforanalysisifatleast50%ofsubjectshadan
SCI,therewereatleast3subjectswithanSCI,andtherewasadefinable
interventionbeingstudied.OnlystudiespublishedintheEnglishlanguage
Reportnumber:0611002R7.3
SR
Thereislevel1evidencefrom1RCTandlevel2evidence
fromaprospectivecontrolledtrialthatacombinationof
intrathecalmorphineandclonidineresultsinasignificant
reductioninneuropathicpain.
Insufficient
evidencetodraw
conclusions
Thereislevel4evidencethatintrathecalbaclofenreduces
musculoskeletalpainafterSCIinconjunctionwithspasticity
reduction.
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Study
design
Conclusion/Recommendation
Recommendation
category
Othercomments
SR
Intrathecalinfusiondevicesusedforthetreatmentof
chronicintractablepainprovidepositivelongtermoutcomes
andmayhavearoleasanadvancedstagetherapyfor
refractorypain.Thepresentsystematicreviewwith5
observationalstudiesmeetingmethodologicquality
assessment(7175)indicatesthattheevidenceisLevelII3or
III(limited)basedonUSPSTFcriteriawitharecommendation
of1C/strongbasedontheevidencederivedfrom
observationalstudies.
Positivebutneeds
furtherevidence
wereincluded.
StudiesexaminingalltypesofpainafterSCI(nocioceptive,neuropathic,
mixed)wereexamined
Exclusion:Notreported
Outcomes:painreduction(VAS,goodtoexcellentscale)
Patel2009
Population:Patientswithchronicnoncancerpain
SystematicReview
ofIntrathecal
InfusionSystemsfor
LongTerm
Managementof
ChronicNonCancer
Pain
Intervention:Intrathecalmorphine(+buprenorphine,bupivacaine,clonidine,
fentanyl,hydromorphoneormethadone,NaCl)
Comparator:Nocomparatorassessedasthestudiesincludedwerecaseseries
(observational).
Inclusion:
Studiesshouldclearlyshowtheuseofintrathecalinfusiondevice/system
(programmableorfixedinfusionrate)implantedfornoncancerpainfor
longtermuse
Studiesmusthaveaspecificindicationforintrathecalinfusionandthe
druginjected.
Aminimumof12monthsoffollowupwasavailable.
Cleardocumentationofpatientoutcomesandcomplicationsshouldhave
beenprovided.
Numberofpatientsevaluatedmustbeatleast25.
Paucityofliterature.Therewerenorandomizedtrials
availablemeetingtheinclusioncriteria.Further,
observationalstudiesarealsoveryfew.
Exclusion:
Lackofcleardocumentationofinfusionsystemsormixeddelivery
methods
Externalizedinfusionsystemsforshorttermuse.
Studiesfornoncancerpainwithlessthan12monthsfollowup.
Lackofcleardocumentationoftheindicationsandpatientpopulation
beingstudied.
Outcomes:Painreduction(%,VASscale),satisfactionlevels,QoL,workstatus,
complications,numberofdoctorsvisits,numberofemergencyvisits,
functionalscoreQUALEFFO
Rauck2009
Population:Patientswithchronicsevere(noncancer)pain
Intrathecal
Reportnumber:0611002R7.3
SR
Evidencefromcasestudies,caseseries,openlabelstudies,
andDBPCtrialssuggeststhatziconotide,aseither
Positivebutneeds
furtherevidence
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1 author,year,title
Ziconotidefor
NeuropathicPain:A
Review.Pain
Practice
Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
Intervention: ITziconotide,ITZiconotidewithbaclofen
Comparator:Nocomparatorassessedasthestudiesincludedwerecaseseries
(observational).
Inclusion:
Forclinicalstudies,bothcontrolled(randomizedornonrandomized)and
uncontrolledstudies(caseseriesorcasereports)wereincluded.
Patientswithanytypeofneuropathicpaincondition.Maleandfemale
patientsofallagesandraces/ethnicitieswereincluded.
ITadministrationofziconotideforneuropathicpain,inanydose,aloneor
inconjunctionwithoneormoredrugs.
Painassessmentasanoutcomemeasure
Conclusion/Recommendation
Recommendation
category
monotherapyorincombinationwithotherITagents,canbe
effectiveintreatingpatientswhohaverefractoryneuropathic
pain.Additionalstudiesevaluatingthelongtermefficacy
andsafetyofziconotideforneuropathicpainmaybe
warranted.
inlongterm
studies
Othercomments
Exclusion:Notreported
Outcomes:VASPIscore,AEs,cerebrospinalfluid(CSF)concentrations,
medicationuse,functionalstatus
Wallace2009
Population:Patientswithchronicpain
Ziconotide
Combination
IntrathecalTherapy:
Rationaleand
Evidence
Intervention:
ITmorphinealoneorwithITziconotide,IThydromorphonewithIT
ziconotide,
ITbaclofenwithITziconotide,
IThydromorphoneorfentanylorsufentanilorbupivacaineor
clonidineorbaclofenwithITziconotide
SR
Cliniciansmustbalancethelackofevidencebaseddatawith
theirownclinicalexpertiseandexperiencewithziconotide
andotherITagentswhendesigningITtherapyregimens.
Thereisaneedforadditionalevidencebasedinvestigations
ofziconotidecombinationtherapies,includinglongterm
clinicaltrials.
Insufficient
evidencetodraw
conclusions
Comparator:N/A
Inclusion:Notreported
Excluded:Notreported
Outcomes:VASPIscore,AEs
Noble2008
Longtermopioid
therapyforchronic
noncancerpain:a
systematicreview
andmetaanalysis
ofefficacyand
Population:Patientswithchronicnoncancerpainrefractorytotreatmentforat
least3months
Setting:Notspecified
Intervention:Longtermopioidtherapy(oral,transdermaland/orintrathecal)
Comparator:Notspecified
Outcomes:Pain,withdrawalrates,adverseeffects
Reportnumber:0611002R7.3
SR
Manypatientsintheincludedstudiesweresodissatisfied
withadverseeventsorinsufficientpainrelieffromopioids
thattheywithdrewfromthestudies.Forpatientsableto
continueonopioids,evidence(albeitweak)suggeststhat
theirpainscoreswerelowerthanbeforetherapybeganand
thatthisreliefcouldbemaintainedlongterm(6months).
However,datadescribinglongtermsafetyandefficacyof
Insufficient
evidencetodraw
conclusions
Onlylongtermopioid
therapystudieswere
includedwhichwould
meanstudieswithshorter
termoutcomeswouldbe
missed.Only6studies
wereincludedinthis
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1 author,year,title
safety
Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
Inclusion:
Conclusion/Recommendation
Recommendation
category
review,but
correspondencewith
reviewauthorsprovided
validexplanationsfor
reasonsforexclusionof
otherpotentiallyrelevant
studies.
opioidsforCNCParelimitedintermsofquantityandquality,
precludingtheformationofevidencebasedconclusions
supportedbystrongqualitativeorstablequantitative
evidence.Anevidencebaseoflowqualityprovidesonlyweak
evidencefromwhichtodrawqualitativeconclusionsandonly
lowstabilityevidencefromwhichtodrawquantitative
conclusions.Thegeneralisabilityoffindingsofthesestudies
torealworldpatientswithchronicnoncancerpainin
generalisunclear.Prescreeningofpatientsinintrathecal
studiesforopioidresponsivenesspriortocommencementof
treatmentmaylimitthegeneralisabilityofthefindingsof
thesestudiestopatientswhoarenotprescreened.We
concludethatmanypatientsdiscontinuelongtermopioid
therapyduetoadverseeventsorinsufficientpainrelief;
however,weakevidencesuggeststhatintrathecalopioids
reducepainlongtermintherelativelysmallproportionof
individualswithCNCPwhocontinuetreatment.
Studiesthat(1)collecteddataonpatientsafteratleast6monthsofopioid
therapy;(2)werepublishedinEnglish;(3)werereportedasfulltextarticles;
(4)didnotincludepatientsalsoreportedoninotherincludedstudies;(5)were
prospective;(6)enrolledatleast10patients;(7)enrolledonlypatientswho
hadchronicnoncancerpain(CNCP),definedaspainlastingatleastthree
monthsasdefinedbyInternationalAssociationfortheStudyofPain(IASP).
Therewerealsotwoadditionalcriteriaforpainoutcomes:(1)painoutcomes
musthavebeenpatientreported;and(2)outcomedatamustnothavebeen
collectedretrospectively.
Exclusion:Notspecified
Othercomments
Onlyobservationstudieswereincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
Turner2007
Population:Patientswithchronicnoncancerpain
Programmable
intrathecalopioid
deliverysystemsfor
chronicnoncancer
pain:asystematic
reviewof
effectivenessand
complications.
Setting:Notspecified
Intervention:Programmableintrathecalopioidorziconotidedeliverysystems
Comparator:Notspecified
Outcomes:Pain,adverseeffects,function,medicationuse,work
Inclusion:Studiesthat:(1)werepublishedinEnglish(publishedconference
abstractswereexcluded);(2)addressedpaintreatmentwithopioidor
ziconotidedeliveredintrathecallyviaprogrammablepumps;(3)patient
diagnosesnotlimitedtospasticityorspecificdiseases(e.g.cancer,sicklecell
disease);(4)containedoriginaldataonpain,functioning,orcomplicationsin
humans.
Also:(1)theonlypumpstudiedwasprogrammableordatawerepresented
separatelyforpatientswithprogrammablepumps;and(2)thefirstmedication
deliveredwasintrathecallywasanopioid(withorwithoutadjuvant
Reportnumber:0611002R7.3
SR
Thestudiesreviewedfoundimprovementinpainand
functioningonaverageamongpatientswithchronic
noncancerpainwhoreceivedpermanentimplantable
intrathecalinfusionpumps.However,theirmethodologic
limitationsprecludeconclusionsconcerningtheeffectiveness
ofthistechnologylongtermandascomparedwithother
treatments.Drugsideeffectsandhardwarecomplications
werecommon.Suggestionsaremadeformethodologic
improvementsinfuturestudies.
Insufficient
evidencetodraw
conclusions
Nostudiesofziconotide
mettheinclusioncriteria
foreithereffectivenessor
thecomplicationsreview
Onlyobservationstudieswereincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
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Study
design
Conclusion/Recommendation
Recommendation
category
Othercomments
HTA
Thelimitedavailableevidencesuggeststhatintrathecal
morphineorhydromorphonedeliveredviaimplanted
infusionpumpcanprovidesubstantialpainreliefandimprove
qualityoflifeforsomepatientswithchronic,intractable,
nonmalignantpainsyndromes.Severalofthestudiesfounda
greatereffectforpatientswithnociceptivepaincompared
withpatientswithneuropathicordeafferentationpain,but
otherstudiesfailedtofindadifferentialeffectaccordingto
typeofpain.Drugtolerancewasreportedinanumberof
studiesandanumberofdrugrelatedsideeffectswere
described,althoughdevicerelatedcomplicationsappearedto
beamoreseriousprobleminmoststudies,withmanyof
thesecomplicationsnecessitatingsurgery.Additionalstudies
areneededtoaddressquestionsregardingthesafety,
optimaldrugdosage,andlongtermbenefitofintrathecal
opioidtherapy.ThereforeaHayesRatingofChasbeen
assignedforintrathecalopioidtherapydeliveredvia
implantablepumpinpatientswithchronicnonmalignant
painwhohavefailedotherlessinvasiveformsofpain
management.AHayesRatingofCmeansPotentialbut
unprovenbenefit.Useofthetechnologyissupportedby
somepositivepublisheddataregardingsafetyand/orefficacy
Insufficient
evidencetodraw
conclusions
Oneofthefaultsofthe
reviewwasthatthesearch
strategywasnot
comprehensive.The
searchtermsusedwere
limitedandwecannot
thereforeexcludethe
possibilityofrelevant
articlesbeingmissed.This
doesappeartobecaseas
studieswhichhavebeen
includedinotherreviews,
werenotincludedinthis
review.Inaddition,there
criteriausedtoappraise
thequalityofthe
individualstudieswasnot
explicit.Lowlevelstudies
includedastheseappear
tobetheonlystudies
undertakeninthisarea.
medications)orziconotide.
