Ziconotide, a new N-type calcium channel blocker, administered intrathecally for postoperative pain

Gagan Mahajan, M.D.
Fellow, UC Davis

Peter G. Atanassoff, Maximillian W.B. Harmannsgruber, James Thrasher, Dan Wermeling William Longton, Raymond Gaeta, Tej Singh, Martha Nayo, Dawn McGuire, and Robert Luther, Regional Anesthesia and Pain Medicine 25 (3); 2000

This study was designed to assess the safety and analgesic efficacy of Ziconotide, a new N-type calcium channel blocker, when administered intrathecally before surgical incision for treatment of acute postoperative pain.

Voltage-gated calcium channels are critical components of the nervous system that signal a painful event. To date, 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non-neuronal cells. The majority of studies looking at intrathecal L-type calcium channel blockers (verapamil, diltiazem and nicardipine) have shown that they do not provide adequate pain relief.

Ziconotide, a synthetically modified w-conopeptide, is a new type of calcium channel blocker that specifically blocks N-type, neuron-specific calcium channels found at presynaptic primary afferent nerve terminals. N-type channels are expressed almost exclusively by neurons and are hypothesized to be the important calcium channels that regulate synaptic transmission in nociceptive neurons. Ziconotide presumably causes analgesia by interfering with the release of neurotransmitters from the nerve terminals. Studies involving intrathecal, IV, and perineural Ziconotide in animal models of acute, chronic and neuropathic pain states have, thus far, been successful.

The authors enrolled thirty patients (ages 39 years-old to 84 years-old) in a randomized, double-blind, placebo-controlled study. The types of surgeries included: elective total abdominal hysterectomy (n = 6), radical retropubic prostatectomy (n = 7) and total hip replacement (n = 17). An intrathecal catheter was placed preoperatively. Before the surgical incision, but after giving the intrathecal anesthetic, the patients either received a continuous infusion of placebo (n = 12), Ziconotide 0.7 micrograms/hr (n = 12) or Ziconotide 7.0 micrograms/hr (n = 6). The medications were continued throughout surgery and for 48-72 hours thereafter. A morphine PCA was also given as rescue analgesia. If analgesics other than morphine were used, the daily dosage of those medications was converted into the parenteral morphine equivalent. Primary and secondary efficacy variables were the mean daily morphine consumption and pain assessment, respectively. Pain assessments were done every four hours using the Visual Analog Scale of Pain Intensity (VASPI), ranging from 0 mm (no pain) to 100 mm (worst imaginable pain).

Four patients were excluded from the study due to protocol violations. Seventeen patients asked for analgesics (fentanyl, hydromorphone, meperidine, or ketorolac) other than morphine. During the time period studied, the amount of morphine equivalent used by the high-dose Ziconotide (7.0 micrograms/hr), low-dose Ziconotide (0.7 micrograms/hr) and placebo groups was 6.6 + 7.7 mg, 20.7 + 17.7 mg and 26.2 + 20.3 mg, respectively. Mean VASPI scores were lower for the Ziconotide groups compared to the placebo groups, especially within the first eight hours. Though similar side-effects were reported in each of the three groups, certain side-effects occurred more frequently in the Ziconotide groups ­ dizziness, nausea, and headache ­ but these adverse reactions seemed to be dose-related. The severity of dizziness, blurred vision, nystagmus and sedation caused the treating physician to discontinue the medication in 4 of 6 patients in the high-dose Ziconotide group. These symptoms resolved after the medication was stopped.

The lower amount of morphine equivalent and lower postoperative VASPI scores seen in the Ziconotide groups indicate that Ziconotide may have beneficial effects on post-surgical pain. This study, along with an earlier study using Ziconotide versus placebo in 240 patients with opioid-resistant nonmalignant chronic pain, supports the hypothesis that intrathecal Ziconotide also may be useful in the management of chronic pain.

1. This was a small study.
2. Though the pain scores were lower for the Ziconotide groups versus the placebo group, the difference was not statistically significant.
3. Though the high-dose Ziconotide group required significantly less morphine equivalent medication(s) than placebo, it was at the expense of severe dizziness, blurred vision, nystagmus and sedation.
4. Though the low-dose Ziconotide group required less morphine equivalent medication(s) than placebo, the difference was not statistically significant.

The optimal dose of Ziconotide probably lies somewhere between 0.7 ­ 7.0 micrograms/hr. Additional studies will need to be done to further elucidate this.