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Pain is a complex phenomenon that is usually unpleasant and aversive. It can range widely in intensity, quality, and duration and has diverse pathophysiologic mechanisms and meanings. Voltage-gated sodium and calcium channels are essential to transmitting painful stimuli from the periphery until the dorsal horn of the spinal cord. Thus, blocking voltage-gated calcium channels (VGCCs) can effectively control pain refractory to treatments currently used in the clinic, such as cancer and neuropathic pain. VGCCs blockers isolated of cobra Naja naja kaouthia (α-cobratoxin), spider Agelenopsis aperta (ω-Agatoxin IVA), spider Phoneutria nigriventer (PhTx3.3, PhTx3.4, PhTx3.5, PhTx3.6), spider Hysterocrates gigas (SNX-482), cone snails Conus geographus (GVIA), Conus magus (MVIIA or ziconotide), Conus catus (CVID, CVIE and CVIF), Conus striatus (SO- 3), Conus fulmen (FVIA), Conus moncuri (MoVIA and MoVIB), Conus regularis (RsXXIVA), Conus eburneus (Eu1.6), Conus victoriae (Vc1.1.), Conus regius (RgIA), and spider Ornithoctonus huwena (huwentoxin-I and huwentoxin-XVI) venoms caused antinociceptive effects in different acute and chronic pain models. Currently, ziconotide is the only clinical used N-type VGCCs blocker peptide for chronic intractable pain. However, ziconotide causes different adverse effects, and the intrathecal route of administration also impairs its use in a more significant number of patients. In this sense, peptides isolated from animal venoms or their synthetic forms that act by modulating or blocking VGCCs channels seem to be a relevant prototype for developing new analgesics efficacious and well tolerated by patients.

Background The association of morphine ziconotide or sufentanil ziconotide was used to manage cancer pain. Moving these patients is sometimes difficult. In order to transport these syringes for pump refilling, it could be interesting to demonstrate the stability of the mixture and so to be able to ensure the best transport conditions of syringes. Materials and methods A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Fur mixtures of each association have been stored in 5 ± 3°C and 25 ± 2°C and were evaluated for seven days and compared to the initial observed concentrations. Results The stability of these associations was demonstrated at 5°C for seven days thanks to relative concentrations (95% confidence intervals of the mean of three samples) systematically positioned between 95% and 105%. No degradation product was observed during the stability study. Conclusion This study shows the stability of these association morphine ziconotide or sufentanil ziconotide at 5°C for seven days in polypropylen syringes. This result will allow the transport of the preparation under optimal conditions. Advance preparations for intrathecal pump refills could also be feasible.

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 β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by 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.

Introduction: Intrathecal (IT) drug therapy is an effective treatment option for patients with chronic pain of malignant or nonmalignant origin, with an established safety profile and fewer adverse effects compared to oral or parenteral pain medications. Morphine (a μ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the U.S. Food and Drug Administration for the treatment of chronic pain. Although both are considered first-line IT therapies, each drug has unique properties and considerations.Areas Covered: This review will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies.Expert Opinion: Morphine and ziconotide are effective IT therapies for patients with chronic malignant or nonmalignant pain that is refractory to other interventions. IT ziconotide is recommended as a first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management.

Background Some patients with chronic pain and implanted spinal cord stimulators or intrathecal (IT) pumps fail to obtain significant pain relief. The use of dual modality treatment with both therapies is understudied. This study evaluated comprehensive outcomes in this patient population and reported outcomes primarily using IT ziconotide. Methods We retrospectively analyzed 11 patients with chronic pain treated with both spinal cord stimulation and IT therapy. When a primary treatment failed to achieve significant pain relief, a secondary device was trialed and implanted. Pain severity (measured by a numeric rating scale) was assessed by the change from baseline to after the first and second intervention. In a subset of patients (n = 6), quality-of-life metrics were also assessed. Outcome measures were analyzed closest to the 1-year follow-up date after implantation of the first modality and then at the most recent follow-up after implantation of the second modality. Results Spinal cord stimulation leads were percutaneous (n = 2) or paddles (n = 9) and commonly covered T8-10. IT medication included ziconotide (n = 8), baclofen (n = 1), hydromorphone (n = 1), and morphine/clonidine (n = 1). There was a mean of 19.64 ± 3.17 months between primary and secondary intervention. There was a significant improvement in pain severity from baseline to implantation of the second modality (P = 0.032) at a mean follow-up of 50.18 ± 11.83 months. Conclusions Dual modality therapy is a potential treatment option in patients who have lost efficacy with a single neuromodulation modality. Further study is required to identify potential responders and nonresponders.