Fortheeffectivenessreview(butnotthecomplicationsreview)studiesalso
hadtobeeitherRCT,controlledtrialorcohortstudy,orotherstudieswhich
had(1)independentobservercompletedorpatientcompletedstandardised
measuresofpainorfunctioningobtainedbothbeforeimplantabledrug
deliverysystem(IDDS)implantationandatplanned,regularfollowups;(2)
datafrompatientbaselinedescriptiveandoutcomesmeasuresreportedfroall
studyparticipantswhounderwentpumpimplantationduringthestudyperiod;
and(3)originaldatareportedonpainorfunctioningbeforeIDDSimplantation
andfor75%ofimplantedpatientsatafollowup6months.
Exclusion:(1)morethan10%ofthesamplewerebeingtreatedforspasticityor
painassociatedwithaspecificdiseaseanddataonpain,functioningor
complicationswerenotpresentedseparatelyforpatientswithoutthese
conditions;(2)studyfocusedonlyonpatientswhodidnotrespondtothefirst
IDDSdrugtheyweregiven;(3)casereports.
HayesInc.2006
Population:Patientswithchronicnonmalignantpain
Intrathecalopioid
therapyforchronic
nonmalignantpain
Setting:Notspecified
Intervention:
Intrathecalopioidtherapydeliveredviaimplantableinfusionpump
Comparator:Notspecified
Outcomes:Pain,adverseeffects,function,medicationuse,work,costs
Inclusion:Studieswithsamplesize>20
Exclusion:Studieswithsamplesize<20
Reportnumber:0611002R7.3
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1 author,year,title
Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
Conclusion/Recommendation
Recommendation
category
Othercomments
Insufficient
evidencetodraw
conclusions
Nostudiesfoundwhich
usedITfentanyl.
forthecitedapplication(s)
Onlyobservationstudieswereincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
WorkSafeBC2005
Population:Chronicnonmalignantpainpatients
Intrathecalfentanyl
forchronic
nonmalignantpain
Setting:Notspecified
SR
Intervention:Intrathecalfentanyl
Comparator:Notspecified
Outcomes:Pain,adverseeffects,function,medicationuse,costs
Inclusion:
Studiesthat:
Allofthesestudiesinvolvedpatientswithfailedbacksurgery.
Thesestudiessuggestthattheremaybesomelowlevel
evidenceontheeffectivenessofintrathecalmorphineinthe
longtermtreatmentofchronicnonmalignantpain.However,
theevidenceisstillinconclusiveduetothevariabilityin
outcomecriteria/measurementtools,followupperiodsand
thesupplementaluseofotheranalgesics,antidepressantsor
sedatives.
Itisofinterestthatsome
ofthesestudies
demonstratedose
escalationofupto20
times,fromthestartofthe
trialtotheendofthe
followupperiod
humanadultsubjects.
atleasttheabstractwasavailableinEnglish.
Exclusion:
publicationsonintraspinalfentanylormorphinewithoutadditional
clarification,whetheritwasepiduralorintrathecalwereexcluded.
systematicreview/reviewarticleswereexcludedifthemethodologyusedto
evaluatethequalityoftheprimarystudieswerenotapparent
Jadad2001
Managementof
ChronicCentral
NeuropathicPain
FollowingTraumatic
SpinalCordInjury
Setting:Notspecified
Onlyoneobservationstudywasincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
Intervention:Anypharmacologicalintervention
Comparator:Notspecified
Insum,researchonpharmacologicalinterventionsforthe
managementofCNPafterTSCIisinitsinfancy.Theevidence
availableissolimitedthatitisimpossibletodrawany
conclusionsregardingtheirroleinclinicalpractice.Although
itappearsthatlocalanaesthetics,opioids,andclonidinegiven
spinallymayplayaroleinthemanagementofCNPafterTSCI,
theevidenceavailablecomesfromfew,small,poorly
reported,andlargelyuncontrolledstudies.
Population:Centralneuropathicpain(CNP)followingTraumaticSpinalCord
Injury(TSCI)
Outcomes:Pain,adverseeffects
Inclusion:Studiesthatwere:(1)inhumans,(2)aboutthecause,management,
ormeasurementofCNPinindividualsafterTSCI.
Exclusion:(1)childrenyoungerthan13years;(2)studieswherethesample
consistedofpeoplewithoutaTraumaticSpinalCordInjury(TSCI)orchronic
neuropathicpain;(3)inabilitytodeterminewhetherchronicpainwascentral
andneuropathic;(4)studieswherethesampleincludedindividualswithTSCI
aswellasothertypesofCNP,butwheretheresultswerenotpresented
Reportnumber:0611002R7.3
HTA/SR
Insufficient
evidencetodraw
conclusions
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Inclusion,Exclusioncriteria(forP.I.C.O)
Study
design
separatelyforindividualswithTSCI;(5)studiesthatonlyusedtheterm
"chronicpain"withoutanyotherdescriptionofthepainexperiencedbythe
individualsinthestudysamplethatcouldhavehelpedusjudgeitascentral
andneuropathic.
Conclusion/Recommendation
Recommendation
category
Othercomments
Insufficient
evidencetodraw
conclusions
Theareasofconcernare
nonreproduciblesearch
strategy(nosearchterms
havebeendocumented)
andnotreporting
appraisalsofthestudyand
theimpactthismayhave
ontheresults.Inaddition,
somestudiesappearto
havenotbeenincludedin
thenoncancergroup.
Findingssuggestthatintrathecalbaclofendoesnotdecrease
chronicneurogenicspinalcordpain
HTA/SR
Therewasnoconclusionmadejustfornoncancerpatients.
Williams2000
Population:Patientswithchroniccancerandnoncancerpain
Intrathecalpumps
forgivingopioidsin
chronicpain:a
systematicreview
Setting:Hospital,hospiceorcommunitysetting
Intervention:
Onlyobservationstudieswereincludedinthisreviewwhich
provideslowlevelevidence.Theresultsneedtobe
interpretedwiththisinmind.
Differenttypesofintrathecalpumpsystemsforgivingopioidsinchronicpain
control
Differenttypesofintrathecallyadministereddrugsgivenbypumpsystems
(e.g.opioids,localanaesthetics,clonidine,midazolam,noradrenaline)
Comparator:Otherroutesofanalgesiadelivery(e.g.oral,subcutaneous,rectal,
intramuscular,intravenous,transdermal,intraventricular,neuroablative,
neurolyticandneurosurgicalinterventions)
Outcomes:Pain,adverseeffects,function,medicationuse,work,costs
Inclusion:Chroniccancerandnoncancerpain
Exclusion:Allacutepainwasexcluded,e.g.labour,postoperativeandtrauma
pain
RANDOMISEDCONTROLLEDTRIALS
Eisenach2010
RoleofSpinal
Cyclooxygenasein
HumanPostoperative
andChronicPain
Population:Patientswithchronicpain,alreadyreceivingITmorphinefor
atleast6weeks
Intervention:ITmorphinewithITketorolac
Comparator:Normalsalineplacebo
Outcomes:
Painintensityandunpleasantness(VASandthermaltesting),proportion
ofpatientswhoexperienced30%or50%painrelief,AEs
RCT
Wefailedtoobservegreateranalgesiafromintrathecal
ketorolacthansalineplaceboinpatientswithprimarilylow
backandlowerextremitypainandacombinationofsomatic
andneuropathiccomponents
Neutral(no
differencein
effectbetween
interventions)
2mgofintrathecalketorolacwasnotassociatedwithserious
sideeffects,failedtoreduceongoingpaininchronicpain
patientsmorethanplacebo.Theseobservationsarelimited
bythesmallnumberofsubjectsstudied,andpatient
population,andtheamountandtimingofketorolacdosing.
Theysuggestthatspinalcyclooxygenaseisnotactivatedin
mostpatientswiththeseclinicalpainconditions.
Reportnumber:0611002R7.3
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APPENDIX5:APPRAISALTABLES
TableA5.1Criticalappraisaltable(Noble,M,2010)
Study:NobleM,TreadwellJR,TregearSJ,CoatesVH,WiffenPJ,AkafomoC,SchoellesKM.Longtermopioidmanagementforchronicnoncancerpain.CochraneDatabaseofSystematicReviews2010,Issue1.
Art.No.:CD006605.DOI:10.1002/14651858.CD006605.pub2.
Descriptionofstudy:SystematicreviewofRCTs(orothertypesofstudies).
Patient/population
Adultsagedatleast18yearswithpainduetoanycauseotherthancancerlastingforatleastthreemonths.
n=231(10studies)
Pleasenoteallthesestudiesmaynothaveassessedouroutcomesofinterest.
Setting
Intervention/indicator
Participantsweretreatedonanoutpatientbasis,withtheexceptionofscreeningandimplantationphasesofintrathecalstudies.
Reference
Intervention
Anderson1999;(caseseries)n=30
Intrathecalmorphine
Anderson2003;(caseseries)n=27
Intrathecalmorphine
Angel1998;(caseseries)n=11
Intrathecalmorphine
Hassenbusch1995;(caseseries)
n=18
Intrathecalmorphineorintrathecalsufentanilcitrate
Kumar2001;(caseseries)n=16
Intrathecalmorphine,withclonidineifneeded
Mironer2001;(caseseries)n=24
Intrathecalmethadone
Pimenta1998(caseseries)n=11
Intrathecalmorphineclorhidrate(n=10)ortramadol(n=1)
Rainov2001;(caseseries)n=26
Intrathecalmorphinewithbupivacaine(n=20)and/orclonidine(n=16)and/ormidazolam
(n=10)
Reportnumber:0611002R7.3
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Shaladi2007;(caseseries)n=24
Intrathecalmorphine
Thimineur2004;(caseseries)n=38
Intrathecalmorphine(n=9),IntrathecalDilaudid(n=21),Intrathecalfentanyl(n=24),Intrathecalclonidine(n=23),
Intrathecalbaclofen(n=2),Intrathecalbupivacaine(n=1),Intrathecalmethadone(n=1)
Comparison/control
None
Outcomes
Weassessedadverseevents(sideeffects),discontinuationfromstudyduetoadverseevents,discontinuationfromstudyduetoinsufficientpainrelief,average
changeinpainscore,proportionofpatientswithatleast50%painrelief,healthrelatedqualityoflife,andfunction.
Outcomemeasuresmusthavebeenvalidatedorusedasastandardofcaretobeincludedintheanalyses.Inadditiontothesegeneralinclusioncriteria,we
employedtwocriteriaforpainoutcomes:
InclusionCriteria
1.
Painandqualityoflifeoutcomesmusthavebeenpatientreported;
2.
Outcomedatamustnothavebeencollectedretrospectively(forexample,posttreatmentsurveys/questionnaires),becausereportsbasedonmemoryof
painmaydifferfromreportsgivenatthetimethatpainisexperienced(Eich1985;Linton1983).Forparticipantswhodiscontinuedparticipationbeforethe
endofthestudy,weintendedtocollectdataonduration,dose,titration,androtationofopioidsfrombeforetheywithdrewfromthestudy.However,
thesedataweregenerallynotavailableinthepublicationsweidentified.
Typesofstudies
1.
