Intraspinal techniques for pain management in cancer patients: a systematic review

REVIEW ARTICLE

Intraspinal techniques for pain management in cancerpatients: a systematic review

Jeff Myers & Vincent Chan & Virginia Jarvis &

Cindy Walker-Dilks

Received: 21 July 2009 /Accepted: 9 November 2009 /Published online: 27 November 2009# Springer-Verlag 2009

AbstractPurpose This systematic review outlines current evidenceregarding the effectiveness of intraspinal techniques forcancer pain and addresses practical implementationissues.Methods A search of electronic databases identifiedsystematic reviews and randomized controlled trials (RCTs)evaluating the effectiveness of intraspinal techniques in thesetting of cancer pain. An environmental scan was completedvia the internet to identify practice guidelines and resourcedocuments addressing organizational and implementationissues in the delivery of intraspinal analgesia. Elementsreviewed included patient selection, contraindications,monitoring, aftercare, follow-up, hospital discharge equipment,health personnel, patient education, and safety.Main results Three systematic reviews, three consensusconferences, and 12 RCTs met the inclusion criteria for

evidence of effectiveness. No single systematic review orconsensus conference included all relevant RCTs orspecifically addressed the use of intraspinal techniques forcancer pain. Six RCTs compared intraspinal techniquesalone or combined with other interventions alone or incombination, four compared different intraspinal medica-tions, and two compared different intraspinal techniques. Ingeneral, the evidence supported the use of intraspinaltechniques for cancer pain management. The two mainindications consistently identified were intractable pain notcontrolled by other conventional medical routes and/or sideeffects from conventional pain management strategiespreventing dose escalation. Reports indicate intraspinalanalgesia is equally or more effective than conventionalmedical management and often associated with fewer sideeffects. Thirteen resource documents addressed issuessurrounding the delivery of intraspinal analgesia andprogram implementation.Conclusions Intraspinal techniques monitored by an inter-professional health care team should be included as part ofa comprehensive cancer pain management program.

Keywords Intraspinal analgesia . Cancer painmanagement .

Neoplasms

Introduction

Through advances in knowledge and use of disease-modifyingtherapies, patients with cancer are living longer. Cancer-related pain, however, remains poorly managed [1]. In aneffort to standardize and improve cancer pain management,the World Health Organization (WHO) endorsed a three-stepapproach outlining the use of opioids and adjuvant medi-cations [2]. Because many of the cancer-related pain

J. Myers (*)Palliative Care Consult Team, Odette Cancer Centre,Sunnybrook Health Sciences,Toronto, ON, Canadae-mail: [email protected]

V. ChanDepartment of Anesthesia, University Health Network,Toronto, ON, Canada

V. JarvisThe Ottawa Hospital Regional Cancer Centre,Ottawa, ON, Canada

C. Walker-DilksProgram in Evidence-Based Care,Department of Clinical Epidemiology and Biostatistics,McMaster University,Hamilton, ON, Canada

Support Care Cancer (2010) 18:137–149DOI 10.1007/s00520-009-0784-2

syndromes are complex, a significant number of patientscontinue to experience refractory pain despite adherence tothe WHO guidelines [3]. In response to this, a revisedapproach was released by the WHO in 1996 identifying thefourth step known as “invasive therapy” [4]. Intraspinal(epidural or intrathecal) analgesia is an example of such atherapy.

Intraspinal catheters have been in routine use for decades invarious surgical and anesthesia settings. In an effort to morespecifically target pain pathways via the spinal cord, cliniciansin the mid 1970s successfully introduced intraspinal catheterinsertion and subsequent analgesic infusion as an effectiveintervention in the setting of refractory cancer pain. Thedelivery of intraspinal pain control is currently dependent onlocal policies and procedures and the interest and competenceof interventional pain physicians, palliative care physicians,nurses, and family physicians in this field of care.

This review is intended to examine the clinical evidencerelated to intraspinal analgesia, as well as outline theresources required to support patient care before, during,and after intraspinal analgesia administration in the settingof cancer-related pain.

Methods

Evidence was selected and reviewed by a three-memberworking group derived from the Cancer Care OntarioPalliative Care Clinical Program that included a palliativecare physician, a palliative care nurse, and an interventionalpain physician.

To inform the evidence base supporting the clinicaleffectiveness of intraspinal pain techniques, MEDLINE(1950 to May, week 2, 2008), EMBASE (1980 to week 20,2008), CINAHL (1982 to week 3, 2008), and the CochraneLibrary were searched using medical subject headings andtextwords pertaining to intraspinal, epidural, or intrathecalinjections, pain and cancer, and combined with relevantstudy design terms and publication types for randomizedcontrolled trials and systematic reviews.

In addition, an environmental scan was undertaken tosearch for clinical practice guidelines and resource documents(nonindexed) using the Google™ search engine on theinternet. This scan was targeted at a list of organizationsknown to develop evidence-based practice guidelines of goodquality or of relevance to the Ontario context. An untargetedsearch to find resource documents of relevant oncology, painmanagement, and anesthesiology professional organizationswas also undertaken. Finally, the reference lists of allretrieved documents were scanned for additional relevantarticles and working group members were asked about localguidelines, standards, and procedure manuals of which theywere aware.

Study selection criteria

The following selection criteria were used to evaluate theclinical effectiveness literature:

1. study design: clinical practice guidelines, systematicreviews of RCTs, and RCTs

2. patient population: cancer patients (any age, anydiagnosis) with cancer-related pain

3. intervention and comparisons:

& intraspinal techniques alone or in combination versus(vs.) other interventions (e.g., medical management)alone or in combination

& different intraspinal techniques& external pumps vs. internal pumps& timing of intraspinal techniques

4. outcomes: pain measured using a validated scale

Studies or reviews on the use of intraspinal techniquesfor procedure-related pain or techniques other than epiduralor intrathecal analgesia (e.g., intracerebroventricular) werenot included. Comments, letters, editorials, case reports,news, and non-English language articles were excluded.

