ziconotide and Chronic-Pain

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Calcium Channel Blockers; Chronic Pain; Drug Approval; Humans; Injections, Spinal; Morphine; omega-Conotoxins

Targeted intrathecal (IT) drug delivery systems (IDDS) are well established as an effective treatment of patients with chronic nonmalignant or malignant pain, and as a tool for management of patients with severe spasticity. The risk to benefit ratio of IDD makes it a relatively safe therapy for both cancer- and noncancer-related pain, but it is not free of risks, so it should be managed at specific centers. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up to date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up and pharmacological recommendations published during recent years that provide evidence-based decision-making process in the management of chronic pain and spasticity in patients.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Baclofen; Cancer Pain; Chronic Pain; Drug Delivery Systems; GABA-B Receptor Agonists; Humans; Infusion Pumps, Implantable; Muscle Relaxants, Central; Muscle Spasticity; Neuroprotective Agents; omega-Conotoxins; Pain Management; Risk Factors

To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain.. Medline was searched (through July 2017) for "ziconotide" or "morphine" AND "intrathecal" AND "chronic pain," with results limited to studies in human populations.. 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.. 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; omega-Conotoxins; Pain Management

Intrathecal drug delivery has been well established an effective and safe method for the treatment of pain, including palliative cancer-related and chronic nonmalignant pain. In this article, we discuss the role of intrathecal pain therapy in the management of chronic, refractory nonmalignant pain. Common indications, patient selection criteria, medication options, complications, and adverse events are discussed within the context of results from randomized controlled trials, clinical consensus guidelines, and best available literature to date.

Topics: Analgesics; Chronic Pain; Humans; Injections, Spinal; Morphine; omega-Conotoxins; Pain Management; Treatment Outcome

Opioids are the primary choice for managing chronic cancer pain. However, many nonopioid therapies are currently prescribed for chronic cancer pain with little published evidence comparing their efficacy.. Electronic databases were searched for randomized controlled trials (RCTs) comparing any systemic pharmaceutical intervention and/or combination thereof in treating chronic cancer pain. The primary outcome was global efficacy reported as an odds ratio (OR). The secondary outcome was change in pain intensity reported as a standardized mean difference (SMD).. We included 81 RCTs consisting of 10,003 patients investigating 11 medication classes. Most RCTs (80%) displayed low risk of bias. The top-ranking classes for global efficacy were nonopioid analgesics (network OR, 0.30; 95% credibility interval [CrI], 0.13 to 0.67), nonsteroidal anti-inflammatory drugs (network OR, 0.44; 95% CrI, 0.22 to 0.90), and opioids (network OR, 0.49; 95% CrI, 0.27 to 0.86), whereas the top-ranked interventions were lidocaine (network OR, 0.04; 95% CrI, 0.01 to 0.18; surface under the cumulative ranking curve analysis [SUCRA] score, 98.1), codeine plus aspirin (network OR, 0.22; 95% CrI, 0.08 to 0.63; SUCRA score, 81.1), and pregabalin (network OR, 0.29; 95% CrI, 0.08 to 0.92; SUCRA score, 73.8). In terms of reducing pain intensity, we found that no class was superior to placebo, whereas the following top-ranked interventions were superior to placebo: ziconotide (network SMD, -24.98; 95% CrI, -32.62 to -17.35; SUCRA score, 99.8), dezocine (network SMD, -13.56; 95% CrI, -23.37 to -3.69; SUCRA score, 93.5), and diclofenac (network SMD, -11.22; 95% CrI, -15.91 to -5.80; SUCRA score, 92.9).. There are significant differences in efficacy among current regimens for chronic cancer pain. Our evidence suggests that certain nonopioid analgesics and nonsteroidal anti-inflammatory drugs can serve as effectively as opioids in managing chronic cancer pain.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bayes Theorem; Bridged Bicyclo Compounds, Heterocyclic; Cancer Pain; Chronic Pain; Codeine; Comparative Effectiveness Research; Diclofenac; Female; Humans; Lidocaine; Male; Middle Aged; Neoplasms; Network Meta-Analysis; Odds Ratio; omega-Conotoxins; Pregabalin; Randomized Controlled Trials as Topic; Tetrahydronaphthalenes; Treatment Outcome; Young Adult

The majority of patients seeking medical care for chronic pain consult a primary care physician (PCP). Because systemic opioids are commonly prescribed to patients with chronic pain, PCPs are attempting to balance the competing priorities of providing adequate pain relief while reducing risks for opioid misuse and overdose. It is important for PCPs to be aware of pain management strategies other than systemic opioid dose escalation when patients with chronic pain fail to respond to conservative therapies and to initiate a multimodal treatment plan.. The Medline database and evidence-based treatment guidelines were searched to identify publications on intrathecal (IT) therapy for the management of chronic pain. Selection of publications relevant to PCPs was based on the authors' clinical and research expertise.. IT administration delivers analgesic medication directly into the cerebrospinal fluid, avoiding first-pass effect and bypassing the blood-brain barrier, thereby requiring lower medication doses. Morphine, a µ-opioid receptor agonist, and ziconotide, a non-opioid, selective N-type calcium channel blocker, are the only analgesics approved by the US Food and Drug Administration to treat chronic refractory pain by the IT route. Patients who are potential candidates for IT therapy may benefit from evaluation by an interventional pain physician. PCPs can play an important role in patient selection and referral for IT therapy and provide ongoing collaborative care for patients receiving IT therapy, including monitoring for efficacy and adverse events and facilitating communication with the treating specialist.. Collaboration between PCPs and pain specialists may improve outcomes of and patient satisfaction with IT therapy and other interventional treatments.

Topics: Analgesics; Chronic Pain; Humans; Infusions, Spinal; Morphine; omega-Conotoxins; Pain Management; Patient Selection; Physician's Role; Physicians, Primary Care; Referral and Consultation

Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European Medicines Agency in 2005 for the treatment of severe chronic pain in patients needing intrathecal analgesia (ITA). The aim of this paper is to provide a practitioner-oriented, educational, narrative, up-to-date review on the use of ziconotide in clinical pain medicine. Of special concern regarding safety is the partial incongruity between dosing statements in the Summary of Product Characteristics and novel low-dosage, slow uptitration recommendations. Even though ziconotide has obvious advantages compared to opioids, pain practitioners pondering the use of ziconotide nonetheless have to balance its proved potential analgesic effect against its neurological side effects, with special consideration being given to dosing and neuropsychiatric dangers. Using a seesaw analogy, the paper discusses what factors pain physicians should weigh in when considering ziconotide as ITA drug, the non-opioid advantages of ziconotide being counterbalanced by its potential psychiatric side effects. Ziconotide is an important part of the armamentarium of modern interventional pain medicine. If ITA is deemed necessary, ziconotide is a rational alternative, at least in chronic (neuropathic) non-cancer pain. However, in many European countries, ziconotide treatment is only available in a few (if any) centres. The safety profile of ziconotide is not fundamentally more worrying than that of opioids or cannabinoids; it is just different. This paper provides a concise, up-to-date and clinically-oriented summary of the use of ziconotide in clinical practice, not least concerning safety and dosage issues.

Topics: Analgesics, Non-Narcotic; Chronic Pain; Europe; Humans; omega-Conotoxins; Practice Patterns, Physicians'; Risk Assessment

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.. 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.. 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).. 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; omega-Conotoxins; Randomized Controlled Trials as Topic

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.. A Medline search was conducted for "ziconotide," supplemented by manual searching of published bibliographies and abstracts from conferences.. 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.. 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.. 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; omega-Conotoxins; Pain, Intractable; Treatment Outcome

Targeted intrathecal (IT) drug delivery systems (IDDS) are an option in algorithms for the treatment of patients with moderate to severe chronic refractory pain when more conservative options fail. This therapy is well established and supported by several publications. It has shown efficacy and is an important tool for the treatment of spasticity, and both cancer and nonmalignant pain. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up-to-date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up, and pharmacological recommendations published during recent years that provide evidence-based decision making process in the management of chronic pain and spasticity in patients.

