ziconotide and Pain

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.. 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.. 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.. 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; omega-Conotoxins; Pain; Spinal Cord

To better characterize safety profiles associated with the intrathecal (IT) administration of morphine and ziconotide and discuss how they relate to mechanisms of action.. Published data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action.. Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration. AEs associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation. AEs that occur usually can be managed and, in some cases, prevented. To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide). Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment.. IT morphine and IT ziconotide are approved by the US Food and Drug Administration for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.

Topics: Affect; Analgesics, Non-Narcotic; Analgesics, Opioid; Cognition; Consciousness; Dose-Response Relationship, Drug; Drug Tolerance; Granuloma; Hallucinations; Humans; Injections, Spinal; Morphine; omega-Conotoxins; Pain; Practice Guidelines as Topic; Respiratory Insufficiency

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 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.. 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.. Eleven relevant publications were identified through a systematic search of multiple databases.. 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.. 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; omega-Conotoxins; Pain; Treatment Outcome

Ziconotide is the only N-type calcium channel blocker approved by the US FDA for the treatment of chronic pain. The approved indication is for the management of severe chronic pain in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatments such as systemic analgesics, adjunctive therapies or intrathecal morphine.. The purpose of this article was to review the available safety, efficacy and dosing information for ziconotide.. The sources searched for literature from 1980 to January 2008 included Pub Med, MEDLINE and PREMEDLINE using the words ziconotide, conotoxins and pain.. Ziconotide is administered intrathecally by infusion pump to block nociceptive signal transmission in the spinal cord. It is a synthetic neuroactive peptide equivalent to the omega conotoxin MVIIA, a constituent of the venom of the fish-hunting marine snail Conus magus. It is highly potent, has a steep dose-response curve, a slow onset of action and a narrow margin of safety and responses to dose adjustments are slow. Patients receiving ziconotide should be under the care of physicians experienced in the management of intrathecal infusion therapy for pain control and should have convenient access to medical facilities.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Drug Interactions; Drug Therapy, Combination; Humans; Injections, Spinal; omega-Conotoxins; Pain; Randomized Controlled Trials as Topic; Treatment Outcome

As it is well known opioids are the most powerful drugs used for acute and chronic pain, although, their several serious side effects, such as respiratory depression, mental clouding, constipation, and tolerance dependence producing capacity, as well as large interpatient variability in responses limit their safe everyday use. Furthermore, the treatment of certain types of pain (e.g. neuropathic pain) is not very satisfactorily managed. Consequently, there is a continuous need to find analgesics efficient against chronic neuropathic pain and avoid these side actions and still retain opioid like potency. There are several possible way to find new targets for these purposes. Recently opioid receptors have been identified on peripheral processes of sensory neurons. These findings provide new insights into intrinsic mechanisms of pain control and suggest innovative strategies for developing drugs and alternative approaches to pain treatment. In the effort to discover better analgesic drugs for chronic pain, attention is being paid to specific ion channels at the periphery, include members of transient receptor potential family (TRPV1, capsaicin receptors), as well as P2x receptors, sensitive to purines released from tissue injury. A special tetradotoxin-resistant, voltage dependent type of sodium channel is associated with dorsal root ganglia neurons is blocked by mexiletine, used in chronic pain. A synthetic peptide analogue of marine snail toxin ziconitine blocks N-type calcium channels. GABA and NMDA receptors are also involved in the antinociceptive actions of gabapentin and ketamine, respectively. Furthermore nicotine and analogues (epibatidine) induce analgesia through nicotinic ACh receptors. We studied mostly the peripheral targets of hydrophilic heterocyclic opioids in antinociceptive processes.

Topics: Amines; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcium Channel Blockers; Chronic Disease; Cyclohexanecarboxylic Acids; Drug Tolerance; Gabapentin; gamma-Aminobutyric Acid; Humans; Ketamine; Mexiletine; Nicotinic Agonists; Nociceptors; omega-Conotoxins; Pain; Pyridines; Receptors, Opioid; Sodium Channels

Ziconotide is a synthetic peptide equivalent of an w-conotoxin, obtained from the marine snail Conus magus, which acts by blocking N-type calcium channels in the spinal cord, reducing the perception of pain. It is a newly marketed drug, exclusively for intrathecal use, indicated for severe chronic pain. Ziconotide came to the physicians' table with both doubts and promises; to determine its safety and efficacy, one of the largest and most well-designed randomized double-blind studies in the history of intrathecal therapy was undertaken, and this drug demonstrated efficacy in relieving chronic pain in patients coming from many years of different therapies and therapy failures. However, the pain relief came with some adverse effects, which are few compared with morphine's adverse effects but in some cases could undermine the course of therapy with this conotoxin. The experience described in this paper began in June 2007 and gave us the opportunity to analyze how the conotoxin works outside of the papers. We noted differences between the well-known activity of morphine on pain and mood, and the more focused action of ziconotide on pain. In addition, it is important to consider the lack of addiction, opioid-induced hyperalgesia and other systemic effects that are common with morphine. These are the reasons why the Polyanalgesic Consensus Conference of 2007 put ziconotide in the first line of intrathecal therapy management.

