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470 Kai On SUN, Henry Ka Fai TONG
the basis for the patient’s complaints. e work of
Racz and associates suggested that lysis of epidural
adhesions was of significant benefit to many
patients with refractory lumbar radiculopathy
[28]. e adhesion formed in the epidural space
of patients with chronic spinal pain syndrome after
surgery or perhaps as a result of inflammation, may
be responsible for pulling and tugging nerve roots
and the dural sac.
Epidural endoscopy is usually performed with
the patient in the prone position using the caudal
approach via the sacral hiatus. A guide-wire placed
through an epidural needle facilitates the insertion
of a flexible and manoeuverable sheath containing
separate channels for the endoscope itself and
for irrigation and injection of solutions. During
endoscopy, the epidural space can be visualised
only if it is distended by repeated injections of
saline flushing solutions. Rigorous control of the
total volume of irrigation solutions is essential to
prevent complications due to over-distension of
the lumbar epidural space, with resultant excessive
increase in intraspinal pressures. e volume limit
advocated by most clinicians is 100 ml. Cases of
macular haemorrhage and visual impairment
following the procedure have been reported.
Epidural endoscopy allows mechanical lysis of
the adhesion that entraps the corresponding
symptomatic root by applying gentle manipulation
of the fibrescope and injection of different
medications at the site of the pathological findings.
Injections of corticosteroids, hyaluronidase,
clonidine, hypertonic saline and opiates have been
described in the literature. e reason for using
this injection technique is the failure of the usual
method of epidural steroid injection to deliver the
drug to the pathological areas because of fibrous
scar tissue or adhesions. Epidural endoscopy offers
a sensible approach to treat a group of patients in
which other treatment options are more invasive
and require either a repeat surgical procedure or the
use of implantable devices for pain control. Spinal
cord stimulation will be discussed in Chapter 30.
Vertebroplasty and
Kyphoplasty
Osteoporotic compression fracture is a common
condition in the elderly. It is estimated that more
than one-quarter of women aged over 65 years will
develop a vertebral fracture due to osteoporosis.
Percutaneous vertebroplasty is a relatively
new procedure which involves injecting poly-
methylmethacrylate cement into the osteoportic
vertebral body fracture percutaneously. By stabilising
vertebral lesions, the injected cement produces
analgesia in these patients. It is an outpatient
procedure, performed under fluoroscopic or CT
guidance. Prophylactic antibiotics are administered
to the patient approximately 30 minutes before
the procedure. e patient is placed in the prone
position and after local anaesthesia, an 11G
bone marrow biopsy needle is directed using a
transpedicular approach into the vertebral body.
Both lateral and anteroposterior projections
provide necessary visualisation of the path of
the needle. After confirming needle placement
in the lateral fluoroscopic views and negative
intravascular contrast spread, the cement is injected
under continuous fluoroscopic guidance into the
collapsed segment. e alternative parapedicular
approach involves inserting the cannula between
the lateral margin of the pedicle of the thoracic
vertebrae and the ribs’ head [15]. Anteroposterior
images are checked regularly to monitor for lateral
leaks. Typically, the injection must be completed
in 6 to 8 minutes before the cement becomes
too viscous to allow reinsertion of the stylus. e
cement will set within 20 minutes and achieve
90% of its strength within an hour [25]. Pain
relief is expected to be noticed in 4 to 24 hours.
Potential complications include leakage of cement
into adjacent structures, with neural damage due
to mechanical compression, theoretical risk of
systemic embolism and thermal necrosis. is
procedure has caused fear that cement extravasation
could have devastating neurological consequences
from intrusion and that the high pressures used
to introduce the cement could potentially lead
to the bolus embolisation of cement through
the venous channels in the vertebral body to the
lungs. Additionally, vertebroplasty was felt to be
an inadequate means of fracture reduction. As the
result of these concerns, the kyphoplasty technique
was devised and was first performed in 1998.
Kyphoplasty is a safer procedure because it involves
the injection of cement with lower pressure.
