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Pain Medicine (Malden, Mass.) Apr 2019To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain. (Review)
Review
OBJECTIVES
To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain.
METHODS
Medline was searched (through July 2017) for "ziconotide" or "morphine" AND "intrathecal" AND "chronic pain," with results limited to studies in human populations.
RESULTS
The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non-cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non-cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time.
CONCLUSION
Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non-cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Chronic Pain; Humans; Injections, Spinal; Morphine; Pain Management; omega-Conotoxins
PubMed: 30137539
DOI: 10.1093/pm/pny132 -
Nature Aug 2021The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a...
The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore blocker that has been clinically used for treating intractable pain. Here we present cryo-electron microscopy structures of human Ca2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca channels.
Topics: Analgesics, Non-Narcotic; Calcium Channel Blockers; Calcium Channels, N-Type; Cryoelectron Microscopy; Humans; Models, Molecular; Phosphatidylinositol 4,5-Diphosphate; Protein Conformation; Protein Stability; omega-Conotoxins
PubMed: 34234349
DOI: 10.1038/s41586-021-03699-6 -
Current Neuropharmacology 2017Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel... (Review)
Review
INTRODUCTION
Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel blocking agent which has been shown in clinical trials to be effective in treating chronic neuropathic pain.
METHODS
EMBASE, MEDLINE, CINAHL Plus and Web of Science electronic databases were searched for English language studies. Reference sections of articles were examined for further papers and the manufacturer of ziconotide was contacted for further unpublished data. Three randomised controlled trials in ziconotide monotherapy were included and subjected to a random effects meta-analysis.
RESULTS
All three studies used the similar main outcome measure (visual analogue scale of pain intensity; VASPI) and were therefore comparable. A Jadad score was performed for each paper. Frequent serious adverse events (SAEs) were observed which resulted in two of the studies revising the protocol. The metaanalysis revealed a pooled odds ratio (responders on ziconotide vs. placebo) of 2.77 (95% CI, 1.37 to 5.59).
DISCUSSION
The results suggest that ziconotide is beneficial for pain reduction in chronic neuropathic pain. However, there remain some methodological issues that may call into question the validity of the results. It is evident that more work needs to be conducted to further validate the efficacy of ziconotide and to discover new areas of use.
Topics: Analgesics, Non-Narcotic; Calcium Channel Blockers; Chronic Pain; Humans; Neuralgia; Randomized Controlled Trials as Topic; omega-Conotoxins
PubMed: 26861472
DOI: 10.2174/1570159x14666160210142056 -
Journal of Pain & Palliative Care... Mar 2014Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more...
Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topics addressed in this issue are ziconotide, a novel approach to pain management that is derived from a snail toxin, its uses and possible side effects.
Topics: Analgesia, Patient-Controlled; Analgesics, Non-Narcotic; Chronic Pain; Humans; Injections, Spinal; omega-Conotoxins
PubMed: 24397285
DOI: 10.3109/15360288.2013.864749 -
CNS Drugs 2006Ziconotide, an intrathecal analgesic for the management of chronic intractable pain, binds with high affinity to N-type calcium channels in neuronal tissue and obstructs...
Ziconotide, an intrathecal analgesic for the management of chronic intractable pain, binds with high affinity to N-type calcium channels in neuronal tissue and obstructs neurotransmission. In three pivotal, well designed trials of 5-6 or 21 days' duration, titrated ziconotide was significantly more effective than placebo in treating chronic malignant or nonmalignant pain as assessed by mean percentage improvements from baseline in Visual Analogue Scale Pain Intensity scores. Improvements in secondary endpoints (e.g. proportion of patients who responded or achieved pain relief and the change in opioid use) generally support the efficacy of ziconotide over placebo. Ziconotide maintains its analgesic efficacy in preliminary results from long-term, open-label trials (data available for up to 12 months). Most ziconotide-related adverse events are neurological, mild to moderate in severity, resolve over time and reverse without sequelae on drug discontinuation. Low initial doses of ziconotide and gradual titration to onset of analgesia reduces the incidence and severity of adverse events. No evidence of respiratory depression has been reported with intrathecal ziconotide.
