ziconotide and Neuralgia

This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations.. Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.

Topics: Analgesics; Calcium Channel Blockers; Humans; Neuralgia; Neuroglia; omega-Conotoxins; Pain Management; Spinal Cord Injuries

Neuropathic pain is a subset of chronic pain that is caused by neurons that are damaged or firing aberrantly in the peripheral or central nervous systems. The treatment guidelines for neuropathic pain include antidepressants, calcium channel α

Topics: Analgesics, Non-Narcotic; Animals; Humans; Neuralgia; omega-Conotoxins; Pain Management; Peptides; Toxins, Biological; Venoms

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

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

Conopeptides from the venoms of marine snails have attracted much interest as leads in drug design. Currently, one drug, Prialt(®), is on the market as a treatment for chronic neuropathic pain. Conopeptides target a range of ion channels, receptors and transporters, and are typically small, relatively stable peptides that are generally amenable to production using solid-phase peptide synthesis. With only a small fraction of the predicted diversity of conopeptides examined so far, these peptides represent an exciting and largely untapped resource for drug discovery. Recent efforts at chemically re-engineering conopeptides to improve their biopharmaceutical properties promise to accelerate the translation of these fascinating marine peptides to the clinic.

Topics: Animals; Clinical Trials as Topic; Conotoxins; Conus Snail; Drug Design; Genomics; Neuralgia; omega-Conotoxins; Solid-Phase Synthesis Techniques; Venoms

Pain is a major burden for affected individuals and society, and controlling neuropathic pain is especially challenging. The number of drugs available is limited and treatments are often marginally effective and burdened by side effects. Voltage-gated calcium channels (VGCC) play a major role in the development and maintenance of neuropathic pain and are thus prime targets for its treatment.. Currently available drugs that target the calcium channel include ziconotide, gabapentin and pregabalin. While there are no VGCC blockers currently in clinical trials, there are many in development. Recently, orally available, use-dependent compounds have been reported. We will review, in detail, compounds currently in development and include a brief review of VGCC and the drugs currently in use.. There is real hope that new drugs targeting calcium channels will soon be available. This hope is based on advancing technologies for peptide synthesis, more efficient drug screening and orally available, use-dependent compounds. Some form of direct VGCC blockade or modulation will always have a place in the treatment of neuropathic pain, but given the complexity and neuroplasticity of pain transmission, polypharmacy will likely be required for many chronic pain sufferers for the foreseeable future.

Topics: Calcium Channels, L-Type; Calcium Channels, T-Type; Conotoxins; Humans; Neuralgia; omega-Conotoxins

Intrathecal drug administration for the control of intractable pain has been practiced over many years in various countries; however, because of government regulation, no drugs except baclofen are approved for chronic intrathecal use in Japan. In this review, I have summarized the current international situation regarding the chronic intrathecal administration of various types of drugs for the control of intractable cancer and non-cancer pain. Morphine is the gold standard for this purpose, but its combination with local anesthetics or clonidine may be essential. Although this combination has presented strong evidence of cancer pain control, it shows weak evidence of non-malignant chronic pain control, probably because of the complex pathophysiology of the latter condition. A few new drugs such as ziconotide and gabapentin have been investigated, but the effective control of neuropathic pain, including complex regional pain syndrome, still appears difficult. Contrary to the general belief, intrathecal drug administration via an implantable pump is cost-effective, and I believe that this intrathecal drug delivery system should be used more extensively used for pain management in Japan.

Topics: Amines; Analgesics, Opioid; Anesthetics, Local; Baclofen; Calcium Channel Blockers; Clonidine; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; GABA Agonists; Gabapentin; gamma-Aminobutyric Acid; Humans; Infusion Pumps, Implantable; Injections, Spinal; Morphine; Neoplasms; Neuralgia; omega-Conotoxins; Pain, Intractable

The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Prialt for the treatment of intractable pain. Prialt is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Prialt, and outlines possible strategies to improve upon Prialt's relatively narrow therapeutic window.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Chronic Disease; Humans; Neuralgia; omega-Conotoxins

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 intrathecal infusion was recently approved by the United States Food and Drug Administration for the treatment of intractable severe chronic pain. Patients with neuropathic pain make up a significant population among those who experience chronic pain for which there are less than optimal pharmacotherapeutic options. Published clinical trials provide a global view of ziconotide efficacy and safety. A subset of patients in clinical trials obtained complete pain relief, a remarkable finding given the history of drug treatment for neuropathic pain. To provide more information regarding those who respond to ziconotide therapy, we discuss three patients with neuropathic pain who received ziconotide infusion. Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-microg epidural test doses. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.