Topics: Analgesics, Opioid; Baclofen; Bupivacaine; Catheters, Indwelling; Chronic Pain; Clonidine; Drug Delivery Systems; Humans; Inflammation; Infusion Pumps, Implantable; Injections, Spinal; Neoplasms; omega-Conotoxins; Psychiatric Status Rating Scales; Spine

Intrathecal drug delivery represents an advanced modality for refractory chronic pain patients as well as intractable spasticity. This article reviews the advantages and indications for intrathecal therapy, as well as recommendations for proper patient selection using a multidisciplinary team to provide a global assessment of the impact of chronic pain on the patient's well-being. The goals and expectations of trialing are discussed alongside advantages and disadvantages of several trialing techniques. A discussion of outcomes is presented for patients with chronic pain due to both malignant and nonmalignant causes.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Chronic Pain; Humans; Infusion Pumps, Implantable; Infusions, Spinal; Morphine; Neuralgia; Nociceptive Pain; omega-Conotoxins; Pain; Patient Selection; Spinal Cord; Treatment Outcome

Ziconotide is an N-type calcium channel antagonist to treat chronic pain that is delivered intrathecally. It is the only intrathecal, FDA-approved, non-opioid analgesic and is recommended as first-line therapy. Despite these advantages, a small therapeutic window limits ziconotide's clinical utility, with adverse event (AE) challenges that include, but are not limited to, dizziness, nausea, and somulence.. Pharmacokinetics, pharmacodynamics, efficacy, safety, trialing, and chronic infusion after searching EMBASE, PubMed, and Cochrane Database of Systemic Reviews were used to search published literature from 1966 to January 1, 2013 to identify studies related to the intrathecal delivery of ziconotide.. Ziconotide is a safe and effective strategy to treat chronic pain, although limitations remain, including a small therapeutic window. Low starting doses and slow incremental increases and long titration intervals may improve tolerability. AEs may be mitigated by also employing combination therapy, although further study is needed. Concomitant use of ziconotide and morphine is an option when considering use of FDA-labeled intrathecal drugs in those resistant to monotherapy.

Topics: Analgesics, Non-Narcotic; Calcium Channel Blockers; Chronic Pain; Clinical Trials as Topic; Humans; Injections, Spinal; omega-Conotoxins

Some patients with chronic pain who are intolerant of or refractory to treatment with systemic analgesics may benefit from intrathecal therapy. Ziconotide is the first nonopioid analgesic approved by the United States Food and Drug Administration for intrathecal administration. Several randomized, double-blind, placebo-controlled clinical trials have demonstrated the efficacy and safety of ziconotide. However, the maximum recommended dosing and titration schedule provided in the prescribing information may be too aggressive for some patients, and experience has demonstrated that ziconotide is better tolerated with slower titration to a lower maximum dose. Efficacy can be assessed by an evaluation of changes in pain, functionality, and quality of life. Cognitive adverse events may be subtle; therefore, it is important that health care professionals not only monitor patients for signs and symptoms of cognitive adverse events, but also teach family members how to do the same. Careful patient assessment and monitoring can help optimize the potential benefit from treatment with ziconotide.

Topics: Analgesics, Non-Narcotic; Chronic Pain; Drug Monitoring; Humans; Injections, Spinal; omega-Conotoxins; Pain Management

Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.

Topics: Analgesics, Non-Narcotic; Chronic Pain; Drug Resistance; Humans; Injections, Spinal; omega-Conotoxins; Pain Measurement; Randomized Controlled Trials as Topic; Treatment Outcome

Previous studies have shown decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy (IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. We prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT-naive patients with neuropathic pain.. We included patients who underwent a successful ziconotide trial and were scheduled for standard-of-care IDT pump placement. Scores were collected at baseline and latest follow-up for the following measures: Short-Form 36 (SF-36), Oswestry Disability Index (ODI), Beck Depression Inventory, and Pain Catastrophizing Scale (PCS). Numeric rating scale (NRS) scores were also collected at each follow-up visit to monitor patients' pain levels and to guide ziconotide dose titration. Responders were identified as patients who had a previously established minimum clinically important difference of a ≥1.2-point reduction in NRS current scores.. Eleven of 14 patients completed long-term follow-up. There were 7 responders based on NRS minimum clinically important difference. At a mean (±standard error of the mean) follow-up of 10.91 ± 0.70 months, SF-36 emotional well-being (P = 0.04), SF-36 pain (P = 0.02), and ODI (P = 0.03) significantly improved for the entire cohort and in responders (SF-36 emotional well-being, P = 0.01; SF-36 pain, P = 0.04; ODI, P = 0.02). PCS-Rumination (P = 0.02), PCS-Helplessness (P = 0.02), and PCS-Total (P = 0.003) scores improved significantly for responders only.. We show that ziconotide IDT improves pain as well as emotional components and function. Our study adds prospective evidence to the literature on IDT for neuropathic pain, specifically its role in improving disability, emotional well-being, and catastrophizing.