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

We will evaluate the usefulness of the new intrathecal analgesic ziconotide in palliative care medicine. We will also examine the place and efficacy of neurolytic celiac plexus blockade in patients suffering from malignancy in the upper abdomen, after introducing better localization methods of the celiac plexus.. The analgesic effects of intrathecally administered ziconotide have been studied in patients suffering from pain due to AIDS or cancer. The results show a moderate to complete pain relief, significantly better than in placebo groups. However, safety studies show a high incidence of side effects. The technique of neurolytic celiac plexus blocks is refined by endoscopic ultrasound techniques.. The place of ziconotide in palliative care is doubtful due to unpredictable and sometimes long-lasting side effects. Real evidence on the efficacy and duration of neurolytic celiac plexus blocks for relief of pancreatic cancer pain is still not available. Future studies will need to be performed applying validated measurement instruments and assessing the patient's impression of the procedure's demands in terms of physical and mental tolerance.

Topics: Analgesics, Non-Narcotic; Autonomic Nerve Block; Celiac Plexus; Chronic Disease; Clinical Trials as Topic; Humans; Injections, Spinal; omega-Conotoxins; Pain; Palliative Care

Severe chronic pain afflicts a large number of people worldwide but satisfactory relief from such pain is difficult to achieve with drugs that are currently available, and so there is a great need for the development of new, efficacious and safe analgesics. Voltage-gated calcium-permeable ion channels are multi-subunit complexes that regulate neuronal excitability, action-potential firing patterns and neurotransmission in nociceptive pathways. Although multiple subtypes of voltage-gated calcium channels exist, pharmacological and ion-channel gene knockdown approaches in animals have revealed N-type and T-type calcium channels to be particularly attractive molecular targets for the discovery and development of new analgesic drugs. The recent approval of Prialt (Elan Pharmaceuticals) provides the ultimate target validation for N-type calcium channels, namely proof that they are key regulators of nociceptive signaling in humans.

Topics: Acute Disease; Analgesics; Animals; Calcium Channels, N-Type; Calcium Channels, T-Type; Chronic Disease; Humans; omega-Conotoxins; Pain; Peripheral Nervous System Diseases

Ziconotide has been introduced as a new nonopioid treatment for chronic pain. Structurally, it is a peptide, the synthetic analog of the omega-conotoxin, derived from the marine snail, Conus magus. N-type voltage-sensitive calcium channels play a role in the transmission of nociceptive stimuli and also are involved in the release of neurotransmitters important in pain transmission. Ziconotide's therapeutic benefit derives from its potent and selective blockade of neuronal-type voltage-sensitive calcium channels. Blockade of the channels results in suppression of abnormal ectopic discharges from the injury site or the dorsal root ganglia, possibly resulting in decreased neuroplasticity, and decreased synaptic transmission that leads to the generation of chronic pain syndromes. The advantage of ziconotide is that tolerance does not occur, while disadvantages associated with ziconotide are the need for intrathecal administration and significant neurotoxicites associated with its use. When tested in clinical trials, ziconotide has been shown to have synergistic or additive value to the effect of morphine. Ziconotide, formerly known also as SNX- 111, represents a new class of agents, the N-type calcium channel blockers. These may represent another option for patients with refractory pain and refractory pain syndromes.

Topics: Analgesics, Non-Narcotic; Animals; Calcium Channel Blockers; Calcium Channels; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; omega-Conotoxins; Pain

Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of "topically" active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 microg/day) and titrated slowly (increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.

Topics: Analgesics, Non-Narcotic; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Chronic Disease; Drug Administration Schedule; Humans; Injections, Spinal; omega-Conotoxins; Pain; Randomized Controlled Trials as Topic; Severity of Illness Index

Ziconotide is a new nonopioid intrathecal agent recently approved for the treatment of chronic pain. Ziconotide is indicated for the management of severe chronic pain in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or intrathecal morphine. Ziconotide blocks the N-type calcium channels located in the superficial dorsal horn of the spinal cord, resulting in potent analgesia. The efficacy of ziconotide has been demonstrated in three randomized, placebo-controlled trials in over 500 patients. In addition, its safety has been demonstrated in over 1200 subjects. Ziconotide is a potent analgesic with a narrow therapeutic window. The drug requires a slow titration in order to achieve analgesia while avoiding dose-limiting side effects. This review examines the currently available information on this new analgesic.

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Chronic Disease; Drugs, Investigational; Humans; Injections, Spinal; omega-Conotoxins; Pain

Topics: Analgesics, Non-Narcotic; Chronic Disease; Humans; Infusion Pumps, Implantable; Infusions, Parenteral; omega-Conotoxins; Pain

Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals. N-type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 microg/hr) and frequent up-titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 microg/hour and limiting infusion rate increases to 2-3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long-term therapy.

Topics: Calcium Channel Blockers; Calcium Channels, L-Type; Chronic Disease; Drug Delivery Systems; Drug Interactions; Humans; Infusion Pumps, Implantable; Injections, Spinal; omega-Conotoxins; Pain; Randomized Controlled Trials as Topic; Synaptic Transmission

Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

Topics: Amino Acid Sequence; Animals; Calcium Channel Blockers; Chronic Disease; Humans; Molecular Sequence Data; omega-Conotoxins; Pain

This review will summarize some of the potentially useful new drugs and therapies, which have already been applied in clinical practice or will potentially become available for cancer pain management in the near future. Included will be an introduction to drugs, which effectively relieve the breakthrough pain, a group of new sustained release long-acting opioids, Cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAIDs), alpha-2 agonists, ion channel blockers, N-methyl-D-aspartate (NMDA) receptor antagonists, and new delivery systems.