Topics: Animals; Clinical Trials as Topic; Humans; Neuroprotective Agents; Pain Measurement; Pain, Intractable; omega-Conotoxins
PubMed: 16599651
DOI: 10.2165/00023210-200620040-00007 -
The Clinical Journal of Pain Sep 2010Ziconotide is a nonopioid intrathecal analgesic used to manage moderate to severe chronic pain. Although ziconotide is approved in the United States for intrathecal... (Review)
Review
BACKGROUND
Ziconotide is a nonopioid intrathecal analgesic used to manage moderate to severe chronic pain. Although ziconotide is approved in the United States for intrathecal monotherapy only, it is often used in combination with other intrathecal drugs in clinical practice.
OBJECTIVES
The need exists for a critical assessment of the currently available published literature on ziconotide combination therapy. This review summarizes and evaluates the publications from preclinical and clinical peer-reviewed experiments that have investigated the safety and effectiveness of ziconotide in combination with a variety of other drugs.
METHODS/RESULTS
Eleven relevant publications were identified through a systematic search of multiple databases.
DISCUSSION
In preclinical studies, additive or synergistic antinociceptive effects were discovered when ziconotide was used in combination with morphine, clonidine, or baclofen; however, no additional antinociceptive effects were observed when bupivacaine was added to ziconotide therapy. Safety data from animal studies revealed that ziconotide did not exacerbate morphine-induced respiratory depression, or clonidine-induced hypotension or bradycardia; however, ziconotide did potentiate morphine-induced hypotension and inhibition of gastrointestinal tract motility. Results from 2 open-label trials indicated that combination ziconotide and morphine therapy produced greater analgesia than was produced by the use of either drug alone. Preliminary support for the use of ziconotide in combination with morphine, baclofen, or hydromorphone was provided by case studies.
CONCLUSIONS
Although clinical and preclinical studies provide some support for the use of ziconotide in combination with morphine, hydromorphone, clonidine, or baclofen, strong evidence-based data are limited. Controlled, long-term clinical trials are warranted.
Topics: Analgesics; Baclofen; Clonidine; Drug Therapy, Combination; Humans; Injections, Spinal; Morphine; Pain; Treatment Outcome; omega-Conotoxins
PubMed: 20639730
DOI: 10.1097/AJP.0b013e3181e017df -
Expert Opinion on Pharmacotherapy Apr 2020
PubMed: 31935126
DOI: 10.1080/14656566.2019.1707182 -
Neuromodulation : Journal of the... Jul 2016Ziconotide is a non-opioid analgesic for intrathecal (IT) administration. The aim of this review is to provide a comprehensive and clinically relevant summary of the... (Review)
Review
INTRODUCTION
Ziconotide is a non-opioid analgesic for intrathecal (IT) administration. The aim of this review is to provide a comprehensive and clinically relevant summary of the literature on dosing and administration with IT ziconotide in the management of refractory chronic pain, and to describe novel dosing strategies intended to improve clinical outcomes.
MATERIALS AND METHODS
A Medline search was conducted for "ziconotide," supplemented by manual searching of published bibliographies and abstracts from conferences.
RESULTS
Early experience with IT ziconotide in clinical trials combined with improved understanding of drug pharmacokinetics in the cerebrospinal fluid have led to a reappraisal of approaches to trialing and initiation of continuous-infusion therapy in an effort to improve tolerability. The traditional paradigm of trialing by inpatient continuous infusion may be shifting toward outpatient trialing by IT bolus, although definitions of success and specific protocols remain to be agreed upon. Expert consensus on IT continuous infusion with ziconotide suggests a starting dose of 0.5 to 1.2 mcg/day followed by dose titration of ≤0.5 mcg/day on a no more than weekly basis, according to individual patients' pain reductions and regimen tolerability.
DISCUSSION
Newer modalities that include patient-controlled analgesia and nocturnal flex dosing have been shown to hold promise of further improvements in ziconotide efficacy and tolerability.
CONCLUSIONS
Clinical trials and experience confirm the feasibility and usefulness of IT ziconotide in the management of refractory chronic pain. Emerging evidence suggests that additional IT delivery options may further expand the usefulness and benefits of ziconotide.
Topics: Analgesics, Non-Narcotic; Chronic Pain; Databases, Bibliographic; Dose-Response Relationship, Drug; Humans; Infusions, Spinal; Pain, Intractable; Treatment Outcome; omega-Conotoxins
PubMed: 26856969
DOI: 10.1111/ner.12392