Introduction In cancer-related pain refractory to systemic opioids, intrathecal (IT) administration of morphine can be a useful strategy. In clinical practice, IT morphine is usually combined with other drugs with different mechanisms of action, in order to obtain a synergistic analgesic effect. However, the discussion on efficacy and safety of IT combination therapy is still ongoing. The aim of this observational study was to report the effects of an IT combination of low doses of ziconotide, morphine, and levobupivacaine in end-stage cancer refractory pain. Methods Sixty adult patients, 21 females and 39 males, were enrolled to an IT device implant. The mean visual analogue scale of pain intensity (VASPI) score was 88 ± 20 mm. All patients started with a triple combination therapy: the initial IT dose of morphine was calculated for each patient based on the equivalent daily dose of morphine; an oral/IT ratio of 400/1 was used. For ziconotide, a standard slow titration schedule was started at 1.2 μg/day and the initial dose of levobupivacaine was 3 mg/day. Results The initial IT mean doses of morphine, ziconotide, and levobupivacaine were 0.8 ± 0.3 mg/day, 1.2 mcg/day and 3 mg/day, respectively. At day 2, a significant reduction in VASPI score was registered (49 ± 17, p

Purpose 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. Recent Findings 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. Summary 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.

The FDA’s approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic β-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas’s capability to produce insulin is still effective.

Introduction: The choice of the proper intrathecal drug to treat neuropathic pain has been subject to much debate in recent years. Areas Covered: Currently, the United States Food and Drug Administration (USFDA) has approved two drugs for chronic intrathecal use for the treatment of pain; however, there has been substantial growth in the development of other intrathecal drugs that can be used for neuropathic pain. We performed a PubMed literature search looking at intrathecal drug research for neuropathic pain between January 2005 to May 2019 and discuss current practices and mechanisms in treating these complex patients. Expert Opinion: On-label intrathecal drugs are recommended if efficacious with acceptable side effects. In those suffering from neuropathic pain, clinical evidence suggests additional drug algorithms for treating these patients are necessary. There is ample room for growth in the development and approval of novel drugs for intrathecal delivery to manage neuropathic pain.

Introduction: Phantom limb pain (PLP) is a chronic debilitating condition, frequently observed in amputees. At present, there is no standard treatment, and its optimal management requires a multidisciplinary approach in which minimally invasive treatment should be considered in more complex cases. Objective: To report successful treatment of 2 cases of PLP treated with ziconotide as part of multimodal intrathecal management. Materials and methods: Descriptive, retrospective case report developed in a multimodal pain treatment unit. Results: A total of 2 cases of patients with diagnosis of PLP refractory to medical therapy, treated with intrathecal multimodal therapy, are presented. Their favorable course, with 50% pain reduction, is described. Conclusion: Implantation of infusion systems for administration of intrathecal analgesia with ziconotide at the cervical and supraspinal level proved to be effective in the described cases; this technique should be evaluated in specific trials for the treatment of PLP refractory to other therapies.