Topics: Adrenal Medulla; Adrenergic alpha-Agonists; Analgesics, Opioid; Cell Transplantation; Cyclooxygenase Inhibitors; Fentanyl; Humans; omega-Conotoxins; Pain; Pain, Intractable; Receptors, N-Methyl-D-Aspartate

Ziconotide, the synthetic form of cone snail peptide pi-conotoxin MVIIA, is a neurone-specific N-type calcium channel blocker with an analgesic and neuroprotective effect. Intrathecal ziconotide has been recommended for approval by the FDA for the management of chronic pain. Spinally administered ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents and prevents the propagation of pain signals to the brain. It has an advantage over intrathecal morphine in that there is no development of tolerance after prolonged use. Systemic toxicity is considerably reduced by administration of smaller doses intrathecally and selective delivery to the site of action in the nervous system. Nevertheless, there are neurological adverse effects due to delay in clearance of ziconotide from the neural tissues. Overall, ziconotide has a favourable risk/benefit ratio with advantages over several currently available intrathecal therapies for pain.

Topics: Animals; Calcium Channel Blockers; Chronic Disease; Humans; Injections, Spinal; omega-Conotoxins; Pain

This open-label multicenter study evaluated the long-term safety and efficacy of intrathecal ziconotide and included 78 patients with chronic pain who had completed one of two previous ziconotide clinical trials. Each patient's initial ziconotide dose was based on his or her dose from the study of origin and was adjusted as necessary on the basis of adverse events and analgesic effect. The median ziconotide dose was 6.48 mcg/day (range, 0.00-120.00 mcg/day) at the Initial Visit and ranged from 5.52 to 7.20 mcg/day across all study visits. The most commonly reported new adverse events that were considered ziconotide related were memory impairment (11.3%); dizziness, nystagmus, and speech disorder (8.5% each); nervousness and somnolence (7.0% each); and abnormal gait (5.6%). There was no evidence of increased adverse event incidence at higher cumulative ziconotide doses. Elevations in creatine kinase were noted, but the proportion of patients with creatine kinase elevations did not change from the Initial Visit to the Termination Visit (4.1% each). Stable mean Visual Analog Scale of Pain Intensity scores during the three years of the study suggested no evidence of increased pain intensity with increased duration of ziconotide exposure. Long-term treatment with ziconotide appeared to be well tolerated and effective in patients whose response to ziconotide and ability to tolerate the drug had been previously demonstrated.

Topics: Analgesics, Non-Narcotic; Chronic Disease; Female; Humans; Injections, Spinal; Long-Term Care; Male; Middle Aged; omega-Conotoxins; Pain; Pain Measurement

Ziconotide is a non-opioid drug indicated for management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatments.. Six-hundred and forty-four patients with severe chronic pain participated in this open-label, multicenter study. Ziconotide titration was followed by long-term infusion. Efficacy assessments included the Visual Analog Scale of Pain Intensity. Safety was assessed via adverse events (AEs), vital signs, and routine laboratory values.. One-hundred and nineteen patients received ziconotide for > or = 360 days; total exposure was 350.9 patient years. Median duration of ziconotide therapy was 67.5 days (range, 1.2-1215.5 days); mean dose at last infusion was 8.4 microg/d (range, 0.048-240.0 microg/d). Median Visual Analog Scale of Pain Intensity scores at baseline, month 1, and the last available observation up to month 2 were 76 mm (range, 4-100 mm), 68 mm (range, 0-100 mm), and 73 mm (range, 0-100 mm), respectively. Most patients (99.7%) experienced > or = 1 AE. Most AEs were of mild (43.5%) or moderate (42.3%) severity; 58.6% of AEs were considered unrelated to ziconotide. The most commonly reported AEs (> or = 25% of patients) included nausea, dizziness, headache, confusion, pain, somnolence, and memory impairment. Clinically significant abnormalities (> 3 times the upper limit of normal) in creatine kinase levels were reported in 0.9% of patients at baseline, 5.7% at month 1, and 3.4% at ziconotide discontinuation. No drug-related deaths, IT granulomas, or permanent adverse sequelae occurred with ziconotide therapy.. We conclude that long-term IT ziconotide is an option for patients with severe, refractory chronic pain.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Chronic Disease; Female; Gastrointestinal Diseases; Humans; Infusion Pumps; Male; Middle Aged; omega-Conotoxins; Pain; Time

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.. Outpatient clinics.. 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.

Topics: Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Injections, Spinal; Male; Middle Aged; Morphine; omega-Conotoxins; Pain; Pain Measurement; Treatment Outcome

To assess the safety and efficacy of adding intrathecal morphine to intrathecal ziconotide in patients treated with stable ziconotide doses.. Multicenter, open-label study with a 4-week morphine titration phase during which ziconotide was held constant and an extension phase during which dosing of either drug could vary.. Outpatient clinics.. Patients with suboptimal pain relief receiving stable ziconotide doses (> or = 4.8 microg/day) in one of two ongoing ziconotide trials.. Ziconotide dosing remained constant during the titration phase; intrathecal morphine titration was based on each patient's daily systemic opioid dose at the study's start. During the extension phase, intrathecal ziconotide and morphine dosing were adjusted per investigator discretion.. Safety was assessed primarily via adverse events. Efficacy was analyzed via percentage change on the visual analog scale of pain intensity and in weekly systemic opioid consumption.. Twenty-five patients enrolled. The most common (> or = 10% of patients in either study phase) study drug-related (i.e., ziconotide/morphine combination [or ziconotide monotherapy in the extension phase only]) treatment-emergent adverse events included dizziness, peripheral edema, pruritus, and nausea. From the initial visit to week 4, visual analog scale of pain intensity scores improved by a mean of 26.3% (95% confidence interval: 15.6%-37.1%) but varied during the extension phase (mean percentage change from the initial visit ranged from -0.4% at week 16 to -35.0% at week 72). Mean percentage decrease in systemic opioid consumption from the initial visit was 49.1% at week 4 and 51.2% at week 56 of the extension phase.. Intrathecal morphine, combined with stable intrathecal ziconotide doses, reduced pain in patients with previously suboptimal pain relief on ziconotide monotherapy.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Chronic Disease; Drug Therapy, Combination; Female; Humans; Injections, Spinal; Male; Middle Aged; Morphine; omega-Conotoxins; Pain; Pain Measurement; Treatment Outcome