Topics: Analgesics, Non-Narcotic; Female; Humans; Injections, Spinal; Male; Middle Aged; Neuralgia; omega-Conotoxins

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

Central neuropathic pain related to spinal cord injury is notoriously difficult to treat. So far most pharmacological and surgical options have shown but poor results. Recently ziconotide has been approved for use both neuropathic and non-neuropathic pain. In this cohort study, we assessed responder rate and long-term efficacy of intrathecal ziconotide in patients with pain related to spinal cord injury.. Patients presenting chronic neuropathic related to spinal cord lesions that was refractory to medical pain management were considered for inclusion. Those accepting were tested by lumbar puncture injection of ziconotide or continuous intrathecal infusion and if a significant decrease in pain scores (>40%) was noted they were implanted with a continuous infusion pump. They were then followed up for at least 1 year with constant assessment of the evolution of pain and side effects.. Out of the 20 patients tested 14 had a decrease in pain scores of more than 40% but only 11 (55%) were implanted with permanent pumps due to side effects and patient choice. These were followed up on average for 3.59 years (±1.94) and in eight patients an above threshold decrease in pain scores was maintained. Overall in patients that responded to the test baseline VAS was 7.91 and 4.31 at last follow-up with an average dose of 7.2 μg of ziconotide per day. Six patients (30%) did not respond to any test and in three patients side effects precluded pump implantation. No significant long-term effects of the molecule were noted.. This study shows response to intrathecal ziconotide test in 40% of the patients of a very specific population in whom other therapeutic options are not available. This data justifies the development further studies such as a long-term randomized controlled trial.. Intrathecal Ziconotide is a posible alternative for the treatment of pain in patients with spinal cord injury and below level neuropathic pain.

Topics: Analgesics, Non-Narcotic; Cohort Studies; Female; Humans; Injections, Spinal; Male; Middle Aged; Neuralgia; omega-Conotoxins; Pain Management; Pain Measurement; Spinal Cord Injuries

MVIIA (ziconotide) is a specific inhibitor of N-type calcium channel, Cav2.2. It is derived from Cone snail and currently used for the treatment of severe chronic pains in patients unresponsive to opioid therapy. However, MVIIA produces severe side-effects, including dizziness, nystagmus, somnolence, abnormal gait, and ataxia, that limit its wider application. We previously identified a novel inhibitor of Cav2.2, ω-conopeptide SO-3, which possesses similar structure and analgesic activity to MVIIA's. To investigate the key residues for MVIIA toxicity, MVIIA/SO-3 hybrids and MVIIA variants carrying mutations in its loop 2 were synthesized. The substitution of MVIIA's loop 1 with the loop 1 of SO-3 resulted in significantly reduced Cav2.2 binding activity in vitro; the replacement of MVIIA loop 2 by the loop 2 of SO-3 not only enhanced the peptide/Cav2.2 binding but also decreased its toxicity on goldfish, attenuated mouse tremor symptom, spontaneous locomotor activity, and coordinated locomotion function. Further mutation analysis and molecular calculation revealed that the toxicity of MVIIA mainly arose from Met(12) in the loop 2, and this residue inserts into a hydrophobic hole (Ile(300), Phe(302) and Leu(305)) located between repeats II and III of Cav2.2. The combinative mutations of the loop 2 of MVIIA or other ω-conopeptides may be used for future development of more effective Cav2.2 inhibitors with lower side effects.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Goldfish; HEK293 Cells; Humans; Locomotion; Male; Membrane Potentials; Mice; Mice, Inbred Strains; Motor Disorders; Mutation; Neuralgia; omega-Conotoxins; Peptides; Protein Conformation; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; Reaction Time; Sequence Homology, Amino Acid; Tremor