Patients who undergo this procedure usually
receive general anaesthesia because elderly patients
do not tolerate the prolonged prone position
required. e procedure can be performed via the
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471
Interventional Procedures for Back and Neck Pain
transpedicular or peripedicular approach. A 1-cm
incision is made just lateral to both pedicles of the
vertebral body to be treated. A Jamshidi needle
is used to enter the superior lateral border of the
pedicle under fluoroscopic guidance. Frequent
anteroposterior and lateral fluoroscopic images
are used to confirm position. Once the Jamshidi
needle enters the vertebral body, the needle is
exchanged for an obturator followed by a working
cannula. A drill is then used to create a tract
into the vertebral body. e balloon catheter is
introduced into the fracture site and the process
is repeated on the contralateral side. Both balloon
tamps are then inflated until either the fracture
is reduced or it is felt unsafe to continue. e
balloons are then removed and the cavities are
filled with methylmethacrylate cement using a
hand plunger system. Intraoperative radiographs
are used to confirm containment of the cement in
the vertebral body [19].
It is important to note that e US Food and Drug
Administration warns that a type of bone cement
used to treat spinal fractures may cause serious side
effects, reports United Press International. (FDA
Issues Bone Cement Warning — November 7,
2002). According to the FDA alert, two procedures,
vertebroplasty and kyphoplasty, have been linked
to tissue damage and nerve root pain due to the
bone cement, called poly-methylmethacrylate,
leaking into the body. Without releasing numbers,
the agency also said it had received reports of blood
clots in the lungs, respiratory and cardiac failure,
and even death.
Conclusion
Chronic neck and low back pain can have a
significant impact on the daily activities of patients.
Symptoms may also result from more than one
pathology; for example, disc degeneration can lead
to facet joint syndrome due to altered biomechanics.
Importantly, psychosocial issues may further
perpetuate the pain, even if the interventional
pain treatment seems to be successful. erefore, a
holistic, multidisciplinary multimodal approach is
required in treating patients with chronic neck and
back pain, as these patients often have work-related
injuries.
References
1. Aronoff GM, Evans WO, Enders PL. A review of follow-up studies of multidisciplinary pain units. Pain 1983;16:1–
11.
2. Barnsley L, Lord SM, Wallis BJ, et al. e prevalence of chronic cervical zygapophyseal joint pain after whiplash. Spine
1995;20:20–6.
3. Benzon HT. Epidural steroids. In:Raj PP, ed. Pain Medicine: A Comprehensive Review. St. Louis: Mosby, 1996.
4. Berstein RM. Injection and surgical therapy in chronic pain. Clin J Pain 2001 Dec;17(4 Suppl):S94-104. 3.
Bogduk N. Lumbar facet syndrome. In Waldman SD eds Pain Management Volume 2, Elsevier 2007:Ch84.
5. Bogduk N. Back pain: Zygapophysial blocks and epidural steroids. In Cousins MJ, Bridenbaugh PO, eds. Neural
Blockade in Clinical Anaesthesia and Management of Pain, 2nd edn. Philadelphia: JB Lippincott, 1988:935–46.
6. Bogduk N. Clinical Anatomy of the Lumbar Spine, 3rd edn. New York: Churchill Livingstone,1997:33–41.
7. Borghouts JA, Koes BW, Vondeling H, et al. Cost-of-illness of neck pain in the Netherlands in 1996. Pain 1999;80:629–
36.
8. Cavanaugh JM, Ozaktay AC, Yamashita T, et al: Mechanisms of low back pain: A neurophysiologic and neuroanatomic
study. Clin Orthop 1997;335:166–80.
9. Cohen SP, Bajwa ZH, Kraemer JJ, et al. Factors predicting success and failure for cervical facet radiofrequency
denervation: A multi-center analysis. Reg Anesth Pain Med 2007;32(6):495–503.
10. Derby R, Bogduk N, Kine G. Precision percutaneous blocking procedures for localizing spinal pain. Part 2: e
lumbar neuroaxial compartment. Pain Digest 1993;3:175–88.
11. Derby R, Howard MW, Grant JN, et al. e ability of pressure controlled discography to predict surgical and
nonsurgical outcomes. Spine 1999;24:364.
12. Fraser RD, Osti OL, Vernon-Roberts B. Iatrogenic discitis: e role of intravenous antibiotics in prevention and
treatment. An experimental study. Spine 1989;14:1025.