Safety and efficacy data from a study of slow intrathecal (IT) ziconotide titration for the management of severe chronic pain are presented. Patients randomized to ziconotide (n = 112) or placebo (n = 108) started IT infusion at 0.1 microg/hour (2.4 microg/day), increasing gradually (0.05-0.1 microg/hour increments) over 3 weeks. The ziconotide mean dose at termination was 0.29 microg/hour (6.96 microg/day). Patients' baseline Visual Analogue Scale of Pain Intensity (VASPI) score was 80.7 (SD 15). Statistical significance was noted for VASPI mean percentage improvement, baseline to Week 3 (ziconotide [14.7%] vs. placebo [7.2%; P = 0.036]) and many of the secondary efficacy outcomes measures. Significant adverse events (AEs) reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Discontinuation rates for AEs and serious AEs were comparable for both groups. Slow titration of ziconotide, a nonopioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials that used a faster titration to a higher mean dose.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Chronic Disease; Double-Blind Method; Female; Humans; Injections, Spinal; Male; Middle Aged; omega-Conotoxins; Pain; Placebos

Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects.. To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment.. Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment.. Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group.. Mean percentage change in VASPI score from baseline to the end of the initial titration period.. Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P =.63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P =.18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001).. Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Aged, 80 and over; Analgesics; Calcium Channel Blockers; Double-Blind Method; Female; Humans; Injections, Spinal; Male; Middle Aged; Neoplasms; omega-Conotoxins; Pain; Pain Measurement; Pain, Intractable

The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 micrograms) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half-life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose-related analgesia was observed. Pharmacokinetic-pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1-hour i.t. infusion.

Topics: Adult; Area Under Curve; Blood Pressure; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Injections, Spinal; Male; Metabolic Clearance Rate; Middle Aged; Neuroprotective Agents; omega-Conotoxins; Pain; Pain Measurement; Supine Position

There have been numerous attempts to develop non-opioid drugs for severe pain, but the vast majority of these efforts have failed. A notable exception is Ziconotide (Prialt®), approved by the FDA in 2004. In this review, we summarize the present status of Ziconotide as a therapeutic drug and introduce a wider framework: the potential of venom peptides from cone snails as a resource providing a continuous pipeline for the discovery of non-opioid pain therapeutics. An auxiliary theme that we hope to develop is that these venoms, already a validated starting point for non-opioid drug leads, should also provide an opportunity for identifying novel molecular targets for future pain drugs. This review comprises several sections: the first focuses on Ziconotide as a therapeutic (including a historical retrospective and a clinical perspective); followed by sections on other promising Conus venom peptides that are either in clinical or pre-clinical development. We conclude with a discussion on why the outlook for discovery appears exceptionally promising. The combination of new technologies in diverse fields, including the development of novel high-content assays and revolutionary advancements in transcriptomics and proteomics, puts us at the cusp of providing a continuous pipeline of non-opioid drug innovations for pain. SIGNIFICANCE: The current opioid epidemic is the deadliest drug crisis in American history. Thus, this review on the discovery of non-opioid pain therapeutics and pathways from cone snail venoms is significant and timely.

Topics: Analgesics, Non-Narcotic; Animals; Conus Snail; Drug Discovery; Mollusk Venoms; omega-Conotoxins; Pain; Pain Management; Proteomics

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.

Topics: Analgesics; Animals; Blood-Brain Barrier; Calcium Channel Blockers; Female; Male; Mice; omega-Conotoxins; Pain; Pain Measurement; Peptides; Recombinant Fusion Proteins; RNA-Binding Protein FUS; tat Gene Products, Human Immunodeficiency Virus; Tremor

Spasticity can be very debilitating and painful. We present a case of severe spasticity from primary lateral sclerosis refractory to intrathecal baclofen in doses up to 1100 μg/d. Baclofen was weaned down and switched to intrathecal ziconotide at 0.6 μg/d. The dose was then titrated up to 3 μg/d with excellent control of spasticity. This case suggests that low-dose intrathecal ziconotide should be considered in patients with lower extremity spasticity refractory to intrathecal baclofen.

