Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain.
ABSTRACT To assess the safety and efficacy of adding intrathecal ziconotide to intrathecal morphine in patients being treated with a stable intrathecal morphine dose.
Phase II, multicenter, open-label study with a 5-week titration phase and an extension phase.
Patients with suboptimal pain relief receiving stable intrathecal morphine doses (2-20 mg/day).
Intrathecal morphine dosing remained constant during the titration phase. Ziconotide therapy began at 0.60 microg/day and was titrated to a maximum of 7.2 microg/day. During the extension phase, ziconotide and intrathecal morphine dosing were adjusted at the investigator's discretion.
Safety was assessed primarily via adverse event reports. Efficacy was analyzed via percentage change on the visual analog scale of pain intensity and in weekly systemic opioid consumption.
Twenty-six patients were enrolled. Treatment-emergent adverse events were generally mild or moderate; the most common (> or = 15% of patients in either study phase) study drug-related (i.e., ziconotide/morphine combination [or ziconotide monotherapy in the extension phase only]) events were confusion, dizziness, abnormal gait, hallucinations, and anxiety. The mean percentage improvement in visual analog scale of pain intensity scores was 14.5% (95% confidence interval: -9.4% to 38.5%) from baseline to week 5 and varied during the extension phase (range: -0.4% to 42.8%). Mean percentage change from baseline in systemic opioid consumption was -14.3% at week 5 and varied considerably during the extension phase.
Ziconotide, combined with stable intrathecal morphine, may reduce pain and decrease systemic opioid use in patients with pain inadequately controlled by intrathecal morphine alone.
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ABSTRACT: Intraspinal drug infusion using fully implantable pump and catheter systems is a safe and effective therapy for selected patients with chronic pain. The options for this approach are increasing, as drugs that are commercially available for systemic administration are adapted to this use and other drugs that are in development specifically for intraspinal administration become available. In 2000 a Polyanalgesic Consensus Conference was organized to evaluate the existing literature and develop guidelines for drug selection. The major outcome of this effort, an algorithm for drug selection, was based on the best available evidence at the time. Rapid changes have occurred in the science and practice of intraspinal infusion and a Polyanalgesic Consensus Conference 2003 was organized to pursue the following goals: 1) to review the literature on intraspinal drug infusion since 1999, 2) to revise the 2000 drug-selection algorithm, 3) to develop guidelines for optimizing drug dosage and concentration, 4) to create a process for documenting minimum evidence supporting the use of a drug for intraspinal infusion, and 5) to clarify issues pertaining to compounding of drugs. Based on the best available evidence and expert opinion, consensus recommendations were developed in all these areas. The panel's conclusions may provide a foundation for clinical practice and a rational basis for new research.Journal of Pain and Symptom Management 07/2004; 27(6):540-63. · 2.60 Impact Factor
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ABSTRACT: The interaction of two synthetic omega-conopeptides SNX-111 (MVIIA) and SNX-230 (MVIIC) both derived from the marine snail Conus magus, with non-L-type neuronal voltage-sensitive calcium channels (VSCC) in rat brain synaptosomal preparations has been investigated with the aid of well-characterized 125I derivatives of the two peptides. To assess the effects of iodination on the binding characteristics of SNX-111 and SNX-230, the corresponding peptides containing monoiodotyrosine in place of tyrosine, namely, SNX-259 ([127I]SNX-111) and SNX-260 ([127I]SNX-230), respectively, were prepared by solid-phase synthesis. Saturation analysis showed that [125I]SNX-111 and [125I]SNX-230 bound to two distinct classes of high-affinity sites with apparent Kd's of 9 and 11 pM and Bmax's of 0.54 and 2.2 pmol/mg protein, respectively. Kinetic analysis revealed that both peptides exhibited high association rates as well as rapid dissociation rates in contrast to the 125I derivative of the synthetic omega-conopeptide from Conus geographus, GVIA (SNX-124), which binds irreversibly to N-type channels in rat brain synaptosomes. Competition binding experiments with [125I]SNX-111 and [125I]SNX-124 established that both of them bind to the same site, namely, N-type VSCC. The site detected by the binding of [125I]SNX-230 is distinct from N-type VSCC since SNX-111 has very low affinity (K(i) = 135 nM) in competition studies. Recent findings that a novel high-voltage-activated calcium channel in rat cerebellar granule neurons is resistant to blockers of L-, N-, and P-type VSCC but is highly sensitive to SNX-230 suggest that the [125I]SNX-230 binding site may represent this novel type of calcium channel or another, as yet undescribed, VSCC.Molecular and Cellular Neuroscience 07/1994; 5(3):219-28. · 3.84 Impact Factor
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ABSTRACT: To analyze, prospectively, the long-term effects of continuous intrathecal morphine infusion therapy in 16 patients with chronic nonmalignant pain syndromes. Twenty-five patients with severe, chronic, nonmalignant pain that had proven refractory to conservative management were considered candidates for trial of intrathecal spinal morphine. Sixteen patients achieved more than 50% pain relief after a trial period of intrathecal morphine infusion. They were implanted with fully implantable and programmable pumps through which morphine was delivered intrathecally on a continuous basis. These patients were followed prospectively and underwent careful evaluation of their functional and mental status, and pain intensity measurements using standardized techniques before treatment and every 6 months thereafter in the follow-up period. The follow-up period ranged from 13 months to 49 months (mean 29.14 months +/- 12.44 months) for the patients who had implanted morphine pumps. The mean morphine dosage initially administered was 1.11 mg/day (range 0.2--6.5 mg/day); after 6 months, it was 3.1 mg/day (range 0.4--8.75 mg/day). In long-term observation, no patient had a constant dosage history. The patients who received intrathecal morphine for longer than 2 years all showed an increase in morphine dosage to more than 10 mg/day. The best long-term results were seen with deafferentation pain and mixed pain, with 75% and 61% pain reduction (visual analog scale), respectively. Nociceptive pain patients had best pain relief initially (78% pain reduction) but it tended to decrease over the follow-up period to 57% pain reduction at final follow-up. The average pain reduction for all groups after 6 months was 67.5% and at last follow-up, it was 57.5%. Ten patients were satisfied with the delivery system and eleven reported improvement in their quality of life. In two patients, morphine was not able to adequately control the pain without producing undesirable side effects requiring the addition of clonidine to their infusion medication. In this series, 12 patients were considered successes and 4 patients were considered failures. In two patients, the intrathecal opioid therapy was unable to produce satisfactory pain relief and in the other two patients the pumps had to be explanted because of intolerable side effects. In our experience, the administration of intrathecal opioid medications for nonmalignant pain is justified in carefully selected patients.Surgical Neurology 03/2001; 55(2):79-86; discussion 86-8. · 1.67 Impact Factor