Motor cortex stimulation is a well-known treatment modality for refractory neuropathic pain. Nevertheless, some cases of therapeutic failure have been described but alternative therapies for these cases are rarely reported.. The patient presented with neuropathic pain in his right arm due to a cervical syrinx which was surgically treated by a shunt in 2003 with no clinical improvement. As alternative therapy, after an evaluation by repetitive magnetic transcranial stimulation with significant benefit, motor cortex stimulation was successfully implanted in 2004. In 2010, a similar pain occurred in the same territory. Local mean pain visual analogical scale (VAS) increased to 82/100. A newer generation stimulation device was then implanted and, within a period of 8months, different stimulation parameter settings were tested, without any pain relief. An intrathecal drug delivery pump was then implanted in 2011, and the upper extremity catheter was located at the cervicothoracic junction. There was no postoperative complication. A bitherapy was initiated at a daily dosage of 0.2mg morphine and 1.3μg ziconotide, not modified since August 2013. At 43months follow-up, mean VAS was 21/100 with improvement of daily life and spare-time activities, anxiety and depression, quality of life (as measured by the SF-36 survey and EQ5D-3L questionnaire).. Refractory neuropathic pain treated by motor cortex stimulation may be considered in palliative situations, and secondary therapeutic failure offers only a few perspectives. Intrathecal ziconotide, indicated as a first-line drug in non-cancer pain, could be proposed in such cases.. Intrathecal drug delivery including ziconotide in refractory neuropathic pain represents a reasonable option with a good clinical tolerance.

Topics: Follow-Up Studies; Humans; Male; Motor Cortex; Neuralgia; omega-Conotoxins; Pain Management; Pain Measurement; Quality of Life; Salvage Therapy

Ziconotide is an intrathecally administered nonopioid analgesic for the treatment of severe chronic pain. Previous reports have noted rhabdomyolysis in patients receiving ziconotide during the initial single-shot trial or due to concurrent medical problems. We present a case of an acute rhabdomyolysis following an intrathecal bolus injection of ziconotide on a patient who had long-term exposure to the drug.. The patient suffered from chronic neuropathic pain with diagnosis of failed back surgery syndrome and received intrathecal ziconotide for 2 years. Moderate side effects resulting from dose escalation led to a discontinuation of the drug. The pump medication was changed to morphine, which failed to provide adequate analgesia even with dose titration. A single intrathecal bolus of ziconotide, as an adjunctive therapy, resulted in good pain control. Two months later, the patient received a second ziconotide injection. Sixteen hours after the injection, she presented to local emergency center with nausea, vomiting, diarrhea, and myalgia. She had significantly increased CK levels and was admitted for intravenous hydration and close observation. Her serum CK level peaked at 4940 IU/L. The patient was discharged on hospital day 3 with a CK level of 808 IU/L. Her symptoms resolved without renal impairment.. The clinical scenario described is a case of acute rhabdomyolysis from an intrathecal bolus injection of ziconotide in a patient with prior long-term exposure to the drug. The decrease in CK levels coincided well with the average half-life of ziconotide; however, the rhabdomyolysis may have been potentiated by hypokalemia.

Topics: Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Therapy, Combination; Failed Back Surgery Syndrome; Female; Humans; Injections, Spinal; Morphine; Neuralgia; omega-Conotoxins; Pain Management; Pain Measurement; Rhabdomyolysis

The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections.. Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5 μg, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage.. We found a low proportion of responders (13%). However 30% of patients experienced ≥30% pain reduction on a least one injection, yielding a number needed to treat of ∼3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6 h) (p = 0.047) after a mean ziconotide dose of 2.75 μg. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide.. Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Female; Humans; Injections, Spinal; Male; Middle Aged; Neuralgia; omega-Conotoxins; Pain Measurement; Postoperative Complications; Treatment Outcome