Topics: Adult; Baclofen; Female; Humans; Injections, Spinal; Motor Neuron Disease; Muscle Spasticity; omega-Conotoxins; Pain; Treatment Outcome

The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients.. A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months.. Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months.. A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Topics: Analgesics, Non-Narcotic; Cohort Studies; Combined Modality Therapy; Female; Humans; Injections, Spinal; Male; Middle Aged; omega-Conotoxins; Pain; Pain Management; Pain Measurement

The marine snail peptide ziconotide (ω-conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side-effects of spider peptide Phα1β in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16-F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1β or ω-conotoxin MVIIA (10-100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side-effects in control and morphine-tolerant mice. The treatment with Phα1β or ω-conotoxin MVIIA fully reversed cancer-related painful hypersensitivity, with long-lasting results, at effective doses 50% of 48 (32-72) or 33 (21-53) pmol/site, respectively. Phα1β produced only mild adverse effects, whereas ω-conotoxin MVIIA induced dose-related side-effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1β was capable of controlling cancer-related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1β was as efficacious as ω-conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid-tolerant mice, indicating that Phα1β has a good profile for the treatment of cancer pain in patients.

Topics: Analgesics; Animals; Cell Line, Tumor; Drug Tolerance; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Morphine; omega-Conotoxins; Pain; Pain Measurement; Peptides; Spider Venoms; Spiders

The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1β, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3-300pmol/site) or Phα1β (10-300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1β (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1β (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1β as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel.

Topics: Acute Disease; Analgesics; Animals; Behavior, Animal; Chronic Disease; Male; omega-Conotoxins; Paclitaxel; Pain; Rats; Rats, Wistar; Spider Venoms

Despite some other known psychiatric adverse effects, ziconotide is recommended for intrathecal pain treatment with a good efficacy and safety. Although some hints in previous studies are apparent, a higher suicidality has not been accepted as a treatment risk of ziconotide treatment by the investigators in the former randomized controlled trials so far. We present two cases supporting the suspicion of ziconotide-induced suicidality. Both showed no depressive symptoms at the time of treatment initiation. One patient performed suicide under low-dose (cumulative dosage: 779μg) 4 weeks after the onset of intrathecal ziconotide treatment despite sufficient pain relief. Another female patient with a history of depression, but free of symptoms under antidepressive medication since more than 15 years, developed severe suicidal ideation 2 months after ziconotide treatment (cumulative dosage: about 2900μg) with rapid recovery after drug discontinuation. The patient, who has completed suicide, had earlier given rise to discuss a potential depressive disorder, however, this diagnosis was scrapped, but the second patient had a clear history of depression. These cases substantiate the suspicion of a causal relationship between ziconotide and suicidality even in symptom-free patients with a history of depression. Therefore, a comprehensive psychiatric evaluation is unavoidable before and during ziconotide treatment.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Depression; Female; Humans; Male; omega-Conotoxins; Pain; Suicide

The Irukandji syndrome is caused by the sting of some small jellyfish species. The syndrome has severe life-threatening consequences. The exacerbating pain and cardiovascular symptoms (tachycardia and hypertension) are hard to control in many cases. We suggest a way to experiment a new possible therapy with an FDA approved analgesic, ziconotide, a synthetic derivative from a marine cone snail (Conus magus) venom component, which is administrated intravenously. The proposed experimental plasma concentration of ziconotide for rats is in the range of 0-6μgml(-1). Based on a molecular biological scenario of the venom action mechanism at cellular level, we suggest that the proposed method should be functional in re-establishing the normal cardiovascular parameters of the experimental animals and concomitantly it should abolish the severe pain caused by envenomation. We expect that positive experimental results in agreement with our theory will lead to the possibility of a new therapy for the Irukandji syndrome and possibly for other envenomations with similar ethyology.

Topics: Algorithms; Animals; Bites and Stings; Blood Volume; Cnidarian Venoms; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Injections, Intravenous; Mollusk Venoms; Neuroprotective Agents; Neurotoxicity Syndromes; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley; Scyphozoa; Sodium-Calcium Exchanger

Questions from patients about analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this query is ziconotide, a novel approach to the management of severe and chronic pain prepared from snail venom, its uses and possible side effects.

Topics: Analgesics, Non-Narcotic; Animals; Humans; Infusion Pumps; Mollusk Venoms; omega-Conotoxins; Pain; Snails

At synaptic terminals, high voltage-activated Ca(v)2.1 and Ca(v)2.2 calcium channels have an essential and joint role in coupling the presynaptic action potential to neurotransmitter release. Here we show that membrane-tethered toxins allowed cell-autonomous blockade of each channel individually or simultaneously in mouse neurons in vivo. We report optimized constitutive, inducible and Cre recombinase-dependent lentiviral vectors encoding fluorescent recombinant toxins, and we also validated the toxin-based strategy in a transgenic mouse model. Toxins delivered by lentiviral vectors selectively inhibited the dopaminergic nigrostriatal pathway, and transgenic mice with targeted expression in nociceptive peripheral neurons displayed long-lasting suppression of chronic pain. Optimized tethered toxins are tools for cell-specific and temporal manipulation of ion channel-mediated activities in vivo, including blockade of neurotransmitter release.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cells, Cultured; Dopamine; Humans; Integrases; Mice; Mice, Inbred C57BL; Mice, Transgenic; omega-Conotoxins; Pain; Rats; Rats, Wistar; Synaptic Transmission

Topics: Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Female; Humans; Meperidine; Myelitis, Transverse; omega-Conotoxins; Pain

