Scandinavian Journal of Pain 14 (2017) 39–43

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Scandinavian Journal of Pain

journal homepage: www.ScandinavianJournalPain.com

Observational study

Multimodal intrathecal analgesia in refractory cancer pain

Thierry C. Mastenbroek a , Bianca J. Kramp-Hendriks b , Jan Willem Kallewaard b ,
Johanna M. Vonk b,∗
a
Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, 6525 GA
Nijmegen, The Netherlands
b
Department of Anaesthesiology and Pain Management, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The Netherlands

h i g h l i g h t s

• 10% of cancer pain patients are not effectively treated according to WHO-guidelines.
• Multimodal intrathecal analgesia is effective in treating refractory cancer pain.
• No severe adverse events occurred in our study with multimodal intrathecal therapy.

a r t i c l e i n f o a b s t r a c t

Article history: Background and aims: Cancer pain treatment has improved over the last decades. The majority of
Received 9 August 2016 this population can be treated effectively with analgesics following the Guidelines of the original
Received in revised form World Health Organisation (WHO). Unfortunately 10–15% of these patients still suffer from severe
30 September 2016
and refractory cancer pain, especially in the terminal phases of disease and require additional pain
Accepted 3 October 2016
management modalities. Therefore, end-stage clinical interventions are particularly needed to minimize
the perception of pain. With intrathecal therapy (ITT), drugs are delivered close to their site of action
Keywords:
in the central nervous system avoiding first-pass metabolism and blood–brain barrier. It may improve
Intractable cancer pain
Neoplasms
analgesia with a smaller dose and possibly achieve a reduction in systemic or cerebral side effects
Intrathecal therapy compared to oral supplied medication alone. Multimodal analgesia enables further dose reduction with
Multimodal analgesia improved analgesia and fewer side effects.
Clonidine Methods: In this retrospective research we investigated the effectiveness and side-effect profile of
intrathecal morphine, bupivacaine and clonidine. Patients were followed until death occurred. Pain scores
and side effects were recorded before initiating ITT (T0), just after initiating ITT (T1), at hospital discharge
(T2), in the ambulant setting (T3) and the last obtained scores before death occurred (T4).
Results: Nine patients were included who suffered from severe and refractory cancer pain, not reacting to
conventional pain management or had intolerable side effects. Primary tumour location was pancreatic
(4), urothelial (3) and prostate (2). Primary pain was considered neuropathic or mixed neuropathic-
nociceptive. The treatment team consisted of an anaesthetist, specialized nurse in coordination with
primary physician, treating oncologist and specialized home care.
All patients were free of pain after initiation of the intrathecal therapy. The average follow-up period
was 11 weeks in which there was a slight increase in NRS-score. In the last days before death occurred,
half the patients were still free of pain. There were no problems during insertion of the catheter, device
malfunction or infection. No severe adverse events defined as hypotension requiring inotropes, respi-
ratory depression or neurological deficits were observed. Three patients experienced mild hypotension
which gradually decreased after clonidine dose adjustment. Lower extremity weakness occurred in three
patients as well. After bupivacaine dose adjustment the weakness disappeared in two patients and in one
patient the lower extremity weakness persisted as a result of conus compression by tumour.
Conclusion and implications: Multimodal IT treatment with morphine, bupivacaine and clonidine is
effective and safe for treating refractory cancer pain in the terminal phase of disease.
The study offers an important contribution to literature where there is still lack of convincing evidence
about the benefits and harms of this type of pain management in patients with otherwise refractory
cancer pain.
© 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

∗ Corresponding author.
E-mail addresses: Thierry.Mastenbroek@radboudumc.nl (T.C. Mastenbroek), BKramp@rijnstate.nl (B.J. Kramp-Hendriks), JKallewaard@rijstate.nl (J.W. Kallewaard),
hvonk@rijnstate.nl (J.M. Vonk).
http://dx.doi.org/10.1016/j.sjpain.2016.10.002
1877-8860/© 2016 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
40 T.C. Mastenbroek et al. / Scandinavian Journal of Pain 14 (2017) 39–43
1. Introduction
Cancer pain impacts all aspects of patients well-being. Although
cancer pain treatment has been improved, it is often inadequately
treated, despite it being a major fear and concern of many patients
[1]. Failure to respond to treatment not only impacts cancer pain
but is also associated with depression, morbid mood and reduced
quality of life [2]. Management of pain related complications with
additional hospital admissions are of major health and economic
concern in this growing population.
The prevalence of cancer pain has been reported to be as high
as 60–70%, particularly in the terminal phases of the disease. After
cure, chronic pain may still be around 21–46% [3]. This high preva-
lence in combination with an increasing cancer survival rate makes
this a growing population that requires extensive pain modulation.
The majority of this population (85–90%) can be treated effec-
tively with analgesics following the Guidelines of the original World
Health Organisation (WHO). Unfortunately 10–15% of the patients
suffer from severe and refractory cancer pain and require additional
pain management modalities [4].
In 1973, specific opioid receptors were discovered in the subs-
tantia gelatinosa of the spinal cord [5], followed by the first
intrathecal injection of morphine [6]. Spinal opioids exert their
analgesic effect by reducing nociceptive transmission in the dorsal
horn of the spinal cord. Since the late 1980s, IT analgesic therapy
has become an alternative for oral and parenteral pain treatment
with opioids.
The implantation of an IT drug delivery system offers many
advantages by improving analgesia with reduction of systemic or
cerebral side effects compared to oral or parenteral opioids [7].
Because IT opioids are still associated with side effects like respi-
ratory depression, opioid dose escalation, granuloma formation,
pruritus and myoclonus, a wide variety of drugs are currently
being used either single, or in a combination to optimize the ther-
apeutic benefit. Non-opioids like bupivacaine [8,9], clonidine [10],
ziconotide [11,12], ketamine [13], baclofen and ketorolac have been
used neuraxial to minimize these opioid associated side effects.
Multimodal therapy in perioperative analgesia has become
common practice. Combinations of different analgesics, acting at
various points in the neurochemical pathway results in addi-
tive analgesia. This synergistic effect allows a reduction in the
individual drug dose and thus lower the incidence of medication-
related adverse effects. Unfortunately, multimodal IT analgesia for
intractable cancer pain is not common practice. Tumber described
a case in which severe cancer pain was controlled by IT infusion of
morphine, bupivacaine and clonidine but no large case series are
published [14].
Single use of clonidine, an ␣2-adrenergic agonist, has shown to
provide effective reduction in intractable cancer pain, particular in
neuropathic type of pain [10]. The use of clonidine is limited as well,
because of potentially side effects like hypotension, bradycardia
and sedation.
In this retrospective research, the trialling combination of mor-
phine, bupivacaine and clonidine was investigated in a group of
terminal patients with refractory cancer pain, in order to gain a
preliminary insight in effectiveness of this regime of multimodal
analgesia in attenuating cancer pain and side effect profile.
2. Methods
2.1. Patients and procedure
In this retrospective research, 9 patients were given an IT-
catheter in the period between August 2012 and August 2013.
All patients suffered from severe and refractory cancer pain, not
reacting to conventional pain management (WHO) or had intolera-
ble side effects. Numeric rating scale (NRS)-score had to be at least
4 out of 10 and patients were required to be over the age of 18.
Exclusion criteria were patient refusal, systemic infection, infec-
tion at the site of catheter placement and an existing uncorrectable
coagulopathy.
All patients received an externalized pump system with patient-
controlled intrathecal analgesia (PCIA) function (PCA-Legacy CADD,
Smiths Medical, London). A full surgical scrub with antiseptic
cleanser was performed. Access was obtained in the lumbar region
under local anaesthesia before placement of the IT-catheter. The
IT-catheter was tunnelled subcutaneously to the anterior flank
hereafter it was connected to the pump system. All procedures were
performed under strict sterile conditions in the operating room of
the Rijnstate hospital in Arnhem.
Supplied medication consisted of a combination of morphine,
bupivacaine and clonidine, converted to the analgesic requirement
before placement of the IT-catheter (T1). Starting dose was based
on previous experience in our centrum. For morphine the start-
ing dose ranged between 2.4 and 4.8 mg/day. Patients using more
than 240 mg morphine a day (or equivalent), the IT starting dose of
morphine was 4.8 mg/day. In case the patient used less than 240 mg
morphine, the IT starting dose was 2.4 mg/day.
Starting dose of bupivacaine ranged between 7.2 and
16.2 mg/day and clonidine maximum clonidine starting dose was
350 mcg/day but most patients start with a dose between 72 and
144 mcg/day.
During hospital stay further dose adjustment took place (T2) to
optimize the analgesic effect and limiting the side effects. Besides
continuous IT analgesia, patients were able to use a PCIA function
to control breakthrough pain. A bolus was equivalent to what the
patient received continuously in 1 h. For the first 24 h after place-
ment, standard lockout period was 4 h. After this, the lockout period
was 1 h. In case the PCIA-function was used more than two times a
day, dose adjustment took place.
After initiation of the intrathecal therapy (ITT), anti-
neuropathic medication were stopped directly. Oral opioids
were halved every day and stopped about 2–3 days after initiating
the ITT.
After hospital discharge patients remained under strict control
by specialized nurses. Further dose adjustment (T3) is regulated by
these nurses following a detailed doctors order. When the max-
imum IT-dose was reached according to the execution request,
consultation with the pain department of the Rijnstate hospital
took place. Patients were followed until they passed away. The last
control and NRS-score taken by the specialized nurses was designed
as T4.
NRS-scores and adverse events were recorded after placement
of IT catheter (T1), at hospital discharge (T2), after hospital dis-
charge (T3) and at the last NRS-score before dying (T4).
Opioid dose escalation index (OEI) was used to index the mean
increase of the starting opioid dosage during ITT, expressed as a
percentage. The OEI was calculated as the difference between the
maximal morphine dose (T4) and starting dose after dose adjust-
ment (T2) using the following formula: [(Morphine T4 − morphine
T2)/morphine T2]/days × 100. These indices have already been val-
idated to monitor opioid requirement [15,16]. Increasing OEI with
increasing NRS-score >4 indicates dose escalation.
2.2. Ethical aspects
The study protocol, judged by the local ethics committee
does not require ethical review and approval. The patients were
informed about the procedure and could refuse intrathecal pain
relief.
 T.C. Mastenbroek et al. / Scandinavian Journal of Pain 14 (2017) 39–43 41

3. Results Table 2
Results.

Nine patients had intrathecal cancer-pain treatment during Mean, standard deviation Range of values
the year from August 2012 to August 2013. The patients were Mean duration IT-catheter 11 weeks 2–29 weeks
between the 48 and 72 years of age with a male–female ratio T1 IT-analgetics
of 5:4. Primary tumour location was pancreatic (4), urothelial (3) Morphine (mg/d) 4.1 ± 1.3 1.4–4.8
and prostate (2). Primary pain was considered neuropathic (n = 2) Bupivacaine (mg/d) 11.4 ± 3.8 9.0–16.2
Clonidine (mcg/d) 142.4 ± 98.7 57.6–345.6
or mixed neuropathic-nociceptive (n = 7) and in 60% of the study
NRS T1 (N = 9) 2.4 1–3
population the cancer was disseminated. Included patients with Hospital stay (days) 6 days 2–17 days
pancreatic cancer were anatomically unsuitable for a plexus coelia- T2 IT-analgetics 6.7 ± 5.9 1.9–15.4
cus or nervus splanchnicus blockade as primary invasive analgesic Morphine (mg/d) 9.5 ± 3.6 6.0–18.0
Bupivacaine (mg/d) 152.0 ± 117.2 43.2–345.6
procedure. Of these patients, one had a para-aortic tumour mass
Clonidine (mcg/d)
and the other patients had locally advanced tumour growth in the NRS T2 (N = 9) 2.3 1–3
truncus coeliacus. T3 IT-analgetics
The average NRS score before initiating ITT was 8.2 with a NRS Morphine (mg/d) 10.3 ± 7.8 0.96–23.0
score between 6 and 9. The mean daily morphine use was 358 mg Bupivacaine (mg/d) 9.4 ± 2.9 6.0–14.4
Clonidine (mcg/d) 196.8 ± 135 57.6–460.8
plus non-opioids before ITT. Four patients used 1 non-opioid and 3
NRS T3 (N = 7) 3.0 1–6
other patients used a combination of 2 non-opioids besides the oral T4 IT-analgetics
opioids. Inadequate pain control was the main reason for initiation Morphine (mg/d) 19.6 ± 10.2 1.0–50.4
of ITT. Mean baseline NRS-score was 8.2. Demographic information Bupivacaine (mg/d) 13.7 ± 5.8 6.0–21.6
Clonidine (mcg/d) 287.4 ± 182.5 57.6–691.2
of the included patients is shown in Table 1.
NRS T4 (N = 8) 4.1a 1–7
After initiating ITT, the average follow-up period was 11 weeks Opioid escalation index (OEI) 4.3% 0–9.1%
(2–29 weeks) during which 3 patients died within a month. a
One patient had a NRS of 7.
All patients included in this study received a combination of
intrathecal morphine, bupivacaine and clonidine with a daily
basal morphine dose range of 1.4–4.8 mg/day (mean 4.1 mg/d).
extremity weakness, the bupivacaine dose was adjusted in two
Daily received bupivacaine ranged from 9 to 16.2 mg/day (mean
patients hereafter the sensation of weakness gradually decreased.
11.4 mg/d) and clonidine ranged from 57.6 to 345.6 mcg/day (mean
Nausea and urinary retention occurred in 2 patients. Both patients
142.4 mcg/d).
with urinary retention received a urinary catheter for 4 days. They
After initiation of ITT, all patients were free of pain with a
were discharged from hospital without a catheter a demeure. There
mean NRS-score of 2.4 (T1) and this remained as such until hospi-
were no signs of meningitis, neurologic sequela, sedation, pruritus,
tal discharge (NRS 2.3). Daily dose of IT medication was gradually
infection or catheter dislocation (Table 3).
increased (Table 2). Patients were admitted in hospital for a mean of
After hospital discharge, there was a gradual increase in NRS-
6 days (2–14 days). During this time, medication adjustment took
score, with an average rating score of 3.0. Six patients were still
place in accordance with patients NRS-scores and side effects. No
free of pain, 1 patient had a NRS-score of 6 (Fig. 1). One patient was
severe adverse events, defined as hypotension requiring inotropes,
discharged to a hospice facility, specialized in terminal health care,
respiratory depression or neurological deficits were observed.
were no pain scores were taken and the NRS-score of one patient
Three patients experienced mild, clinical insignificant hypoten-
was not recorded. All patients were hemodynamically normal and
sion which resolved after clonidine dose adjustment. Mild lower
stable with no signs of hypotension. Of the 3 patients who experi-
extremity weakness occurred in three patients. All patients were
enced mild lower extremity weakness after initiation of ITT, only
still able to walk after initiating the ITT. Because of the of this lower
one patient still experienced mild lower extremity weakness as a
result of conus compression by tumour.
Table 1 Before dying the mean NRS-score was increased to 4.1 by which
Demographic patient characteristics. 5 patients were still free of pain, 2 patients reported NRS-score of
Age, years (mean, standard deviation) 59 ± 7.5
6 and 1 patient reported a NRS-score of 7. The NRS score of one
Male gender 56% patient admitted in a hospice was not taken.
Type of cancer Opioid dose escalation with an increasing OEI and NRS-score
Pancreatic 44% >4 was seen in 2 patients. Both patients showed the opioid dose
Prostate 22%
escalation in the last days of the ITT, without any sign of catheter
Urothelial 33%
Type of pain
Neuropathic 22%
Nociceptive 0% Table 3
Mixed 78% Side effects/adverse events.
Side effects 56%
T1–T2 T3 T4
Drowsy 44%
Obstipation 11% Hypotension 20% (N = 2) 0% (N = 0) 0% (N = 0)
Hallucinations 11% - Postural 10% (N = 1) 0% (N = 0) 0% (N = 0)
Pruritis 11% - Serious 0% (N = 0) 0% (N = 0) 0% (N = 0)
Morphine oral equivalent dose (mg/d) 358 Respiratory depression 0% (N = 0) 0% (N = 0) 0% (N = 0)
Baseline medication usea Motor blockade 33% (N = 3) 11% (N = 1) 0% (N = 0)
Opioids alone 22% Urinary retention 22% (N = 2) 0% (N = 0) 0% (N = 0)
Amitriptyline 33% Sedation/Somnolence 0% (N = 0) 0% (N = 0) 0% (N = 0)
Dexamethasone 22% Headache 11% (N = 1) 11% (N = 1) 11% (N = 1)
Gabapentin 33% Nausea 22% (N = 2) 11% (N = 1) 0% (N = 0)
Pregabalin 11% Dry mouth 0% (N = 0) 0% (N = 0) 0% (N = 0)
Baseline NRS pain score (N = 7) 8.2 Neurological deficit 0% (N = 0) 0% (N = 0) 0% (N = 0)
a Myoclonus 0% (N = 0) 0% (N = 0) 22% (N = 2)
3 patients use combination of 2 non-opioids in combination with an opioid.
Hyperalgesia 0% (N = 0) 0% (N = 0) 11% (N = 1)
4 patients use 1 non-opioid in combination with an opioid.
42 T.C. Mastenbroek et al. / Scandinavian Journal of Pain 14 (2017) 39–43
Fig. 1. NRS scores off all 9 patients during different time intervals. T0: NRS score before initiating ITT. T1: NRS score just after initiating ITT. T2: NRS score at hospital discharge.
T3 mean NRS score in the ambulant setting. T4: the last NRS score taken before death occurred.
dislocation. All other patients showed reaction by increasing the IT
opioid dosing without showing side effects.
Further observations during the multimodal IT-therapy showed
reduced psychological distress in all patients. With reducing NRS-
scores, patients were finally able to process the course of disease.
By processing the disease, most patients also start worrying (N = 8),
had concerns about family (N = 3), or had problems dealing with the
cancer (N = 1).
4. Discussion
In this retrospective case series, multimodal IT analgesia con-
sisting of morphine, bupivacaine and clonidine show a remarkable
reduction of pain in terminal cancer patients with otherwise
intractable cancer pain. In accordance with literature, most of our
included patients experience neuropathic or mixed neuropathic-
nociceptive cancer pain [7]. As a result, systemic or neuraxial
delivered opioids fail to reduce pain, despite large doses with
concomitant side effects like respiratory depression, opioid dose
escalation, granuloma formation, pruritus or myoclonus.
Morphine combined with clonidine administered epidurally
seemed to be particularly effective in intractable neuropathic can-
cer pain, although hypotension was reported as substantial side
effect [10]. Adding bupivacaine to morphine improved analgesia
and reduced side effects compared to morphine alone [8]. Bupiva-
caine blocks nerve impulses and provides a degree of nociceptive,
sensory and motor nerve block. Intrathecal starting dosage below
the 30 mg/day are not associated with bupivacaine induced side
effects [15]. Evidence suggest that bupivacaine acts synergisti-
cally with morphine, reducing the need for increasing IT morphine
dose [9,15]. Also in chronic noncancer pain patients, adding
IT bupivacaine to morphine attenuates opioid dose escalation
[16].
