Ziconotide Trialing by Intrathecal Bolus Injections

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Ziconotide Trialing by Intrathecal Bolus Injections
Key Take-Away: 

Ziconotide was earlier approved for continuous intrathecal infusions, not for bolus injections. Therefore, this study revealed the feasibility of ziconotide trialing by intrathecal bolus injections.

Use of continuous intrathecal infusion of morphine in humans was first described in 1981. The majority of patients treated with Intrathecal analgesia (ITA) have non-cancer types of pain. The most significant ITA-related development in recent years has been the introduction of ziconotide, a synthetic analogue of a conopeptide found in the venom of the fish-hunting marine snail Conus magus.

ABSTRACT: 
Background: 

Use of continuous intrathecal infusion of morphine in humans was first described in 1981. The majority of patients treated with Intrathecal analgesia (ITA) have non-cancer types of pain. The most significant ITA-related development in recent years has been the introduction of ziconotide, a synthetic analogue of a conopeptide found in the venom of the fish-hunting marine snail Conus magus.

Ziconotide is a non-opioid that selectively blocks N-type voltage-sensitive calcium channels in the Rexed lamina I and II of the spinal cord dorsal horn.

Rationale behind research

  1. As ziconotide has a narrow therapeutic window with several neurological adverse effects (AE), so a slow-titration strategy is recommended. Therefore, ziconotide has been administered by bolus injections
  • Objective

To evaluate the feasibility of trialing ziconotide by intrathecal bolus injections in patients with posttraumatic and/or postoperative, peripheral, neuropathic pain refractory to conventional pharmacological treatment.

Methods: 

 

Study outcomes

  • Primary outcome: Reduction in pain at visual analogue scale pain intensity
  • Secondary outcomes: Reduction in pain at Patient Global Impression of Change
  • Time points
    • Efficacy: Baseline, 0-24 hour
    • Safety: Before injection, creatine kinase (CK) and pregnancy test was performed
Results: 

 

Baseline: Treatment groups were well balanced with no significant baseline differences

  • Thirteen percent were responders according to the strict criteria of the study, 7 patients (30%) achieved ≥ 30% pain reduction on a least one injection, i.e. almost a third of patients experienced clinically meaningful pain reduction at some time during the trial.
  • Repeated measures analysis of variance RM-ANOVA of pre-injection Visual Analogue Scale Pain Intensity-now and hourly for six hours after injection revealed significant changes over time (p = 0.047) after a mean ziconotide dose of 2.75 μg
  • VASPI-mean was significantly lower than pre-injection VASPI-now (p = 0.019)
  • The Patients' Global Impression of Change (PGIC) mode was “no change,” both after 6 and 24 hours

Note: No serious AE occurred

Conclusion: 

The proportion of responders in the study was low, but there was a subgroup of responders. Ziconotide bolus injection trailing is feasible.

Ziconotide directly inhibits norepinephrine release, resulting in decrease in Mitogen-activated protein, but this is said to be negligible when ziconotide is given intrathecally as opposed to intravenously. According to Summary of Product Characteristics, hypotension is a common AE. However, it is important to stress that there wasn’t any clinically significant change in MAP or heart rate. The Polyanalgesic Consensus Conference (PACC) recommendations on trialing for intrathecal analgesia suggest that a patient can be discharged from hospital 12 hours after a single-shot ziconotide trial.

Neuromodulation. 2015; 18: 404–413
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