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13. Guez M, Hildingsson C, Stegmayr B, et al. Chronic neck pain of traumatic and non-traumatic origin: A population-
based study. Acta Orthop Scand 2003;74:576–9.
14. Hasue M, Kikuchi S, Sakuyama Y, et al. Anatomic study of the interrelation between lumbosacral nerve roots and their
surrounding tissue. Spine 1983;8:50–8.
15. Hide IG, Gangi A. Percutaneous vertebroplasty: History, technique and current perspectives. Clin Radiol 2004;59:461–
7.
16. Kikuchi S, Hasue M, Nishiyama K. Anatomic and clinical studies of radicular symptoms. Spine 1984;9:23–30.
17. Kikuchi S, Sato K, Konno S, et al. Anatomic and radiographic study of dorsal root ganglia. Spine 1994;19:6–11.
18. Kurobane Y, Takahashi T, Tajima T, et al. Extraforaminal disc herniation. Spine 1984;11:260–8.
19. Lavelle WF, Cheney R. Recurrent fracture after vertebral kyphoplasty. Spine J 2006;6(5):488–93.
20. Lord SM, Barnsley L, Bogduk N. e utility of comparative local anaesthetic blocks versus placebo-controlled blocks
or the diagnosis of cervical zygapophyseal joint pain. Clin J Pain 1995;11:208.
21. Lord SM, Barnsley L, Wallis BJ, et al. Chronic zygapophyseal joint pain after whiplash: A placebo-controlled prevalence
study. Spine 1996;21:1737–44.
22. Manchikanti L. Role of neuraxial steroids in interventional pain management. Pain Physician 2002;5:182.
23. Manchikanti L, Singh V, Rivera J, et al. Prevalence of cervical facet joint pain in chronic neck pain. Pain Physician
2002;5:243–9.
24. Maniadakis N, Gray A. e economic burden of back pain in the UK. Pain 2000;84:95–103.
25. Mathis JM, Barr JD, Belkoff SM, et al. Percutaneous vertebroplasty: A developing standard of care for vertebral
compression fractures. Am J Neuroradiol 2001;22(2):373–81.
26. Ng KFJ, Tsui SL, Chan WS. Prevalence of common chronic pain in Hong Kong adults. Clin J Pain 2002;18:275–
81.
27. Pawl RP. Headache, cervical spondylosis, and anterior cervical fusion. Surg Ann 1971;9:391.
28. Racz GB, Holubec JT. Lysis of adhesions in the epidural space. Techniques of Neurolysis. Boston: Kluwer Academic,
1989.
29. Ramamurthy S, Alanmanou E, Rogers JN. Decision Making in Pain Management, 2nd edn. San Antonio, Mosby
Elsevier,2006:302–3.
30. Schwarzer AC, Aprill CN, Derby R, et al. e false-positive rate of uncontrolled diagnostic blocks of the lumbar
zygapophyseal joints. Pain 1994;58:195.
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Introduction
e discovery of opioid receptors and potent opioid peptides
in the nervous system in the early 1970s provided the rationale
for the neuraxial delivery of opioid drugs for analgesia [49,
69]. is was demonstrated in experimental animals and
patients with chronic pain via intrathecal and epidural routes
[11, 99, 103]. e phrase “selective spinal analgesia” was
used to describe this specific analgesic state produced by a
small dose of morphine without significant sensorimotor or
haemodynamic side effects [21]. is heralded a new phase
in the management of pain which has expanded to the area
of acute postoperative, obstetrical, cancer and chronic non-
malignant pain.
e first catheter for intraspinal delivery was developed by Du
Pen. Later bolus injections of morphine were administered
via intrathecally placed catheters which were connected to
subcutaneous reservoirs. e concept of a totally implantable
drug pump was developed in 1969 at the University of
Pennsylvania with the first intrathecal pump to administer
morphine implanted in 1981 for the treatment of chronic
intractable pain [17, 97]. Neuraxial analgesia using a
combination of analgesics, chiefly morphine, clonidine and
bupivacaine, is fairly well established in the management
of chronic cancer and non-malignant pain states. Other
alternative neuraxial agents are also being introduced and
tested. e delivery systems, especially those of the intraspinal
catheter and the implantable pumps, are now very robust,
reliable and safe, and this contributes to the efficiency of
neuraxial analgesic therapy.