Abstract The N-type voltage-gated calcium channel (Cav2.2) has been intensively explored as a target for novel, small-molecule analgesic drugs because of its distribution in the pain pathway and its role in nociceptive processing. For example, Cav2.2 is localized at presynaptic terminals of pain fibers in the dorsal horn, and it serves as a downstream effector of μ-opioid receptors. Most importantly, antagonism of the channel by the highly specific and potent Cav2.2 blocker ω-conotoxin MVIIA (ziconotide) produces clinical efficacy in the treatment of severe, intractable pain. To identify novel small-molecule Cav2.2 inhibitors, we developed new tools and screening methods critical to enhance the efficiency and probability of success. First, we established and characterized a new cell line stably expressing the three subunits of the Cav2.2, including an α-subunit splice variant that is uniquely expressed by dorsal root ganglion neurons. Second, using this cell line, we validated and employed a fluorescence-based calcium flux assay. Third, we developed a new "medium-throughput" electrophysiology assay using QPatch-HT to provide faster turnaround on high-content electrophysiology data that are critical for studying ion channel targets. Lastly, we used a therapeutically relevant, ex vivo spinal cord calcitonin gene-related peptide-release assay to confirm activities in the other assays. Using this approach we have identified compounds exhibiting single-digit nM IC₅₀ values and with a positive correlation across assay methods. This integrated approach provides a more comprehensive evaluation of small-molecule N-type inhibitors that may lead to improved therapeutic pharmacology.

Topics: Analgesics; Animals; Calcitonin Gene-Related Peptide; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line; Ganglia, Spinal; HEK293 Cells; High-Throughput Screening Assays; Humans; Luminescent Measurements; Neurons; omega-Conotoxins; Pain; Patch-Clamp Techniques; Presynaptic Terminals; Rats; Small Molecule Libraries; Spinal Cord

N-type Ca2+ channels (Ca(v)2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.. Here we identify a new CTx, FVIA, from the Korean Conus Fulmen and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca2+ channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.. The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.

Topics: Analgesics, Non-Narcotic; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, N-Type; Dose-Response Relationship, Drug; Hot Temperature; Male; Mice; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley

Topics: Analgesics, Non-Narcotic; Catheters, Indwelling; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Germany; Humans; Infusion Pumps; Injections, Spinal; omega-Conotoxins; Pain

Seven cases of combination of intrathecal (IT) ziconotide and baclofen therapy in patients with refractory neuropathic pain and spasticity were reviewed. Five of the seven adult patients were receiving IT baclofen treatment when ziconotide was initiated. All five patients had experienced at least one previous failed IT treatment regimen. Pain intensity scores improved by a mean of 50.3% with the use of ziconotide-baclofen therapy. Mean time to onset of pain relief was 15 weeks, at a mean ziconotide dose of 3.7 microg/day. Within this group of patients, adverse events were observed in one patient, but they were not considered to be ziconotide related and subsequently resolved. The remaining two patients were receiving ziconotide treatment when baclofen was initiated. Pain intensity scores improved by 75% and 30%, respectively. Pain relief was evident at two weeks and one week, with corresponding ziconotide doses of 2.4 microg/day and 14.4 microg/day, respectively. One patient in this group reported adverse events, but all resolved during continued treatment with the study drugs. Treatment regimens varied between patients in these case series; each regimen used a different titration strategy and different concentrations of ziconotide and baclofen. Combination IT ziconotide and baclofen therapy may be a treatment option for patients with neuropathic pain and spasticity. Future studies are warranted to determine the optimal dosing and titration schedules for ziconotide-baclofen usage.

Topics: Adult; Baclofen; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscle Relaxants, Central; Muscle Spasticity; Neuralgia; Neuroprotective Agents; omega-Conotoxins; Pain; Pain Measurement; Treatment Outcome

To examine the cost-effectiveness of using intrathecal ziconotide in the treatment of severe chronic pain compared to best supportive care for patients with intractable chronic pain in the United Kingdom.. Using a simulation model, the analysis evaluated the cost and health economic consequences of using ziconotide as a treatment for severe chronic pain. The modelled population and clinical data were based on a randomised controlled trial in which the main outcome was reduction in pain as measured by the visual analogue scale of pain intensity (VASPI). Resource use data were elicited using a modified Delphi panel and costed using published sources. Utility values were derived from a separate research study. The main outcome measure was the cost per quality-adjusted life-year (QALY). Extensive scenario analysis was conducted to evaluate parameter uncertainty.. Overall, findings were robust to most assumptions. The cost-effectiveness of ziconotide compared to best supportive care (BSC) was pound 27,443 per QALY (95% CI pound 18,304-38,504). Scenarios were investigated in which discount rates, the time horizon, the threshold for qualifying as a responder, pump-related assumptions, utilities, ziconotide drug dose, and the patient discontinuation rate with ziconotide were varied. The most sensitive parameter was the dosage of ziconotide: using the lower and upper bounds of the average ziconotide dosage observed in the long-term open-label study changed the incremental cost-effectiveness ratio (ICER) to pound 15,500 [pound 8206-25,405] and pound 44,700 [pound 30,541-62, 670].. Ziconotide may offer an economically feasible alternative solution for patients for whom current treatment is inappropriate or ineffective. The main study limitation is that some model inputs, mainly related to resource use, are based on assumptions or expert interviews.

Topics: Adult; Aged; Chronic Disease; Cost-Benefit Analysis; Double-Blind Method; Humans; Injections, Spinal; Middle Aged; Models, Theoretical; Neuroprotective Agents; omega-Conotoxins; Pain; Pain Measurement; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Severity of Illness Index; United Kingdom

Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.