Randomizedcontrolledtrials(RCTs)andnonrandomizedcontrolledtrials.
2.
Prepostcaseseriesstudies(includinglongtermopenlabelcontinuationsofshorttermRCTs)
3.
Studiesthatenrolledandadministeredopioidstoatleast10participants.
4.
Prospectivestudiesorstudiesthatcouldnotdefinitivelybedeterminedtobeprospectiveafterunsuccessfullyattemptingtoquerytheirauthorsbecause
webelievetheirexclusioncouldnotbejustified.
5.
Fulltextarticlesonly
6.
Anylanguage
Typesofparticipants
Reportnumber:0611002R7.3
Adultsagedatleast18yearswithpainduetoanycauseotherthancancerlastingforatleastthreemonths(thatis,meetingtheIASPdefinitionforchronic
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pain)priortotrialenrolment.Previousnonopioidpharmacotherapymusthavefailedbeforebeginningopioids.
Typesofinterventions
Anyopioidtakenbyanyrouteinanydoseforatleastsixmonths.
Typesofoutcomemeasures
Adverseevents(sideeffects),discontinuationfromstudyduetoadverseevents,discontinuationfromstudyduetoinsufficientpainrelief,painscore,
healthrelatedqualityoflife,andfunction.Outcomemeasuresmusthavebeenvalidatedorusedasastandardofcaretobeincludedintheanalyses.
Painandqualityoflifeoutcomesmusthavebeenpatientreported
Wesearchedforstudiesthat:collectedefficacydataonparticipantsafteratleast6monthsoftreatment;werefulltextarticles;didnotincluderedundantdata;
wereprospective;enrolledatleast10participants;reporteddataofparticipantswhohadCNCP.Randomizedcontrolledtrials(RCTs)andprepostcaseseriesstudies
wereincluded.Prospective,fulltext,andanylanguage
Inmoredetail,theauthorselaboratedonthetypeofstudieswhichwereincludedweonlyfoundonecontrolledtrialthatevaluatedtheefficacyandsafetyof
opioidsforCNCPandreportedlongtermoutcomes.Thatstudycomparedtwoopioidsandwasnotcontrolledusingplacebooranonopioidtreatment.Wedefined
longtermopenlabelcontinuationsofshorttermRCTsascaseseriesstudies
Previousnonopioidpharmacotherapymusthavefailedbeforebeginningopioids.
ExclusionCriteria
Nomeetingabstractsorposterpresentationswereincluded.Wedidnotincluderedundantdataonparticipantswhowerealsoreportedoninotherincluded
studies,nordidweincludestudieswithduplicatedata.Studieswhereoutcomedatahasbeencollectedretrospectively.
StudyValidity.
Isitclearthattherewerenoconflictsof
interestinthewritingorfundingofthis
review?
Yes
DeclarationsofinterestwerestatedasnoneknownandSourcesofsupportwerestatedas
internalsourcesECRIInstitute,USAandexternalsourcesTheMaydayFund,USA.
Itwasnotreportedwhetherthereviewerswereblindtoauthorsofarticlesthattheywere
reviewing,howevernoneoftheauthorsoftheSRwereauthorsofstudiesontheincludedand
excludedstudieslist.
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Doesthereviewhaveaclearlyfocused
question?
Yes
Thepurposeofthissystematicreviewistosummarizetheevidencepertainingtotheefficacyand
safetyoflongtermopioidtherapyforCNCP.Specifically,weseekto:
1.DeterminetheeffectivenessoflongtermopioidtherapyforCNCP;
2.IdentifytheadverseeffectsoflongtermopioidtherapyforCNCP;and
3.Assesswithdrawalratesfromtreatmentbyreasonsforwithdrawalbasedonpatient
statements.
Isasystematicreviewtheappropriate
methodtoanswerthequestion?
Yes
Doesthereviewhavespecified
inclusion/exclusioncriteria?
Yes
Asabove
Iftherewerespecifiedinclusion/
exclusioncriteria,werethese
appropriate?
Yes
Doesthereviewdocumenta
comprehensivesearchstrategy?
Yes
Werereviewersblindtoauthors,
institutionsandaffiliations?
Notreported
Were2ormoreindependentreviewers
usedfor:
Yes
Tworeviewauthorsscreenedabstractsofallidentifiedstudiesagainsttheinclusioncriteria(MN,
PW).Weretrievedallpossiblyrelevantarticlesinfulltextforcomprehensiveassessmentof
internalvalidity(quality)andsatisfactionofinclusioncriteria.
Yes
Tworeviewauthors(MN,CA)independentlyextracteddatafromEnglishlanguagearticles.
extractionofdatafromstudy
Reportnumber:0611002R7.3
1. applicationofinclusioncriteriato
assesseligibilityofstudies?
2.
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reports?
Discrepanciesweresettledbyconsensus.DatafromnonEnglishlanguagearticleswereextracted
byvolunteersaffiliatedwithTheCochraneCollaboration.
3.
appraisalofstudyquality?
Yes
Werethestrengthsandlimitationsof
includedstudiesandpotentialimpacton
theresultsdiscussed?
Yes
Tworeviewauthors(MN,CA)independentlyextracteddatafromEnglishlanguagearticles.
Discrepanciesweresettledbyconsensus.DatafromnonEnglishlanguagearticleswereextracted
byvolunteersaffiliatedwithTheCochraneCollaboration.
Someofthequantitativeestimateswerenotrobust,meaningthatanestimateofthetreatment
effectsizecannotbeaccuratelyestimatedwiththecurrentlyavailableevidence,andtheestimates
maythereforebeunstableandshouldbeinterpretedcautiously.Thelowinternalvalidityratings
indicatethattheevidencesupportingourconclusionsishighlysubjecttochangeandthatthe
likelihoodishighthatfindingsoffuturestudiesmayoverturntheseconclusions.Furthermore,
theremaybeaparticularriskofpublicationbiasinuncontrolledcaseseriesstudies,asjournals
maybelesslikelytoacceptstudiesofthisdesign,investigatorsmaybelesslikelytosubmitthem
forpublication(giventhelesserfinancialinvestmentinconductingthem),andnoclinicaltrial
registryforuncontrolledstudiesiscurrentlyinwidespreaduse.
Investigation(ofheterogeneity)waspossibleforintrathecallyadministeredopioids,andpotential
relationshipsbetweenproportionofparticipantswithclinicallysignificantpainrelief(>50%)and
yearofpublicationandprospectivestudydesign,andbetweenaveragepainreliefand
predominantcauseofpaininthestudy,wereidentified.However,theserelationshipsdonotseem
stable.Theonlyconvincingcovariateweidentifiedwasalowerrateofdiscontinuationdueto
adverseeventsfromclinicalstudyinstudiesthatadministeredoralweakopioidscomparedwith
studiesthatadministeredstrongoralopioids.
PredominantcauseofpainwastheonlyfactorsignificantlyassociatedwiththeSMD(P=0.01).As
arobustnesstest,werepeatedtheregressionusingthreeothermetaregressionmodels(i.e.,
fixedeffect,methodofmoments,unrestrictedmaximumlikelihood),whichconsistentlyshowed
significantfindings.Failedbacksurgerysyndrome(k=5)wasassociatedwiththeleastamountof
painrelief,unspecified(k=2)andneuropathicpain(k=1)wereassociatedwithmorepainrelief,
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andosteoporoticvertebralfractures(k=1)wereassociatedwiththemostpainrelief.However,
thefactthatfewstudieswereavailableforthreeofthefourcausesofpainunderminesthe
stabilityofthisfinding.
Wasthevalidityofincludedtrials
appraisedusingappropriatecriteria?
Yes
Isthereasummaryoftheresultsof
individualstudies?
Yes
Ifmetaanalyseswereconducted,wasit
reasonabletodoso?
Yes
Ifmetaanalyseswereconducted,wasit
doneappropriately?
Yes
Other
Whatistheoverallriskofbias?
Low
Tworeviewauthors(MN,CA)independentlyassessedtheinternalvalidityofEnglishlanguage
studies(nonEnglishlanguagearticleswereassessedbyvolunteersaffiliatedwithTheCochrane
Collaboration).Discrepancieswereresolvedbyconsensus.Weassessedtheriskofbiasinincluded
studiesusinga10questioninternalvalidityassessmentinstrumentdevelopedbymethodologists
atECRIInstitutefortheassessmentofcaseseriesusingdomainsidentifiedasimportantfactorsby
expertsinthefield(Table1;AHRQ2002;Deeks2003;Egger2003).Toevaluatelongterm,open
labelcaseseriesthatwerecontinuationstudiesofshorttermRCTs,weconsultedtheoriginal
publicationoftheRCTwhenevernecessary(seeCharacteristicsofincludedstudiesfororiginal
citations).
Weperformedsensitivityanalysesonevidencebasescomprisedofatleastthreestudies.
Evidencebasesconsistingofonlyoneortwostudieswereconsideredtoinherentlylack
robustness.
Foranalyseswithoutsubstantialheterogeneity(I<50%)andatleast10studies,weplannedto
usethetrimandfillmethodtotestforfunnelplotasymmetry,whichsuggestsmissingstudies,
possiblyduetopublicationbias(Duval2000a;Duval2000b).However,noneoftheevidencebases
foranyoftheoutcomesmetthesecriteria,precludinganinvestigationonpublicationbias.
Selectionbiascannotberuledoutoftheanalysisasdatafromuncontrolledcaseserieswasused
andthiscouldhaveledtothepossibleunexplainedheterogeneityintheoutcomesassessed,as
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wellastheoveralltreatmenteffectsize.Weconsidereddatafromuncontrolledcaseseries
shouldbekeptinmindwhenconsideringthestudiesresults;influencesfromregressiontothe
meanandselectionbiascannotberuledout.Furthermore,caseseriesdatacannotbe
extrapolatedtodrawconclusionsregardingcomparativeeffectiveness.Hence,thedifferentdrug
typescannotbeassessedasbeingmoresuperiortooneortheother.
Results.
SideeffectsofITopioids
Tenstudieswhichincludedatotalof228patients,themostcommonadverseevents(AEs)includedpumpandcathetermalfunctionsandmalpositioning,surgicalcomplications,andpostsurgicalcomplications.
Thehighestamountofdevicecomplicationsrequiringreoperationwasreportedas27%(Hassesnbusch).Twostudiesreportedatotalofsixdeaths,withonedeathdescribedasaneuropsychologicalevent,
suicide(Thimineuretal,2004).
DiscontinuationfromstudyduetoAEs
Fivestudieswhichincludedatotalof86patientsassesseddiscontinuationfromthetrialduetoAEs.Thepooledeffectratewas8.9%[95%CI:4.0%to26.1%],andwasnotsubstantiallyheterogenous(Figure3).
Discontinuationfromstudyduetoinsufficientpainrelief
Atotalof6studieswhichincluded113patientsdocumenteddiscontinuationduetoinsufficientpainrelief.Theoveralleventratewas7.6%(95%CI:3.7%to14.8%).Nosubstantialheterogeneitywasdetected(I2
<0.001),andtheestimatewasrobusttosensitivityanalyses(seefigure6).
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Averagechangeinpainscoresthroughouttreatment
Atotalof9studiesinvolving220patientsassessedthemeanchangeinpainscoresfrombaselineafteradministrationofintrathecalopioids.Atbaseline,thepooledscoreofthestudieswas8.70(95%CI:8.37to
9.04),whichwasanindicationofseverepain.Afterfollowup,atthelongestdurationoftreatment,thispooledscoreofthestudiesdecreasedto4.45(95%CI:3.44to5.47),anindicationofmoderatepain.The
overall effect size of the nine studies was 2.01 (95% CI: 1.37 to 2.66) (see below). Individually, the studies showed clinically significant mean reductions in pain score, however a considerable amount of
heterogeneitywaspresent,I2=87.1%.Afterunivariatemetaregressionanalysis,thepredominantcauseofpainwassignificantly(P=0.01)relatedtothechangeinpainscore.
