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EMERGING TREATMENT AND DIAGNOSIS | WEBSTER & FAKATA<br />
reorganization of peripheral afferent neurons may occur. Fibers<br />
that do not normally transmit pain start expressing the pain<br />
transmitters, so that nonnoxious stimuli that normally activate<br />
these fibers would transit pain.<br />
Ziconotide represents a new class of potent analgesics called<br />
neuronal calcium channel blockers (NCCBs). Its exact mechanism<br />
of action has not been established in humans; however,<br />
animal studies confirm its specificity for N-VSCCs found<br />
throughout the nervous system and concentrated in the spine<br />
on the presynaptic terminals of peripheral nociceptors.<br />
Ziconotide blocks the N-VSCC and prevents release of excitatory<br />
amino acids from the presynaptic terminal, thereby reducing<br />
the amount of stimulation at the dorsal horn neurons. It is<br />
proposed that ziconotide may unwind central sensitization over<br />
time through this mechanism (5).<br />
Clinical Use of Ziconotide<br />
ZICONOTIDE IS CURRENTLY FDA-APPROVED for monotherapy in<br />
patients with chronic severe pain where IT therapy is warranted.<br />
Currently there are no published clinical data on the<br />
efficacy of ziconotide in combination with other IT medications.<br />
The Polyanalgesic Consensus Committee has not made<br />
any formal recommendations regarding the use of ziconotide as<br />
monotherapy or in combination with IT therapies at this time<br />
(6). There is little information on other IT medications in combination,<br />
yet combination IT therapy has been an accepted<br />
standard of practice. The rationale for ziconotide in combination<br />
with other common IT medications is combining different<br />
mechanisms of action for possible additive or synergistic analgesia.<br />
Preclinical studies in animals demonstrated additive or synergistic<br />
effects with opioids, clonidine, and bupivacaine when<br />
utilized in combination with ziconotide (5). Clinicians who<br />
wish to use ziconotide in combination with other IT medications<br />
should first obtain consent.<br />
Some stability data have been published regarding<br />
ziconotide in combination with other common IT medications.<br />
It is important to note that the data represented stability<br />
with 25 mcg/ml formulation of ziconotide with fixed concentrations<br />
of other IT meds. Ziconotide was found to have<br />
relatively good stability with hydromorphone, bupivacaine,<br />
and baclofen. It was completely stable with clonidine (7-10).<br />
Formulated IT products such as Infumorph ® (IT morphine)<br />
and Sublimaze ® (fentanyl) should be avoided because of low<br />
stability. Ziconotide stability is pH dependent and is most<br />
stable at pH of 4.5.<br />
In choosing to use ziconotide in combination with other IT<br />
meds, a clinician should be aware of some inherent stability<br />
considerations because ziconotide is a peptide. On the initial<br />
fill, ziconotide adheres to the titanium in the pump. The initial<br />
concentration may also be altered by the residual volume in the<br />
pump. Ziconotide degrades due to exposure to high temperature<br />
(body temperature), and it is susceptible to oxidation.<br />
Ziconotide may be most effective<br />
in reducing pain and preventing<br />
central sensitization by its<br />
mechanism of action.<br />
The authors of this article recommend keeping ziconotide<br />
at or above a working concentration of 10mcg/ml. This also<br />
allows for the convenience and practicality of utilizing the100<br />
mcg/ml (1ml) vial formulation, taking cost of medication into<br />
consideration. The rinses in the prescribing information can be<br />
conducted through the following steps:<br />
[1] dilute 0.5 ml of the 100 mcg/ml formulation to 6 ml (8.33<br />
mcg/ml);<br />
[2] rinse the pump three times utilizing 2 ml aliquots of step 1<br />
above; and,<br />
[3] utilize the remaining 0.5 ml to dilute to a working concentration<br />
of 10 mcg/ml in 5 ml, or 5 mcg/ml in 10 ml if<br />
lower concentration is necessary for first pump fill with<br />
ziconotide.<br />
Subsequent refills should occur monthly due to stability<br />
concerns; however, further rinses are not required. The entire<br />
vial of 100 mcg/ml 1 ml vial can be used for the refill. The<br />
same concepts are utilized for monotherapy or compounding<br />
ziconotide with other IT medications (11).<br />
Ziconotide is associated with adverse events such as nausea/vomiting,<br />
dizziness, abnormal gait, abnormal vision, and<br />
confusion. These adverse events may present themselves within<br />
the first few days of therapy if treatment is initiated with too<br />
high of a dose. Experienced clinical investigators realize that<br />
ziconotide should be started at 1 mcg/day and titrated by 0.5<br />
mcg/day no more than once a week. This dose is significantly<br />
lower than the maximum recommended starting dose in the<br />
prescribing information. Cognitive effects such as memory loss,<br />
confusion, and psychosis tend to have a later onset of approximately<br />
three weeks. Therefore, to be safe and to not overshoot<br />
the therapeutic window, it is advisable to titrate no more often<br />
than weekly—once a month may be preferable. If adverse<br />
events do occur, they usually resolve after a dose reduction.<br />
Early onset adverse events usually resolve in a few days, whereas<br />
it may take up to three additional weeks to resolve late onset<br />
adverse events. If patients cannot tolerate adverse events,<br />
ziconotide may be abruptly removed from the pump without<br />
any withdrawal sequelae.<br />
Monitoring Considerations<br />
PATIENTS SHOULD BE CONTINUALLY ASSESSED for adverse<br />
events related to ziconotide. They should be instructed to<br />
immediately notify clinic personnel or to seek emergency<br />
medical attention if any serious adverse events should occur.<br />
In clinical studies with ziconotide, a significantly elevated<br />
serum, Creatinine Kinase isoenzyme MM (CK-MM) found in<br />
(Continued on page 66)<br />
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