Topics: Administration, Oral; Amines; Analgesics; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cyclohexanecarboxylic Acids; Dihydropyridines; Formaldehyde; Gabapentin; gamma-Aminobutyric Acid; Male; Models, Animal; Nifedipine; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord

Queries from European physicians about analgesic pharmacotherapy and responses from the author are presented. The topics addressed are the safety of propoxyphene, the risk of opioid dependence in nonmalignant pain, the role of ziconotide in pain management, and titration of sustained acting opioids.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Dextropropoxyphene; Humans; omega-Conotoxins; Opioid-Related Disorders; Pain

Ziconotide is a synthetic analogue of a peptide found in the poison of the marine snail Conus magus. Ziconotide blocks N-type calcium channels, which play an important role in the transmission of pain signals in the dorsal ganglia of the spinal cord. The drug is indicated for 'severe chronic pain' and is administered intrathecally.

Topics: Analgesics, Non-Narcotic; Chronic Disease; Humans; omega-Conotoxins; Pain

Topics: Calcium Channel Blockers; Calcium Channels, N-Type; Chronic Disease; gamma-Aminobutyric Acid; Humans; NAV1.8 Voltage-Gated Sodium Channel; Neurons, Afferent; omega-Conotoxins; Pain; Peptides; Pregabalin; Sodium Channels

Topics: Analgesics, Non-Narcotic; Contraindications; Drug Approval; Humans; omega-Conotoxins; Pain

Topics: Analgesics, Non-Narcotic; Animals; Chronic Disease; Clinical Trials as Topic; Drug Costs; Drug Design; Humans; Mollusk Venoms; omega-Conotoxins; Pain; Technology, Pharmaceutical

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Topics: Analgesics; Animals; Binding Sites; Butanones; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cerebral Ventricles; Drug Design; In Vitro Techniques; Male; Mice; Pain; Pain Measurement; Pain Threshold; PC12 Cells; Peripheral Nervous System Diseases; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Agents which decrease conductance of N-type voltage-gated Ca(2+) channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The omega-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED(50) (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for omega-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27-0.48), 0.12 (0.06-0.24), 0.32 (0.23-0.45) and 4.4 (2.9-6.5) microg/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED(50) 2.3 (1.1-4.9) microg/kg). Of the omega-conotoxins, omega-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. Omega-conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.

Topics: Analysis of Variance; Animals; Calcium Channel Blockers; Dose-Response Relationship, Drug; Injections, Spinal; Male; Morphine; omega-Conotoxin GVIA; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley; Venoms

Opioids, alpha(2)-adrenoceptor agonists and blockers of voltage-gated calcium channels (VGCCs) have been attributed antinociceptive activity in various experimental set-ups. The present study tested the ability of morphine, clonidine and drugs acting at various VGCCs to inhibit the transmission of noxious stimuli from the mesentery at the level of the spinal cord. In rats under barbiturate anaesthesia traction of 20 g was applied to a bundle of mesenteric blood vessels. This caused immediate transient changes of mean arterial pressure that were taken as indication of nociception. Similar reflexes were elicited by applying 0.6% acetic acid to the same bundle of vessels. The reflexes were dose-dependently reduced by intrathecal administration of morphine or clonidine, but were left unaltered by intrathecal administration of verapamil, Bay-K 8644 or omega-conotoxin MVIIA. Neither verapamil nor Bay-K 8644 influenced clonidine-induced analgesia. Conotoxin markedly enhanced the effectiveness of all doses of clonidine against both types of mesenteric stimuli. Verapamil, Bay-K 8644, as well as conotoxin reduced the ability of morphine to inhibit mechanically evoked reflexes, while there was no statistically significant effect in chemonociception. These data suggest that, at the spinal level, both morphine and clonidine are effective drugs to decrease the cardiovascular changes caused by acute mesenteric pain. In the dorsal spinal cord neither L-type nor N-type VGCCs are responsible on their own for the transmission of noxious stimuli from the mesentery. Inhibition of N-type channels markedly augments the action of clonidine, whereas blocking either VGCC seems to inhibit antinociceptive mechanisms induced by morphine. It is suggested that in patients the combined administration of clonidine with omega-conotoxin MVIIA might lead to effective pain control with reduced side effects.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Adrenergic alpha-Agonists; Analgesics, Opioid; Animals; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, N-Type; Clonidine; Dose-Response Relationship, Drug; Female; Mesentery; Morphine; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord; Synaptic Transmission; Verapamil

Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) chronic intrathecal ziconotide administration produces neither tolerance nor cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not prevent or reverse morphine tolerance.

Topics: Analgesics, Opioid; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Drug Administration Schedule; Drug Synergism; Drug Tolerance; Formaldehyde; Hot Temperature; Injections, Spinal; Male; Morphine; Nociceptors; omega-Conotoxins; Pain; Pain Measurement; Pressure; Rats; Rats, Sprague-Dawley

The omega-conopeptide, ziconotide, is an N-type calcium-channel blocker that has been shown to produce antinociception in animals using formalin and hot-plate tests. Initial reports of intrathecal administration of ziconotide in cancer and AIDS patients whose pain was unrelieved with opioids demonstrated analgesic efficacy. Although adverse effects were reported, these appeared to be easily managed through dose reduction or symptomatic treatment. This clinical report describes the experiences of three patients with serious adverse effects associated with intrathecal ziconotide.