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

Purpose Persistent idiopathic facial pain (PIFP) is a poorly defined and debilitating chronic pain state with a challenging and often inadequate treatment course. This is the first case report identifying the novel use of low-dose lumbar intrathecal ziconotide to successfully treat PIFP with nearly complete resolution of pain and minimal to no side effects. Methods The patient was a 37 year-old female whose PIFP was refractory to multimodal medication management and multiple neurovascular surgical interventions. A single-shot lumbar intrathecal trial of ziconotide (2.5 mL, equivalent 2.5 μg) was injected when she was at her baseline pain level - VAS 7/10. She received complete resolution of her pain for about 9 hours, concordant with ziconotide's half-life. She was subsequently implanted with a lumbar intrathecal delivery system. Results The patient experienced complete resolution of her facial pain with a single-shot intrathecal trial of ziconotide. The intrathecal pump system has provided nearly complete (VAS 1/10) pain relief. Two flares of pain occurred 10 and 18 months after pump placement, which subsequently resolved after increasing the ziconotide dose by 0.5 μg/day on each occasion. The patient is currently maintained on a dose of 2.0 μg/day and is pain-free. Conclusion This is the first case report describing the use of a single-shot lumbar intrathecal trial of ziconotide and subsequent placement of lumbar (as opposed to thoracic) intrathecal ziconotide pump for PIFP. A single-injection intrathecal trial is a low-risk, viable option for patients with this debilitating and frustrating pain condition. Successful trials and subsequent intrathecal pump placement with ziconotide may supplant multimodal medication management and/or invasive orofacial surgical intervention for PIFP.

ɷ-Conotoxin MVIIA (ziconotide or SNX-111) is an atypical analgesic drug with the water-soluble formulation and routinely is injected into the brain and spinal regions in human and animal model stud...

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.

This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence‐based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under‐used in Europe, adding that ziconotide ITA has potential to be a first‐line alternative to morphine; both are already first‐line options in the USA. Ziconotide ITA (initiated using a low‐dose, slow‐titration approach) is suitable for many patients with noncancer‐ or cancer‐related chronic refractory pain and no history of psychosis. Adopting ziconotide as first‐line ITA could reduce opioid usage in these patient populations. The group advocated a risk‐reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US–European alignment of the licensed starting dose for ziconotide: the low‐and‐slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low‐and‐slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core., Adopting ziconotide as first‐line intrathecal analgesia in Europe could provide adequate pain relief and reduce the opioid burden in patients with chronic refractory pain and no history of psychosis. This paper provides preliminary recommendations for ziconotide usage in Europe, using evidence‐based risk‐reduction strategies, tailored for patients with cancer‐ or noncancer‐related chronic pain.

Background Neuropathic pain (NeuP) is a complex, debilitating condition of the somatosensory system, where dysregulation between pro- and anti-inflammatory cytokines and chemokines are believed to play a pivotal role. As of date, there is no ubiquitously accepted diagnostic test for NeuP and current therapeutic interventions are lacking in efficacy. The aim of this study was to investigate the ability of three biofluids - saliva, plasma, and cerebrospinal fluid (CSF), to discriminate an inflammatory profile at a central, systemic, and peripheral level in NeuP patients compared to healthy controls. Methods The concentrations of 71 cytokines, chemokines and growth factors in saliva, plasma, and CSF samples from 13 patients with peripheral NeuP and 13 healthy controls were analyzed using a multiplex-immunoassay based on an electrochemiluminescent detection method. The NeuP patients were recruited from a clinical trial of intrathecal bolus injection of ziconotide (ClinicalTrials.gov identifier NCT01373983). Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was used to identify proteins significant for group discrimination and protein correlation to pain intensity. Proteins with variable influence of projection (VIP) value higher than 1 (combined with the jack-knifed confidence intervals in the coefficients plot not including zero) were considered significant. Results We found 17 cytokines/chemokines that were significantly up- or down-regulated in NeuP patients compared to healthy controls. Of these 17 proteins, 8 were from saliva, 7 from plasma, and 2 from CSF samples. The correlation analysis showed that the most important proteins that correlated to pain intensity were found in plasma (VIP > 1). Conclusions Investigation of the inflammatory profile of NeuP showed that most of the significant proteins for group separation were found in the less invasive biofluids of saliva and plasma. Within the NeuP patient group it was also seen that proteins in plasma had the highest correlation to pain intensity. These preliminary results indicate a potential for further biomarker research in the more easily accessible biofluids of saliva and plasma for chronic peripheral neuropathic pain where a combination of YKL-40 and MIP-1α in saliva might be of special interest for future studies that also include other non-neuropathic pain states.

Background 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. Methods 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. Results 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. Conclusions 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.