To inform recommendations on clinical indications andorganizational and implementation issues, clinical practiceguidelines and resources documents (policy statements,position papers, practice parameters, care pathways, andmanuals) were considered if they commented on at leastone of: patient selection, contraindications, monitoring,aftercare, follow-up, hospital discharge, equipment, practiceteam, professional competencies, patient education, andpatient safety.

Results

Systematic reviews, consensus conferences,and randomized controlled trials

Three systematic reviews [5–7], three consensus conferences[8–10], and 12 RCTs [11–22] met the selection criteria ofstudies examining clinical effectiveness. Although thesystematic reviews and consensus conferences includedsome relevant RCTs, no single systematic review orconsensus conference included all relevant RCTs or suffi-ciently discussed the effectiveness of intraspinal analgesiafor cancer-related pain to support recommendations. Further,while all included cancer patients, only two systematicreviews [6, 7] and one [9] consensus conference commentedspecifically on or presented separate data specificallyrelevant to this population. The remainder combined studiesacross all patient populations and did not provide specificcancer pain information.

138 Support Care Cancer (2010) 18:137–149

Of the 12 RCTs, six compared intraspinal techniques aloneor in combination with other interventions alone or incombination, four compared different intraspinal medications,and two compared different intraspinal techniques. Indicatorsof quality extracted from each study were publication status(full publication or meeting abstract), allocation concealment,blinding, statement of statistical power or sample sizecalculation, intention-to-treat analysis, and statement ofsponsorship or funding.

Characteristics of the included systematic reviews,consensus conferences, and RCTs, including quality features,are in Tables 1, 2, and 3.

Clinical practice guidelines and resource documents

The environmental scan yielded 13 documents that weresummarized and reviewed for quality and their utility ininforming recommendations on the delivery of intraspinalpain management: eight documents were practice guidelines[23–30], four were local internal use clinical care algorithmsor policy and procedure documents [31–34], and one was apractice standard [35]. The eight practice guidelines wereevaluated using the Appraisal of Guidelines for Researchand Evaluation instrument [36]. The guidelines varied inquality, but most could be recommended for use. Thecoverage of these resources for organizational guidanceconcerning intraspinal pain management is shown inTable 4.

Clinical effectiveness

Two systematic reviews met inclusion criteria [6, 7]. Raffaeli[6] reviewed the literature on intraspinal medication forchronic pain between 1990 and 2005. Of the 34 studiesidentified, 19 were on cancer pain and two of these wereRCTs [12, 18]. Overall, the review demonstrated that intra-spinal administration of opioids was effective in attenuatingpain in patients with cancer pain and noncancer pain. A 2002Agency for Healthcare Research and Quality evidence report[7] focused on the prevalence, assessment, and treatment ofcancer-related pain, depression, and fatigue. RCT evidencewas used to assess the efficacy of interventions. Intraspinalanalgesia as an intervention was addressed in a summary ofRCTs evaluating adjuvant analgesics. Three of the six RCTswere relevant [17–19]. The review concluded insufficientRCTevidence was available to determine the relative efficacyof the spinal versus systemic route of drug administration.

Informed by a polyanalgesic consensus conference onthe management of pain by intraspinal drug delivery acrosspatient types [10], a similar multidisciplinary meeting washeld to arrive at consensus-based recommendations for theuse of intrathecal drug delivery for intractable cancer pain[9]. Based on consensus and citing the Smith 2002 RCT[12], the panel supported the use of intrathecal drugdelivery in the management of cancer pain but noted thatfew RCTs have been conducted on the optimal medicationfor cancer pain, prompting reluctance among the medical

Table 1 Characteristics of systematic reviews and consensus conferences

Review Question Data sources Study selection Outcomes # relevantRCTs

Raffaeli [6] What is the recent evidence(1990 to 2005) on the useof intrathecal opioids forcancer and noncancerpain?

MEDLINE, reviewingjournals, and searchingpertinent internet sites

Studies on intrathecaladministration of drugsfor patients withchronic (cancer andnoncancer) pain

Pain intensity, opioiddosage reduction, sideeffects, and devicecomplications

3Systematicreview

Carr [7] Among several questions,are different analgesicdrug formulations androutes of administrationassociated with differentpatient preferences ordifferent efficacy rates?

Update of the 2001 AHRQreport on management ofcancer pain and 2002conference on symptommanagement in cancer.Searched MEDLINE,Cochrane, CancerLit, andreferences of reviews

RCTs evaluating theefficacy of treatmentsfor cancer-related pain

Pain 3Systematicreview

Stearns [9] What are the benefits andpractical managementconsiderations ofintraspinal analgesia forcancer pain?

Multidisciplinary expertpanel consensus based onexperience fromparticipation inPolyanalgesic ConsensusConference 2003,Hassenbusch [8]

Role of intrathecaltherapy, patientselection, deliverysystems,contraindications andrisks, best practicealgorithm

1Consensusconference

AHRQ Agency for Healthcare Research and Quality, RCT randomized controlled trial

Support Care Cancer (2010) 18:137–149 139

community to accept intraspinal analgesia for widespreadclinical use. The algorithm created by the polyanalgesicconsensus conference was updated again in 2007, addingziconotide to the list of first-line intrathecal medications[37].

The quality, characteristics, and results of the 12 eligibleRCTs are in Tables 2 and 3. While most of the studies weredouble blinded, the reporting of the quality features was

typically incomplete. Further, sample sizes varied widely,but most studies were small and likely underpowered.