Topics: Ataxia; Back Pain; Calcium Channel Blockers; Confusion; Humans; Hypotension, Orthostatic; Injections, Spinal; Male; Middle Aged; Multiple Sclerosis; Nystagmus, Pathologic; omega-Conotoxins; Pain; Urinary Bladder Neoplasms

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Drugs, Investigational; Humans; Neuroprotective Agents; omega-Conotoxins; Pain; Peptides; Rats; Stroke

High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. Spinal administration (through a microdialysis fiber placed in dorsal horn) of an N-type calcium channel blocker (MVIIA, SNX 111, ziconotide, 0.001-0.1 mM), before induction of inflammation, prevents the decrease in PWL. Treatment with SNX 111 4 hr after inflammation reverses heat hyperalgesia. A small reduction in spontaneous pain-related behaviors (guarding of the limb) occurs after pre- or post-treatment with SNX 111. Spinal blockade of P/Q-type calcium channels (with omega-agatoxin IVA) had no effect on the decrease in PWL to radiant heat when administered after induction of inflammation. However, pre-treatment with omega-agatoxin IVA prevents secondary heat hyperalgesia. omega-Agatoxin IVA has no effect on spontaneous pain-related behaviors whether administered before or after induction of inflammation. In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.

Topics: Animals; Arthritis; Calcium Channel Blockers; Calcium Channels; Hot Temperature; Hyperalgesia; Male; Microdialysis; Nifedipine; omega-Agatoxin IVA; omega-Conotoxins; Pain; Peptides; Rats; Rats, Sprague-Dawley; Spider Venoms

Male Sprague-Dawley rats were used to evaluate the antinociceptive properties of the selective N-type voltage-sensitive calcium channel (VSCC) blocker, SNX-111, when the compound is administered spinally by either bolus injection or continuous, constant-rate infusion into the subarachnoid space. SNX-111 produced significant, dose-dependent antinociceptive effects by suppressing both the acute (phase 1: ED50, 14 ng/hr) and tonic (phase 2: ED50, 0.82 ng/hr) phases of the formalin test when it was infused for 72 hr immediately before testing. Phase 2 nociceptive responses were suppressed by bolus injections of 100 ng SNX-111. SNX-111 was approximately 1000-fold more potent than morphine in blocking phase 2 responses when the compounds were administered by intrathecal bolus injection. In rats with an experimentally induced painful peripheral neuropathy, intrathecal bolus injections of 30 to 300 ng SNX-111 blocked mechanical allodynia in a dose-dependent manner. Subacute administration of SNX-111 (1, 10 and 100 ng/hr) by continuous intrathecal infusion produced a reversible blockade of mechanical allodynia without apparent development of tolerance. These results show that: 1) selective N-type VSCC blockers are potent and efficacious antinociceptive agents when they are administered by the spinal route; 2) selective N-type VSCC blockers are effective in rat models of acute, persistent and neuropathic pain; and 3) N-type VSCCs play a significant role in the spinal processing of noxious somatosensory input.

Topics: Analgesics; Animals; Calcium Channel Blockers; Disease Models, Animal; Formaldehyde; Ion Channel Gating; Male; Neurons; omega-Conotoxins; Pain; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Spinal Cord

In patients and animals with painful peripheral neuropathies, spontaneous ectopic discharge from injured primary afferents is hypothesized to maintain a central state of hyperexcitability that underlies hyperalgesia and allodynia. Temporary suppression of this discharge allows the central state to normalize, such that hyperalgesia and allodynia are absent or reduced until the resumption of the discharge rekindles central hyperexcitability. Previous work suggests that Ca++ channels are involved in the genesis of spontaneous discharge from injured afferents. We applied SNX-111 and SNX-124 (0.1-3.0 micrograms), synthetic homologs of omega-conopeptides (MVIIA and GVIA, respectively) and potent blockers of neuronal N-type voltage-sensitive Ca++ channels, to the site of nerve injury via chronically implanted perineural cannulae in rats with an experimental painful peripheral neuropathy (the chronic constriction injury model). Heat-hyperalgesia and mechano-allodynia were reduced for at least 3 hr. Drug application to a normal nerve had no effect on responses to heat or mechanical stimuli. These results suggest that N-type Ca++ channel blockers may be useful in the treatment of the abnormal pains that occur after nerve injury.

Topics: Animals; Calcium Channel Blockers; Hyperalgesia; Male; omega-Conotoxin GVIA; omega-Conotoxins; Pain; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve

Peripheral nerve lesions can result in exaggerated pain responses to low intensity mechanical stimuli (tactile allodynia). In the present work, the pharmacology of voltage-dependent calcium channels (VDCCs) involved in the transmission of neuropathic pain was characterized by examining the effects of antagonists specific to the N-, L- and P-type VDCCs, as well as an antagonist at a non-L-, non-N-type site. Drugs were administered via chronic lumbar intrathecal, i.v. or regional nerve block catheters implanted in rats with tactile allodynia induced by tight ligation of the left fifth and sixth lumbar spinal nerves. Intrathecally delivered N-type VDCC (omega-conopeptides SNX239, SNX159 and SNX111) produced dose-dependent blockade of tactile allodynia. Intrathecal L-type (diltiazem, verapamil and nimodipine), non-N-, non-L-type (omega-conopeptide SNX230) and P-type (omega-agatoxin IVA) VDCC antagonists had no effect on pain behavior at the highest doses examined. No VDCC antagonist suppressed paw withdrawal when administered i.v. SNX239, although effective when administered intrathecally, was without effect when applied regionally to the injured portion of the nerve. These results emphasize the importance of N-type, but not L- or P- type, VDCCs in the spinal cord on systems mediating persistent tactile allodynia after nerve injury.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dose-Response Relationship, Drug; Male; omega-Conotoxins; Pain; Peptides; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves