SPIDOL study protocol for the assessment of intrathecal ziconotide antalgic efficacy for severe refractory neuropathic pain due to spinal cord lesions.

RATIONALE: Central neuropathic pain resulting from spinal cord injury is notoriously debilitating and difficult to treat with few currently available treatments. A novel molecule with intrathecal administration: Ziconotide has been approved for treatment of refractory neuropathic pain in general. It acts as a presynaptic calcium channel blocker. A pilot study has shown its potential in SCI neuropathic pain patients. OBJECTIVE: The aim of this study is to determine the long-term (6 months) efficacy of chronic intrathecal ziconotide for the treatment of neuropathic SCI pain. STUDY DESIGN: Multicenter, Randomized, Comparative, Placebo controlled, Double blind clinical trial, with a crossover of random alternated periods of 6 months (placebo or ITZ) for a total of 15 months including a total of 44 patients. STUDY POPULATION: • Patients with SCI of various etiologies exhibiting neuropathic pain refractory to non-invasive treatments. • > 18 years. INTERVENTION: Intrathecal administration of ziconotide via an implanted pump. STUDY OUTCOMES: Primary study outcome Difference in pain intensity for all patients between effective treatment and placebo periods. Secondary study outcomes 1. Continuous evaluation of pain intensity. 2. Percentage of patients with at least 30% of pain reduction. 3. Satisfaction level of the patient pain relief. 4. Declarations of serious adverse events. 5. Duration and intensity of spontaneous and provoked pain. 6. Quality of life. 7. Patient global impression of change. 8. Quantification of daily dosages of analgesic drug intake. 9. Long term memory and neurocognitive effects. 10. Assessment of the patient's physical and emotional distress. NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT, AND GROUP RELATEDNESS: Participation in this study is in accordance with current treatment protocols for SCI neuropathic pain in France therefore it proposes a treatment that would currently be considered regular practice even though no RCT evidence is yet available. The study gives patients the advantage of directly testing versus placebo a treatment that otherwise entails significant constraints. A Data Safety Monitoring board (DSMB) will be created for continuous safety analysis. Furthermore, patients will be followed in specialized pain centers offering the possibility of continuing their treatment after the study period.

Intrathecal ziconotide for the treatment of chronic pain: a collection of clinical experiences and literature review.

OBJECTIVE: Despite the wide use of ziconotide in the USA for treating refractory cancer- and noncancer-related pain, this agent is little used in Europe, even if licensed by the European Medicines Agency (EMA). The reason could be attributed to the high, fixed starting dose required for ziconotide, as stated in the EMA Summary of Product Characteristics (SmPC). This dosage recommendation is based on the results of pivotal clinical studies of ziconotide, which utilized aggressive titration schedules. Thus, a reappraisal of the available evidence, as well as a reflection on real-life clinical experiences, might be useful to identify practice adjustments to improve the clinical application of ziconotide in the European scenario. In line with this need, this paper reports some clinical experiences of patients with chronic pain treated with ziconotide intrathecal (IT) therapy in Italy, particularly focusing on long-term treatment to further characterize and improve the use of this agent in real practice. Moreover, a literature review of the available data on the effectiveness and safety of IT ziconotide is provided. CASE SERIES: Collected clinical experiences suggested that the use of IT ziconotide represents a valuable option, particularly in cases where other treatments have been ineffective or poorly tolerated. Ziconotide was shown to not cause severe side effects in the long-term treatment, leading to a constant pain relief effect at stable doses, without adverse events that caused therapy interruption. The overall constant ziconotide dosages also suggest the absence of a tolerance effect. In parallel, the evidence in the literature aligns with real-world evidence and further supports the use of IT ziconotide as an important option for the management of chronic pain. CONCLUSIONS: IT ziconotide represents a valuable addition to the armamentarium of pain management strategies, offering hope for improved quality of life for patients suffering from chronic, treatment-resistant pain. Continued research and clinical experience will further elucidate its optimal use and role in comprehensive pain care.

Natural pain killers from marine sources: a new frontier in neurosurgical pain management.