With ITT, drugs are delivered close to their site of action in
the central nervous system avoiding first-pass metabolism and
blood–brain barrier. It may improve analgesia with a smaller dose
and possibly achieve a reduction in systemic or cerebral side effects
compared to oral or parenteral opioids alone. By delivering multiple
medication, acting at various points in the neurochemical path-
way, multimodal analgesia can provide additive analgesia and can
potentially reduce side effects as well.
Intrathecal therapy is used for many years. Nevertheless, there
is still lack of quality evidence regarding the benefits and harms
Table 4
Recommended multimodal IT starting dose.
Medication Start dosing IT
Morphine 2.4–4.8 mg/d
Bupivacaine 7.2–16.2 mg/d
Clonidine 72–144 mcg/d
of this technique for intractable cancer pain. Small sample sizes,
heterogeneous characteristics in medication, dosages and route
of neuraxial administration are among limiting factors [17]. A
GRADE (Grades of Recommendation, Assessment, Development
and Evaluation)-type meta-analysis showed a weak strength of rec-
ommendation for administration of neuraxial analgesics based on
four included randomized controlled trials [18,19]. Unfortunately
the studies were small and with a high degree of heterogenicity.
Another systemic review recommended intraspinal techniques for
pain management in cancer patients, although they did formalize
the development of their recommendation [20].
The placement of an intrathecal catheter requires expertise.
Possible complications are related to insertion, device malfunc-
tion and medication related complications [17]. Ways to reduce
common catheter related complications are outlined by Follett and
colleagues [21]. They found reduction of complications by gain-
ing dural excess in mid-to-upper lumbar region, precise catheter
anchoring and tunnelling techniques. Systemic antibiotic prophy-
laxis, attention to pump pocket location and surgical wound closure
were among other factors reducing complications [21].
In our population an ITT combination of morphine, bupivacaine
and clonidine resulted in a remarkable reduction of pain. No severe
adverse events did occur. Clinically insignificant hypotension and
mild lower extremity weakness occurred at start of ITT. After dose
adjustment these side effects were diminished. Two patients expe-
rienced an opioid dose escalation in the last days of ITT, not an
uncommon side effect before dying. Recommendation of starting
doses is shown in Table 4. This retrospective case study gives a pre-
liminary insight in the effectiveness of multimodal IT analgesia.
Further research by means of large prospective conducted ran-
domized controlled trials are needed to verify these conclusions.
Because of the promising results of this study we are now perform-
ing a prospective cohort study to assess the effectiveness of this
multimodal IT analgesia regime as well as the impact of multimodal
ITT on psychological aspects.
 T.C. Mastenbroek et al. / Scandinavian Journal of Pain 14 (2017) 39–43
5. Conclusion
Multimodal intrathecal medication consisting of morphine,
bupivacaine and clonidine is effective in treating refractory can-
cer pain in the terminal phase of disease and has an acceptable
side effect profile. Consequently, synergistic analgesia is produced
in which the IT dosage can be reduced compared to monotherapy
and thereby reducing potential side effects.
Ethical issues
The ‘centrale commisie mensgebonden onderzoek’ (CCMO)
Arnhem-Nijmegen approved this retrospective chart review case
series. The study is registered under number: 2016-2864.
Conflict of interest
The authors report no conflict of interest concerning the mate-
rial or methods used in this study. There are no financial interests
to disclose.
References
[1] Cleeland C. Research in cancer pain: what we know and what we need to know.
Cancer 1991;67(Suppl.):823–7.
[2] Ferrel B. The cost of comfort: economics of pain management in oncology. Oncol
Econ 2000;1:56–61.
[3] van den Breuken-van everdingen MH, de Rijke JM, Kessels AG, Schouten HC,
van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic
review of the past 40 years. Ann Oncol 2007;18:1437–49.
[4] Sloan PA, Melzack R. Long-term patterns of morphine dosage and pain intensity
among cancer patients. Hosp J 1999;14:135–47.