Denition
Neuraxial analgesia is defined as the epidural or intrathecal
administration of analgesics; these are usually opioids, but
Neuraxial Analgesia
29
Kok Eng KHOR
INTRODUCTION
DEFINITION
RATIONALE FOR NEURAXIAL
ANALGESIA IN CHRONIC PAIN
PATIENT SELECTION
MEDICATIONS
DELIVERY SYSTEMS FOR
NEURAXIAL ANALGESIA
EFFICACY
COST EFFECTIVENESS
RISKS AND COMPLICATIONS
SPECIAL SITUATIONS
PATIENT MANAGEMENT
CONCLUSION
REFERENCES
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474 Kok Eng KHOR
also include those from other classes such as
alpha-2 agonists, local anaesthetics and gamma
aminobutyric acid (GABA) agonists for the
management of severe pain.
Rationale for Neuraxial
Analgesia in Chronic Pain
e spinal cord is the major relay pathway for
nociceptive processing and modulation involving
multiple neurotransmitters, receptors and
intracellular mediators. By delivering the opioid
analgesics, such as morphine, directly to the site
of action, equivalent or better analgesia can be
achieved with a small fraction of the systemic dose
and a lower incidence of central nervous system
(CNS) and systemic side effects such as sedation
[74, 96].
Other “selective” agents such as clonidine and
subanaesthetic doses of bupivacaine can be used to
target other mechanisms of nociceptive processing
in the spinal cord. eir co-administration enhances
the analgesic effect of the opioid by an additive or
synergistic action. ey allow an overall reduction
in dosages of the neuraxial opioid and prevent
their escalation and thereby further reduce the
risk of side effects and development of tolerance.
In addition, incident pain and neuropathic pain
syndromes which are inadequately controlled by
conventional treatments and single-drug therapy
may be more responsive to the drug combinations
[25, 53, 65, 79, 96].
Patient Selection
Indications for neuraxial
analgesia
Neuraxial analgesic therapy is a costly and invasive
intervention with associated risks and complications.
It is considered, therefore, only when less invasive
pain treatments have been exhausted, such as
when severe pain continues to be experienced,
compromising the patient’s quality of life, or side
effects from systemic analgesics become intolerable.
Benefits of neuraxial therapy must clearly outweigh
the risks. It should also be considered as the-end-of-
the-line therapy after spinal cord stimulation and
corrective spinal decompressive and stabilisation
procedures [25, 53, 55]. e place of neuraxial
analgesia can be ranked in a pain treatment
continuum in the multidisciplinary management
of chronic pain (see Fig. 29.01).
Scrupulous patient selection through a
multidisciplinary assessment is mandatory for a
successful clinical outcome. Patients should have
a clear medical diagnosis which would account
for the presenting signs and symptoms and be
supported by documented evidence of nociceptive
source and/or neuropathy from investigations [62].
Patients with nociceptive or neuropathic pain
may be suitable candidates for neuraxial analgesia,
although the latter may require higher opioid doses
and addition of adjuvants [48, 70]. For cancer
pain, neuraxial analgesic administration may be
considered when patients are unable to control
their pain with conventional management using
the World Health Organization (WHO) opioid/
adjuvant analgesic ladder or in those intolerant to
high-dose opioids due to systemic side effects [53,
72].
Suitable patients for neuraxial analgesia are those
with at least a partially opioid responsive pain and
those with widely distributed areas of pain who
may not be suitable for nerve blocks. Nociceptive
and neuropathic pain syndromes which may be
amenable to neuraxial analgesic therapy are listed
in Table 29.01.
