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Transport Accident Commission & WorkSafe Victoria

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.

Accompanying documents to this report


Title

Report number

Implantable pain therapies: Intrathecal (IT)


infusions Evidence Summary

Research Report No. 0611-002-R7.1

Implantable pain therapies: Intrathecal (IT)


infusions Plain Language Summary

Research Report No. 0611-002-R7.2

Implantable pain therapies: Intrathecal (IT)


infusions Technical Report

Research Report No. 0611-002-R7.3

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Transport Accident Commission & WorkSafe Victoria

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):

Only low level evidence based on a single case series study


exists for the
effectiveness of IT baclofen in the treatment of persistent pain. Therefore, there is
insufficient evidence to determine whether IT baclofen is effective for chronic,
persistent non-cancer pain.

CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):

The most comprehensive, up-to-date high quality SR identified, found that no


studies for ziconotide met the inclusion criteria for either effectiveness or
complications. No further primary studies were identified according to the inclusion
criteria requested in this report. Hence, there is insufficient evidence to determine
the benefits of IT ziconotide treatment for chronic, persistent non-cancer pain.

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]

Intrathecal infusions Evidence Review

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.

In what clinical conditions is this intervention indicated for use?


Drug infusions through implantable pumps are indicated and approved for use by the TGA for baclofen only. Morphine
(opioids), ziconotide and other medications (ketorolac) are not approved and are prescribed by some physicians in an
off label capacity. For off label use appropriate patient consent is required.
Findings in the following report identify the target group for use of IT infusions (opioids and ketorolac) to be adults with
chronic non-cancer pain that have not experienced pain relief with conventional treatments. Insufficient evidence is
available to confirm which patients IT baclofen and IT ziconotide can be used for.

What is the efficacy and effectiveness of this intervention on persistent pain in these
conditions?
ANALGESICS (OPIOIDS):

There is insufficient evidence to answer this question.

ANTI-SPASMODICS
(BACLOFEN):

There is insufficient evidence to answer this question.

CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):

There is no evidence to answer this question.

OTHER MEDICATIONS
(KETOROLAC):

There is insufficient evidence to answer this question.

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):

There is insufficient evidence to answer this question.

ANTI-SPASMODICS
(BACLOFEN):

There is insufficient evidence to answer this question.

CALCIUM CHANNEL
ANTAGONISTS (ZICONOTIDE):

There is no evidence to answer this question.

OTHER MEDICATIONS
(KETOROLAC):

There is insufficient evidence to answer this question.

In what patient groups/conditions is use of this intervention contraindicated?


Patient groups/conditions in which use of IT infusions are contraindicated are
[7]

When infection is present

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

Allergy or hypersensitivity to the drug being used

Blood thinning medications

In patients who have another implanted device, such as a pacemaker

[7]

[7]

[7, 8]

[9]

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[8]

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[7]

Drugs with preservatives

Epilepsy refractory to therapy

Previous history of psychosis

[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.

What are the risks associated with use of this intervention?


[2]

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

Little or no evidence exists to answer this question

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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Transport Accident Commission & WorkSafe Victoria

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.

Intrathecal (IT) infusions


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. This involves implanting a specialised device (pump) subcutaneously in the
abdominal region. Tubes from the pump are inserted into the intrathecal space around the spine
which contains cerebrospinal fluid that bathes the spinal cord, delivering medication to where it has
its action, and therefore eliminating side effects of taking the drug orally or parenterally.
According to the Australian and New Zealand College of Anaesthetists guidelines, IT delivery of
drugs for long term pain management can be used for a small, carefully selected subgroup of
patients. They recommend that IT infusion be used as last line therapy in those whose pain is not
adequately controlled by less invasive measures (e.g. physical therapy, psychological therapy, oral
and parenteral medication and neural blockade) or where other routes of medication cause side
effects.[10, 11] They also caution the use of IT infusions in patients where psychological factors are
considered to be a major pain modifying factor and recommend that psychological evaluation be
done on all patients before starting IT treatment.
Several medications, diverse in their mechanisms of action, have been reported for use in IT pumps
and can be grouped into the following categories
analgesics (opioids),
anti-spasmodics (baclofen),
calcium channel blockers (ziconotide), and
other medications (including ketorolac and midazolam)

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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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3. Calcium channel blockers (ziconotide)


Ziconotide is the man-made equivalent of a pain relieving chemical found in the venom of a certain
type of sea snail. It is a calcium channel antagonist which is thought to inhibit neurotransmitter
release from N-type calcium channels abundantly present on neurons located in the spinal cord.
In Australia ziconotide is classed as an experimental drug and is not approved for IT use by the TGA.