Intraspinal techniques alone or in combination vs. otherinterventions alone or in combination

Three RCTs compared an intraspinal technique alone or incombination with another pain intervention alone or in

Table 2 Study quality of RCTs meeting inclusion criteria

Study Publicationstatus

Allocationconcealment

Blinding Statisticalpower

Intention-to-treatanalysis

Sponsorshipfunding

Comments andlimitations

Vainio [11] Fullpublication

NR No NR Unclear Finnish Cancer Societyand Durascan MedicalProducts (implantableports)

Smith [12] Fullpublication

Yes No NR Yes Medtronic <80% follow-up

Kalso [13] Fullpublication

NR Double NR Unclear Academy of Finland;Paulo Foundation;Pharmacia (pump)

Staats [14] Fullpublication

Yes Double 96% to detect>30% changein VAS betweengroups (70ziconotide and35 placebo)

Yes Neurex/ElanPharmaceuticalsand Medtronic

Eisenach[15]

Fullpublication

NR Double NR NR Fujisawa USA <80% follow-up

Pasqualucci[16]

Fullpublication

NR Double NR Unclear NR

Dahm [17] Fullpublication

NR Double NR Unclear Faculty of Medicine ofGoteborg University andInga-Britt and ArneLundberg ResearchFoundation

<80% follow-up

van Dongen [18] Fullpublication

NR Double NR No NR Five patients were notrandomized and receivedopen-label treatment.Five patients in themorphine-alone groupcrossed over to comboRx and were analyzedin the combo group.

Lauretti [19] Fullpublication

Unclear Double Sample sizecalculationdone—detailsnot given

NR Fundação de Amparoa Pesquisas de São Paulo

Yang [20] Fullpublication

NR Double NR Unclear National Science Council,Republic of China

Pain intensity comparedwith pretrial, not betweenstudy groups

Gourlay[21]

Fullpublication

NR No NR Unclear Anti Cancer Foundationof the Universities of SouthAustralia; Shiley Infusaid;Pharmacia (Port-a-Cath)

Georgiou[22]

Fullpublication

NR No NR Unclear NR

NR not reported, VAS visual analog scale


Tab

le3

Characteristicsandresults

ofinclud

edRCTs

Study

Patient

characteristics,

patient

follo

w-up

Lengthof

follo

w-up

Interventio

nOutcomes

Results

Intraspinaltechniques

aloneor

incombinatio

nvs.otherinterventio

nsaloneor

incombinatio

n

Vainio[11]

30patientswith

severe

cancer

pain

(meanage52

years,range

23to

86);follo

w-up,

30/30

Toendof

treatm

ent(usually

deathof

patient)

Epiduralopiate

usinga

conventio

naltunneled

catheter

(n=10),im

plantedcatheter,and

injectionport

(n=10),or

system

icperoral

opiate

(n=10)

Painintensity

(10-cm

VAS),

performance

status

(100-point

[100

=norm

al]Karnofsky

scale),

side

effects,andcomplications

Groupsdidnotd

ifferforVASscores,w

hich

were<5in

allthreegroups.The

oral

grouphadmoreside

effectsthan

the

epidural

groups.Karnofsky

scores

were

nonstatistically

significantly

betterin

the

epidural

groups

than

theoral

group.

Twelve

incidences

ofcomplications

occurred

intheepidural

groups

compared

with

nocomplications

intheoral

group.

Smith

[12]

(intentio

n-to-

treat)

202patients≥1

8years(m

ean

age57

years,55%

men)with

advanced

cancer

andmean10-

pointVAS(10=worst)score

≥5;follo

w-up,

143/202(71%

)

6months

Intrathecalmorphinedeliv

ered

throughan

implantabledrug

deliv

erysystem

plus

comprehensive

medical

managem

ent(n=101)

vs.

comprehensive

medical

managem

entalone(n=99)

Clin

ical

success,≥2

0%reductionin

VASor

equalVASwith

≥20%

reductionin

drug

toxicity

at4

weeks

VASpain

scorereduction52%

with

implantablesystem

vs.39%

comprehensive

medical

managem

ent

(p=0.055).Clin

ical

success85%

with

implantablesystem

vs.71%

with

comprehensive

medical

managem

ent

(p=0.05).Thirtypatientsin

whom

comprehensive

medical

managem

ent

failedcrossedover

toim

plantablesystem

andhadsignificantly

reducedVAS(27%

reduction)

anddrug

toxicity

(51%

reduction)

scores

with

in4weeks

[38].

The

as-treated

analysisshow

edgreater

clinical

successwith

implantablesystem

than

nonimplantablesystem

(89%

vs.71%

,p=0.02)[39].

Smith

[38]

(crossovers

from

comprehensive

medical

managem

ent)

Smith

[39]

(as-treated)

Kalso

[13]

10hospitalized

patients(age

range22

to75

years,60%

wom

en)with

severe

cancer-

relatedpain

requiringopioids;

follo

w-up,

9/10

Two48-h

periods

Crossover

design:epidural

orsubcutaneous

continuous

infusion

ofmorphine

A100-mm

VASscore

(100

=worst)andadverse

effects

Painatrestwas

less

during

subcutaneous

morphinethan

oralmorphine(pretrial)and

pain,w

hilemovingwas

less

during

subcutaneous

andduring

epiduralmorphine

than

pretrialoralmorphine;subcutaneous

andepiduraldidnotd

ifferforeither

measurement.Pretrialoralmorphinehad

moreadverseeffectsthan

subcutaneous

(P<

0.05).Epiduraldidnotdiffer

from

either

oral

orsubcutaneous

foradverseeffects.