Background and ObjectivesThe Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide.MethodsThe study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit.ResultsThe registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%).ConclusionsFinal study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

OBJECTIVE To determine the physicochemical stability of ziconotide solutions for intrathecal administration in the Medication Cassette Reservoir (MCR). MATERIALS AND METHODS A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Two mixtures of ziconotide (0.40 μg/mL and 0.60 μg/mL) stored in MCR stored at 25 ± 2°C were evaluated for 14 days and compared to the initial observed concentrations. RESULTS The physicochemical stability of the two solutions was demonstrated for two days thanks to relative concentrations, pH measurement, visual inspections, and turbidity assays. A degradation product was observed and increased during the study. CONCLUSION This study showed a very low physicochemical stability of diluted ziconotide stored at 25 ± 2°C in the MCR. The intrathecal administration of ziconotide does not seem appropriate with this device for outpatients.

N-type calcium channels (Neuronal-type Calcium channel, Cav2.2) is a member of high voltage activated calcium channels. There are two native small peptides for N-type calcium channels (NTCC) directly which are derived from cone snail, ω-conotoxin-GVIA isolated from Conus geographus and ω-conotoxin-MVIIA (SNX-111, Ziconotide, PrialtTM), from Conus magus which both directly block the α1-ion conducting pore. NTCCs, have been shown to play a key role in nociceptive transmission due to their strategic location, presynaptically in afferent C & Aᵹ fiber terminals and postsynaptically in descending neuron. NTCCs, which are highly expressed at the pre-synaptic terminals of nociceptive neurons in dorsal horn of the spinal cord regulate release of the key pro-nociceptive neurotransmitters such as glutamate, substance P, neurokinin A, and CGRP. There have been many preclinical studies demonstrating the effect of different NTCC blockers in various acute, inflammatory and neuropathic animal pain models. In 2004 ziconotide has been approved in US and Europe to be used in clinical practice. Furthermore, many clinical trials have been performed in more than 1000 patients studying the efficacy and safety of ziconotide. IT administrated of ziconotide showed significant decrease in pain scores in patients with malignant and nonmalignant pain which are practically in neuropathic pain characteristic and resistant to IT opioids.

Objective Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. Methods To evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 μg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 μg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. Results In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. Conclusion Ziconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

Pain is one of the most prevalent medical conditions but with limited therapeutic options. Morphine and salicin are not only the first analgesics but also played an important role in modern day medicinal chemistry, pharmacology and therapeutics. Despite the search for better agents for the management of pain, most of the newly introduced agents are either analogues of these old drugs or work in the same way. Ziconotide, capsaicin and botulinum toxin type A are the natural products that received FDA approval as analgesics. Each of them represents novel mechanisms of their analgesic action. Some other Conus venom peptides (MrIA, Contulakin G, Vc1.1, conantokin G), capsaicinoids, capsinoids and their synthetic analogues are also under investigations for the development of new analgesics. Natural products including nonpeptide toxins, mitragynine, salvinorin A, and flavonoids represent important scaffolds for the development of analgesics with novel mechanism of actions.

Ziconotide is an intrathecally administered medication indicated for the treatment of severe chronic pain in patients who are intolerant of or refractory to other treatment options. A black box warning is included in the packaging and states ziconotide is contraindicated in patients with a preexisting history of psychosis. Patients taking ziconotide should be monitored for evidence of cognitive impairment, hallucinations, or changes in mood, and ziconotide should be discontinued if neurological or psychiatric signs and symptoms appear. We present a case of a 49-year-old white male with no previous neuropsychiatric history who received ziconotide for several years before he developed command auditory hallucinations within 24 hours of a dose increase. Upon admission to the emergency room, the patient's pain management physician was contacted and the ziconotide dose was decreased and eventually discontinued. Because of a continuation of symptoms, the patient was transferred from the emergency room to an acute care psychiatric hospital where he was started on risperidone 1 mg orally at bedtime. At discharge, the patient was noted to be in good behavioral control without any hallucinations. The patient was encouraged to follow up with his pain management physician to determine if ziconotide should be reconsidered.