Ptswithatleast50%painrelief
Sevenstudiesincludingatotalof151patientsprovidedanindicationoftheproportionthatexperienceatleast50%painrelief.Theoveralleventrateforthesevenstudieswas44.5%(95%CI:27.2%to63.2%),
withareflectedheterogeneityof71.7%.Multiplemetaregressionanalysesfoundthattheyearofstudypublicationwasassociatedwithalargerproportionofparticipantswithatleast50%painrelief(P=0.02).
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Whenthemodelwascorrectedforpublicationyear,heterogeneitywasreducedbutwasstillconsiderableat52.2%.
Qualityoflife(QoL)
Threestudieswithatotalof92patientsassessedqualityoflifefollowinglongtermadministrationofintrathecalopioids,allusingdifferentinstrumentsformeasurementtheTollisonQualityofLifeScale
(Mironer2001),theSF36(Thimineur2004),andtheQuestionnaireoftheEuropeanFoundationforOsteoporosis(Shaladi2007).Hence,itwasnotstartlingthateachstudyrevealeddifferentoutcomes.Oneof
thestudieshadinconclusivefindings(Mironer2001),onereportedasmallbenefit(Thimineur2004),andonereportedalargebenefit(Shaladi2007).Theoveralleffectsizeinthecombinedmetaanalysiswas
SMD1.02,withalarge95%CI0.04to2.09.Heterogeneityamongthemwassubstantial(I2=93.4%)butduetothesmallnumberofstudiescouldnotbeinvestigated.
Functionalstatuslevels
Again,only3studiesassessedfunctionalstatus,involvingatotalof98patientsinitiallyandatfollowupthiswasreducedto82patients.Threedifferentinstrumentswereutilisedtoassessfunctionalstatus,the
OswestryDisabilityIndex(Thimineur2004),theshortformSicknessImpactProfile(Anderson2003),andtheChronicIllnessProblemInventory(Anderson1999).Studyfindingswereinconsistentwithonestudy
beinginconclusive(Anderson1999),anotherrevealingamoderateeffectsize(Thimineur2004),andanotherrevealingalargereffectsize(Anderson2003).TheoverallSMDwas0.56(95%CI0.02to1.13),
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statisticallyinconclusiveandheterogeneitywasconsiderablyhighat81.2%,howeverduetothesmallnumberofstudiescouldnotbeinvestigated.
AuthorsConclusions.
Manypatientsdiscontinuelongtermopioidtherapy(especiallyoralopioids)duetoadverseeventsorinsufficientpainrelief;however,weakevidencesuggeststhatpatientswhoareabletocontinueopioids
longtermexperienceclinicallysignificantpainrelief.Whetherqualityoflifeorfunctioningimprovesisinconclusive.Manyminoradverseevents(likenauseaandheadache)occurred,butseriousadverseevents,
includingiatrogenicopioidaddiction,wererare.
Implicationsforpractice
ConcernthatanindividualwithCNCPmaydevelopdependenceonthedrugduringlongtermadministrationrepresentsapotentialbarriertotreatment.However,therateofobservedsignsofopioidaddiction
wasextremelylowinthebodyofevidenceconsideredinthisreview(0.27%,conservatively).Thisratewouldbe0.14%ifnoaddictivebehavioursoccurredamongthestudiesthatdidnotmentionaddictionrates
atall.Onlythreeparticipantswerereportedashavingpotentialabuseproblems.
Intheinterestofcapturingtheoveralleffectofopioidtherapyonqualityoflife,wesoughttoanalysehealthrelatedqualityoflifeoutcomesinthisreview.However,findingsonqualityoflifewereinconclusive
forallmodesofadministration.
Implicationsforresearch
Protocolsshouldspecifyuniformdiagnosticanddatacollectioncriteria(e.g.,painetiology,drugsprescribed,dosingregimens)andmimicclinicalpractice(e.g.,drugcombinationscouldbeused,drugchanges
couldbemade,drugdosagecouldbetitratedslowlyandadjusted,adverseeffectscouldbeaggressivelymanaged).
Reasonsfordiscontinuation,includingsatisfieddepartures,mustbedocumented.
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Studiesshouldalwaysreportdataneededformetaanalysis(mean,standarddeviation,numberofparticipants,ordatatocalculatethem),andauthorsofstudiesforwhichthesedatawerenotoriginally
publishedshouldconsidermakingthempubliclyavailable.Studiesshouldalsousevalidatedscales,reportintentiontotreatdatainadditiontocompleteranalyses,andconductposthocanalysestoidentify
prognosticfactorsfortreatmentsuccess.
OurComments/Summary.
Thissystematicreviewwasofhighqualityconsideringthattheevidencebaseofincludedstudieswasweak.Inlightofthis,theauthorsinvestigatedtheheterogeneityusingsensitivityanalysesfindingthata
relationshipwaspresentwiththeproportionofparticipantswithclinicallysignificantpainrelief(>50%)andyearofpublicationandprospectivestudydesign,andbetweenaveragepainreliefandpredominant
causeofpaininthestudy.Intermsofgeneralisabilityitisdifficulttosaywithanylevelofcertaintyiftheoveralltreatmenteffectforthevariousoutcomesisrepresentativeduetoattritionrates.Theauthorsdid
notdiscoveranystudieswhichassessedprognosticfactorsforpatientdropout.
Thepotentialbiasinthereviewwaslow.Missingdataandstudiescouldnotbedetectedduetothesmallstudiesavailable.Hence,quantitativeestimatesprovidedfromtheanalysesinthereviewdonotprovide
atruereflectionofthetreatmenteffectsizeandastheauthorssayshouldbeinterpretedwithcaution.
Diversityinsystematicreviewdesign,i.e.areviewinTheCochraneLibraryvs.otherpeerreviewedjournals,allowedtheauthorstoincludeoutcomesincludinghealthrelatedqualityoflifeandfunctionalstatusin
thisreview.Thisisincontrasttoothersystematicreviewsinvolvingsimilarinclusion/exclusioncriteriabutonlyfocusingonoutcomesofpainreliefandpatientsatisfactionandadverseevents.Higherquality
assessmentinthisreviewusingprospectivestudies,leadtheauthorstoreclassifypreviousstudiesincludedasretrospectiveafterpersonalcommunicationwithstudyauthors.Methodologically,metaregression
wasalteredinthisreviewtousefivestudiesratherthantenstudiesinaprevioussystematicreview.Withthesmallnumberofprospectivestudies,thisallowedrelationshipstobeexploredbetweenpatient
characteristics/covariatesandoutcomesbeingassessed.
ThisSRwasbroaderinitsscopethanthequestionwewererequiredtoanswer,notsolelyinvestigatinglongtermintrathecalopioidsbutalsooralandtransdermalopioidsinthemanagementofnoncancerpain.
Theincludedstudiesforintrathecalopioidsusedcaseseriesasastudydesign,thusnocontrolledstudieswereassessed.
Overall,theriskofbiaswaslow,resultinginahighqualitySRwhichwillbeusedforourreport.Althoughtheevidencebaseofincludedstudieswasweak,theappraisaloftheincludedstudieswasofahigh
standard.
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TableA5.2Criticalappraisaltable(Eisenach,J,2010)
Study:Eisenach,J,Curry,R,Rauck,R,Pan,P,andYaksh,T.RoleofSpinalCyclooxygenaseinHumanPostoperativeandChronicPain.Anesthesiology.May2010.112(5):12251233.
Descriptionofstudy:Randomisedcontroltrial
Patient/population
Patientswithchronicpain,alreadyreceivingITmorphineforatleast6weeks
Totalof12witheachpatientrandomisedtoreceiveeithersalineor2mgketorolaconthefirstvisit,withthealternativetreatmentontheirsecondvisit.
Setting
Outpatientcentre
Intervention/indicator
ITmorphine(mean9.8mg;range1.350mg/day)withITketorolac(2.0mg)
Comparison/control
Saline+ITmorphine(mean9.8mg;range1.350mg/day)
Outcomes
Painintensity(painscoreand30%or50%painrelief),unpleasantnessandadverseevents
InclusionCriteria
Notclear,howeverallpatientshadAmericanSocietyofAnesthesiologistsphysicalstatus1,2,or3;nohistoryofallergytoketorolac,morphineorbupivacaine;patients
receivingITchronicmorphineforatleast6weeksduration.
ExclusionCriteria
Notreported
StudyValidity
Isitclearthatthereareno
conflictsofinterestinthe
writingorfundingofthis
study?
Yes
Doesthestudyhaveaclearly
focusedquestion?
Yes
IsaRCTtheappropriate
methodtoanswerthis
question?
Yes
Reportnumber:0611002R7.3
Supported,inpart,bygrantGM48805fromtheNationalInstitutesofHealth,Bethesda,Maryland.
TotesttheroleofspinalcyclooxygenaseinhumanpostoperativeandchronicpainwithITinjectionof
NSAIDketorolac.
Initialstudiesinanimalsshowedthatcommerciallyavailableketorolacissafeandfollowingthese
studies,humanstudieswithITketorolacshowednosignificantadverseeventsbutalsoshowedno
reductioninpainduetoacutenoxiousheatstimuliortopicalcapsaicin.However,theeffectivenessof
ITketorolacinstatesofcentralsensitizationsuchaschronicpainwasnotknown,henceanRCTtesting
thiswastheappropriatemethod.
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Doesthestudyhavespecified Yes
inclusion/exclusioncriteria?
Seeabove.
Iftherewerespecified
inclusion/exclusioncriteria,
weretheseappropriate?
Yes
Didthestudyhavean
adequatemethodof
randomisation?
Yes
Wasallocationtointervention Notreported
groupconcealed?
Patientswererandomized,usingacomputergeneratedseriesofrandomnumbers,toreceiveeither
preservativefreeketorolac(2mg)orsalineontheirfirstvisit,withthealternativetreatmentontheir
secondvisit.
Werepatientsblindto
interventiongroup?
Yes
Wereinvestigatorsandcare
providersblindto
interventiongroup?
Yes
Patientswererandomized,usingacomputergeneratedseriesofrandomnumbers,toreceiveeither
preservativefreeketorolac(2mg)orsalineontheirfirstvisit,withthealternativetreatmentontheir
secondvisit.Theintrathecalinjectionsolutionwaspreparedbyanindividualnotinvolvedinthe
patientscareorresearchevaluation.
Wereoutcomeassessorsblind Yes
tointerventiongroup?
Theauthorswerecontactedbyemailandstatedthattheoutcomeassessorswereblindtothe
interventiongroup.
Alloutcomesweremeasured
inastandard,validand
reliableway?
Patientsreportedpainusingastandard10cmvisualanalogscale(VAS)beforeinjectionandatthe
timesofbloodpressuremonitoring...Inaddition,VASpainassessmentstoheatstimuliappliedtothe
skinonalowerextremityatasitewithoutspontaneouspainwereobtainedusingacommercially
availablePeltiercontrolledthermode.
Partial
NoreferencetoanystudiesusingtheVASscaleorthermodewasmade.Additionally,theauthorsofthe
studydidnotreportiftheyhadusedthesemeasurespreviouslyresultinginvalidoutcomes.
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Wereoutcomesassessed
objectively?
Partial
Wereoutcomesassessed
independently?
Yes
Werethegroupssimilarat
baselinewithregardstokey
prognosticvariables?