4. Other medications (including ketorolac and midazolam)


There are other medications which have been given intrathecally via a pump. Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) which has inhibitory effects on cyclooxygenase (COX), an
enzyme responsible for the production of prostanoids (prostaglandins, prostacyclin and
thromboxane) which relieve pain and inflammation in the body. Ketorolac is an experimental IT drug
which has only recently been tested for chronic pain in humans and animals.[6] The drug was initially
administered systemically as a potent pain relief agent in postoperative pain. As severe, chronic
pain may originate in the central nervous system, an attempt was made to test IT ketorolac to see if
the central nervous system was also a site of action in the body. In an early open-label study, IT
ketorolac did not reduce pain from applying heat stimuli to the skin, although no serious adverse
events were reported.[6]
Ketorolac has not been approved by the TGA for IT use.
Other medications have been used intrathecally for the treatment of chronic, severe pain. These
include clonidine, bupivacaine, sufentanil, fentanyl, midazolam and gabapentin. However, most of
these drugs have only shown effectiveness in the treatment of pain in pre-clinical studies and hence
are not approved by the TGA for IT use.

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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:

In what clinical conditions is this intervention indicated?

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?

In what patient groups/conditions is this intervention contraindicated?

What are the risks associated with use of this intervention?

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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Is there any synthesised research available? (e.g. EBGs, HTAs, SRs)


Yes

No

Is this good quality research?

Are RCTs available?

Yes

No

Yes

No

Undertake new SR

Undertake new SR

Consider looking for


lower levels of evidence

Is it current (within 2 years)?


Yes

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*

SRs & HTAs*

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.

Results are reported in more detail below by 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

Patient/population: n = 231 (10 case series)


Conditions indicated for use: Adults aged at least 18 years with pain due to
any cause other than cancer lasting for at least three months
Intervention: IT morphine, IT sufentanil citrate, IT methadone, morphine
clorhidrate or tramadol, IT morphine with bupivacaine and/or clonidine and/or
midazolam, IT dilaudid, IT fentanyl and IT baclofen (see Appendix 4 for further
details)
Outcomes assessed:
We assessed adverse events (side effects), discontinuation from study due to
adverse events, discontinuation from study due to insufficient pain relief,
average change in pain score, proportion of patients with at least 50% pain
relief, health-related quality of life, and function.

Efficacy and effectiveness of IT


drug infusion for persistent
pain

Average change in pain scores, as assessed by visual analogue scale (VAS) (n =


220)
Before treatment commenced, the VAS scores of the included studies were
combined, giving a score of 8.70 out of 10 (95% CI: 8.37 to 9.04), indicating
severe pain. After treatment, this pooled VAS score was reduced to 4.45 out of
10 (95% CI: 3.44 to 5.47), indicating moderate pain.
Pts with at least 50% pain relief (n = 151)
The summarized proportion of participants (from combined included studies)
who had at least a 50% reduction in pain was 44.5% (95% CI: 27.2% to 63.2%).

Effect of IT drug infusion on


function, quality of life, return
to work, medication use and
use of the healthcare system?

Quality of life (QoL) (n = 92)


Each study used a different instrument to assess quality of life (QoL). One of
[25]
[26]
the studies had inconclusive findings, one reported a small benefit, and
[27]
one reported a large benefit.
The overall effect size (or standardized mean difference, SMD) following

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statistical analysis revealed no significant improvement in quality of life after


administration of IT opioids 1.02 (95% CI -0.04 to 2.09).
Function Levels (n = 98)
Each study used a different instrument to assess function. Study findings were
[28]
inconsistent, with one study showing inconclusive findings, another showing
[26]
a moderate difference (effect size), and another a large difference (effect
[29]
size). Following statistical analysis, all the studies showed that there was no
significant improvement in functional levels after administration of IT opioid
(SMD 0.56, 95% CI -0.02 to 1.13).
These results however are limited by the high heterogeneity between studies.
Which patient groups/

Not reported

conditions is use of IT drug


infusion contraindicated?
Risks associated with use of IT
drug infusion

Adverse Events (AEs) (n = 228, 10 studies)


Pump and catheter malfunctions and malpositioning, surgical complications,
and postsurgical complications were reported. The percentage of participants
whose device complications required reoperation was quite high in some
studies (20-27%). Two studies reported a total of six deaths, due to chronic
obstructive pulmonary disease, pericolonic abscess, and myocardial infarction
(n=2), suicide, and an unknown cause (n = 1). The SR did not report if these
events were due to the drug or the implantable pump itself.
Discontinuation from study due to AEs (n = 86)
Following pooled analysis of all included studies it was estimated that 8.9% of
patients discontinued the study due to adverse events, however this result was
not statistically significant.
Discontinuation from study due to insufficient pain relief (n = 113)
The summary rate of discontinuation due to insufficient pain relief was 7.6%
(95% CI: 3.7% to 14.8%).

Conclusion/
Recommendation

Many patients discontinue long-term opioid therapy (especially oral opioids)


due to adverse events or insufficient pain relief; however, weak evidence
suggests that patients who are able to continue opioids long-term experience
clinically significant pain relief. Whether quality of life or functioning improves
is inconclusive. Many minor adverse events (like nausea and headache)
occurred, but serious adverse events, including iatrogenic opioid addiction,
were rare.

Recommendation category

Insufficient evidence

Quality assessment results

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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and insufficient evidence for health-related quality of life outcomes.

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.

