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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 -
Pharmacological Reviews Oct 2015Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described... (Review)
Review
Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.
Topics: Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Channels, T-Type; Cardiovascular Diseases; Cyclic AMP-Dependent Protein Kinases; GTP-Binding Proteins; Hearing Disorders; Humans; Metabolic Diseases; Nervous System Diseases; Night Blindness; Phospholipids; Receptor Protein-Tyrosine Kinases
PubMed: 26362469
DOI: 10.1124/pr.114.009654 -
Current Neuropharmacology 2017Intrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and... (Review)
Review
BACKGROUND
Intrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and outcomes, clinicians are motivated to rethink the traditional spinal infusion pump patient selection criteria and indications. We review the current understanding of the pharmacology of commonly employed intrathecal agents and the clinical relevance.
METHODS
Search strategies for data acquisition included Medline database, PubMed, Google scholar, along with international and national professional meeting content, with key words including pharmacology of opioids, intrathecal therapy, ziconotide, pharmacokinetics, and intrathecal drug delivery. The search results were limited to the English language.
RESULTS
Over 300 papers were identified. The literature was condensed and digested to evaluate the most commonly used medications in practice, sto serve as a foundation for review. We review on-label medications: ziconotide and morphine, and off label medications including fentanyl, sufentail, and hydromorphine.
CONCLUSION
Intrathecal therapy has level-one evidence for use for malignant pain and nonmalignant pain, with continued cost savings and improved safety. To most effectively serve our patients, a clear appreciation for the pharmacology of these commonly employed medication is paramount.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Databases, Bibliographic; Humans; Pain; Spinal Cord; omega-Conotoxins
PubMed: 26861471
DOI: 10.2174/1570159x14666160210142339 -
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 -
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 -
Pain Physician 2010Before long-term intrathecal analgesic therapy is initiated, patients often undergo a spinal analgesia trial. Ziconotide is a nonopioid intrathecal analgesic used to... (Comparative Study)
Comparative Study Review
BACKGROUND
Before long-term intrathecal analgesic therapy is initiated, patients often undergo a spinal analgesia trial. Ziconotide is a nonopioid intrathecal analgesic used to manage severe chronic pain, and a variety of methods have been used to trial ziconotide.
OBJECTIVES
The purpose of this review is to compare and discuss the different methods of ziconotide trialing.
METHODS
Various databases (i.e., PubMed, Excerpta Medica, Cumulative Index to Nursing and Allied Health Literature, Biological Abstracts, Cochrane Database of Systematic Reviews, EMBASE, International Pharmaceutical Abstracts, and Google Scholar) and association meeting abstracts were searched with the use of the terms ziconotide, Prialt, trial, and trialing. In addition, a search was conducted for abstracts/posters presented at a variety of association meetings.
RESULTS
Nine sources, including one expert opinion piece, were identified. Three methods of ziconotide trialing were discovered: continuous infusion, limited-duration infusion, and bolus injection. Results indicate that patients often achieve analgesia during trialing, regardless of the trialing method. Adverse events reported during ziconotide trialing studies were similar to those reported during ziconotide clinical trials. Preliminary evidence suggests that both effectiveness and safety may be dose-related. In 3 studies the value of ziconotide trialing in predicting long-term patient response to ziconotide therapy was investigated; however, the results were preliminary. The expert opinion piece from 2008 recommended trialing ziconotide via continuous infusion, using a starting dose of 1.2 mcg/d and dose increases of 1.2 mcg/d every 12 to 24 hours, for up to 3 days; the trial may be extended in some cases.
LIMITATIONS
Given the small samples size and lack of controlled ziconotide trialing studies, it is currently not possible to determine the relative safety and effectiveness of different methods of ziconotide trialing, nor is it possible to determine if trialing is predictive of patient response to long-term ziconotide therapy.
CONCLUSIONS
All 3 methods of ziconotide trialing appear to be viable options, and no method can be considered superior on the basis of the evidence presented in this review. Controlled studies comparing ziconotide trialing methods may be warranted.
Topics: Analgesics, Non-Narcotic; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Humans; Injections, Spinal; Pain, Intractable; Spinal Cord; Time; omega-Conotoxins
PubMed: 20119460
DOI: No ID Found -
European Review For Medical and... Feb 2023The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated... (Review)
Review
The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated therapeutically active ingredients from these venoms and continue to explore them for drug leads. These efforts lead to the discovery of therapeutic molecules that the US-FDA has approved to treat different diseases, such as hypertension (Captopril), chronic pain (Ziconotide), and diabetes (Exenatide). The main active constituents of most venoms are proteins and peptides, which gained more attention because of advancements in biotechnology and drug delivery. The utilization of newer screening approaches improved our understanding of the pharmacological complexity of venom constituents and facilitated the development of novel therapeutics. Currently, with many venom-derived peptides undergoing different phases of clinical trials, more are in pre-clinical drug development phases. This review highlights the various sources of venoms, their pharmacological actions, and the current developments in venom-based therapeutics.
Topics: United States; Animals; Humans; Venoms; Chronic Pain; Drug Delivery Systems; Hypertension; United States Food and Drug Administration
PubMed: 36876699
DOI: 10.26355/eurrev_202302_31408