Com

parisons

ofdifferentintraspinaladministrationtechniques

Staats[14]

111patients,24

to85

years

(meanage56

years,50%

men)

with

cancer(n=95)or

AID

S(n

=13)andmean100-mm

VAS

(100

=worst)score≥5

0;follo

w-up,

108/111(97%

)

Initialtitratio

nperiod

5to

6days

plus

a5-dmaintenance

phase

Ziconotide(n=71)or

placebo

(n=40)by

alreadyim

planted

pumpor

byintrathecalcatheter

with

external

infusion.Atendof

titratio

n,responders

received

5days

ofmaintenance

and

nonresponderscrossedover

toalternatetreatm

ent.

Meanpercentage

change

inVASto

endof

titratio

nphase

53%

improvem

entwith

ziconotid

evs.18%

with

placebo(p<0.001)

Eisenach[15]

85patients(age

range31

to83

years,mean56

years,60%

men)with

severe

cancer-

15days

Contin

uous

epidural

infusion

ofclonidine,

30μg/h(n=38)or

placebo(n=47)by

patient-

Treatmentsuccess:anyreductionin

morphineuseor

VAS,or

either

variable

decreasing

with

theother

Treatmentsuccesswas

achieved

bymore

clonidinepatientsthan

placebopatients

(45%

vs.21%

,p=0.016).Greatestsuccess


Tab

le3

(con

tinued)

Study

Patient

characteristics,

patient

follo

w-up

Lengthof

follo

w-up

Interventio

nOutcomes

Results

relatedpain

despite

system

icor

epidural

morphineor

mor-

phineequivalents;follo

w-up,

56/85(66%

)

controlledanalgesiapumpfor14

days;allpatientshad

rescue

epidural

morphine.

remaining

constant

was

seen

inneuropathicpain

control(50%

vs.11%

).Groupsdidnotdiffer

foradverse

events(33%

vs.33%

).

Pasqualucci

[16]

12patients(age

range45

to75

years,75%

men)with

severe,

continuous

cancer-related

pain

(VAS5/10)notrespondingto

common

analgesicdrugs;

follo

w-up,

12/12

18h

Singledose

viaepidural

ofmorphine,

3mg(n=6)

orbuprenorphine,

0.3mg(n=6)

Pain(10-cm

VAS)andventilatory

functio

n(breathing

controland

gasexchange)

Paincontrolim

proved

inboth

groups

throughthefirst6h.

Buprenorphine

had

significantly

betterpain

controlcompared

with

baselin

ethan

morphinecompared

with

baselin

eat

18h.

Dahm

[17]

21patients26

to76

years

(medianage63

years)

with

refractory

pain

conditions(15

cancer);follo

w-up:12/21

(9cancer)

Two7-dperiods

Crossover

design:continuous

intrathecalinfusion

ofropivacaine

orbupivacaine

Needforlocalanesthetics,mean

10-point

VASscore

(10=worst),side

effects

Needforlocalanestheticshigher

with

ropivacaine(62vs.58mg/day,

P<0.02),VASscores

nodifference

(P>0.3),no

difference

inside

effects

vanDongen[18]

20patients(age

range35

to82

years)

with

refractory

cancer

pain;follo

w-up,

20/20

Patientswerefollo

wed

until

death(m

eanfollo

w-up58

to85

days)

Intrathecaladministrationof

morphine+

bupivacaine

(n=11)or

morphinealone

(n=9)

Progression

ofmorphinedose

and

side

effects

Adequatepainreliefwas

achieved

inboth

groups.T

herateof

dose

progressionof

morphinewas

lessinthemorphine+

bupivacainegroupthan

themorphinealone

group(0.0003vs.0.005

mg/h,p=0.0001).

Lauretti

[19]

48patients(m

eanagerange50

to56

years,63%

men)with

refractory

cancer

pain;

follo

w-up,

48/48

25daya

Epiduraladministrationof

morphine+

ketamine,neostig

mine,

midazolam

,or

placebo(12

patientspergroup)

wheneverVAS

scorewas

≥4/10

A10-cm

VAS(10=worst),tim

eto

complaint

ofpain

(VAS≥4

/10),

andadverseeffects

VASscores

60min

afterdrug

administration

werelowerwith

ketaminethan

midazolam

(P=0.018).Patientsin

theketamineand

neostig

minegroups

hadalonger

timeto

pain

complaint

than

placebopatients.

Groupsdidnotdiffer

foradverseevents.

Yang[20]

20hospitalized

patients22

to69

years(50%

men)with

cancer

usingopioid

analgesics

for

paincontrol;follo

w-up,20/20

Two48-h

periods

Crossover

design:intrathecal

morphine+

ketamineor

morphine

alonetwicedaily

Intrathecalmorphineandrescue

morphinerequirem

ents;pain

intensity

on10-point

VASscore

(10=worst);pain

frequencyon

4-pointverbal

ordinalscale

(3=constant)

The

required

dose

ofintrathecalm

orphineto

beeffectivewas

less

inthemorphine+

ketaminegroup(0.17vs.0.38mg,P<0.05);

pain

intensity

andpain

frequencywereboth

decreasedaftereither

interventio

ncomparedwith

pretrial.

Com

parisons

ofdifferentintraspinalmedications

Gourlay

[21]

29Patientswerefollo

wed

until

death(m

ean140to169days);

follo

w-up28/29

Epiduralm

orphineadministered

ascontinuous

infusion

via

pump(n=15)or

interm

ittent

bolusviacatheter

(n=14)

Epiduralmorphineadministeredas

continuous

infusion

viapump

(n=15)or

interm

ittentbolusvia

catheter

(n=14)])

VASandproblemsencountered

with

thedevices(0

to4[very

troublesom

e])

VASscores

werelow

(good)

inboth

infusion

andbolusgroups

anddidnot

differ,1.48

vs.1.23)andvery

few

problemsoccurred

with

thedevices(0.52

vs.0.49).