The lack of oral or injectable formulations of ziconotide (ω-conotoxin peptide), a novel analgesic agent, limits research on potential neurobehavioral protective properties of this substance, including antidepressant-like effects. Here we expose rats to a stress paradigm that induces depression and memory impairment to assess the effects of ziconotide treatment. Ziconotide was administered intracerebroventricular (i.c.v.) to rats undergoing stereotaxic surgery at a single dose (1 μg/rat) or in repeated long-term applications (dosage groups: 0.1, 0.3, and 1 μg/rat). The antidepressant activity and memory-enhancing effects of ziconotide were examined via the forced swimming test, the Morris water maze test, and the passive avoidance learning test. Behavioral results showed that long-term i.c.v. ziconotide administration significantly decreased the immobility time and delayed the latency period to immobility in a dose-dependent manner compared to controls. In the passive avoidance learning test, the latency period increased, and in the Morris water maze test, the platform location latency time decreased. A single dose of ziconotide (1 μg/rat) did not show a significant effect on memory function or depression parameters during the same tests. Animals were sacrificed immediately after behavioral testing, and both hippocampi were removed and prepared for BDNF evaluation. Hippocampal BDNF levels were significantly increased in rats receiving long-term i.c.v. ziconotide compared to controls. Our results suggest that long-term consumption of ziconotide may attenuate the severity of depression-like behavior and could be useful for preventing memory impairments in various learning models by elevating BDNF levels.

Objectives To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain. Methods Medline was searched (through July 2017) for “ziconotide” or “morphine” AND “intrathecal” AND “chronic pain,” with results limited to studies in human populations. Results The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non–cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non–cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time. Conclusion Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non–cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.

Intrathecal analgesia has increased over the past two decades in various indications: chronic refractory pain from cancerous or non-cancerous origins, spasticity. These different indications involve the use of different molecules alone or in combination such as morphine, ropivacaine, bupivacaine, fentanyl, sufentanil, clonidine, baclofen and ziconotide. Pump refills are prepared at the pharmacy under a laminar flow hood. An analytical control should be carried out before release of the preparation. A new method of analytical control by chromatography has been developed and validated according to the International Conference on Harmonization guideline in order to secure the production process.

Voltage-gated calcium channels (VGCCs) play a critical role in neuroinflammatory diseases, such as multiple sclerosis (MS). CTK 01512-2 is a recombinant version of the peptide Phα1β derived from the spider Phoneutria nigriventer, which inhibits N-type VGCC/TRPA1-mediated calcium influx. We investigated the effects of this molecule in the mouse model of experimental autoimmune encephalomyelitis (EAE). The effects of CTK 01512-2 were compared to those displayed by ziconotide-a selective N-type VGCC blocker clinically used for chronic pain-and fingolimod-a drug employed for MS treatment. The intrathecal (i.t.) treatment with CTK 01512-2 displayed beneficial effects, by preventing nociception, body weight loss, splenomegaly, MS-like clinical and neurological scores, impaired motor coordination, and memory deficits, with an efficacy comparable to that observed for ziconotide and fingolimod. This molecule displayed a favorable profile on EAE-induced neuroinflammatory changes, including inflammatory infiltrate, demyelination, pro-inflammatory cytokine production, glial activation, and glucose metabolism in the brain and spinal cord. The recovery of spatial memory, besides a reduction of serum leptin levels, allied to central and peripheral elevation of the anti-inflammatory cytokine IL-10, was solely modulated by CTK 01512-2, dosed intrathecally. The intravenous (i.v.) administration of CTK 01512-2 also reduced the EAE-elicited MS-like symptoms, similarly to that seen in animals that received fingolimod orally. Ziconotide lacked any significant effect when dosed by i.v. route. Our results indicate that CTK 01512-2 greatly improved the neuroinflammatory responses in a mouse model of MS, with a higher efficacy when compared to ziconotide, pointing out this molecule as a promising adjuvant for MS management.