Topics: Analgesics, Non-Narcotic; Catastrophization; Chronic Pain; Disability Evaluation; Emotions; Female; Humans; Injections, Spinal; Male; Middle Aged; Neuralgia; omega-Conotoxins; Pain Management; Treatment Outcome

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of -7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to -3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC.

Topics: Analgesia; Analgesics; Animals; Chronic Pain; Exosomes; Liposomes; Neuralgia; omega-Conotoxins

Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca

Topics: Animals; Calcium Channel Blockers; Chronic Pain; Mice; Micelles; omega-Conotoxins; Peptides

Topics: Analgesics, Non-Narcotic; Arachnoiditis; Chronic Pain; Female; Follow-Up Studies; Humans; Injections, Spinal; omega-Conotoxins; Pregnancy

Development of chronic pain has been attributed to dysfunctional GABA signaling in the spinal cord. Direct pharmacological interventions on GABA signaling are usually not very efficient and often accompanied by side effects due to the widespread distribution of GABA receptors in CNS. Transplantation of GABAergic neuronal cells may restore the inhibitory potential in the spinal cord. Grafted cells may also release additional analgesic peptides by means of genetic engineering to further enhance the benefits of this approach. Conopeptides are ideal candidates for recombinant expression using cell-based strategies. The omega-conopeptide MVIIA is in clinical use for severe pain marketed as FDA approved Prialt in the form of intrathecal injections. The goal of this study was to develop transplantable recombinant GABAergic cells releasing conopeptide MVIIA and to evaluate the analgesic effect of the grafts in a model of peripheral nerve injury-induced pain. We have engineered and characterized the GABAergic progenitors expressing MVIIA. Recombinant and nonrecombinant cells were intraspinally injected into animals after the nerve injury. Animals were tested weekly up to 12 weeks for the presence of hypersensitivity, followed by histochemical and biochemical analysis of the tissue. We observed beneficial effects of the grafted cells in reducing hypersensitivity in all grafted animals, especially potent in the recombinant group. The level of pain-related cytokines was reduced in the grafted animals and correlation between these pain markers and actual behavior was indicated. This study demonstrated the feasibility of recombinant cell transplantation in the management of chronic pain.

Topics: Analgesics; Animals; Chronic Pain; Cytokines; gamma-Aminobutyric Acid; omega-Conotoxins; Peptides; Peripheral Nerve Injuries; Rats; Receptors, GABA

Prialt® was approved by the European Medicine Agency in February 2005. Besides morphine, it is the only analgesic approved for long-term intrathecal infusion in the treatment of chronic pain. As it does not bind to opioid receptors, its use in the treatment of chronic pain seemed to be safer and to lead to less adverse events compared with morphine. However, it is an orphan drug and studies of its long-term use are rare.. What role does Prialt® play in the treatment of chronic pain compared with other analgesics given intrathecally? What impact do the initial dose and the rate of infusion have on the analgesic effect and on the incidence of side effects?. Medical reports were used to identify all patients receiving ziconotide monotherapy from February 2005 to the end of the analysis period in October 2018 in our department. Furthermore, a questionnaire was created and given to the patients to find out more about their experience with ziconotide.. The study included 12 patients, all of whom suffered from at least one adverse event. The most common adverse events were forgetfulness and paraesthesia, each affecting 25% of the patients. One third of the patients discontinued ziconotide therapy due to severe adverse events. The mean initial dose was 1.98 µg/day.. Ziconotide was used at the Jena University Hospital according to the latest guidelines. Nevertheless, morphine and other opioid analgesics are still more frequently used in the intrathecal management of chronic pain. There are various reasons for this, but the narrow therapeutic index, the high incidence of adverse events, and the difficulties in finding the right dose are among the most important.. HINTERGRUND: Prialt® ist seit Februar 2005 von der europäischen Arzneimittelbehörde zugelassen und ist neben Morphin das einzige Analgetikum, welches über die offizielle Marktzulassung in der intrathekalen Schmerztherapie verfügt. Da es nicht über Opioidrezeptoren wirkt, galt es zum Zeitpunkt der Markteinführung als nebenwirkungs- und risikoärmer in der Behandlung chronischer Schmerzen als Morphin. Trotzdem gilt es noch heute als Orphan Drug und Studien über den Langzeiteinsatz und hierunter aufgetretene Nebenwirkungen sind rar.. Welchen Stellenwert nimmt Prialt® verglichen mit anderen intrathekal verabreichten Analgetika ein? Wie wirken sich die Startdosis und die Geschwindigkeit der Aufdosierung auf die schmerzlindernde Wirkung und das Auftreten von Nebenwirkungen in der Langzeittherapie aus?. Zum einen wurden anhand von Arztbriefen retrospektiv alle Patienten erfasst, die zwischen Februar 2005 und dem Ende des Beobachtungszeitraums im Oktober 2018 Ziconotid in Monotherapie in der Neurochirurgie des Universitätsklinikums Jena erhielten. Zum anderen wurden diese Patienten anhand eines erstellten Fragebogens hinsichtlich ihrer Erfahrung mit Ziconotid befragt.. Bei allen zwölf in die Studie eingeschlossenen Teilnehmern kam es zu mindestens einer Arzneimittelnebenwirkung. Am häufigsten wurde über Vergesslichkeit und Sensibilitätsstörungen mit jeweils 25 % berichtet. Ein Drittel der Patienten musste die Behandlung aufgrund von Nebenwirkungen beenden. Die mittlere Initialdosis betrug 1,98 µg/Tag.. Trotz leitliniengerechter Behandlung hat sich Ziconotid am Universitätsklinikum Jena nicht gegen Morphin und andere Opioidanalgetika in der intrathekalen Schmerztherapie durchgesetzt. Die Gründe hierfür sind vielfältig, wobei die enge therapeutische Breite, das häufige Auftreten von Nebenwirkungen und die schwierige therapeutische Handhabung, vor allem im ambulanten Setting, von besonderer Bedeutung sind.