Psychological assessment [54,
55, 65, 73]
Unlike cancer pain with ongoing tissue destruction,
chronic non-malignant pain often occurs with no
tissue damage and psychological factors play an
important role in the pain presentation. When
considering implantable therapies, even before the
screening trial, a thorough psychological evaluation
with a clinical psychologist (or psychiatrist) is
essential. is is to rule out serious psychopathology
or a psychological aetiology for the pain and to
delineate the psychological issues associated with
chronic pain which may be an impediment to a
successful outcome. Should remedial behavioural
issues be identified, the patient should be willing
to undergo mental health treatment. Major
contraindications to implantation include:
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Neuraxial Analgesia 475
• Medical comorbidities such as coagulopathy,
infection, known allergies to pump or catheter
components and in the case of cancer pain,
tumour encroachment of the thecal sac and
patient emaciation.
• Major affective disorders such as depression
and anxiety.
• Psychopathologies such as psychosis,
malingering or personality disorders.
• Significant drug addiction issues.
• Excessive pain behaviours, disability and
somatisation which are inconsistent with
known pathology.
• Lack of resources for long-term management
such as lack of social support and access to
medical care.
Outcomes may be improved by ensuring realistic
expectation, having an understanding of the
Neuroablation
Neuraxial analgesia
Spinal cord stimulation
Strong opioid medication
Cognitive behavioural therapies
Injection and nerve block therapies
Adjuvant analgesics
Physical therapies
Exercise and simple analgesics
PAIN RELIEF
PAIN
Increasing complexity of pain
Figure 29.01 Pain treatment continuum in multidisciplinary pain management. The treatments are listed in
general order of increasing complexities of pain and often used in parallel and in combination (rather than
individually and sequentially)
Table 29.01 Pain syndromes which may respond to
neuraxial analgesia
Neuropathic pain Complex regional pain
syndromes
Arachnoiditis
Peripheral neuropathies
Phantom limb pain
Postherpetic neuralgia
Spinal cord injury
Plexopathy
Multiple sclerosis
Mixed neuropathic-
nociceptive pain
Failed back surgery
syndrome
Diffuse cancer pain
Nociceptive pain Osteoporosis
Visceral pain
Cervical, thoracic, lumbar
spinal pain
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476 Kok Eng KHOR
implantable device (its use and mechanism of
action), the surgical procedure and follow-up,
and devising strategies for coping with post-
implantation pain for both the patient and patient’s
support person.
Screening trial procedures
After psychological clearance, adequate education
and preparation, the patient undergoes a screening
trial procedure. It should be conducted in a
medically supervised environment where the
patient can be assessed and monitored. Patients
should understand the goals of the trial and that the
aims are to assess the analgesic efficacy, change in
functional status, behavioural response and adverse
effects to the neuraxial drugs. Analgesic efficacy
is determined by pain intensity, percentage pain
relief and rescue analgesic used, while functional
outcomes are determined by the effects on sleep,
mood and activity levels [53, 71].
A variety of screening protocols exist: trials can be
conducted via epidural or intrathecal administration
using a bolus, a series of injections or continuous
infusion; and be conducted on an inpatient or
outpatient basis. e choice of protocol is influenced
by the patient’s condition, physician preference,
available facilities and resources [71]. ere is little
evidence to demonstrate the superiority of one
method over another [6]. Logically, the more closely
a screening trial resembles the actual conditions of
the implantable pump therapy, the more accurate
will the results be in mimicking those of long-term
therapy. us, performing a trial with a continuous
intrathecal infusion would be the most suitable way
of assessing long-term intrathecal efficacy.
A temporary lumbar percutaneous intraspinal
catheter is usually placed and connected to an
external pump. e daily neuraxial morphine dose
infused is based on the patient’s systemic morphine
dose using a morphine bioequivalent conversion of
100:10:1 for oral, epidural and intrathecal routes
respectively. e patient’s usual opioid dose is
reduced by 25–50%. e neuraxial dose can be
increased stepwise by 50% until a positive response
is obtained. Adjuvants such as clonidine can also
be added to the morphine. e trial is usually
conducted over a period of 3 to 5 days. To reduce
the risk of a placebo response, a saline infusion can
be considered. is is an important issue as up to
40% of patients who initially respond to neuraxial
analgesics fail subsequent long-term therapy [48].
Other trial variants have also been described [4,
6].