Georgiou(2000)

[22]

29patients(m

eanage68

y,97%

men)with

term

inal

head

orneck

cancer

with

pain

notcontrolledby

oral

morphine;

follo

w-up,

28/29

Patientswerefollowed

untildeath;

painwas

measuredup

to10

day.

Morphineadministeredepidurally

inthethoracic

(n=16)or

cervical

region

(n=13).

100-mm

VASscore(100

=worst),

morphineuse,

andcomplications.

Groupsdidnotd

ifferin

pain

scores.T

hebolusdose

anddaily

dose

ofmorphinewere

lowerin

thecervicalgroup(P<0.05)and

theduratio

nof

analgesiaaftereach

bolus

dose

was

longer

inthecervical

group

(P<0.05).Nausea/vomiting

andpruritu

sweremild

ormoderateandmorecommon

inthoracic

patients,as

was

constipation.

hho

ur,momon

th,VA

Svisual

analog

scale,

wkweek,

yyear


combination. In a three-arm trial, Vainio [11] (n=30)compared morphine given orally by conventional tunneledcatheter or by implanted catheter. All three groups achievedmarked pain relief and did not differ statistically from oneanother, but a higher rate of side effects was observed in theoral morphine group (16 occurrences compared with sevenoccurrences in the conventional epidural group and threeoccurrences in the port group). Technical complications weremore common in the epidural groups and included dislocationin the epidural space (three times in the conventional cathetergroup), disconnection of the port (three times in the portgroup), and local infection of the skin (once in theconventional catheter group and twice in the port group).

Smith [12] (n=202) compared intrathecal delivery ofmorphine through a programmable infusion system pluscomprehensive medical management with medical manage-ment alone in 202 patients with refractory cancer pain.Clinical success was defined as ≥20% reduction in visualanalog pain scale and ≥20% reduction in drug toxicity at4 weeks. The difference between the two groups metborderline statistical significance (P=0.05). The reductionin pain scores was greater in the intrathecal group, but thedifference was just short of statistical significance (P=0.055).Significant reductions in fatigue and depressed level ofconsciousness occurred in the intrathecal delivery group(P<0.05). In two separately published reports, preplannedanalyses of crossovers [38] and as-treated patients [39]showed statistically significantly greater clinical success withcombined therapy.

Kalso [13] (n=10) compared epidural with subcutaneouscontinuous infusion of morphine in a crossover trial. Bothgroups improved in pain control compared to that of oralmorphine at baseline. The groups did not differ for adverseeffects.

Comparisons of different intraspinal medications

Seven RCTs compared different types of drugs or compareddrug with placebo in patients receiving an intraspinal drugdelivery system. Staats [14] (n=111) compared ziconotidewith placebo by implanted pump or intrathecal catheterwith external infusion. Patients who received ziconotideshowed an improvement of 53% at the initial titration phase(5 to 6 days) compared with 18% improvement withplacebo. Adverse effects such as somnolence, confusion,urinary incontinence, and fever were more common withziconotide than placebo but were easily recognized anddecreased when the dose of ziconotide was decreased. Along-term follow-up of open-label ziconotide [40] showedsignificant improvement in pain intensity scores frombaseline at all time points and past 12 months.

Eisenach [15] (n=85) compared a continuous epiduralinfusion of clonidine with placebo, both administered byT

able

4Organizationalgu

idance:summaryof

evidence

Sectio

nPracticeGuidelin

esResou

rcePapers:PolicyandStand

ards

ONS

2004

[23]

BPS

2006

[24]

CCNS

2005

[25]

SIG

N20

00[26]

Sing

2003

[27]

APS

2005

[28]

NCCN

2007

[29]

ASA

1996

[30]

StWilf

2001

[34]

Cal

2004

[31]

Corn

2001

[32]

Ott

2007

[33]

INS

2006

[35]

Indicatio

nsforuse

Patient

selection

√√

√√

√√

√√

√√

√Con

traind

ications

√√

√√

√Practicesetting

Mon

itoring

,aftercare,

follo

w-up

√√

√√

√√

√√

√

Hospitaldischarge

√√

√√

Equ

ipment

√√

√√

√Practiceteam

Practiceteam

√√

√√

√Professionalcompetencies

√√

√√

√Patient

education

√√

√√

√√

√√

Patient

safety

√√

√√

√


patient-controlled pump. Significantly greater treatmentsuccess (defined as a decrease in morphine use or decreasein pain) was seen with clonidine than placebo (45% vs.21%). Adverse events occurred in 33% of patients in bothgroups. Groups did not differ for sedation or decreasedrespiratory function, but clonidine decreased blood pressureby about 10 mmHg.

Pasqualucci [16] (n=12) compared epidural administra-tion of morphine with buprenorphine and showed significantreduction in pain in both groups at 6 h. At 18 h, better paincontrol (compared with baseline) was seen with buprenor-phine in three pain indices compared with morphine in onepain index. Adverse reactions occurred in four of sixbuprenorphine patients and in two of six morphine patients.

In a crossover RCT comparing intrathecal bupivacainewith ropivacaine (n=21), Dahm [17] showed no significantdifference in pain scores but higher daily doses of localanesthetic to achieve a similar degree of pain relief wereused with ropivacaine. Groups did not differ for side effectsor complications.

Van Dongen [18] (n=20) compared intrathecal delivery ofmorphine plus bupivacaine with morphine alone. Both groupshad adequate pain relief, but the rate of morphine alone doseprogression from day 10 to day 30was greater in the morphinegroup than in the combined group (P<0.001). No severebupivacaine-related neurological deficits were observed.

Lauretti [19] (n=48) evaluated patients allocated toepidural administration of morphine plus ketamine, neostig-mine, midazolam, or placebo. Patients receiving ketamine hadlower pain scores than those receiving midazolam at 60 minafter administration. Pain relief lasted longer in the ketamineand neostigmine groups than the placebo group. Morphineconsumption up to day 25 was lower in the ketamine groupthan the placebo group (P=0.003). There were no differencesamong the groups for adverse effects, the most commonbeing somnolence, constipation, diminished appetite, andskin redness around the epidural catheter and one patientexperienced hallucinations.

In a crossover trial, Yang [20] (n=20) compared intrathecalmorphine plus ketamine with intrathecal morphine alone.Pain intensity and pain frequency were both decreased frombaseline. The addition of ketamine resulted in a lower dose ofmorphine being required. Side effects did not differ betweengroups and were not serious. No cases of respiratorydepression occurred.

Comparisons of different intraspinal administrationtechniques

Two small RCTs (each n=29) compared different intraspinaltechniques. Gourlay [21] evaluated epidural morphineadministered as a continuous infusion by Infusaid pump orintermittent bolus by Port-a-Cath. Pain scores were low in

both groups and did not significantly differ. Mean scores forproblems associated with the devices were also low in bothgroups.

Giorgiou [22] evaluated epidural administration ofmorphine in the thoracic compared with the cervical regionand showed no difference in pain scores. The cervical routerequired smaller bolus doses and gained longer lastinganalgesia than the thoracic route. The thoracic route led to agreater rate of adverse effects (constipation, nausea andvomiting, and pruritus).

Indications for use

Among the documents that provided guidance on patientindications for the use of intraspinal analgesia [9, 23–32],two indications were supported by all groups: intractablepain that could not be controlled by other conventionalmedical routes and side effects from conventional medicalroutes that prevented dose escalation. Table 5 outlines allthe indications that were identified and the documents thatsupported those indications.

Five documents [9, 23, 24, 31, 32] addressed contra-indications for the administration of intraspinal analgesia.Anticoagulation and active systemic or local infection werethe most commonly reported contraindications. Uponreviewing, the working group felt that anticoagulationshould be considered a contraindication to intraspinalanalgesia at the time of catheter insertion, but not if thepatient was anticoagulated after intraspinal analgesia wasadministered.

With respect to infectious considerations, septicemia isan absolute contraindication because of the high risk ofcatheter infection after implantation. This can lead toepidural abscess formation and the possibility of spinalcord compression resulting from a space-occupyingabscess. This can also result in a CNS infection (e.g.,meningitis and encephalitis). Sepsis or any systemicinfection controlled after institution of antibiotic treatmentis not a contraindication. Any local superficial infectionafter successful treatment is not a contraindication. Anepidural/spinal catheter or an internalized pump may beimplanted at a site or segmental level that is distant fromthe infected area. Patients with immunosuppression orinsulin-dependent diabetes have a higher risk of infection.

Bleeding diathesis or any hemorrhagic conditions that canincrease the risk of an epidural or spinal hematoma formationand long-term neurologic deficit is a contraindication. Patientson therapeutic or prophylactic anticoagulation treatment canreceive intraspinal catheter treatment provided that antico-agulation is reversed prior to procedure. Similarly, patientswith significant thrombocytopenia can receive intraspinalcatheter treatment after adequate platelet transfusion. Patientswith other coagulation disorders (e.g., von Willebrand


disease, hemophilia) should be treated prior to procedure.Patients with known epidural metastases have a higher risk ofspinal bleeding and hematoma if the catheter passes throughthe tumor mass. It is advisable to insert the catheter cephaladto the level of known or suspected spinal metastases.

Certain neurologic conditions were also consideredcontraindications for intraspinal pain control. Theseincluded unmotivated, noncompliant patients; preexistinguncontrolled or unstable CNS disorders (e.g., raisedintracranial pressure); spinal canal pathology (e.g., spinalstenosis) that may predispose the patient to developmentof neurologic symptoms as a result of long-term spinalinfusion and increased spinal canal pressure; and spinepathology (e.g., previous fusion or laminectomy) thatmay impair successful catheter placement. For the settingof active spinal cord compression, the working group feltcareful consideration is warranted; however, this condi-tion should not be considered a contraindication. Basedon case reports and anecdotal experience, caution mustbe exercised with these patients as an evolving neuro-logic deficit may in fact represent either medicationtoxicity or a catheter placement related intraspinal bleed.

Seven documents [23–25, 28, 30–32] recommended a trialof intraspinal analgesia using a temporary epidural or spinalcatheter to determine efficacy and appropriate dose range.One document [31] cautioned that limiting intraspinalanalgesia to patients whose pain has failed to be controlled

by other methods causes unnecessary waiting resulting inunacceptable suffering that leads to an even more complexpain management problem. Earlier consideration ofintraspinal analgesia may lead to more rapid pain controland less patient suffering. The Polyanalgesic ConsensusConference recommended a screening trial before proceedingwith pump implantation to evaluate patient response andpotential side effects but indicated that a trial was notnecessary for patients receiving external intraspinal systems[9].

Implementation issues for safe delivery of intraspinalanalgesia

Several issues related to the safe delivery of intraspinalanalgesia as it relates to equipment, aftercare, monitoring,hospital discharge, follow-up, practice team, professionaleducation and competency, patient and family education,and patient safety were identified (Table 4).

