American Society of Regional Anesthesia and Pain Medicine August 2016 - 33

CON

Use of Ziconotide as First Line Intrathecal Therapy?

INTRODUCTION
Intrathecal therapy is a mainstay
in the armamentarium of the
pain physician for the most
challenging patients suffering
from chronic pain. Its efficacy in
both malignant and nonmalignant
pain has been proven repeatedly
in the literature and seen in
clinical experience. Utilizing
targeted drug delivery allows
physicians to take advantage
of administering analgesics
Dawood Sayed, MD
directly to the cerebrospinal
Assistant Professor of
fluid, achieving pain relief at a
Anesthesiology and Pain Medicine
fraction of the systemic dose.
The University of Kansas Hospital
Although various medications are
Kansas City, KS
utilized for intrathecal therapy,
only morphine and ziconotide
Section Editor: Kevin Vorenkamp, MD
are approved by the Food and
Drug Administration (FDA) for intrathecal administration in chronic
pain. Ziconotide has also been recommended as first-line therapy
for targeted drug delivery in both neuropathic and nociceptive
pain states by the Polyanalgesic Consensus Guidelines in 2012.1
Morphine's usage in the neuraxial space, both epidural and
intrathecal, is well established. It has the potential for significant
adverse effects when administered improperly but has an excellent
safety profile when used appropriately in targeted drug delivery.1
Respiratory depression remains
the biggest consequence of
chronic opioid therapy-both
systemic and intrathecal. With
the release of ziconotide in
2004, the first FDA-approved
nonopioid for intrathecal usage
in chronic pain, a solution to
our biggest fears in regard to
chronic opioid infusion was
answered. Little to no risk of respiratory depression, overdose,
tolerance, or withdrawal make ziconotide the IDEAL intrathecal
agent for pain...in theory.2 Despite these theoretical advantages,
several factors have led to limited clinical utilization of this drug
derived from the toxin of the cone snail species Conus magus.

formation have not been associated with ziconotide, its adverse
effects make it an unacceptable treatment option for many
patients.3 Possible adverse effects include nausea, vomiting,
confusion, postural hypotension, abnormal gait, urinary retention,
nystagmus/amblyopia, drowsiness/somnolence (reduced level of
consciousness), dizziness or lightheadedness, weakness, visual
problems (eg, double vision), elevation of serum creatine kinase,
and vestibular side effects.3
Of all these adverse effects, the most serious and disturbing to
most who ultimately fail ziconotide therapy are cognitive and
neuropsychiatric adverse effects. Rates for confusion (33%),
memory impairment (22%), speech disorder (14%), aphasia
(12%), and abnormal thinking (8%) have been cited in previous
studies.5 Severe psychiatric disturbances remain the most
serious adverse effect reported with intrathecal ziconotide.
Hallucinations (12%), paranoid reactions (3%), hostility (2%),
delirium (2%), psychosis (1%), and manic reactions (0.4%) have
all been reported.5 Although most of these cognitive effects are
reversible with discontinuation of therapy, it can ultimately lead
the patient and physician to abandon targeted drug delivery
altogether.
CON #2 - DIFFICULT TO TRIAL
It is generally believed that to optimize patient outcomes and
improve cost effectiveness, a preliminary trial of spinal analgesia
must be performed to assess candidacy for intrathecal pump
implantation. Moreover, most insurance companies and government
payers require specific trialing
criteria to be met before a
patient qualifies for long-term
intrathecal therapy.6 On the
surface, ziconotide's lack
of respiratory depressant
effects would appear to make
it a very appropriate choice
for outpatient, single-shot,
intrathecal bolus or short-term
spinal infusion. However, the clinical data on ziconotide trialing
paints a very different picture. Again, this stems from ziconotide's
narrow therapeutic window. An open label study published in 2013
documented an overall responder rate to intrathecal ziconotide
trial of only 13%.7 A comprehensive clinical review by Burton et al.
also failed to come to a consensus on optimal trialing technique
for ziconotide.6 The actuality is that many patients will not be
able to tolerate the side effects associated with ziconotide at the
dosages required to provide an analgesic response during a trial
(recommended dosages for trial are 0.5-5 mcg.).1 Consequently,
patients will more than likely be implanted with drug-delivery
systems prior to knowing if long-term infusion of ziconotide will be

"Many factors have led to a palpable
paradigm shift away from the utilization
of targeted drug delivery in chronic pain
over the past 10 years."

CON #1 - NARROW THERAPEUTIC INDEX AND ADVERSE EFFECTS
The therapeutic index (TI) is the range of doses at which a
medication is effective without unacceptable adverse events.
Drugs with a narrow TI have a slender window between their
effective doses and those at which they produce adverse toxic
effects.4 Ziconotide has the most restricted TI of any of the
commonly utilized intrathecal agents. Although serious adverse
effects such as respiratory depression, withdrawal, and granuloma

"Con" continued on page 35

American Society of Regional Anesthesia and Pain Medicine
2016

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