A 50% pain relief accompanied by objective
evidence of functional improvements, reduced
analgesic use, absence of severe adverse effects
and absence of behavioural difficulties would be
considered a positive response [25, 53]. A case can
then be made for implantation of the intraspinal
catheter and infusion pump. Additionally, especially
in cancer pain, the analgesic medication needed for
pain control should also be able to be replicated
through the pump. If a very large volume is
required, e.g. to deliver high doses of bupivacaine,
this may not be feasible with the implantable pump
and alternative strategies such as delivery through
an externalised catheter using an external pump
should be considered. For patients undergoing the
placement of a tunnelled catheter-external pump
system, the screening trial and catheter “implant”
procedure are virtually identical [25].
Medications
Opioids [12, 47, 53, 96, 97]
Neuraxial opioids work by binding to pre- and
postsynaptic opioid receptors in the dorsal horn and
lead to the inhibition of nociceptive transmission in
C fibers [97]. e main differences in the opioids
relate to their lipid solubility and opioid receptor
affinity, which determine their onset of action,
distribution and duration of action. e quality
of analgesia seems to be similar for all intrathecal
opioids, although comparative data are lacking
[53].
Morphine
Opioids with low lipid solubility (highly
hydrophilic) such as morphine diffuse slowly into
the spinal cord and are bound for prolonged periods,
thus accounting for the slow onset but prolonged
duration of analgesia. Morphine’s hydrophilicity
allows more drug to circulate throughout the
cerebrospinal fluid (CSF) and ascend to the
supraspinal centres. is is advantageous in terms
of treating more widespread patterns of pain.
Analgesia in the thoracic and cervical areas can be
achieved from a lumbar-placed catheter. However,
morphine’s hydrophilicity may be associated with
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Neuraxial Analgesia 477
greater risk of delayed CNS side effects such as
sedation and respiratory depression. Morphine
continues to be the gold standard neuraxial agent
because of its proven effectiveness, safety, long
history and ease of use [53, 71]. Long-term stability
and compatibility studies with bupivacaine and
clonidine in implantable systems have also been
conducted [19].
Hydromorphone
Hydromorphone is about five times more potent
than morphine. It is mainly used when there
is intolerance or a poor response to morphine.
Hydromorphone is well tolerated and has an
equivalent safety, stability, compatibility with other
agents and side-effect profile to morphine [7, 8, 29,
78].
Sufentanil and fentanyl
ese highly lipid-soluble opioids diffuse into the
spinal cord rapidly but are also quickly eliminated
from the CSF, thus accounting for their rapid onset
but short duration of action. ey spread beyond
no more than a few neurotomes and placing the
catheter tip in close proximity to the spinal segments
involved in the nociceptive process is essential.
Sufentanil is about 1000 times more lipid soluble,
and has a greater potency and opioid receptor affinity
than morphine. eoretically, it would be useful in
situations of morphine tolerance. A bioequivalence
of 1 mg morphine to 1 mcg sufentanil is suggested
for long-term intrathecal infusion [53]. A report
of six patients with neuropathic pain successfully
treated with long-term intrathecal sufentanil
infusion showed a dose range of 12–72 mcg/day
[50]. Long-term use of intrathecal fentanyl is
limited to a few case reports showing an efficacious
dose range of 10–115 mcg/day [95].
ere is a lack of long-term neurotoxicity, stability
and drug compatibility data for both these drugs
[95]. Sufentanil has some weak local anaesthetic
effects and may cause some hypotension and
respiratory depression [53].
Methadone
Methadone shows incomplete cross-tolerance
to other opioids and can provide analgesia for
neuropathic pain. e racemic mixture has the
dual actions of a potent μ-receptor agonist and a
non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonist which blocks morphine
tolerance and exerts neuropathic antinociception
[12, 60]. A prospective case series of intrathecal
methadone in patients unresponsive to other
neuraxial agents reported that 54% had improved
analgesia, with 38% maintaining good pain relief
at 6 months at a dose range of 5–36 mg. ere was
significant reduction in sedation, probably because
of the short half-life of intrathecal methadone. e
suggested bioequivalence is about 1 mg morphine
to 1.5 mg methadone [60].
Pethidine
Pethidine is intermediate in its lipid solubility. Its
main advantage relates to its combined opioid and
local anaesthetic properties. Its higher lipid solubility
limits cephalad spread and thus central side effects.
ere is a lack of neurotoxicity, stability and clinical
data for long-term use of pethidine [12].
