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EMERGING TREATMENT AND DIAGNOSIS | WEBSTER & FAKATA
reorganization of peripheral afferent neurons may occur. Fibers
that do not normally transmit pain start expressing the pain
transmitters, so that nonnoxious stimuli that normally activate
these fibers would transit pain.
Ziconotide represents a new class of potent analgesics called
neuronal calcium channel blockers (NCCBs). Its exact mechanism
of action has not been established in humans; however,
animal studies confirm its specificity for N-VSCCs found
throughout the nervous system and concentrated in the spine
on the presynaptic terminals of peripheral nociceptors.
Ziconotide blocks the N-VSCC and prevents release of excitatory
amino acids from the presynaptic terminal, thereby reducing
the amount of stimulation at the dorsal horn neurons. It is
proposed that ziconotide may unwind central sensitization over
time through this mechanism (5).
Clinical Use of Ziconotide
ZICONOTIDE IS CURRENTLY FDA-APPROVED for monotherapy in
patients with chronic severe pain where IT therapy is warranted.
Currently there are no published clinical data on the
efficacy of ziconotide in combination with other IT medications.
The Polyanalgesic Consensus Committee has not made
any formal recommendations regarding the use of ziconotide as
monotherapy or in combination with IT therapies at this time
(6). There is little information on other IT medications in combination,
yet combination IT therapy has been an accepted
standard of practice. The rationale for ziconotide in combination
with other common IT medications is combining different
mechanisms of action for possible additive or synergistic analgesia.
Preclinical studies in animals demonstrated additive or synergistic
effects with opioids, clonidine, and bupivacaine when
utilized in combination with ziconotide (5). Clinicians who
wish to use ziconotide in combination with other IT medications
should first obtain consent.
Some stability data have been published regarding
ziconotide in combination with other common IT medications.
It is important to note that the data represented stability
with 25 mcg/ml formulation of ziconotide with fixed concentrations
of other IT meds. Ziconotide was found to have
relatively good stability with hydromorphone, bupivacaine,
and baclofen. It was completely stable with clonidine (7-10).
Formulated IT products such as Infumorph ® (IT morphine)
and Sublimaze ® (fentanyl) should be avoided because of low
stability. Ziconotide stability is pH dependent and is most
stable at pH of 4.5.
In choosing to use ziconotide in combination with other IT
meds, a clinician should be aware of some inherent stability
considerations because ziconotide is a peptide. On the initial
fill, ziconotide adheres to the titanium in the pump. The initial
concentration may also be altered by the residual volume in the
pump. Ziconotide degrades due to exposure to high temperature
(body temperature), and it is susceptible to oxidation.
Ziconotide may be most effective
in reducing pain and preventing
central sensitization by its
mechanism of action.
The authors of this article recommend keeping ziconotide
at or above a working concentration of 10mcg/ml. This also
allows for the convenience and practicality of utilizing the100
mcg/ml (1ml) vial formulation, taking cost of medication into
consideration. The rinses in the prescribing information can be
conducted through the following steps:
[1] dilute 0.5 ml of the 100 mcg/ml formulation to 6 ml (8.33
mcg/ml);
[2] rinse the pump three times utilizing 2 ml aliquots of step 1
above; and,
[3] utilize the remaining 0.5 ml to dilute to a working concentration
of 10 mcg/ml in 5 ml, or 5 mcg/ml in 10 ml if
lower concentration is necessary for first pump fill with
ziconotide.
Subsequent refills should occur monthly due to stability
concerns; however, further rinses are not required. The entire
vial of 100 mcg/ml 1 ml vial can be used for the refill. The
same concepts are utilized for monotherapy or compounding
ziconotide with other IT medications (11).
Ziconotide is associated with adverse events such as nausea/vomiting,
dizziness, abnormal gait, abnormal vision, and
confusion. These adverse events may present themselves within
the first few days of therapy if treatment is initiated with too
high of a dose. Experienced clinical investigators realize that
ziconotide should be started at 1 mcg/day and titrated by 0.5
mcg/day no more than once a week. This dose is significantly
lower than the maximum recommended starting dose in the
prescribing information. Cognitive effects such as memory loss,
confusion, and psychosis tend to have a later onset of approximately
three weeks. Therefore, to be safe and to not overshoot
the therapeutic window, it is advisable to titrate no more often
than weekly—once a month may be preferable. If adverse
events do occur, they usually resolve after a dose reduction.
Early onset adverse events usually resolve in a few days, whereas
it may take up to three additional weeks to resolve late onset
adverse events. If patients cannot tolerate adverse events,
ziconotide may be abruptly removed from the pump without
any withdrawal sequelae.
Monitoring Considerations
PATIENTS SHOULD BE CONTINUALLY ASSESSED for adverse
events related to ziconotide. They should be instructed to
immediately notify clinic personnel or to seek emergency
medical attention if any serious adverse events should occur.
In clinical studies with ziconotide, a significantly elevated
serum, Creatinine Kinase isoenzyme MM (CK-MM) found in
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