Neuropathic pain is a severe painful pathology that is difficult to treat. One option for its management is the continuous intrathecal (i.t.) infusion of ziconotide (the Conus magnus peptide ω-conotoxin MVIIA), which, in addition to being effective, produces serious adverse effects at analgesic doses. Single i.t. administration of Phα1β, a peptide purified from the venom of the spider Phoneutria nigriventer, has antinociceptive effects with a greater therapeutic window than ziconotide in rodents. To further evaluate its analgesic potential, we investigated the antinociceptive and toxic effects of Phα1β after single or continuous i.t. infusion in a rat model of neuropathic pain.. Adult male Wistar rats (200-300 g) bred in-house were used. Chronic constriction injury (CCI) of the sciatic nerve was used as the neuropathic pain model. Nociception was assessed by detecting mechanical hyperalgesia, considering a significant reduction in 50% paw withdrawal threshold values after CCI compared with baseline values. First, we assessed the antinociceptive effect of a single i.t. injection of Phα1β (10, 30, or 100 pmol/site) in a model of neuropathic pain 8 days after nerve injury. In a different experiment, we delivered Phα1β (60 pmol/μL/h) or vehicle (phosphate-buffered saline, 1.0 μL/h) through continuous infusion using an osmotic pump by spinal catheterization for 7 days in rats submitted to nerve injury. Behavioral adverse effects were evaluated after single or continuous Phα1β i.t. administration, and histopathological analysis of spinal cord, brainstem, and encephalon was performed after continuous Phα1β i.t. injection.. We observed that CCI of the sciatic nerve but not sham surgery caused intense (reduction of approximately 2.5 times in mechanical withdrawal threshold) and persistent (up to 14 days) nociception in rats. The single i.t. injection of Phα1β (30 or 100 pmol/site) reduced neuropathic nociception from 1 to 6 hours after administration, without showing detectable side effects. Similarly, the continuous infusion of Phα1β (60 pmol/μL/h for 7 days) was also able to reverse nerve injury-induced nociception from 1 to 7 days, but did not cause either behavioral side effects or histopathological changes in the central nervous system.. Thus, we have shown for the first time that the continuous i.t. delivery of Phα1β produces analgesia disconnected from toxicity in a relevant model of neuropathic pain, indicating that it is an effective and safe drug with a great potential to treat pain.

Topics: Analgesics; Animals; Hyperalgesia; Injections, Spinal; Male; Neuralgia; omega-Conotoxins; Rats; Rats, Wistar; Spider Venoms

Antagonists of the N-type voltage gated calcium channel (VGCC), Cav 2.2, have a potentially important role in the treatment of chronic neuropathic pain. ω-conotoxins, such MVIIA and CVID are effective in neuropathic pain models. CVID is reported to have a greater therapeutic index than MVIIA in neuropathic pain models, and it has been suggested that this is due to faster reversibility of binding, but it is not known whether this can be improved further.. We examined the potency of CVID, MVIIA and two intermediate hybrids ([K10R]CVID and [R10K]MVIIA) to reverse signs of neuropathic pain in a rat nerve ligation model in parallel with production of side effects. We also examined the potency and reversibility to inhibit primary afferent synaptic neurotransmission in rat spinal cord slices.. All ω-conotoxins produced dose-dependent reduction in mechanical allodynia. They also produced side effects on the rotarod test and in a visual side-effect score. CVID displayed a marginally better therapeutic index than MVIIA. The hybrids had a lesser effect in the rotarod test than either of their parent peptides. Finally, the conotoxins all presynaptically inhibited excitatory synaptic neurotransmission into the dorsal horn and displayed recovery that was largely dependent upon the magnitude of inhibition and not the conotoxin type.. These findings indicate that CVID provides only a marginal improvement over MVIIA in a preclinical model of neuropathic pain, which appears to be unrelated to reversibility from binding. Hybrids of these conotoxins might provide viable alternative treatments.

Topics: Analgesics, Non-Narcotic; Animals; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Male; Neuralgia; omega-Conotoxins; Peptides; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Spinal Cord; Synaptic Transmission

Presynaptic voltage-gated calcium Ca(V)2.2 channels play a privileged role in spinal level sensitization following peripheral nerve injury. Direct and indirect inhibitors of Ca(V)2.2 channel activity in spinal dorsal horn are analgesic in chronic pain states. Ca(V)2.2 channels represent a family of splice isoforms that are expressed in different combinations according to cell-type. A pair of mutually exclusive exons in the Ca(V)2.2 encoding Cacna1b gene, e37a and e37b, differentially influence morphine analgesia. In mice that lack exon e37a, which is enriched in nociceptors, the analgesic efficacy of intrathecal morphine against noxious thermal stimuli is reduced. Here we ask if sequences unique to e37a influence: the development of abnormal thermal and mechanical sensitivity associated with peripheral nerve injury; and the actions of two other classes of analgesics that owe part or all of their efficacy to Ca(V)2.2 channel inhibition. We find that: i) the analgesic efficacy of morphine, but not ziconotide or gabapentin, is reduced in mice lacking e37a, ii) the induction and maintenance of behaviors associated with sensitization that accompany peripheral nerve injury, do not require e37a-specific sequence, iii) intrathecal morphine, but not ziconotide or gabapentin analgesia to thermal stimuli is significantly lower in wild-type mice after peripheral nerve injury, iv) the analgesic efficacy of ziconotide and gabapentin to mechanical stimuli is reduced following nerve injury, and iv) intrathecal morphine analgesia to thermal stimuli in mice lacking e37a is not further reduced by peripheral nerve injury. Our findings show that the analgesic action of morphine, but not ziconotide or gabapentin, to thermal stimuli is linked to which Cacna1b exon, e37a or e37b, is selected during alternative pre-mRNA splicing.