3. CALCIUM CHANNEL BLOCKERS (ziconotide)


Evidence identified
Searches yielded one SR for IT ziconotide for the treatment of persistent pain. The SR[5] was
appraised and found to be well conducted with a low risk of bias. Details of the appraisal are in
Appendix 5.
The authors of the SR found that no studies for ziconotide met the inclusion criteria for either
effectiveness or the complications review.

4. OTHER MEDICATIONS (ketorolac)


Evidence identified
Searches yielded a total of 2 studies (1 EBG and 1 Randomised Cross Over Trial) for other IT
medications for the treatment of persistent pain published between 1996 and 2011. The number of
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[22] was appraised and found to be of low quality with a potentially high risk of bias. It
included a section on IT medication delivery systems, however it did not indicate the patient group
(condition or age), the drug used or the outcomes reported. We chose to use the most-up-to-date,
high quality evidence which was a randomised cross over trial by Eisenach[6] as the basis of this
section of the report.
This cross-over trial randomised patients with chronic pain already receiving IT morphine for 6 weeks
to receive preservative free ketorolac, 2mg, or placebo (saline) on their first visit, with the
alternative treatment on their second visit. Patients returned after at least one week, but no more
than 3 months later, for the crossover treatment. This study reported no significant difference in
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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

Randomised cross-over trial

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

Efficacy and effectiveness


of IT drug infusion for
persistent pain

Both pain intensity (P = 0.01) and unpleasantness (P = 0.02) decreased with


time after intrathecal injections, but there was no difference between ketorolac
and saline, and there was no significant interaction between treatment and
time.

Effect of IT drug infusion on


function, quality of life,
return to work, medication
use and use of the
healthcare system?

Not reported

Which patient
groups/conditions is use of
IT drug infusion
contraindicated?

Patients allergic to ketorolac or morphine

Risks associated with use


of IT drug infusion

No significant difference in the occurrence of adverse events was reported


between ketorolac and placebo.

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

We failed to observe greater analgesia from intrathecal ketorolac than saline


placebo in patients with primarily low back and lower extremity pain and a
combination of somatic and neuropathic components.
2 mg of intrathecal ketorolac was not associated with serious side effects,
failed to reduce ongoing pain in chronic pain patients more than
placebo.These observations are limited by the small number of subjects
studied, and patient population, and the amount and timing of ketorolac
dosing.
Under the conditions of these studies, it seems that spinal cylcooxygenase
activity does not contribute to chronicpain.

Recommendation category

Insufficient evidence

Quality assessment results

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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DISCUSSION & CONCLUSION


As a number of evidence syntheses assessing the effectiveness of IT infusion for chronic, persistent
pain were identified, a pragmatic yet rigorous approach was taken whereby the best quality, most
up-to-date source of evidence for each drug category was used to answer the review questions.
For all drug categories there is insufficient evidence to determine whether IT infusion is effective in
relieving persistent pain and improving functional outcomes and quality of life in non-cancer
patients. Although a number of well conducted SRs were identified, the evidence base of these was
poor as the included studies were case series. Furthermore individual studies had no control groups
and small sample sizes. The results of case series are difficult to interpret as influences of regression
to the mean and selection bias cannot be ruled out. Furthermore the lack of a control group has the
potential to obscure a relationship between treatment and outcome or suggest an association
where one does not exist.
More studies are required to assess the risks associated with IT infusion. Only one systematic review
reported on adverse events associated with the pump/device.[2] These included pump and catheter
malfunctions and malpositioning, surgical complications, and postsurgical complications. Drugrelated adverse events associated with the use of IT morphine, baclofen, ziconotide, and ketorolac
alone were not reported by the primary studies. Only the randomised cross-over trial comparing
morphine/ketorolac and morphine/saline combination therapy reported drug-related adverse
events [6]. Although no significant difference was observed between groups, mild sedation and
headache were the most commonly occurring adverse effects.
Based on the evidence, the indication for IT use is unclear. The patient groups recruited by the
studies were broad, e.g. adults with non cancer pain of three months duration,[2] patients with
persistent pain[3] or patients with chronic pain receiving IT morphine for at least 6 weeks.[6]
Furthermore, none of the studies reported the origin or type of pain experienced by the patients.
Currently there is limited evidence to assess the efficacy of IT therapy for persistent non-cancer pain.
Further studies are needed to address long term effectiveness and safety of IT agents both alone and
in combination and assess in which population these are most suitable.

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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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Patel, V.B., et al., Systematic review of intrathecal infusion systems for long-term
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Wallace, M.S., R.L. Rauck, and T. Deer, Ziconotide combination intrathecal therapy: rationale
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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

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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

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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

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Page4of62

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

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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

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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.

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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
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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

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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

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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

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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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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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st

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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st

1 author,year,title

Inclusion,Exclusioncriteria(forP.I.C.O)

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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st

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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st

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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st

1 author,year,title

Inclusion,Exclusioncriteria(forP.I.C.O)

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

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st

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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st

1 author,year,title

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.

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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)

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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

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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

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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

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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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