Topics: Analgesics, Non-Narcotic; Chronic Pain; Humans; Injections, Spinal; omega-Conotoxins; Pain Measurement

There have been numerous recommendations for a starting dose of intrathecal ziconotide. The therapy remains underutilized partially due to reports of inefficacy and/or intolerance. This study describes short-term outcomes of a high-volume, low-concentration bolus (HVLC-B) ziconotide starting dose technique for patients with chronic spine pain. Intrathecal pumps are available with a Patient Therapy Manager (PTM), or patient-controlled intrathecal bolus device. Commonly published recommendations for a bolus dose has been 10% of the daily dose. This article describes an inversion of the traditional 10% rule-of-thumb. This article describes using the basal rate at a lowest programmable dose and utilizing the bolus for the majority of the medication delivery. Such an inversion may be considered a high volume bolus. The lowest commercially available concentration of ziconotide from the manufacturer is 25 mcg/mL. Pope and Deer (Neuromodulation, 18, 414-420 [2015]) described use of a dilution down to 5 mcg/mL. For purposes of this article, such dilutions to one-fifth of the commercially available solution are considered sufficiently dilute to qualify for the term "low concentration." Furthermore, the patients in this analysis received dilutions down to one-fiftieth of the lowest commercially available solution.. A case series of patients with chronic spine pain with or without radicular pain received a starting dose intrathecal ziconotide regimen based on a specific HVLC-B technique. Efficacy, tolerability, and pump settings are reported and analyzed.. In total, 17 patients were identified who started ziconotide with the specified HVLC-B starting regimen. One of the 17 patients reported side effects that led to discontinuation of the therapy, although the side effect was not typical of ziconotide but rather likely attributable to other medications the patient was taking. Fifteen of the 17 reported improved pain control with intrathecal ziconotide. Sixteen of the 17 patients remained on intrathecal ziconotide throughout the 4.7-month average follow-up period. One patient who failed to obtain pain relief chose to remain on the therapy because of reported resolution of lower limb numbness.. The HVLC-B starting regimen was effective and well tolerated in this short-term study of patients with chronic spine pain. More studies are needed to better elucidate long-term outcomes in larger patient populations.

