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Ziconotide Combination Intrathecal Therapy

Retrospective case studies in intrathecal drug therapy patients with severe chronic pain demonstrate the safety and efficacy of ziconotide in improving pain management while reducing—or halting—oral and intrathecal narcotic pain medications.
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The expert panel of the 2007 Polyanalgesic Consensus Conference has recommended ziconotide as one of three medications for first-line intrathecal monotherapy. There are many times when ziconotide will be appropriate for first-line therapy, but it is currently used most often in combination. The article by Eastman and Johnson provides us more clinical insight into ziconotide use and the potential impact in reducing opioid use and improving functional outcome. I applaud the authors in their attempt to try to understand the clinical impact this drug can have in their practice. It is this type of work which should be a model for all of us who are not academics but who want to understand and apply the best clinical care for our patients.

Intrathecal drug therapy using implantable intrathecal pump and catheter systems is a safe and efficacious therapy for selective patients with chronic pain syndromes. Ziconotide (Prialt® from Elan Pharmaceuticals) represents a new class of medication that is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of, or refractory to, other treatments such as systemic analgesics, adjunctive therapies, or IT morphine. It was developed to combat chronic, severe, intractable neuropathic and nociceptive pain. It is a synthetic peptide originally derived from a marine snail, Conus Magus, that binds N-type calcium channels (NCC’s) which are exclusively found on neurons. Ziconotide targets the laminae I and II layers of the dorsal horn of the spinal cord. NCC’s are concentrated here where primary afferent fibers in the pain signal pathway synapse for the first time. Ziconotide blocks calcium transportation into the presynaptic terminal. This blocks neurotransmitter release thus making pain transmission more difficult or blocking it completely. Unlike opioids, ziconotide does not suppress respiratory function. Once a therapeutic dose is reached, tolerance does not appear to develop and it does not have addiction potential.1,2

The safety and efficacy of intrathecal ziconotide has previously been evaluated in over 1,200 patients. The most frequently reported adverse events were dizziness, nausea, headache, confusion, nystagmus, somnolence, pain, memory impairment, and abnormal gait which are reversible within a few days of dose reduction or discontinuation.3, 4

In certain individuals, opioids have been implicated in causing central sensitization and, as a result, hyperalgesia. In central sensitization, the peripheral afferent nerves fire spontaneously resulting in an increased sensitivity to the dorsal root neurons. As a result of inflammation, reorganization of peripheral afferent neurons may occur. Neural fibers that do not normally transmit pain start expressing as pain transmitters so that non-noxious stimuli that normally activate these fibers results in pain transmission instead. Ziconotide blocks the N-VSCC and prevents release of the excitatory amino acid, glutamate, from the presynaptic terminal and thereby reduces the amount of stimulation at the dorsal horn neurons. It is proposed that ziconotide may unwind central sensitization over time by this mechanism.5

Ziconotide was added to the existing intrathecal therapies of thirty patients with pre-existing intrathecal pain pumps and a minimum six month retrospective evaluation was completed and the data analyzed during a period that began on August 9, 2005 and ended on November 22, 2006. Of the thirty patients evaluated, twenty-nine patients were evaluated in our Las Vegas, Nevada center and one patient evaluated in our Kalispell, Montana center, ranging in age from 29 to 79 years of age. Medications used in a variety of combinations with ziconotide included morphine, hydromorphone, fentanyl, meperidine, clonidine, baclofen, bupivacaine, ketamine, and droperidol.

It is common practice in pain management and IT therapy to utilize multiple medications having different mechanisms of action in IT pumps to provide analgesia to the patient. Adverse events from opioid utilization can be debilitating and often increase consistently over time as opioid dose requirements increase due to analgesic tolerance. Combining ziconotide with hydromorphone intrathecally may allow reduced doses of both ziconotide and hydromorphone compared to monotherapy doses while still maintaining analgesic efficacy. It is also possible that these agents in combination will be synergistic—i.e. have an effect greater than simple additivity. Lowering the doses of two agents with different side effect profiles may also result in a reduced overall side effect profile.6


Study Design. This study is a retrospective evaluation of data collected from twenty-three patients with existing intrathecal therapies that had completed six refills in thirty to forty-five day intervals of Prialt® (ziconotide) combination therapy subsequent to FDA approval of Prialt. Medications used in a variety of combinations with ziconotide included morphine, hydromorphone, fentanyl, meperidine, clonidine, baclofen, bupivacaine, ketamine, and droperidol. See Table 1 for a breakdown of these medications.

At baseline, patients completed pain questionnaires that asked them to determine their current pain level based on a scale of 1 to 10 and completed an Oswestry Questionnaire in order to determine their level of activity and functioning. Patients completed pain questionnaires at each subsequent pump refill and a follow-up Oswestry Questionnaire at their sixth and final pump refill to determine changes in activity and function.

Study Population. To be eligible for study participation, patients from two study centers in the U.S. must have been suffering from chronic malignant or non-malignant pain where intrathecal therapy was necessary. Each participant was required to have current intrathecal therapy initiated with one or more intrathecal medications through an FDA-approved infusion device and intrathecal catheter prior to study enrollment.

Potential study participants were excluded because of current pregnancy, participation in another investigational drug or device trial within the preceding thirty days, or for known hypersensitivity to ziconotide or any of its components. Exclusion criteria also included the presence of any condition that the investigators felt may impair the patient’s ability to be an active study participant, i.e., psychiatric conditions, active substance abuse, or history of poor medical treatment compliance.

Last updated on: January 5, 2012
First published on: November 1, 2007