Non-opioid analgesics [12, 47,
53, 96, 97]
Alpha-2 agonists
is group of drugs binds to pre- and postsynaptic
alpha-2 receptors in the dorsal horn of the spinal
cord leading to the inhibition of neurotransmitter
(e.g. substance P) release and C fibre transmission
[97]. e prototype alpha-2 agonist is clonidine.
It is used in the treatment of neuropathic pain
including complex regional pain syndrome
(CRPS), management of pain-related spasticity,
as an adjuvant to reduce opioid tolerance and to
enhance analgesia when combined with opioid [31,
79, 91, 97]. e starting intrathecal dose is about
25mcg/day, titrating gradually to about 50–300
mcg daily.
e use of intrathecal clonidine monotherapy
(144–1200 mg/day) in the treatment of chronic
non-malignant pain was reported in a study
to be successful in 42% of a cohort of patients
who were resistant to opioids [44]. Smaller-dose
monotherapy (10–90 mcg/day) is also effective
in neuropathic pain and can be enhanced by the
addition of small doses of opioids [91]. However,
clonidine monotherapy analgesia can be short lived
and is not always successful long term; it usually
requires the addition of opioids [2].
Extensive neurotoxicity studies have found
clonidine to be safe [44, 102]. Clonidine also
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478 Kok Eng KHOR
maintained long-term stability in implantable
infusion pumps and is compatible with morphine,
hydromorphone and bupivacaine [19, 78].
Local anaesthetics
Local anaesthetics bind to nerve cells and block the
fast sodium channels thus inhibiting the sodium
influx that initiates the action potential. ey also
block potassium and calcium channels. ey have
a predilection for unmyelinated axons and are
effective even at subanaesthetic doses [97].
e main local anaesthetic which is commonly
used is bupivacaine. It is rarely used as sole therapy
and is often combined with morphine where it acts
synergistically to enhance analgesia. Bupivacaine
has been shown to re-establish analgesia when
combined with morphine in opioid tolerant
chronic pain states with intrathecal administration
being more effective than epidural [24, 93, 97].
e starting dose is about 3 mg/day, titrating to
about 4–8 mg/day; most pain relief can be achieved
without significant adverse effects with intrathecal
doses of less than 30 mg daily. Higher doses may
not necessarily be more effective [52, 80, 82, 92].
Neurotoxicity studies of neuraxial bupivacaine at
clinical concentrations in humans and animals
have shown no toxicity [12, 24, 81]. However,
because of the potential for neurotoxicity, it has
been recommended to avoid concentrations greater
than 0.75% in patients with non-cancer pain [71].
Stability testing of the drug, either as a sole agent
or in combination with morphine and clonidine,
showed stability and compatibility up to 90 days
[19, 47].
Ropivacaine has also been used and when compared
with bupivacaine showed similar efficacy and side
effects; however, the required dosage range to achieve
the same effect was 23% higher than bupivacaine.
ere are no data on safety and efficacy of long-
term intrathecal use of ropivacaine [12, 47].
Ziconotide
Ziconotide is the synthetic equivalent of a -
conopeptide, which is present in the venom of
the marine snail Conus magus. It binds selectively
to N-type voltage-sensitive calcium channels on
the primary nociceptive afferent nerves in the
dorsal horn and blocks the release of substance
P. It is administered only intrathecally. Long-
term, open-label studies showed maintenance of
pain relief in about 40% of patients with a stable
dose of 14 mcg/day without the development
of tolerance [56]. ree randomised controlled
trials confirmed ziconotide to be effective in the
management of chronic intractable cancer, AIDS
and non-malignant pain of diverse aetiologies
with significant reduction in pain intensities and a
higher proportion of patients achieving moderate
to complete pain relief compared with placebo [76,
87, 98].
Ziconotide has a narrow therapeutic index and
adverse events are common and can be severe.
