A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain

Rauck, Richard; Wallace, Mark; Leong, Michael S.; Minehart, M.; Webster, Lynn R.; Charapata, Steven G.; Abraham, Jacob E.; Buffington, Daniel E.; Ellis, David; Kartzinel, Ronald

doi:10.1016/j.jpainsymman.2005.10.003

Cited by 272 publications

(249 citation statements)

References 22 publications

(22 reference statements)

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“…This agent is only effective via intrathecal delivery and is thought to exert its anti-nociceptive properties by binding to and directly blocking voltage-sensitive calcium channels without interfacing with opioid receptors. 7 This medication has demonstrated effectiveness in refractory pain conditions, 8 including in AIDS and cancer. 9 A recently published clinical trial of ziconotide included a very high percentage of neuropathic pain patients.…”

Section: Introductionmentioning

confidence: 99%

Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report

Saulino

2007

Spinal Cord

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Study design: Case report. Objectives: To report a novel management strategy for neuropathic pain management after spinal cord injury. Setting: Outpatient spinal cord injury (SCI) clinic. Methods: The patient demonstrated two neuropathic pain syndromes, namely at-and belowlevel pain. These syndromes were recalcitrant to conservative measures and a decision was made to proceed with intrathecal therapies. Results: The patient's at-level pain was responsive to intrathecal hydromorphone but the below-level pain was unaffected by this intervention. Intrathecal ziconotide provided an opposite response with a positive effect observed on the below-level pain and minimal effect on the at-level pain. The combination of intrathecal ziconotide and hydromorphone provided effective relief for both components of the patient's SCI associated neuropathic pain. Conclusions: The combination of intrathecal ziconotide and hydromorphone has the potential to provide significant pain relief for patients with neuropathic pain associated with spinal cord injury.

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Section: Introductionmentioning

confidence: 99%

Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report

Saulino

2007

Spinal Cord

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“…The compound, termed a conopeptide, blocks N-type voltage-gated calcium channels and is likely effective as an analgesic through an action that prevents transmission across the first synapse in the pain pathway. Consistent with the mechanism of action, the compound is effective in patients with intractable pain when delivered either alone or in combination with other analgesics and in whom intrathecal therapy is acceptable (52,55,56). Maximal therapeutic benefit requires careful titration in order to minimize the range of CNS side effects associated with its use.…”

Section: Targeting Ion Channelsmentioning

confidence: 95%

The discovery and development of analgesics: new mechanisms, new modalities

Burgess¹,

Williams²

2010

J. Clin. Invest.

105

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Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met. IntroductionDrug discovery and development continue to be a challenge, with increasingly high investments in R&D and increased numbers of submissions failing to translate into the delivery of novel chemical entities onto the market. The wide availability of generic and overthe-counter analgesics based on non-steroidal antiinflammatories (NSAIDs), acetaminophen, and "weak" opiates (and their combinations) provides many individuals with an accessible source of relief for mild to moderate pain. However, many patients with chronic conditions such as osteoarthritis remain poorly treated (1, 2).Opiates continue to provide an important choice for the treatment of moderate to severe pain but are associated with a number of unwanted side effects such as constipation, nausea, vomiting, itching, and somnolence (3), and negative effects on patients' wellbeing, including sleep quality and ability to concentrate, which can be of such significance that they result in treatment discontinuation (4). Indeed, a recent Internet survey indicated that patients taking opiates for pain (and prescribing physicians) are willing to "trade-off " pain relief for a better toleration profile, with 50% of patients and physicians reporting that improved side effects represent the biggest unmet need (5).Neuropathic pain has a complex pathophysiology and is difficult to treat (6). It has been estimated that about one-third of patients are likely to achieve 50% pain relief with monotherapy (7); for example, in patients treated with the first-line therapy pregabalin, the patient global impression of change rating of much improved or very much improved was about 35% in postherpetic neuralgia, 50% in painful diabetic neuropathy, and 40% in fibromyalgia (8). A recent review identified a 66% increase in published randomized, placebo-controlled trials in a range of neuropathic pain populations over the last five years and concluded that only a limited improvement in the relief of pain had been achieved and that a large proportion of patients remained poorly treated (9).The challenge for drug discovery and development can therefore be very simply stated: we need to bring forward analgesics that will provide more effective pain relief, are safe...

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“…No ITA-drug has been as thoroughly investigated as ziconotide, including three pivotal RCTs [199,229,246] and many open-label studies [2,68,73,77,196,214,247,258,260]. Typical opioid adverse events (AEs) such as respiratory depression, tolerance or dependence have not been described for ziconotide [215].…”

Section: Ziconotidementioning

confidence: 99%

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

Bäckryd¹

2015

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The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain. In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question. In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor. In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses

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A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain

Cited by 272 publications

References 22 publications

Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report

Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report

The discovery and development of analgesics: new mechanisms, new modalities

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

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