Yes
TheVASscalecanbeinterpretedinasubjectivefashionasthepatientreportstheirownviewofpainin
termsofhighesttolowestpain.Thethermalnociceptivetestingisalsoaproductofthepatientsown
viewofpainreflectedasascoreontheVASscale,hencethereissubjectiveinterpretation.Although,
theseoutcomemeasuresarenotobjective,theyarehoweverappropriateintermsofthefieldofstudy
beingpain.
Theauthorswerecontactedbyemailandstatedthattheoutcomeswereassessedindependently
The12subjectsrecruitedintotherandomized,controlled,chronicpainstudy(fivewomenandseven
men)were519yrold,17410cmtall,andweighed919kg.Durationofpainwas122yr(range,
523yr;meanSD).
Allsubjectshadbackorlegpain,threewereassociatedwithdegenerativediscdisease,onewas
associatedwithchronicregionalpainsyndromeofthelowerextremities,andonewasassociatedwith
phantomlegpain.Inallpatients,thecathetertipwasinthelowthoracicintrathecalspace.
Asidefromtheexperimental Yes
intervention,werethegroups
treatedthesame?
Theauthorswerecontactedandasked,statingthatthegroupsweretreatedinasimilarfashion.
Weretheoutcomesmeasured Yes
appropriate?
Painintensitywastheprimaryoutcome(measuredwithVASpainscale).Otheroutcomesincluded
bloodpressureandheartrateduetothedrugbeingexperimentalinhumanwithchronicpain.
Wastheresufficientduration Partial
offollowup?
AuthorsreportthatSubjectsweredischargedandcontacteddailyfor2days,then1weekafterthe
studyandquestionedaboutneurologicsymptoms,symptomsofpostduralpunctureheadache,orother
complaints.
Wasthere20%dropout?
Allpatientsremainedinthestudyfromthebeginningtotheconclusion,possiblyduetofinancial
incentive
Yes
Patientswerepaid$50forcompletionofthefirststudydayandanadditional$100forcompletionof
thesecondstudyday.
Onepatientcommittedsuicide6monthsafterthestudycompletion.
Wasthestudysufficiently
poweredtodetectany
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Yes
Basedonourpreviousstudiesinpatientswithchronicpain,911astudyof12individualswasplanned
todistinguishanaveragedifferenceinpainscoresoverthetimeoftestingbetweenplaceboand
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differencesbetweenthe
groups?
ketorolacof2.2withanof0.05and1of0.8,assumingameanpainscoreof5inthecontrol
conditionandagroup
SDof2.5.
Ifstatisticalanalysiswas
undertaken,wasthis
appropriate?
Yes
DataarepresentedasmeanSEMunlessotherwiseindicated.Theeffectsofintrathecalinjections
overtimeweredeterminedbytwowayANOVAforrepeatedmeasureswithfactorstimeanddose
(openlabelchronicpainstudy)orinjectiondrug(randomized,controlledchronicpainstudy,and
postoperativepainstudy).IncidenceofsideeffectswascomparedacrossdosesortreatmentsbyChi
SquareorFisherexacttest.ExploratoryanalyseswereperformedusingPearsoncorrelationandlinear
regression.AvalueofP<0.05wasconsideredsignificant.
Wereallthesubjectsanalysed Notreported
inthegroupstowhichthey
wererandomlyallocated(i.e.
intentiontotreatanalysis)?
Isthepaperfreeofselective
outcomereporting?
Yes
Forcrossoverstudiesonly
Wasthisinterventionsuitable Yes
foracrossoverstudy?
Painstudiesarecomplexinnatureduetotheheterogenousnatureofpain.Crossoverwasappropriate
todetecttheeffectivenessofITketorolac,asallpatientswerecontrolsforthemselves.Crossover
trialsaresuitableforevaluatinginterventionswithatemporaryeffectintreatmentofstable,chronic
conditions(CochraneHandbook16.4.2).
Wasthewashoutperiod
adequate?
Yes
Other
Whatistheoverallriskof
bias?
LowModerate
Reportnumber:0611002R7.3
ThehalflifeofITketorolacinyoungadultsis3.59.2hrs(Wiki).Consideringthattheauthorsreported
thatpatientsreturnedatleast1week,butnomorethan3monthslater,forthecrossovertreatment,
thewashoutperioddoesseemadequate.
Noallocationconcealmentwasreportedaswellasblindingofthepatientsorinvestigatorsofthestudy
tothedrug.Attritionratewasalsonotreported.
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Results.
Thestudyincludedatotalof12patientswithahistoryofchronicpain(meanduration122years)whichhadbeenpreviouslyreceivingITmorphineforatleast6weeks.Bothpainintensity(P=0.01)and
unpleasantness(P=0.02)decreasedwithtimeafterintrathecalinjections,buttherewasnodifferencebetweenketorolacandsaline(fig.3),andtherewasnosignificantinteractionbetweentreatmentand
time.Howeveritwasnotsignificantlydifferenttowhenpatientsreceivedplacebo.Patientswhoexperiencedatleast30or50%painrelieffollowingITadministrationdidnotdifferbetweensalineand
ketorolacgroups.StatisticalanalysiswithANOVArevealednosignificantinteractionbetweentreatmentandtime.Therewasnocorrelation,however,betweenintrathecalmorphinedailydoseandresting
painscore,minimumpainscoreafterketorolac,averagepainscoreafterketorolac,orsummedpainintensitydifferencescoresafterketorolacadministration.Similarly,therewasnocorrelationbetween
intrathecalmorphinedailydoseandpainscoresafterintrathecalsaline,orbetweenintrathecalmorphinedailydoseandthedifferenceinpainscoreafterketorolacandsaline.
Sideeffects
Statisticalanalysisonadverseeventsbetweenpatientgroupsdidnotrevealanydifferences.AheadofITsalineorketorolacadministration,patientsreportedexistingadverseeventsincludingheadache(n
=5beforesaline,n=6beforeketorolac),lowerextremityweakness(n=6),anxiety(n=2),nausea(n=1)andsedation(n=1).FollowingITketorolacadverseeventsincludedmildsedationlastinglessthan
2hours(n=2),milddizzinesslastinglessthan2hours(n=1),hotsensationintheback,headache,urinaryretentionandhives(n=1)4daysafterinjection,lastinglessthan4hours.FollowingITsaline
adverseeventsincludedmildsedationlastinglessthan1hr(n=2),mildnausealastinglessthan1hr(n=2),mildheadachelastinglessthan2hr(n=1).Twoseriousadverseeventsoccurred.Onepatient
experiencedanumbleftlegforlessthan2hafterintrathecalinjectionofsaline,and,asnoted,thissubjectspumpcontainedbupivacaine.Onepatientcommittedsuicide6monthsafterstudy.
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AuthorsConclusions.
Wefailedtoobservegreateranalgesiafromintrathecalketorolacthansalineplaceboinpatientswithprimarilylowbackandlowerextremitypainandacombinationofsomaticandneuropathic
components.
2mgofintrathecalketorolacwasnotassociatedwithserioussideeffects,failedtoreduceongoingpaininchronicpainpatientsmorethanplacebo.Theseobservationsarelimitedbythesmallnumberof
subjectsstudied,andpatientpopulation,andtheamountandtimingofketorolacdosing.
Undertheconditionsofthesestudies,itseemsthatspinalcylcooxygenaseactivitydoesnotcontributetochronicorpostoperativepain.
OurComments/Summary.
Theallocationconcealmentwasnotreportedinthestudy,potentiallyintroducingintotheresultsselectionbias.Althoughtheauthorsreportthatitwasarandomised,controlledstudy,inwhichtheIT
solutionswerepreparedbyanindividualnotinvolvedinthepatientscareorresearchevaluation,theydidnotsaywhetherthepatientorpersonadministeredthedrugtothepatientwereblinded.They
didnotcommentonwhetherthesolutionsweresimilarinappearanceetcorifbothgroupsweretreatedsimilarlyduringthestudy.Thisdoesnotgiveconfidenceintheaccuracyofthetrueeffectsizeand
mayhaveattributedtothenonsignificantdifferenceinpainintensitybetweensalineandketorolacgroups.
ThestudydidnotreporttheoriginorpainsyndromeofpatientsenrolledintheRCT,i.e.neuropathicorcomplexregionalpainsyndrome(CRPS)etc.Thismighthaveanimpactontheresponsetopain
reductionandshouldbeinvestigatedinfurtherITinfusionstudies.Patientswerestudiedtwice(crossoverstudy),hencetheyreceivedplaceboandketorolacbutattwoalternativevisits.Awashoutperiod
ofatleast1weekbutnogreaterthan3monthswasreported,suggestingsomeassuranceofnodirectplaceboketorolacinteractionswhichwouldmodifythetrueeffectsize.However,itisunknownifthe
initialpainintensityandsymptomsreturnedtotesttheefficacyoftheseconddrugtreatment,eithersalineorketorolac.
Theattritionrateseemedtobeunaffectedafterthepatientssecondvisit,howeverthiscouldhavebeenduetothefinancialincentiveofferedbythestudyauthors.Theattritionratewasnotreportedon
bytheauthorsateithervisit.
Thedegreeoferrorinthestudywasnotreportedon.Itcannotbeassumedthatduetothestudydesignthepatientsserveastheirowncontrolsandhencenoerrorispresent.Furthermore,theauthors
didnotreportifanytestfornormalityhadbeenconductedonthedatabeforeperformingtheANOVA,henceitisdifficulttoknowiftheresultsfollowedanormaldistributionornot.Theconfidence
intervalswerealsonotreportedwhichisaneffectivemeansofdetermininganyrandomerrorintheresultsofthestudy.
Interestingly,intheresultstheauthorsreportTwoseriousadverseeventsoccurred.Onepatientexperiencedanumbleftlegforlessthan2hafterintrathecalinjectionofsaline,and,asnoted,this
subjectspumpcontainedbupivacaine.Onepatientcommittedsuicide6monthsafterstudy.However,wedonotknowifthiswasaresultofthedrugtreatmentorotherfactors,althoughtheauthorsdo
statethattherewasnosignificantinteractionbetweentreatmentandtime.
Wecontactedtheauthorofthestudytoassesswhetherthegroupsweretreatedthesame,ifoutcomemeasureswereassessedindependentlyandiftheoutcomeassessorswereblindtotheintervention
group,towhichtheystatedayestoall.Theauthorsalsocommented,Thatpaperismorefundamentalthanpractical,sincetherenolongerexistsapreservativefreesolutionofketorolacforspinal
administration.ThismaysuggestthatothermedicationswithasimilarpainrelievingactionshouldbeutilisedasagentsusedinITwithpreservativesaretoxictothebodyandshouldbeusedinnon
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cancerpatientsiftheyareatendoflife(Deer,Tetal,2007).
Theoverallriskofbiaswaslowmoderatewiththeauthorsnotreportingontheallocationconcealmentordegreeoferror.However,overallthestudyrevealednogreaterpainreliefwithITketorolacand
ITmorphineincomparisontoITmorphineandsaline(control).Althoughtheoutcomemeasurementsweresubjective(patientreported,VASscoreandthermalthreshold),incontextofthefieldofstudy
beingpain,theevidencecanbeconsideredaspositive.
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TableA5.3Criticalappraisaltable(Teasell,R,2010)
Study:TeasellRW,MehtaS,AubutJA,FoulonB,WolfeDL,HsiehJT,Townson,AF,Short,CtheSpinalCordInjuryRehabilitationEvidenceResearchTeam.ASystematicReviewofPharmacological
TreatmentsofPainAfterSpinalCordInjury.Archivesofphysicalmedicineandrehabilitation.May2010.91(5):81631
Descriptionofstudy:SystematicreviewofRCTs(orothertypesofstudies).