Objectives: To assess the efficacy and the safety of our rapid detoxification protocol in preventing signs and symptoms of withdrawal and pain severity. Design: Prospective, open-label case series study. Settings: Public primary care at the Pain and Palliative Care Unit of the Infermi Hospital of Rimini, Italy. Patients: The authors studied 10 consecutive patients suffering from chronic noncancer pain who were refractory to intrathecal (IT) morphine, and hence indicated for ziconotide therapy. Interventions: IT pump was refilled with saline solution, and each patient received endovenous morphine, oral clonidine, ketoprofen, and lorazepam for the first 3 days, and slow-release tramadol, oral clonidine, and ketoprofen for 10 days. Ziconotide therapy was started at the end of the 2-week detoxification treatment. Main outcome measures: The observer-rated opioid withdrawal scale (OOWS) was used for the assessment of withdrawal signs, visual analogue scale was used for pain intensity assessment, and also adverse events were recorded. Results: Withdrawal symptoms were experienced by 3 patients (30 percent). Their average OOWS decreased significantly (p < 0.05) from 4.3 ± 2.5 to 1.7 ± 0.6 at days 3 and 14 of protocol, respectively, with no increment of pain intensity. Withdrawal symptoms were resolved in 4 days on average without the need of adjuvant medications. One patient with high morphine dosage (20 mg/d), interestingly, did not show any withdrawal symptoms. Conclusions: The detoxification protocol was effective in preventing withdrawal signs without increasing pain severity, allowing to rapidly convert IT morphine to ziconotide monotherapy in patients who are refractory to morphine.

Objective Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs. Methods Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain. Results The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication selection, outcome assessment, and treatment adjustment. Currently, morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker) are the only agents approved by the US Food and Drug Administration for IT analgesia. We provide relevant information on the dosing, titration, and adverse effect management of these medications for PAs, NPs, and RNs responsible for administering IT therapy. Conclusion PAs, NPs, and RNs are valuable members of IT pain management teams. Treatment success requires ongoing monitoring of efficacy and adverse effects, with corresponding adjustments to medication selection and dosing, in addition to good communication among the health care professionals involved in patient care.

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

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

μ-conotoxins are a group of marine Conus peptides that inhibit sodium currents, so μ-conotoxins are valuable in sodium channel research and new analgesic drug discovery. Here, a novel μ-conotoxin TsIIIA was identified from a worm-hunting Conus tessulatus. TsIIIA was chemical synthesized according to its amino acid sequence GCCRWPCPSRCGMARCCSS and identified by mass spectrum. Patch clamp on rat dorsal root ganglion cells showed that 10 μM TsIIIA specifically inhibit TTX-resistant sodium currents but has no effect on TTX-sensitive sodium currents. TsIIIA inhibits TTX-resistant sodium currents by a dose-dependent mode with an IC50 of 2.61 μM. Further study showed 10 μM TsIIIA has no obvious effect on the current-voltage relationships, conductance-voltage relationships and voltage-dependence of steady-state inactivation of TTX-resistant sodium channels. Mice hotplate analgesic assay indicated that TsIIIA obviously increase the pain threshold at 0.5-4 h. In addition, TsIIIA has better analgesic effects than Ziconotide, indicating that TsIIIA was a valuable lead compound for development of new analgesic drug.

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Cav2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators.

A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24-48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient. Genetic testing was negative for an EM-associated mutation in the SCN9A gene, encoding the NaV1.7 sodium channel, suggesting a mutation in an alternate gene.

Background Intrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and outcomes, clinicians are motivated to rethink the traditional spinal infusion pump patient selection criteria and indications. We review the current understanding of the pharmacology of commonly employed intrathecal agents and the clinical relevance. Methods Search strategies for data acquisition included Medline database, PubMed, Google scholar, along with international and national professional meeting content, with key words including pharmacology of opioids, intrathecal therapy, ziconotide, pharmacokinetics, and intrathecal drug delivery. The search results were limited to the English language. Results Over 300 papers were identified. The literature was condensed and digested to evaluate the most commonly used medications in practice, sto serve as a foundation for review. We review on-label medications: ziconotide and morphine, and off label medications including fentanyl, sufentail, and hydromorphine. Conclusion Intrathecal therapy has level-one evidence for use for malignant pain and nonmalignant pain, with continued cost savings and improved safety. To most effectively serve our patients, a clear appreciation for the pharmacology of these commonly employed medication is paramount.