The development of new analgesics for the management of neurosurgical pain is a great opportunity in marine environments. Particular secondary metabolites with strong biological activity that have developed for defense are produced by marine bioresources. The analgesic potential of marine-derived peptides, alkaloids, terpenes and polyketides-such as discodermolide from marine sponges and ziconotide from cone snail venom-is highlighted in this letter. These substances work through novel methods that minimize the negative effects associated with conventional analgesics while focusing on particular pain pathways. Despite obstacles in sustainable sourcing and regulatory validation, the development of these marine-derived analgesics requires interdisciplinary collaboration to fulfill their potential in enhancing pain management.

Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly.

Peptide drugs have disadvantages such as low stability, short half-life and side effects, which limit their widespread use in clinical practice. Therefore, peptide drugs can be modified to improve these disadvantages. Numerous studies have shown that alkyl-modified peptide drugs can self-assemble to prolong the duration of efficacy and/or reduce side effects. However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming. To overcome this, a simple reductive amination reaction was employed, which can directly graft the alkyl chain to the peptide sequence and effectively avoid stepwise synthesis from C- to N-terminal with amino acids. In this study, ω-conotoxin MVIIA was used as the peptide drug, while myristic aldehyde was used as the alkylating agent. To obtain the maximum productivity of modified peptides, the molar ratio of peptide MVIIA to myristic aldehyde in the reductive amination reaction was optimized. Furthermore, the peptide modification sites in this reaction were confirmed by secondary mass spectrometry analysis. Besides, alkyl-modified peptide MVIIA was able to form micelles by self-assembly and improved stability in serum, which was related to our previous work where myristoylated peptide MVIIA micelles can improve the drug stability. Finally, this study was intended to provide a methodological basis for modifying the alkyl chain of peptide drugs.

An orally available Cav2.2 calcium channel inhibitor for the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Cav2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Cav2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour. EXPERIMENTAL APPROACH AND KEY RESULTS: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Cav2.2 at nanomolar concentrations and inhibits Cav2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only at concentrations higher than 10 µM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg-1) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg-1) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test. CONCLUSIONS AND IMPLICATIONS: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need.

Essential oil of Sicilian Prangos ferulacea (L.) Lindl. and its major component, ß-ocimen, affect contractility in rat small and large intestine.

ETHNOPHARMACOLOGICAL RELEVANCE: Prangos ferulacea (L.) Lindl is an Apiaceae plant, widely used in traditional medicine. Recently, chemical composition and biological activities of its essential oil (Prangroil) have been reported, but there are no studies on possible effects on intestinal contractility. AIMS OF THE STUDY: We investigated the effects of essential oil Sicilian Prangoil on the contractility of rat small (duodenum) and large (colon) intestine and the related action mechanism. MATERIALS AND METHODS: Responses to Prangoil and to its major component ß-ocimen in intestinal segments were assessed in vitro as changes in isometric tension. RESULTS: Prangoil, induced in duodenum, depending upon doses, contraction and/or muscular relaxation. Instead, in colon Prangoil only reduced the phasic contractions and induced muscular relaxation. ß-ocimen, in both segments, produced only reduction of the spontaneous contractions without affecting basal tone. Prangoil contractile effects were abolished by ω-conotoxin, neural N-type Ca2+ channels blocker, atropine, muscarinic receptor antagonist, neostigmine, acetylcholinesterase (AChE) inhibitor, suggesting that Prangoil-induced contraction would be the result of an increase in neuronal cholinergic activity. Prangoil and ß-ocimen inhibitory effects were unaffected by ω-conotoxin, L-NAME, blocker of the NO synthase, ODQ, soluble guanylate cyclase inhibitor, excluding involvement of neurotransmitter release or NO synthesis in the inhibitory effects. Potassium channel blocker did not affect Prangoil or ß-ocimen inhibitory responses. Prangoil or ß-ocimen inhibited the Ca2+ and high-KCl solution -induced contractions and the Carbachol-induced contractions in calcium free solution. CONCLUSION: Prangoil affects the contractility of small and large intestine in rat, with regional differences, via potentiation of neural cholinergic activity, blockade of L-type voltage-gated calcium channel and reduction of Ca2+ release from the intracellular store. The Prangroil main components, ß-ocimen, contributes to the inhibitory effects.

A Chemoenzymatic Approach To Produce a Cyclic Analogue of the Analgesic Drug MVIIA (Ziconotide).

Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (CaV 2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins.

Self-Assembly Nanostructure of Myristoylated ω-Conotoxin MVIIA Increases the Duration of Efficacy and Reduces Side Effects.

Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, severe neurological side effects and low stability associated with peptide MVIIA have restricted its widespread use. Fortunately, self-assembly endows the peptide with high stability and multiple functions, which can effectively control its release to prolong its duration of action. Inspired by this, MVIIA was modified with appropriate fatty acid chains to render it amphiphilic and easier to self-assemble. In this paper, an N-terminal myristoylated MVIIA (Myr-MVIIA, medium carbon chain length) was designed and prepared to undergo self-assembly. The present results indicated that Myr-MVIIA can self-assemble into micelles. Self-assembled micelles formed by Myr-MVIIA at higher concentrations than MVIIA can prolong the duration of the analgesic effect and significantly reduce or even eliminate the side effects of tremor and coordinated motor dysfunction in mice.

Microneedle-mediated delivery of Ziconotide-loaded liposomes fused with exosomes for analgesia.

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.

Physicochemical Stability Study of the Morphine-Ropivacaine-Ziconotide Association in Implantable Pumps for Intrathecal Administration.

PURPOSE: This study aimed to investigate the physicochemical stability of morphine-ropivacaine-ziconotide mixtures used in intrathecal analgesia. MATERIALS AND METHODS: Eight mixtures were studied to assess their stability profiles according to the initial drug concentrations used. The solutions obtained were put in implantable pumps and stored at 37 °C over a period of 60 days. Assays were performed using ultra high-pressure liquid chromatography. Turbidity and pH were also measured throughout the study. RESULTS: Results confirmed excellent physicochemical stability for morphine and ropivacaine. Concerning ziconotide, three of the eight mixtures did not show any sign of chemical instability: average concentrations remained constant throughout the 60 days. A decrease of the concentration was observed for the five other mixtures. Moreover, the appearance of a degradation product linked to oxidation confirmed the ziconotide degradation. CONCLUSIONS: All these results are in favor of a physicochemical stable preparation for three of the mixture profiles when stored in implantable pumps at 37 °C up to 60 days. For the five others, the efficacy should decrease over time owing to the degradation of ziconotide. The decrease in kinetics of the ziconotide concentration depends on the mixing profile. One possibility is to adapt the filling intervals according to the profile of the mixture. Finally, the results show the period of stability ensuring maximum analgesic efficacy for the eight mixture profiles studied.

Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis.

OBJECTIVES: Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain. MATERIALS AND METHODS: An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios. RESULTS: Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England. CONCLUSIONS: The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options.

2022 Golden Goose Award honors serendipitous science.

Ceremony recognizes unexpected breakthroughs on pain relievers, microscopes, and laser surgery.

Analgesic effect of recombinant GABAergic precursors releasing ω-conotoxin MVIIA in a model of peripheral nerve injury in rats.

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

The Role of Intrathecal Pumps in Nonmalignant Pain.

Intrathecal pumps deliver analgesic medication directly into the central nervous system. In patients with chronic nonmalignant pain, intrathecal therapy using morphine or ziconotide has been shown to be an effective option when traditional noninvasive methods do not provide adequate relief. There has been increasing use of intrathecal drug administration in the management of patients with nonmalignant pain in recent years given the advances in technology and research on the topic. However, due to its invasive nature, intrathecal pumps remain the last option among patients with chronic pain.

Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512-2 Toxin in Persistent Pain Models.

CTK 01512-2 toxin is a recombinant peptide of the Phα1ß version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512-2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1-4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512-2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512-2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.

Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2.

N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II-III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.

Structure of human Cav2.2 channel blocked by the painkiller ziconotide.

The neuronal-type (N-type) voltage-gated calcium (Cav) channels, which are designated Cav2.2, have an important role in the release of neurotransmitters1-3. Ziconotide is a Cav2.2-specific peptide pore blocker that has been clinically used for treating intractable pain4-6. Here we present cryo-electron microscopy structures of human Cav2.2 (comprising the core α1 and the ancillary α2δ-1 and ß3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Cav2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Cav2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Cav channels.

Short-Term Outcomes of a High-Volume, Low-Concentration Bolus Starting Dose Technique With Ziconotide: A Case Series.

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

Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy.

The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p < 0.0001, p < 0.0001, and p < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p < 0.0001, p < 0.01, and p < 0.05, respectively), and 300 nM and 100 nM GVIA (p < 0.0001 and p < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.