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Abstract

• When oral morphine does not relieve severe pain and when there is no specific treatment for the underlying cause, the first option is to try subcutaneous or intravenous administration. If this standard treatment fails or is poorly tolerated, intrathecal injection is usually preferred as the direct route to the central nervous system. However, one-quarter to one half of patients still do not achieve adequate pain relief, and adverse effects are relatively frequent.
  

• Ziconotide is not an opiate and is not related to the usual classes of drugs that interfere with nervous transmission in the posterior horn of the spinal cord. Marketing authorisation has been granted for “severe, chronic pain in patients who require intrathecal analgesia”. The Summary of Product Characteristics (SPC) recommends continuous infusion via an intrathecal catheter connected to a pump.
  

• Clinical evaluation of ziconotide does not include any trials versus morphine in patients with nociceptive pain, or any trials versus tricyclic or antiepileptic drugs in patients with neurogenic pain.
  

• In a trial in 220 patients in whom systemic morphine had failed, the mean pain score on a 100-mm visual analogue scale was 69.8 mm after three weeks on ziconotide, compared to 75.8 mm with placebo. This difference, although statistically significant, is clinically irrelevant. The proportion of “responders” (reduction of at least 30% in the initial pain score) was respectively 16.1% and 12.0% (no statistically significant difference).
  

• The two other placebo-controlled trials 112 patients with pain linked to cancer or HIV infection, and 257 patients with non-cancer pain. After a titration phase lasting 5 to days, a combined analysis of the two trials showed that the mean pain score was 48.8 mm with ziconotide and 68.4 mm with placebo (statistically significant difference). However, many patients did not complete the titration phase. Efficacy also appeared to differ according to the type of pain; ziconotide was more effective on cancer pain than on neurogenic pain.
  

• The main adverse effects of ziconotide in clinical trials were cerebellovestibular disorders such as ataxia, dizziness, and gait disorders, as well as confusion, hallucinations increased in cases of overdose), nausea, vomiting, postural hypotension, and urine retention. About 40% of patients had an elevation in muscle creatine kinase activity, through an unknown mechanism.
  

• Intrathecal administration carries a risk of infection (especially meningitis). Some patients might experience a paradoxical increase in pain with ziconotide.
  

• In practice, the efficacy of ziconotide in relieving neurogenic pain remains to be established. In cancer pain, the available evidence showing that ziconotide is effective after opiate failure is too weak in view of the potential risks. It is better to re-examine and, if possible, correct the reasons for opiate treatment failure rather than prescribe ziconotide.
  
  ©Prescrire November 2008
  
  Source: Prescrire International 2008; 17 (97): 179-182.
  
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