Topics: Alternative Splicing; Amines; Analgesia; Animals; Calcium Channels, N-Type; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Male; Mice; Morphine; Neuralgia; omega-Conotoxins; RNA Precursors

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

There are a number of neurologically active ion channel blocking peptides derived from cone snail venom, such as conantokin-G and omega-conotoxin MVIIA. Conantokin-G inhibits NMDA receptors containing the NR2B subunit whereas omega-conotoxin MVIIA blocks N-type Ca(2+) channels. Separately, these peptides induce antinociceptive effects in pre-clinical pain models following intrathecal injection. In the current study, the efficacies of these peptides were determined separately and in combination by intrathecal injection into rats with a spinal nerve ligation, in rats with a spinal cord compression injury and in the formalin test. Separately, both conantokin-G and omega-conotoxin MVIIA dose-dependently attenuated nociceptive responses in all of these models. However, at high antinociceptive doses for both formalin and nerve injury models, omega-conotoxin MVIIA evoked untoward side effects. Using isobolographic analysis, the combination of sub-antinociceptive doses of peptides demonstrated additive antinociception in rats with a nerve ligation and in the formalin test, without apparent adverse side effects. In a model of neuropathic spinal cord injury pain, which is clinically difficult to treat, the combination of conantokin-G and omega-conotoxin MVIIA resulted in robust synergistic antinociception. These data suggest that a combination of these peptides may be analgesic across diverse clinical pains with limited untoward side effects, and particularly potent for reducing spinal cord injury pain.

Topics: Analgesics; Animals; Conotoxins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Hyperalgesia; Male; Motor Activity; Neuralgia; omega-Conotoxins; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Rotarod Performance Test; Time Factors

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

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

Topics: Adult; Analgesics; Drug Therapy, Combination; Female; Humans; Hydromorphone; Injections, Spinal; Neuralgia; omega-Conotoxins; Pain Measurement; Spinal Cord Injuries

Topics: Analgesics, Non-Narcotic; Animals; HIV Infections; Humans; Injections, Spinal; Neoplasms; Neuralgia; omega-Conotoxins; Pain Measurement; Snails

The present study was designed to determine the contribution of N-type, P/Q-type and L-type calcium channels in the rostral ventromedial medulla to tactile allodynia following peripheral nerve injury. L5/L6 spinal nerve ligation in rats produced tactile allodynia, which was dose-dependently inhibited by intrarostral ventromedial medulla microinjection of the N-type calcium channel antagonist omega-conotoxin MVIIA. Similarly, intrarostral ventromedial medulla microinjection of the P/Q-type calcium channel antagonist omega-agatoxin IVA inhibited spinal nerve ligation-induced tactile allodynia, whereas intrarostral ventromedial medulla microinjection of the L-type calcium channel antagonist nimodipine had no effect. These results demonstrate that N-type and P/Q-type calcium channels in the rostral ventromedial medulla contribute to tactile allodynia following peripheral neuropathy, likely via neurotransmitter-mediated activation of descending facilitatory systems from the rostral ventromedial medulla.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Hyperalgesia; Ligation; Male; Medulla Oblongata; Microinjections; Neuralgia; omega-Agatoxin IVA; omega-Conotoxins; Rats; Rats, Sprague-Dawley; Spinal Nerves; Touch

We investigated the effects of intrathecally administered N-type and P-type voltage-sensitive calcium channel (VSCC) blockers on the level of thermal hyperalgesia in two neuropathic pain models: the chronic constriction injury (CCI) model and the partial sciatic nerve injury (PSNI) model. N-type, but not P-type, VSCC blockers attenuated the level of thermal hyperalgesia induced by CCI in a dose-dependent manner. In the PSNI model, both N-type and P-type VSCC blockers had no effect on thermal hyperalgesia. This suggests that some types of neuropathic pain may be treatable with N-type VSCC blockers.

Topics: Analysis of Variance; Animals; Calcium Channel Blockers; Constriction; Disease Models, Animal; Injections, Spinal; Male; Membrane Potentials; Neuralgia; Neuroprotective Agents; omega-Agatoxin IVA; omega-Conotoxin GVIA; omega-Conotoxins; Peptides; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spider Venoms