Equipment

Specific equipment requirements for delivering intraspinalanalgesia were included in six documents [9, 23, 24, 31, 33,35]. None of the documents contained evidence comparingdifferent types of delivery systems, but various options andthe technical considerations in their use were presented. It is

Table 5 Indications and contraindications for use of intraspinal analgesia for cancer pain

Category ON[23]

BPS[24]

CCNS[25]

SIGN[26]

Sing[27]

APS[28]

NCCN[29]

ASA[30]

Cal[31]

Corn[32]

Stearns[9]

Indications for use of intraspinal analgesia

Intractable pain control √ √ √ √ √ √ √ √ √ √ √Dose-limiting side effects √ √ √ √ √ √ √ √ √ √ √Appropriate equipment and expertise available √ √ √Expectation that intraspinal analgesia would improvepatient’s quality of life

√ √ √

Life expectancy of weeks or months √Informed consent √ √ √Contraindications

Bleeding diathesis √ √ √ √ √Active or local infection √ √ √ √Psychosocial distress √ √Unstable angina, severe left ventricular dysfunction,critical aortic stenosis, prohibitive spinalabnormality, and previous spinal fusion

√

Unfit for surgery or anesthesia √Disseminated disease contraindicated for regionaltherapy

√ √

Unstable vital signs, hematologic abnormalities,wound infections, emaciation, and spinal lesions

√

Requirement for large volume infusions √Presence of another implanted device √


recommended that the choice of delivery system (e.g.,epidural vs. intrathcal or implanted vs. external) be basedon the HCP expertise at each institution factoring in anyrelevant practical considerations. Guidance covers generalequipment requirements, as well as details concerningdifferent kinds of intraspinal delivery systems: external,partially external, and fully implanted. Two issues concerningequipment that were considered particularly important in theadministration of intraspinal analgesia were the use ofpreservative-free medication and the appropriate cleansingof the catheter site. The working group agrees with the INS[35] recommendations that straight alcohol or acetone shouldnever be used for site preparation or cleansing but supportsthe use of staining disinfectants that contain alcohol becauseseveral studies comparing proviodine–iodine, chlorhexidine,and chlorhexidine with alcohol have found reduced epiduralinfection rates using chlorhexidine with alcohol as the skindisinfectant [41–45].

Aftercare

Four documents provided advice concerning care to begiven immediately after intraspinal analgesia insertion[23, 24, 31, 33]. Aftercare issues included the applicationof generic postoperative principles delivered by nursestrained in intraspinal drug delivery techniques, existence ofappropriate protocols, availability of medical support andequipment, and protection of patients from any infectiousenvironment (such as not being cared for on a ward wherethere are methicillin-resistant staphylococcus aureuspatients). Immediate concerns after the procedure alsoincluded monitoring patients’ vital signs and pain levels;assessing the insertion site for such complications asleakage, bleeding, and infection; checking and changingthe dressing; and assessing the proper functioning of theequipment.

Monitoring

Nine documents [9, 23–25, 28, 31–33, 35] providedguidance regarding monitoring of patients receiving intra-spinal pain management. The careful assessment of paincontrol and monitoring for complications and side effectswere emphasized. Many monitoring issues surroundingintraspinal patients pertain to the management of cancer-related pain in general. Tools and instruments for monitoringpain and detecting complications and adverse effects werefound in three documents [25, 31, 33].

The inspection of intraspinal drug delivery devices wasalso emphasized as an important aspect of monitoring. Sevendocuments [9, 23, 24, 28, 31, 32, 35] warned of problemsthat could be encountered, including catheter malpositionor migration, catheter disconnection, catheter occlusion

(dislodgement, kinking, and erosion), and device failure ormalfunction.

Hospital discharge

Four documents [24, 30–32] provided advice regarding thehospital discharge of intraspinal patients. These documentsstressed the importance of having a discharge plan in placebefore the initiation of the intraspinal analgesia procedure.The plans should ensure that properly trained professionalsand an adequately equipped care setting are ready to receivethe patient. In addition, the plans should include details aboutordering equipment, drugs, and refills; the contact details ofhealth professionals who will be involved in the patient’s care;and provision for the education of the patients, families, andhome-care staff.

Follow-up

Six documents [23, 24, 31–33, 35] provided advice for thefollow-up of patients with intraspinal pain medication in thecommunity. The interprofessional nature of follow-up carewas emphasized, as was the importance of establishingprotocols, so that all healthcare personnel are aware of theprocedures to be followed in the intraspinal care of a patient,particularly in dealing with complications. Importantelements for patient follow-up included ensuring theavailability of pain management physicians outside ofworking hours to resolve problems that cannot be managedby nursing staff or local on-call medical staff. Suchcomplications included increased sedation score, respiratorydepression, signs of infection, persistent pain, and equipmentmalfunction. Provision should also be in place shouldpatients require referral to hospital or hospice if their needscan no longer be met in the community. Similarly, if apatient moves away from the center where intraspinalanalgesia was initiated, a plan should be in place to allowfor the smooth transfer of care.

Practice team: interprofessional roles

The roles of healthcare professionals involved in cancerpain management emphasized the interprofessional natureof intraspinal care, the need for accurate communicationamong all persons involved, and the importance of workingas a team that includes all healthcare professionals andpatients and their families [23, 24, 30, 31, 34, 35].Responsibilities should be in keeping with quality standardsof relevant professional college or association certification.Participants in intraspinal care may include the referringhealthcare professional (palliative care physician, advancedpractice/specialist nurse, nurse practitioner, oncologist, orprimary physician), interventional pain physician, regis-


tered nurse (palliative care unit, community, and inpatient),pharmacist (inpatient and community), and patient andfamily members.

Professional education and competencies

Six documents [23, 24, 26, 31, 34, 35] provided advice withrespect to the necessary training and competencies forhealthcare professionals involved in intraspinal care. Specificeducation training is required for healthcare professionalscaring for patients receiving intraspinal analgesia. Forexample, the BPS [24] recommended a mentoring systemamong healthcare professionals and the establishment of anetwork of trained clinicians in order to provide coverage.Practitioners who do the implanting must have appropriatetraining and a caseload sufficient to maintain expertise. Atthis time, the ideal caseload is not known.