Patient/population
Patientswithmixedpain(neuropathicandmusculoskeletal/spastic)afterspinalcordinjury(SCI)
26(ITstudiesonly)
Setting
Notreported
Intervention/indicator
Comparison/control
Outcomes
Reference
Intervention
Siddall,Petal,2000RCT(n=8)
Eachpatientwasrandomisedtoeither:0.21mgofmorphine,50to100gofclonidineorplacebo;dosageincreasedif
thesubjecthadnosideeffectsandnopainrelief.Onceeachreceivedsatisfactorypainrelief(ordevelopedsideeffects
fromdrugtheywereon),heorshewasgivenamixtureofmorphineandclonidine.
UhleEetal,2000
Subjectswereimplantedwithanintrathecalpump,originallyweregiven3mlsalinefollowedby1mlmorphine;thiswasfollowedby
aseconddoseofmorphine(0.02mg)providedthatnosideeffectsorbenefitshadbeennoted.Thiswasfollowedbyclonidine(30ug
in1ml);then,dependingonsideeffects,afinaldoseofclonidine(50ugin1ml).
Loubser,PandAkman,N,1996
BaclofeninfusionpumpwasimplantedintoSCIpatients.
ITsaline(Siddall,Petal,2000)
Reference
Intervention
Siddall,Petal.,2000(RCT,
n=8)
1.Theadministrationofmorphineorclonidineresultedinameanreductioninpainlevels;however,thisis
notstatisticallysignificantcomparedwiththeeffectsofplacebo.
2.Whenmixtureofmorphineandclonidinewasadministered,therewasasignificantreductioninpainvs.
thatachievedonplacebo(P=0.008).
UhleEetal,2000
1.Subjectsreportedgoodtoexcellentpainreductionafterclonidineadministration.
2.Afterclonidinebolus,subjectsexperiencedtheoptimumpainreduction.Averageinitialdoseof
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clonidinewas53g/d;thisdecreased(orstabilized)to44g/d.
Loubser,PandAkman,N,1996
1.12/16patientsdescribedchronicpainbeforeprocedure,experiencedareductiononVASmeasuringseverityof
neuropathicpainat6and12months;however,thisdifferencewasnotstatisticallysignificant
(P=.26)
2.NosignificantdifferenceswerenotedbetweenVASatthe6and12monthassessmentsafterpumpimplantation.
3.Forthosewithneuropathicpainsymptoms,ANOVArevealedanonsignificanteffectofintrathecalbaclofenonpain
atboth6and12months(P=.26).
4.In5of6patientswithmusculoskeletalpainsymptoms,painseveritydecreasedinconjunctionwithcontrolof
spasticity.Musculoskeletalpainrespondedtobaclofeninfusion,whileneuropathicpaindidnot.
InclusionCriteria
ExclusionCriteria
Studieswereonlyincludedforanalysisifatleast50%ofsubjectshadanSCI,therewereatleast3subjectswithanSCI,andtherewasadefinableinterventionbeing
studied.OnlystudiespublishedintheEnglishlanguagewereincluded.
StudiesexaminingalltypesofpainafterSCI(nocioceptive,neuropathic,mixed)wereexamined
Notreported
StudyValidity.
Documentevidenceofthisfromthearticle(includingquotingfromthearticle).
Addanyotherrelevantcomments,includingifthisislikelytoinfluencetheresultsofthestudy.
Isitclearthattherewerenoconflictsofinterest
inthewritingorfundingofthisreview?
Yes
SupportedbyOntarioNeurotraumaFund(grantno.2007SCISCIRE528),RickHansenManinMotionFoundation(grantno.Rick
Hansen200813),andSCISolutionsNetwork(grantno.201001).
Nocommercialpartyhavingadirectfinancialinterestintheresultsoftheresearchsupportingthisarticlehasorwillconferabenefit
ontheauthorsoronanyorganizationwithwhichtheauthorsareassociated.
Doesthereviewhaveaclearlyfocusedquestion? Yes
Toassesstheresearchevidenceoftreatmentapproachescurrentlyusedinthepharmacologicmanagementofpaininpersonswith
SCI.
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Isasystematicreviewtheappropriatemethodto
answerthequestion?
Yes
Doesthereviewhavespecified
inclusion/exclusioncriteria?
Yes
Seeabove
ThereviewincludedRCTsandnonRCTs,whichincludedprospectivecontrolledtrials,cohort,caseseries,casecontrol,prepost
studies,andpoststudies.Casestudieswereincludedonlywhentherewerenootherstudiesfound
Iftherewerespecifiedinclusion/exclusion
criteria,weretheseappropriate??
Yes
Doesthereviewdocumentacomprehensive
searchstrategy?
Yes
Asystematicreviewofallrelevantliterature,publishedfrom1980toJune2009,wasconductedbyusingmultipledatabases
(MEDLINE,CINAHL,EMBASE,PsycINFO).Keywordsincludedthefollowing:pain,paintreatment,pharmacology,painmanagement,
secondarycomplications,anticonvulsants,cannabinoids,antidepressants,medications,anesthetic,analgesic,andantispastic.
Retrievedreferenceswerescannedforrelevantcitationsthatmighthavebeenmissedbythesearchesofthevariousdatabases.
Werereviewersblindtoauthors,institutionsand Notreported
affiliations?
Were2ormoreindependentreviewersusedfor:
Notreported
4.
applicationofinclusioncriteriatoassess
eligibilityofstudies?
5.
extractionofdatafromstudyreports?
Notreported
6.
appraisalofstudyquality?
Yes
Amethodologicqualityassessmentwasconductedforeacharticleby2reviewersbyusingeitherthePEDroscoring27systemforRCTs
ortheD&Btool28fornonrandomizedstudies.Scoringdiscrepancieswereresolvedbyathirdblindreviewer.
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Werethestrengthsandlimitationsofincluded
studiesandpotentialimpactontheresults
discussed?
Yes
DespitethefactthatthetotalnumberofstudiesexploringpainmanagementafterSCIwassmall,over70%ofthestudiesreviewed
wereRCTs.
Moststudieslackedevidenceofnumberstotreatandeffectsizecalculations.
WhilsttheVASandMcGillPainQuestionnairehavebeenshowntobereliableandvalidintheassessmentofpainneitherhasbeen
specificallyvalidatedfortheassessmentofpostSCIpain.
Severalofthestudiesreviewedwereunblinded.Oneareaofconcernwithunblindedstudiesisthepatientsawarenessthatthey
werereceivingtheactivemedication,whichlikelybiasedtheirresponsestothedrugortheirreportingofpainafterSCI.
Moststudiesdidnotspecifythetypeofneuropathicpain,and,hence,effectivelyevaluatingtreatmentswasnotpossible.
IntrathecalbaclofenonlyreducesSCIpainwhenthepainisrelatedtomusclespasms.Thereisaneedforconfirmatoryresearch
becauseofthesmallsamplesizeandthelackofsignificantimprovementinalaterbeforeandaftertrial
Wasthevalidityofincludedtrialsappraisedusing Yes
appropriatecriteria?
Amethodologicqualityassessmentwasconductedforeacharticleby2reviewersbyusingeitherthePEDroscoring27systemforRCTs
ortheD&Btool28fornonrandomizedstudies.Scoringdiscrepancieswereresolvedbyathirdblindreviewer.
Isthereasummaryoftheresultsofindividual
studies?
Yes
Tables4and6
Ifmetaanalyseswereconducted,wasit
reasonabletodoso?
N/A
Ifmetaanalyseswereconducted,wasitdone
appropriately?
N/A
Other
Whatistheoverallriskofbias?
Low
Results.
PainreductionfollowingITdrugadministration
Atotalof8patientswereinitiallyrandomisedtoreceiveplacebo,morphine(0.21mg)orclonidine(50100g)throughimplantedlumbarintrathecalpumps(Siddaletal,2000).Onceasubjectachievedsatisfactory
painrelieforsuffereddrugsideeffectswith1ofthe3treatments,thatsubjectwastreatedwithamixtureofclonidineandmorphine.Bothmorphineandclonidinegivenaloneshowedatrendtowardpainreduction;
however,whenthecombinationofmorphineandclonidinewasadministered,therewasasignificantreductioninpain(p=0.008).
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Atotalofeightpatients(Uhle2000)wereimplantedwithpumpsdispensingITmorphine(doseof0.02mg)followedbyITclonidine(meandose44g)inaprospective,controlledtrial.PainreliefwasmeasuredbyVAS
scale,howevernoquantitativedatawasreported.Theresultsofthisstudyshowedthatpatientsreportedgoodtoexcellentpainreductionafterclonidineadministration.
Similarly,aprepostcaseserieswithatotalof12patientswithchronicpain(neuropathicandmusculoskeletal)wereimplantedwithpumpsdispensingbaclofen(dosenotreported).VASpainscalewasrecordedat6
and12monthperiods,revealingareductioninscoreatbothtimepoints,howeverusingANOVAthiswasnotstatisticallysignificant(P=0.26).Atotalof5outof6patientswithmusculoskeletalpainhaddecreased
painseverityandcontrolofspasticity.
Thereviewalsolookedattheeffectivenessofpainreliefwithoralmedications(gabapentin/pregabalin,lamotrigine,levetiracetam,valproate,trazadone,amitriptyline,lidocaine,tramadol,cannabinoids,mexiletine
andcapsaicin)andintravenousmedications(ketamine,alfentanil,andbotulinumtoxin)whichwerenotpartofourquestion.
AuthorsConclusions.
Thereislevel1evidencefromoneRCTandlevel2evidencefromaprospectivecontrolledtrialthatacombinationofintrathecalmorphineandclonidineresultsinasignificantreductioninneuropathicpain.Thereis
level4evidencethatintrathecalbaclofenreducesmusculoskeletalpainafterSCIinconjunctionwithspasticityreduction.
OurComments/Summary.
Oneofthelimitationsofthestudiesusedinthereviewisthatsmallsamplesizeswereutilised,hencetheoutcomesarelesspreciseandmaylikelychangewithlargernumbers.Funnelplotsorsensitivityanalysis
couldbeusefulindeterminingifanysmallstudyeffectsarepresent.
OnlylowlevelevidenceexistedforintrathecalbaclofenreducingpainafterSCIinconjunctionwithspasticityreduction.Furtherhighlevelstudiesneedtobeconductedtosaywithcertaintythatintrathecalbaclofen
hasthiseffectivenessornot.ThereviewdidnotreportthequantitativechangesinVASpainscores,makingitdifficulttoestimatethetrueeffectsize.
Duetothetypeofpainpatientspresentedwithinthestudiesbeingofaheterogenousnature,thegeneralisabilityislow.However,theoveralllevelofbiasinthereviewislow.
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TableA5.4Criticalappraisaltable(Rauck,R,2009)
Study:Rauck,R,Wallace,M,Burton,A,Kapural,L,andNorth,J.IntrathecalZiconotideforNeuropathicPain:AReview.PainPractice.2009.9(5):303327337.
Descriptionofstudy:SystematicreviewofRCTs(orothertypesofstudies).
Patient/population
Patientswithchronicsevere(noncancer)pain
n/a
Setting
Notreported
Intervention/indicator
Comparison/control
Outcomes
InclusionCriteria
Reportnumber:0611002R7.3
Reference
Intervention
WermelingDetal,2003(openlabel)n=22
ITziconotide(1hourinfusion,doses1mcg,n=5;5mcg,n=8;7.5mcg,n=6;10mcg,n=5)
TaqiDetal,2002(openlabel)n=25
ITZiconotide
KapuralLetal,2009(caseseries)n=7
ITziconotide(n=3),ITcombinationtherapyonly(n=1),ITmonotherapyfollowedbycombinationtherapy(n=3).IT
concomitantmedicationsincludedBupivacainewithsufentanil,morphine,hydromorphoneandclonidinewith
hydromorphone
SaulinoMetal,2009(caseseries)n=5
ITZiconotidewithbaclofen
None
Reference
Intervention
WermelingDetal,2003(OL)
Ziconotidecerebrospinalfluid(CSF)concentrations,meanVASPIscoresandadverseevents
TaqiDetal,2002(OL)
MeanVASscoresandadverseevents
KapuralLetal,2009(caseseries)
MeanVASscores,functionaloutcomesandadverseevents
SaulinoMetal,2009(caseseries)
VASPIscores,qualityoflifeandfunctionaloutcomes,andadverseevents.
Forclinicalstudies,bothcontrolled(randomizedornonrandomized)anduncontrolledstudies(caseseriesorcasereports)wereincluded.
Patientswithanytypeofneuropathicpaincondition.Maleandfemalepatientsofallagesandraces/ethnicitieswereincluded.
ITadministrationofziconotideforneuropathicpain,inanydose,aloneorinconjunctionwithoneormoredrugs.
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ExclusionCriteria
Painassessmentasanoutcomemeasure
Notreported
StudyValidity
Documentevidenceofthisfromthearticle(includingquotingfromthearticle).
Addanyotherrelevantcomments,includingifthisislikelytoinfluencetheresultsofthestudy.
Isitclearthattherewerenoconflictsof
interestinthewritingorfundingofthis
review?
No
FinancialsupportforthisreviewwasprovidedbyElanPharmaceuticals,Inc.,andeditorialsupportwasprovidedbyMedLogix
Communications,LLC.Dr.RauckisapaidconsultantandastudyinvestigatorfundedbyElanPharmaceuticals,Inc.Dr.Wallaceisa
consultantforElanPharmaceuticals,Inc.,andhasreceivedresearchsupportfromMedtronic,Inc.Dr.Burtonhasreceivedaresearch
grantfromMedtronic,Inc.Dr.KapuralandDr.NortharepaidconsultantsforElanPharmaceuticals,Inc.
Doesthereviewhaveaclearlyfocused
question?
Partial
Thepurposeofthisarticleistoreviewcurrentinformationregardingtheuseofziconotideinthetreatmentof
neuropathicpain.
Isasystematicreviewtheappropriate
methodtoanswerthequestion?
Yes
Doesthereviewhavespecified
inclusion/exclusioncriteria?
Yes
Seeabove.
Iftherewerespecifiedinclusion/exclusion Yes
criteria,weretheseappropriate??
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Doesthereviewdocumenta
comprehensivesearchstrategy?
Yes
RelevantpublicationswereidentifiedthroughsearchesofallyearsofPubMed,EMBASE,CINAHL,Biological
Abstracts,CochraneDatabaseofSystematicReviews,InternationalPharmaceuticalAbstracts.Thesearchtermswere:ziconotide,SNX
111,MVIIA,Prialt,andneuropathicpain.Thereferencelistsofpublicationsidentifiedthroughelectronicliteraturesearcheswere
searchedmanuallyforanyadditionalrelevantliterature.
Inaddition,associationmeetingsthatcoverITtherapytopicswereidentified;abstractsfromthefollowingassociationmeetingswere
searched(yearsweredeterminedonthebasisoftheonlineavailabilityofpublishedabstractsasofJanuary27,2009):American
AcademyofPainMedicine(2001to2008),NorthAmericanNeuromodulationSociety(2006to2007),andAmericanPainSociety(2003
to2008).AllsearcheswerelimitedtotheEnglishlanguage.
Werereviewersblindtoauthors,
institutionsandaffiliations?
Notreported
Were2ormoreindependentreviewers
usedfor:
Notreported
7.
applicationofinclusioncriteriato
assesseligibilityofstudies?
8.
extractionofdatafromstudyreports? Notreported
9.
appraisalofstudyquality?
Notreported
Partial
Resultsfromthe2DBPCziconotidetrialsthatusedhighstartingdosesandrapiddoseescalationindicatedthatneurologicalAEswere
reversiblewithaziconotidedosedecreaseordiscontinuation.
Werethestrengthsandlimitationsof
includedstudiesandpotentialimpacton
theresultsdiscussed?
Fortheseveralcasestudiespresentedinthisreview,thereisapossibilityforselfselectionbiasbecausepatientswithavery
favorableresponsetoziconotidemaybemorelikelytobereported.Otherlimitingfactorsincludethevariabletherapeuticwindowof
ziconotideandtheseverityofAEsreportedwithziconotide.
Becauseofthevarietyofmeasurementtoolsusedinpainstudies,thesedatawerenotextractedorevaluatedinthisreview.
Wasthevalidityofincludedtrials
appraisedusingappropriatecriteria?
Notreported
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Isthereasummaryoftheresultsof
individualstudies?
Yes
Ifmetaanalyseswereconducted,wasit
reasonabletodoso?
N/A
Ifmetaanalyseswereconducted,wasit
doneappropriately?
N/A
Other
Whatistheoverallriskofbias?
Insufficient
information
Results.
Openlabelstudies
Wermeling,2003
Atotalof22patientsreceiveda1hourITinfusionofziconotide.Ziconotidecerebrospinalfluid(CSF)concentrationswerefoundtobesignificantly(P<0.05)positivelycorrelatedwithefficacymeasures,
includingVASPIscoredifferences,summedpainintensitydifferences,andtotalpainreliefscores.Furthermore,ziconotideCSFconcentrationswerefoundtobesignificantly(P<0.05)positivelycorrelatedwith
theincidenceofbothallAEsandnervoussystemrelatedAEs.ThemostcommonlyreportednervoussystemrelatedAEsweredizziness,somnolence,paresthesia,andabnormalgait.Ziconotidedoseswere
foundtobesignificantly(P<0.05)positivelycorrelatedwiththeincidenceofbothallAEsandnonnervoussystemrelatedAEs.ThemostcommonlyreportednonnervoussystemrelatedAEswerenausea,
headache,andamblyopia.
Taqi,2002
Inanotheropenlabelstudy25patientsreceivedITziconotideforatleast3months.Mostpatients(72.0%)reportedimprovedanalgesiawithlowdosesofziconotide;however,manypatientsdiscontinued
ziconotidebecauseofAEsassociatedwithupwardtitration.AllpatientswereswitchedtoITopioidtherapy;21of25patients(84.0%)reportedtheywouldliketohaveziconotideaddedtotheirITopioid
regimen.
Caseseries
Kapural,2009
Outof7patientsinthecaseseries,meanVASscoreschangedby52%(89.3mmdecreasedto42.9mm).Twopatientshadsubstantialimprovementsinpainand/orfunctionalitywithziconotidetherapy.After
treatmentwithziconotide,3patientswereabletodiscontinueallITmedications;2ofthesepatientswerepainfreeattheirlastassessment,andtheremainingpatientrequiredonlyintermittentoraloxycodone
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tomanagepain.
Twootherpatientshadsubstantialimprovementsinpainand/orfunctionalitywithziconotidetherapy.Foreachpatientinwhomedemaandskindiscolorationwerenoted(3of7cases),thesesymptoms
resolvedorsubstantiallyimprovedduringthecourseofziconotidetherapy.Allbut1ofthepatientsinthesecasestudiesexperiencedAEs.ThemajorityofAEswereneuropsychiatricorcognitiveinnature.AEs
includedurinaryretention,depression,anxiety,andhallucinations;urinaryretentionwasreported5timesin4patients.OnepatientwithCRPStypeII,whohadanaggressiveziconotidetitrationregimen,
experiencedsevereneuropsychiatricAEsthateventuallyledtodrugdiscontinuation.
Saulino,2008
VASPIscoresimprovedfrombaselinebyameanof50.3%(range,33.3%to75.0%).Themeantimetoonsetofpainreliefwas15weeks(range,7to26weeks),withacorrespondingmeanziconotidedoseof3.7
mcg/day(range,1.3to8.1mcg/day).
All5patientshadimprovementsinactivitiesofdailylivingand/orinqualityoflife.OnepatienthadSAEsofnausea,vomiting,anddehydration;theseSAEswerenotconsideredrelatedtoziconotideandresolved
withtreatment.
AuthorsConclusions.
Evidencefromcasestudies,caseseries,openlabelstudies,andDBPCtrialssuggeststhatziconotide,aseithermonotherapyorincombinationwithotherITagents,canbeeffectiveintreatingpatientswhohave
refractoryneuropathicpain.
Additionalstudiesevaluatingthelongtermefficacyandsafetyofziconotideforneuropathicpainmaybewarranted.
OurComments/Summary.
ThereisalowriskofbiasinrelationtothefinancialsupporttheauthorswereprovidedbyElanPharmaceutical,Inc.AllauthorsarereceivingsupportfrompharmaceuticalcompaniesthatproduceITziconotide
andtheinfusionpumps,thestudyinvestigatorisfundedbyElanPharmaceuticals,Inc.Dr.WallaceisaconsultantforElanPharmaceuticals,Inc.,andhasreceivedresearchsupportfromMedtronic,Inc.Dr.
BurtonhasreceivedaresearchgrantfromMedtronic,Inc.Dr.KapuralandDr.NortharepaidconsultantsforElanPharmaceuticals,Inc.Thisislikelytoimpactonthepresentationandreportingofresultsfrom
studiesconductedonITziconotideforneuropathicpain.
Onestudythatconductedametaanalysis(Collinsetal,2005)couldnotbeappraisedasitincludedastudy(Staats,2004)thatusedpatientswithcancerorAIDSandcombinedtheresultswithanothertwo
studies(Rauck,2006andWallace,2006)whichdidnothavepatientsofthistype,whichwasanexclusioncriteriaofthecommitteeforthisevidencereview.
Thereisverylittleinformationinthispaperinregardstothemethodsundertaken.Assessmentofthequalityofthestudiesincludedinthepaperisnotreportedandthereisnoreferencetoanysupplemental
papersthatmaycontainthisinformation.
Thereisinsufficientinformationtoassessthequalityofthispaperandtodeterminetheriskofbias
NoteThestudyincludedtitledSaulino,Metal,2009isthesamestudyintheWallacecriticalappraisaldatedas2008.
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TableA5.5Criticalappraisaltable(Wallace,M,2010)
Study:Wallace,M,Rauck,RandDeer,T.ZiconotideCombinationIntrathecalTherapy:RationaleandEvidence.ClinicalJournalofPain.September2010.26(7):635644.
Descriptionofstudy:SystematicreviewofRCTs(orothertypesofstudies).
Patient/population
Patientswithchronicpain
114(8studies)
Pleasenoteallthesestudiesmaynothaveassessedouroutcomesofinterest.
