Ziconotide for Chronic Severe Pain
Ziconotide intrathecal [IT] infusion represents a novel breakthrough in combatting intractable pain. It is a synthetic derivative (w-conotoxin) of a toxin isolated from the Magician’s cone snail, Conus magus (formerly known as SNX-111) and has shown to be a powerful non-opioid analgesic. Its conception began in the early 1970s in the Philippines when, due to lack of resources, native scientist Baldomero Olivera abandoned his work on enzymes involved in DNA synthesis in favor of his passion for shell collecting, preferably the species Conus magus. In 1978, he returned to the United States and took a position with the University of Utah with plans to resume his DNA research; however, his focus changed after an inquisitive undergraduate student rotating through his lab performed some crude basic science on Olivera’s isolated conopeptides. The astonishing results made Olivera once again abandon his DNA research and form a collaboration with biochemist George Miljanich from the University of Southern California, who had received funding from the National Institutes of Health (NIH) to research conopeptides and their effects on various molecular pathways. Miljanich went on to join a small biotech company and to proceed with the development of SNX-111.1
After three decades of trial and error and extensive clinical research, including three double-blind, placebo-controlled multi-center studies and four open-label long-term studies, ziconotide is now the first new FDA-approved IT analgesic since morphine was approved by the FDA over 20 years ago. Ziconotide is one of the most extensively studied new medications prior to FDA approval with experience in over 1,200 patients.
Mechanism of Action
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-type voltage-sensitive calcium channels (N-VSCC) found throughout the nervous system and concentrated in the spine on the presynaptic terminals of primary nociceptors. Ziconotide blocks the N-VSCC and prevents release of the excitatory amino acid, glutamate, from the presynaptic terminal, thereby reducing the amount of stimulation at the dorsal horn neurons (see Figure 1).2 N-VSCC are not affected by dihydropyridine calcium channel blockers, which are commonly used to treat headaches and cardiovascular disease and are known to block L-type calcium channels.3,4
Ziconotide does not interact with opioid receptors and, therefore, will not prevent withdrawal symptoms from opioids. Also, tolerance does not develop as seen with opioids.3,4 Clinicians must be careful to titrate downward other IT medications if their intention is to withdraw the patient from current IT therapy before starting monotherapy with ziconotide.
Ziconotide is a hydrophilic peptide, and its membrane permeability is low thus necessitating direct delivery to the site of action. The elimination half-life of ziconotide is 4.5 hours which is approximately equal to the turnover rate of the cerebral spinal fluid (CSF). Its volume of distribution of 140 ml is also equal to that of CSF, which indicates that it is eliminated by the turnover of CSF. With continuous IT infusion, once ziconotide reaches systemic circulation, it is expected to be rapidly cleaved by peptidases and proteases present in most organs. The half-life in the systemic circulation is approximately 1.5 hours.5
Ziconotide is indicated for the management of severe chronic pain in patients for whom IT therapy is warranted and who are intolerant of, or refractory to, other treatments such as systemic analgesics, adjunctive therapies or IT morphine. Ziconotide is approved as a monotherapy.5 Formal studies with ziconotide in combination with other IT pump medications are now being conducted.
It is important to note that concomitant use of oral opioid analgesics and adjunctive therapies are not contraindicated with ziconotide. The 1,254 clinical trial patients received several non-IT medications with 98% of patients remaining on their oral opioids, 66% on anxiolytics, 52% on anticonvulsants, 47% on neuroleptics and 34% of patients on sedatives for pain management and symptom control. Patients on several central nervous system (CNS) depressant medications are at higher risk of having confusion and dizziness or an altered level of consciousness.5
Ziconotide has a black box warning stating that a patient with a pre-existing history of psychosis should not be treated with ziconotide due to the risk of severe psychiatric symptoms and neurological impairment that may occur during therapy. It advises that all patients should be monitored for cognitive impairment, hallucinations or changes in mood and consciousness that would be consistent with serious psychiatric conditions or neurological impairment.5
At this time, there is no antidote or antagonist for the reversal of adverse events related to ziconotide. If adverse events are severe or intolerable, ziconotide may be immediately removed from the pump without precipitating withdrawal effects. Ziconotide may worsen depression, including the risk of suicidal ideations. The appropriateness of using ziconotide in patients with psychiatric comorbidities should be left to the judgment of treating physicians.
Who Are Candidates?
Potential candidates for ziconotide are patients with severe pain in which IT pump therapy is warranted. Based on the authors’ clinical experience, ziconotide appears to be as effective with nociceptive and visceral pain as with neuropathic pain, but prospective studies are needed to determine if there is a difference in efficacy among pain types or pain mechanisms. Ziconotide should not be used with patients who have a known hypersensitivity to ziconotide or L- methionine, an antioxidant in the formulation.
Patients who have a history of pre-existing psychosis or a high baseline of cognitive impairment that occurs with severe dementia or advanced Alzheimer’s disease should probably not receive the drug unless the risk/benefit has been fully considered and the family informed of the potential for the underlying mental disease to be worsened. However, a chronic pain patient that is being treated for mild-to-moderate depression and is currently well controlled on an antidepressant may be considered a candidate for ziconotide.