Nursing care of intraspinal patients is an advanced nursingcompetency requiring certification. Educational activities fornurses should cover the operation of intraspinal drug deliverysystems, insertion and access procedures, care andmaintenance(assessment of site, dressing change, and flushing andaspiration procedures), potential complications and interven-tions, and patient and family education. Routine continuingeducation opportunities to maintain knowledge and clinicalcompetency are recommended [23, 31, 34, 35].

Patient and family education

Eight documents [23–25, 28, 30–33] included advice onpatient and family education. The use of intraspinal analgesiain the community setting requires that patients and familymembers are frequently educated about and highly motivatedand competent in the use of the drug delivery system.Documentation of what has been taught should be part of thepatient record so that all healthcare providers can reinforcethe teaching points. Several guidelines stressed that patientsmust understand the importance of communicating worseningor unrelieved pain and reporting adverse effects. Fourdocuments [23, 24, 31, 32] contained patient-specificinformation on intraspinal drug delivery systems.

Patient safety

Six documents [23, 24, 31–33, 35] provided advice onpatient safety. Two safety measures were emphasized acrossall documents: (1) The maintenance of strict asepticconditions in all aspects of intraspinal analgesia administration,including wearing a mask and gloves when accessing anintraspinal device and (2) the clear labeling of all equipment.All intraspinal drug delivery equipment must be appropriatelylabeled (yellow for epidural and blue for intrathecal) as to itspurpose and the date and time of initiation of infusion.

The use of intraspinal analgesia can confer increasedmobility for patients, thus, raising special safety concerns thatpatients should be aware of such as avoiding scanners inairports and shops, saunas and sunbeds, and sports oractivities that may cause injury or dislodgement of the pump.Some intraspinal drug delivery systems are at risk forsignificant damage and malfunction from magnetic resonanceimaging scanners and advice on how to proceed will berequired from individual scanning departments and thespecific drug delivery system manufacturers. It was advisedthat patients have a MedicAlert emblem that alerts healthcareprofessionals to the presence of an intraspinal device inemergency situations or carry an identification card indicatingthe make and model of any intraspinal device, the drugswithin the pump, and the current or last prescribed dose.

Discussion

In general, moderate to severe cancer-related pain tends tobe poorly managed. Common barriers to adequate paincontrol include the belief that patients are not good judgesof the severity of their pain; the inability to distinguishbetween tolerance, physical dependence, and addiction; fearof opioid side effects or addiction; and lack of knowledgeabout the multiple approaches to managing pain [28].Because few cancer patients will require intraspinalanalgesia, such barriers are magnified with respect to theuse of intraspinal analgesia. According to Stearns [9], ageneral lack of understanding exists about the relevantindications for intraspinal analgesia and the types of patientswho would benefit from it. Furthermore, at centers whereexpertise in intraspinal analgesia is limited, oncologists areunlikely to be familiar with its use and unlikely to referpatients for this type of pain control.

The main advantages of intraspinal analgesia for cancerpain are the delivery of adequate pain control and fewerside effects than with conventional analgesia routes.Disadvantages of intraspinal analgesia include the technicallydemanding insertion procedure and close patient follow-uprequired by skilled healthcare personnel.

Because intraspinal techniques are an infrequently usedintervention for treating cancer pain, high-quality evidenceevaluating their effectiveness and the provision of practicalguidance for their delivery are sparse. Some of the mostmethodologically rigorous documents identified had verylittle information specifically on intraspinal techniques, whilerelevant guidance was more often obtained from internal usecare pathways or nonevidence-based procedure manuals. Theevidence for this organizational guideline was based on twosystematic reviews, one consensus conferences, 12 RCTs, and13 advice documents (practice guidelines, standards, and localpolicies and procedures). The clinical evidence confirmed the


effectiveness of intraspinal analgesia in carefully selectedpatients with intractable cancer pain. Among the RCTs, somelimitations with respect to the small numbers of patients bothentered and followed-up were apparent. With this in mind anddespite the proportionally small number of patients withcancer pain for whom intraspinal analgesia is the appropriateintervention, this review confirms well-designed randomizedtrials intending to clarify clinical efficacy issues can reachstatistical significance. Adequate accrual, however, willrequire both a firm commitment from investigators andensuring adequate funding.

The most clinically relevant studies achieving statisticalsignificance involved the use of nonopioids (i.e., ziconotideand clonidine). This suggests “opioid refractory pain”should serve as a focus for future investigations and giventhe geographic variation in availability for these particularmedications, their use in the setting of intraspinal analgesiacould serve as a focus for advocacy.

Advice pertaining to organizational guidance wasobtained from practice guidelines, standards, and localpolicy and procedures manuals. With these documents plusthe clinical expertise of the working group, we were able tomake recommendations regarding specific indications foruse of intraspinal analgesia, practice setting requirementsfor caring for a cancer patient receiving intraspinalanalgesia, the roles and responsibilities of the healthcareprofessionals involved in providing intraspinal care, thetraining and education required for healthcare professionalsand patients and families, and the elements of patient safety.

Conclusions

As part of a comprehensive cancer pain management strategy,intraspinal catheter insertion should be a consideration forappropriately selected patients. For institutions that have theresources available to safely insert and subsequently manageintraspinal infusions, it is essential that the institution developthe necessary policies, procedures, and competencies tosupport the healthcare professionals involved in the care ofthese patients.

Conflict of interest The authors declared no actual or potentialconflicts of interest in relation to this report.

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Intraspinal techniques for pain management in cancer patients: a systematic review

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