Setting
Notreported
Intervention/indicator
Reference
Intervention
Webster,Letal,2008
ITmorphine(averagedoseTitration:0.251.25mg/d;Extension:02.1mg/dmorphinewithITziconotide(averagedose4.8
24.20mcg/d)
Wallace,Metal,2008
ITmorphine(5.713.0mg/d)withITziconotide(Titration:0.607.20mcg/d;Extension:0.844.20mcg/d)
Madaris,Letal,2008
ITmorphine(0.51.5mg/d)withITziconotide(0.54.5mcg/d)
Saulino,Metal,2007
IThydromorphone(0.44mcg/d1.32mg/d)withITZ(2.411.0mcg/d)
SaulinoMetal,2008
ITbaclofen(62500mcg/d)withITZ(1.216.0mcg/d)
Deer,T,2009(shortstudy,notlong
term)
ITHydromorphone,4.6mg/d#;morphine,5.2mg/d#;fentanyl,990mcg/d#;sufentanil,1100mcg/d#;bupivacaine,0.5mg/d#;
clonidine,113mcg/d#;baclofen,14mcg/dwithITZ(Start:0.5mcg/d;
Week12:0.65.7mcg/d)
Comparison/control
Outcomes
Reportnumber:0611002R7.3
KrakovskyAandBowieE,2007
N/A(abstractonly)
StantonHicksMandKapural,2006
ITZ(0.524.0mcg/d)withITN/A
Asstudieswereobservational,nocomparison/control
Reference
Intervention
Webster,Letal,2008
VASPI:26.3%improvement
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AEs:dizziness,peripheraledema,pruritus,nausea
Wallace,Metal,2008
VASPI:14.5%improvement
AEs:confusion,dizziness,abnormalgait,hallucinations,anxiety
Madaris,Letal,2008
Painscore:20%60%improvement
AEs:none
Saulino,Metal,2007
VASPI:85%90.0%improvement
AE:increasedintermittentcatheterization
SaulinoMetal,2008
VASPI:improvementof30.0%75.0%
AEs:nauseaandvomitingwithdehydration;sedation,urinaryhesitancy,lossofbladdercontrol,andanorexia
Deer,T,2009(shortstudy,notlong
term)
VAS:20%ofpatientsexperiencedsubstantialimprovementsinanalgesia
KrakovskyAandBowieE,2007
83.8%ofpatientsreportedanimprovedpainscore(rangeofimprovement,10%50%)
AEs:increasedpainanddepressionin1patient
AEs:none
StantonHicksMandKapural,L,
2006
InclusionCriteria
Notreported
ExclusionCriteria
Notreported
VAS:50.0%improvementfrombeforestartingziconotidetreatmenttolastavailableassessment
AEs:none
StudyValidity
Documentevidenceofthisfromthearticle(includingquotingfromthearticle).
Addanyotherrelevantcomments,includingifthisislikelytoinfluencetheresultsofthestudy.
Isitclearthattherewereno
No
conflictsofinterestinthewriting
Reportnumber:0611002R7.3
FinancialsupportforthisprojectwasprovidedbyElanPharmaceuticals,Inc.MedLogix
Communications,LLC,providededitorialsupportforthisproject.
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orfundingofthisreview?
Doesthereviewhaveaclearly
focusedquestion?
Yes
Thisreviewsummarizesandevaluatesthepublicationsfrompreclinicalandclinicalpeerreviewed
experimentsthathaveinvestigatedthesafetyandeffectivenessofziconotideincombinationwitha
varietyofotherdrugs.
(Notedoesnotmentionthepopulationthough)
Isasystematicreviewthe
appropriatemethodtoanswer
thequestion?
Yes
Doesthereviewhavespecified
inclusion/exclusioncriteria?
No
Iftherewerespecifiedinclusion/
exclusioncriteria,werethese
appropriate??
N/A
Partial
ThePubMed,EMBASE,andCumulativeIndextoNursingandAlliedHealthLiteraturedatabaseswere
searchedwithoutanyrestrictions.Thesecombinedsearchtermswereused:ziconotide,PRIALT,MVIIA,
orSNX111andcombination,morphine,hydromorphone,bupivacaine,baclofen,clonidine,fentanyl,or
sufentanil.Inaddition,associationmeetingsthatcoverITtherapytopicswereidentified;onlythose
meetingswithpublishedabstractswereincluded.Abstractsfromtheseassociationmeetingswere
searched(yearsweredeterminedonthebasisoftheavailabilityofpublishedabstractsasofJanuary
27,2009):AmericanAcademyofPainMedicine(2001to2008),NorthAmericanNeuromodulation
Society(2006to2007),andAmericanPainSociety(2003to2008).
Doesthereviewdocumenta
comprehensivesearchstrategy?
Werereviewersblindtoauthors,
institutionsandaffiliations?
Notreported
Were2ormoreindependent
reviewersusedfor:
Notreported
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10. applicationofinclusion
criteriatoassesseligibilityof
studies?
11. extractionofdatafromstudy Notreported
reports?
12. appraisalofstudyquality?
Notreported
Werethestrengthsand
limitationsofincludedstudies
andpotentialimpactonthe
resultsdiscussed?
No
Wasthevalidityofincludedtrials Notreported
appraisedusingappropriate
criteria?
Isthereasummaryoftheresults
ofindividualstudies?
Yes
Ifmetaanalyseswereconducted, N/A
wasitreasonabletodoso?
Ifmetaanalyseswereconducted, N/A
wasitdoneappropriately?
Other
Whatistheoverallriskofbias?
Insufficientinformation
Results.
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5studiesused,n=111
Webster,2008
Anopenlabelstudyinvolving25patientsshowedthatITmorphinewithziconotiderevealedmeanVASPIscoresimprovedby26.3%frombaseline(titrationphase).Onthe
CategoricalPainReliefScale(CPRS),17of25patients(68.0%)reportedmoderateoralotofpainimprovementattheendofthetitrationphase,and14of18patients
(77.8%)reportedthislevelofpainimprovementattheextensionphaseterminationvisit.AdditionalpainreliefwasreportedontheClinicalGlobalImpression(CGI)scaleby23of25patients(92.0%)attheend
ofthetitrationphaseandby15of17patients(88.2%)attheextensionrevealedthatgood,verygood,orexcellentoverallpaincontrolwasreportedby17of25patients(68.0%)attheendofthe
titrationphaseandby14of19patients(73.7%)attheextensionphaseterminationvisit.
Themostcommon(occurringinZ10%ofpatientsineitherstudyphase)treatmentemergentAEsconsideredtoberelatedtothestudydrugsweredizziness(titrationphase,
28.0%;extensionphase,4.2%),peripheraledema(titrationphase,12.0%;extensionphase,12.5%),pruritus(titrationphase,24.0%;extensionphase,0%),andnauseatitrationphase,16.0%;extensionphase,
4.2%).NounexpectedAEswerereported,andnoserioustreatmentemergentAEsthatwereconsideredtoberelatedtothestudydrugswerereported.
Wallace,2008
Anotheropenlabelstudyinvolving25patientswhichsimilarlyutilisedITmorphinewithziconotide(differentdosesseetableonpage1),14outof25(56%)reportedslighttocompleteimprovementin
painreliefontheCPRS.ImprovedpainreliefontheCGIscalewasreportedby17of25patients(68.0%)attheendofthetitrationphaseandby11of17patients(64.7%)attheextensionphasetermination
visit.ResultsfromtheCGIscalerevealedthatgood,verygood,orexcellentoverallpaincontrolwasreportedby8of25patients(32.0%)attheendofthetitrationphaseandby6of17patients(35.3%)
attheextensionphaseterminationvisit.
Themostcommon(occurringinZ15%ofpatientsineitherstudyphase)treatmentemergentAEsconsideredtoberelatedtothestudydrugswereconfusion(titrationphase,30.8%;extensionphase,16.7%),
dizziness(titrationphase,26.9%;extensionphase,11.1%),abnormalgait(titrationphase,23.1%;extensionphase,5.6%),hallucinations(titrationphase,11.5%;extensionphase,16.7%),andanxiety(titration
phase,7.7%;extensionphase,16.7%).Creatinekinaselevels>3timestheupperlimitofnormalwererecordedfor5patientsduringthetitrationphaseandby6patientsduringtheextensionphase.
Saulino,2008
Acaseseriesof5patientsadministeredITbaclofenwiththeadditionofITziconotideshowedanimprovementinVASPIscoresbyanaverageof50.3%frombaselinetolastassessment.Adverseeventswere
reportedby1patient(nauseaandvomitingwithdehydration),buttheseAEswereconsideredunrelatedtoziconotidetreatment.Thepatientwashospitalizedfor5days,andtheAEsresolvedafterrehydration
andareductionofthepatientstransdermalfentanyldose.TwopatientsalsohadITtreatment,buttheadditionofbaclofentoITziconotide.
Deer,2009
Inaretrospectiveobservationalstudyatotalof16patientsreceivedITziconotidewithconcomitantITopioidshydromorphone(n=7),morphine(n=5),fentanyl(n=3),andsufentanil(n=1);otheradjunctiveIT
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drugswerebupivacaine(n=4),clonidine(n=3),andbaclofen(n=1).Onepatientreportedincreasedpainanddepression2weeksaftertheinitiationofziconotidetherapy.Ziconotidetherapywasdiscontinued,
andthepatientreceivedtreatmentfordepression.AllAEsresolvedinthispatientovera4weekperiod.NootherAEswerereportedbythisoranyotherpatient.Amongthe15patientswhocompleted12
weeksofziconotidecombinationtherapy,3(20.0%)reportedsubstantialpainrelief,10(66.7%)reportednotomoderatepainrelief,and2(13.3%)reportedincreasedpain.
KrakovskyandBowie,2007
Anotherrespectiveobservationalstudyinvolvingatotal37patientsinvolvedITziconotidewithconcomitantITdrugs(informationnotgiven).Ofthe37patients,31patients(83.8%)experiencedimproved
analgesia(rangeofimprovement,10%to50%;nodatawereprovidedfortheremaining6patients),9patients(24.3%)reportedincreasedactivity,4patients(10.8%)decreasedtheirITopioiddose,5patients
(13.5%)decreasedtheirITadjuvantdrugdose(s)(bupivacaineandclonidine),and6patients(16.2%)decreasedtheiroralopioiddose(s).NoAEswerereported.
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ThereviewalsoreportedonpreclinicaloutcomesfollowingITziconotidewithotherdrugs,howeverthiswasnotpartofourquestion.
AuthorsConclusions.
Onthebasisoftheliteratureevaluatedinthisreview,itisevidentthatziconotideincombinationwithotherITdrugshasbeenstudiedmoreextensivelyinpreclinicalinvestigationsthaninclinical
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investigations.Itisimportanttonotethattheeffectsofdrugsinanimalmodelsdonotalwaysaccuratelyreflecttheeffectsofthosedrugsinhumans.
AlthoughthereareonlyalimitednumberofstudiesthathaveevaluatedziconotidewhenusedincombinationwithotherITdrugs,ziconotideisusedascombinationtherapyinclinicalpractice.1416
Therefore,cliniciansmustbalancethelackofevidencebaseddatawiththeirownclinicalexpertiseandexperiencewithziconotideandotherITagentswhendesigningITtherapyregimens.Thereisaneedfor
additionalevidencebasedinvestigationsofziconotidecombinationtherapies,includinglongtermclinicaltrials.
OurComments/Summary.
Thereisverylittleinformationinthispaperinregardstothemethodsundertaken.Assessmentofthequalityofthestudiesincludedinthepaperisnotreportedandthereisnoreferencetoanysupplemental
papersthatmaycontainthisinformation.
Oneoftheretrospectiveobservationalstudies(KrakovskyandBowie,2007)reportedthatpatientsreceivedITziconotidewithotherITdrugs,howevertheydidnotmentionwhichdrugsthesewereorwhat
dosesweregiven.Noadverseeventswerereported,buttheauthorsofthereviewdidnotreportiftheyhadcontactedthestudyauthorstoconfirmthisobservationfromtheironlyavailablepublicationofthe
studyasanabstract.
TheauthorsofthereviewdidnotreportthetrueeffectsizeforITziconotidewithmorphineorbaclofentoobserveifonetreatmentwasmoreeffectivethantheother.
MultipledrugscombinedwithITziconotidewerestudiedinsmallsamplesizes(n=16,Deer,2009)andforshorttimeperiods(12wks,durationunknownforKrakovskyandBowie,2007).Thenumberof
adverseeventsmaybeincreasedifthestudywerelongerinduration.
Thereisinsufficientinformationtoassessthequalityofthispaperandtodeterminetheriskofbias.
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