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 (Continued on page 66) 64 | T H E PA I N P R A C T I T I O N E R | S P R I N G 2 0 0 6
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