Most adverse effects are neurological and include
dizziness, confusion, somnolence, memory
impairment, hallucinations, vertigo, nystagmus,
ataxia, gait disorders, nausea and diarrhoea. ese
events occur largely in the first week and resolve
upon drug discontinuation. Tolerance develops
slowly over time [56]. e recommended initial
dosage of ziconotide is 2.4 mcg/day and dosage is
titrated by ≤2.4 mcg/day at intervals of at least ≥48
hours to analgesic response or occurrence of adverse
events to a maximum dosage of 21.6 mcg/day [56].
A significantly lower starting dose of not more
than 0.5 mcg/day using slower titration has been
recommended to significantly limit the incidence,
severity and duration of side effects [34].
Baclofen
Baclofenbinds to GABA
B
receptors in the substantia
gelatinosa, opens the potassium channels and
restricts calcium influx into presynaptic nerve
terminals leading to hyperpolarisation and reduction
of presynaptic neurotransmitters (glutamate and
substance P) release [84]. It is usually used in the
treatment of intractable spasticity associated with
spinal cord injury. Apart from relieving pain related
to spasms and spasticity, baclofen has also been
reported to provide analgesia in central pain and
CRPS [40, 94, 106]. It can also relieve dystonia
associated with CRPS and improve function [94].
Combination therapy with clonidine and morphine
has also been reported [40, 106]. e dose for
antinociceptive effect is in the range of 100–250
mcg/day.
Adverse effects include drowsiness, headache,
confusion, hypotension, slurred speech, weight
gain, constipation, nausea and sexual dysfunction.
Abrupt discontinuation can lead to a potentially
life-threatening withdrawal syndrome with altered
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Neuraxial Analgesia 479
Ketamine
Although well known as an NMDA antagonist,
neuraxial ketamine has limited efficacy as a sole
analgesic. When used in combination, ketamine
enhances the analgesic effect of morphine and
reduces opioid requirement and tolerance [96,
104]. Significant psychotomimetic effects can occur
with neuraxial ketamine. Neurotoxicity studies
have shown histological changes and spinal cord
inflammation with intrathecal ketamine which
may be related to preservatives [47].
Other neuraxial agents
Other neuraxial analgesics being evaluated include
ketorolac, gabapentin, neostigmine, adenosine
and octreotide. ere is still a paucity of efficacy
and safety data regarding long-term neuraxial
administration of these agents and their use cannot
be recommended at this time [12, 47, 96].
Drug admixture
Drug combinations are used when neuraxial
analgesia is compromised by development
of tolerance, dose-limiting side effects and
reduced efficacy of single agents. Combining
drugs of different classes targets the different
pathophysiological mechanisms of the pain
mental status and profound muscular rigidity.
Overdosing can also be potentially life-threatening
and this usually occurs during the improper refilling
of the pump, such as overfilling and accidental
injection into the pump pocket, resulting in loss
of consciousness, seizures and cardiorespiratory
depression [84].
Safety studies showed no neurotoxicity and
chemical stability studies have shown sufficient
stability for long-term intrathecal infusion of at
least 10 weeks [47].
Midazolam
Midazolam binds to GABA
A
receptors in the dorsal
horn to produce antinociception. At the spinal
level, it interacts with opioids in an additive or
synergistic manner. Neuraxial administration of
midazolam in chronic non-malignant pain states
is still not established as neurotoxicity studies in
animals remain inconclusive. ere is also a paucity
of safety data for long-term human administration
and its use should not be routine [12, 47]. A number
of case reports for severe cancer pain reported
improvements when intrathecal midazolam is added
to an opioid and local anaesthetic combination [3,
9].
Use of intraspinal drug infusion in pain management — clinical guidelines
Morphine Hydromorphone
Morphine (or Hydromorphone) + Clonidine
Morphine (or Hydromorphone) + Bupivacaine
Morphine (or Hydromorphone) + Clonidine + Bupivacaine
Fentanyl, Sufentanil (in place of Morphine/Hydromorphone),
Midazolam, Baclofen, Ziconotide (?)
Methadone, Ketamine, Neostigmine, Ketorolac, Octreotide, Adenosine,
Ropivacaine, Pethidine
OR
Line 1
Line 2
Line 3
Line 4
Line 5
Figure 29.02 Clinical guidelines for the use of neuraxial analgesic infusion for persistent pain (adapted from
Hassenbusch SJ [47], with permission from Elsevier)
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