The intrathecal delivery of drug (ITD) has clear theoretical advantages, as it bypasses the blood-brain barrier and allows for an increase in medication potency of an order of magnitude. Clinically ITD has been shown to be more effective than oral administration in the treatment of intractable spasticity.1 There is however no well controlled study to demonstrate the superior pain relief of ITD over systemic administration in chronic non-cancer pain patients.2 One large multicentre randomised controlled trial in end-stage cancer patients, comparing ITD with the ‘best current medical treatment’ has shown a significant decrease in side effects in patients receiving ITD. There was however no significant difference in the intensity of pain.3 Despite appealing features, the clinical benefit of ITD is hampered by a number of biological, pharmacological and organisational problems.4 Even the most enthusiastic supporters will agree that this treatment is far more complicated and resource-demanding than the oral route. As with any surgery, there is a modest risk of infection, but meningitis and encephalitis are major, potentially life-threatening complications. Other surgical problems include pocket, epidural or spinal haematomas.5 The choice of drugs to be used with intrathecal pumps is limited and only baclofen and ziconotide have been unanimously recognised. the FDA has accepted morphine but not the EMA, and in Europe, the use of morphine depends on the decision of each countries. To complicate matters, the overwhelming clinical experience suggests that IT morphine is often insufficient to achieve pain relief in the most difficult pain patients, particularly when neuropathic and mechanical components are predominant. Yet the data shows the majority of clinicians do use a large number of other drugs,6 which means that intrathecal administration of drugs is mostly performed off label7. Though compounding is endorsed by an international consensus, the theoretical risk of litigation remains. Finally, the provision of ITD cannot be done by one physician but requires a team of doctors and specifically trained nurses. Patients have to be seen in the clinic at regular intervals to refill the pump, which necessitates an infrastructure to ensure that patients are followed and called in time. Furthermore, an on-call system has to be put in place as technical problem (such as pump stalls) can occur and have the potential of precipitating severe withdrawal symptoms that may not necessarily be recognised by a medical team unfamiliar with ITD. In addition, the pump refill procedure requires trained personnel as it carries a risk of overdose either because of an error in the selection of the Injection site (site port instead of pump reservoir), or more frequently pocket site injection.8 9 In conclusion the efficacy of ITD for the management of severe pain is essentially supported by personal experience and limited uncontrolled case series and is therefore still debatable. the fact remains that no controlled trial has documented its superiority over oral administration, whether in cancer or non-cancer pain. Admittedly, the administration of drugs such as local anaesthetics and clonidine are not possible through a systemic route and may be necessary in severe mechanical and/or neuropathic pain. But theses are relatively uncommon situations that do not justify the widespread use of this technique. References Coffey JR, et al. Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study. J Neurosurg 1993;78:226–232. Turner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin J Pain 2007;23:180–195. Smith TJ, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: Impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20:4040–4049. doi:10.1200/Jco.2002.02.118 Prager J, et al. Best practices for intrathecal drug delivery for pain. Neuromodulation 2014;17:354–372; discussion 372. doi:10.1111/ner.12146 Deer TR, et al. The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks. Neuromodulation 2017;20:155–176. doi:10.1111/ner.12579 Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy-a survey of clinical trends and decision making. J.Pain Symptom.Manage. 2000.Aug;20(2):S4–11. 2000;20:S4–11. Deer TR, et al. The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines. Neuromodulation 2017;20:96–132. doi:10.1111/ner.12538 Maino P, Perez R, Koetsier E. Intrathecal pump refills, pocket fills, and symptoms of drug overdose: a prospective, observational study comparing the injected drug volume vs. the drug volume effectively measured inside the pump. Neuromodulation 2017;20:733–739. doi:10.1111/ner.12597 Wankhede V, Buchser E. a case of pocket fill causing baclofen withdrawal. Neuromodulation 2018. doi:10.1111/ner.12887