[5] Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science
1973;179:1011–4.
[6] Wang JK, Nauss LA, Thosam JE. Pain relief by intrathecally applied morphine in
man. Anesthesiology 1979;50:149–51.
[7] Smith T, Staats S, Deer T, Stearns L, Rauck R, Bootz-Marx R, Bucher E, Catala E,
Bryce D, Coyne P, Pool G. Randomized clinical trial of an implantable drug deliv-
ery system compared with comprehensive medical management for refractory
43
cancer pain: impact on pain, drug related toxicity, and survival. J Clin Oncol
2002;20:4040–9.
[8] DuPen S, Kharash E, Williams A, Peterson D, Sloan D, Krembs A. Chronic epidural
bupivacaine-opioid infusion in intractable cancer pain. Pain 1992:293–300.
[9] van Dongen RT, Crul BJ, van Egmond J. Intrathecal coadministration of bupi-
vacaine diminishes morphine dose progression during long-term intrathecal
infusion in cancer patients. Clin J Pain 1999;15:166–72.
[10] Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D. Epidural clonidine anal-
gesia for intractable cancer pain. The Epidural Clonidine Study Group. Pain
1995;61:391–9.
[11] Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MX, Byas-Smith M.
Intrathecal ziconotide in the treatment of refractory cancer pain in patients
with cancer or AIDS: a randomized controlled trial. JAMA 2004;29:63–70.
[12] Ellis DJ, Dissanayake S, McGuire D, Charapata SG, Staats PS, Wallace MS. Con-
tinuous intrathecal infusion of ziconitide for treatment of chronic malignant
and non-malignant pain over 12 months: a prospective, open label study. Neu-
romodulation 2008;11:40–9.
[13] Yang CY, Wong CS, Chang JY, Ho ST. Intrathecal ketamine reduces morphine
requirements with terminal cancer pain. Can J Anesth 1996;43:379–83.
[14] Tumber P, Fitzgibbon D. The control of severe cancer pain by continuous
intrathecal infusion and patient controlled intrathecal analgesia with mor-
phine, bupivacaine and clonidine. Pain 1998:217–20.
[15] van Dongen RT, Crul BJ, de Bock M. Long-term intrathecal infusion of mor-
phine and morphine/bupivacaine mixtures in the treatment of cancer pain: a
retrospective analysis of 51 cases. Pain 1993:119–23.
[16] Veizi I, Hayek S, Narouze S, Pope J, Mekhail N. Combination of intrathecal opi-
oids with bupivacaine attenuates opioid dose escalation in chronic noncancer
pain patients. Pain Med 2011:1481–9.
[17] Smyth C, Ahmadzai N, Wentzell J, Pardoe A, Tse A, Nguyen T, Goddard Y, Nair
S, Poulin P, Skidmore B, Ansari M. Intrathecal analgesia for chronic refractory
pain: current and future prospects. Drugs 2015;75:1957–80.
[18] Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Har-
bour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N,
Mason N, Mason J, Middleton P, Mrukowicz J, OÇonnell D, Oxman AD, Phillips
B, Schunemann HJ, Edejer TT, Varonen H, Vist GE, Williams JW, Zaza S, GRADE
Working Group. Grading quality of evidence and strength of recommendations.
BMJ 2004;328:1490–4.
[19] Kurita G, Benthien K, Nordly M, Mercadante S, Klepstad P, Sjogren P. The
evidence of neuraxial administration of analgesics for cancer-related pain: a
systemic review. Acta Anaesthesiol Scand 2015;59:1103–5.
[20] Myers J, Chan V, Farvis V, Walker-Dilks C. Intraspinal techniques for pain
management in cancer patients: a systemic review. Support Care Cancer
2010;18:1370149.
[21] Follet KA, Burchiel K, Deer T, DuPen S, Prager J, Turner MS, Coffey RJ. Prevention
of intrathecal drug delivery catheter-related complications. Neuromodulation
2003;6:32–41.