Topics: Analgesics, Non-Narcotic; Animals; Chronic Pain; Deer; Humans; Injections, Spinal; omega-Conotoxins; Pain Measurement

Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.. Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.. Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Chronic Pain; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; omega-Conotoxins

The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice.. Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores.. Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP-). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP- patients, respectively. Mean (SEM) percentage changes in NPRS scores were -29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP- patients (n = 17) at month 6 and -34.4% (9.1%) in FIP+ patients (n = 14) and -3.4% (10.2%) in FIP- patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP- (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP- (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP- patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%).. Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Chronic Pain; Female; Humans; Infusion Pumps, Implantable; Injections, Spinal; Longitudinal Studies; Male; Middle Aged; omega-Conotoxins; Pain Management; Pain Measurement

Ziconotide use in intrathecal drug therapy (IDT) has been limited by dosing related side effects. We examine our experience with ziconotide as a first line IDT monotherapy in patients with chronic pain and present our low and slow dosing algorithm aimed at reducing these patient experienced side effects while adequately managing pain.. We retrospectively reviewed demographics, dosing, and outcomes of 15 consecutive patients with complete three-month data sets implanted with intrathecal pain pumps more than three years utilizing ziconotide as a first-line monotherapy.. Ziconotide response was assessed at visit 5 (69 ± 10 days) and responders were characterized by having 30% or greater improvement in numerical rating scale scores (n = 7), or activities of daily living (ADL) (n = 7). Eight of our patients had a response in at least one measure (53%). In our eight responders, NRS score decreased from 8.4 ± 0.7 at baseline (consult visit) to 2.4 ± 1.0 at 2.6 months and 4.0 ± 1.3 at most recent follow-up, mean of 12.9 months after implant. We noted that our responders tended to have neuropathic pain with an objective etiology. Initial dosing in 12 patients was 1.2 mcg/day (range for the other three patients was 0.6-1.4). Following initial dosing, visits were at 2-4 week intervals with mean titration doses between 1.1 and 2.8 mcg/day. Slight dizziness in two patients and transient urinary retention in one patient occurred, all resolving with dose reduction. No patients had discontinued use at three-month follow-up.. We present our experience with low and slow ziconotide IDT as a first-line monotherapy, which showed no side effects resulting in discontinuation of the medication at three-month follow-up. Using a conservative dosing strategy, we were able to effectively treat 53% of patients.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Chronic Pain; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infusion Pumps, Implantable; Injections, Spinal; Male; Middle Aged; omega-Conotoxins; Retrospective Studies; Treatment Outcome

Intrathecal ziconotide is used for the treatment of chronic pain and is delivered by an implanted drug delivery device. Anesthesiologists should be familiar with the perioperative management of the pump as well as the potential adverse events related to continued ziconotide infusion during general anesthesia. A case is presented demonstrating the perioperative management of an intrathecal drug delivery device infusing ziconotide in a patient presenting for radical cystectomy with pelvic lymphadenectomy and ileal conduit diversion.

Topics: Aged; Analgesics, Non-Narcotic; Anesthesia, General; Carcinoma, Transitional Cell; Chronic Pain; Cystectomy; Deprescriptions; Humans; Infusion Pumps, Implantable; Infusions, Spinal; Intraoperative Complications; Low Back Pain; Lymph Node Excision; Male; omega-Conotoxins; Pelvis; Perioperative Care; Urinary Bladder Neoplasms; Urinary Diversion; Vasoplegia

The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.

Topics: Administration, Intranasal; Administration, Intravenous; Analgesics; Animals; Biological Availability; Chronic Pain; Drug Delivery Systems; Gels; Injections, Spinal; Male; Olfactory Mucosa; omega-Conotoxins; Pharmaceutical Solutions; Rats; Rats, Sprague-Dawley; Viscosity

Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability.. Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project.. All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5%. The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions.. We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Chronic Pain; Female; Humans; Injections, Spinal; Male; Middle Aged; omega-Conotoxins; Pain Measurement; Prospective Studies; Radiculopathy; Treatment Outcome

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

Topics: Abdominal Pain; Adrenal Cortex Hormones; Analgesia; Analgesics; Analgesics, Non-Narcotic; Anesthesia, Conduction; Anesthetics; Catheters, Indwelling; Chronic Pain; Complex Regional Pain Syndromes; Headache Disorders; Humans; Injections, Epidural; Injections, Spinal; Narcotics; Neoplasms; Nerve Block; omega-Conotoxins; Phantom Limb; Post-Dural Puncture Headache; Post-Traumatic Headache; Quality of Life; Syndrome; Trigeminal Neuralgia; Vascular Headaches

Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.

Topics: Analgesics; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line; Chronic Pain; High-Throughput Screening Assays; Humans; Neuralgia; omega-Conotoxins; Patch-Clamp Techniques; Piperidines; Pyrazoles; Rats; Structure-Activity Relationship