Intrathecal analgesia offers proven benefits over oral analgesics for the treatment of patients with chronic intractable pain. Intrathecal (IT) therapy delivers analgesic medication directly to the site of action of the dorsal horn of the spinal cord, thereby bypassing first-pass metabolism and the blood-brain barrier. the advantages of IT drug delivery may be relevant given the opioid abuse epidemic in the US, which has led to an excessive number of deaths (33,091 opioid-related overdose deaths in 2015). Intrathecal drug delivery system (IDDS) is a targeted therapy system for treating pain and muscle spasm and is recommended for the treatment of chronic non-malignant pain which does not respond to optimal medical management and also for intractable cancer pain and for spasticity. Patients with cancer pain receiving orally opioids and adjuvant drugs may experience adequate pain control in 80%-90% of cases. In the rest, 10–20% of the cases some form of invasive therapies will be needed. The implantable pump is an effective treatment in order to control stable pain. the main indications, pre-implantation trials, the licensing of drugs for intrathecal use and the adverse effects and benefits of this therapy will be discussed. Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non-cancer-related pain. The trialing for IT drug delivery systems remains an area of continued controversy. Considering the use of invasive devices we must fully aware of all the potential complications of the procedure, the device and the drugs used. the advantages of IDDS are: a) long term of analgesia b) decrease in opioid consumption and c) decrease in adverse events. References Deer T, et al. Intrathecal therapy for chronic pain: a review of morphine and ziconotide as firstline options. Pain Med 2018. Sayed D, et al. Retrospective Analysis of Intrathecal Drug Delivery: Outcomes, Efficacy, and Risk for Cancer-Related Pain at a High Volume Academic Medical Center. Neuromodulation 2018.

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.

The avulsion of nerve roots of the brachial plexus that is commonly seen in motorcycle accidents is a type of neuropathy due to deafferentation. This type of pain is clinically challenging since therapeutical protocols fail or have severe side effects. Thus, it is proposed to evaluate the antinociceptive activity of the recombinant CTK 01512-2 peptide that is derived from the venom of the Phoneutria nigriventer spider, as a future new therapeutical option. The neuropathic pain was surgically induced by avulsion of the upper brachial plexus trunk in groups of male Wistar rats and after 17 days, they were treated intrathecally with morphine, ziconotide, and CTK 01512–2. Behavioral tests were performed to evaluate mechanical and thermal hyperalgesia, cold allodynia, the functional activity of the front paw, and exploratory locomotion after the treatments. The peripheral blood samples were collected 6 h after the treatments and a comet assay was performed. The spinal cord was removed for the lipoperoxidation dosing of the membranes. The cerebrospinal fluid was analyzed for the dosage of glutamate. The recombinant peptide showed an antinociceptive effect when compared to the other drugs, without affecting the locomotor activity of the animals. Mechanical and thermal hyperalgesia, as well as cold allodynia, were reduced in the first hours of treatment. The levels of glutamate and the damage by membrane lipoperoxidation were shown to be improved, and genotoxicity was not demonstrated. In a scenario of therapeutical failures in the treatment of this type of pain, CTK 01512–2 was shown as a new effective alternative protocol. However, further testing is required to determine pharmacokinetics.

Intrathecal drug delivery systems (IDDS) have been successfully utilized for both chronic, refractory cancer and non-cancer pain. Currently, only three pharmacologic agents are approved for intrathecal (IT) use by the Food and Drug Administration (FDA): morphine, baclofen, and ziconotide. Historically, morphine has been relied upon as a first-line agent for pain with (IT) therapy given its profound analgesic properties. However, even at the small doses typically used with IT therapy, morphine can lead to adverse events, complications with therapy, and even death. Baclofen is a power agent used for spasticity with no application in the treatment or management of chronic pain. Ziconotide is the only non-opioid analgesic agent currently available for IT use in the United States. Its pharmacologic effects are modulated via a selective block of presynaptic neuronal N-type calcium channels in the spinal cord. Given the unique mechanism of action of ziconotide, it holds significant advantages over IT opioids when implemented within IDDS. In this chapter, we will overview the current role of ziconotide for IT use in patients with refractory chronic pain.

As the first in a new class of non-opioid drugs, &omega, 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&rsquo, 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.

Intrathecal drug delivery (IDD) is an effective means to treat refractory pain of malignant and nonmalignant origin. In 2017, Polyanalgesic Consensus Conference guidelines were published to provide the physician with best practices to identify patients, stratify risks, and initiate and maintain therapy. The successful use of IDD resides in the knowledge and ability of a physician to diagnose the underlying disease, stratify risks, initiate timely therapy, and identify and manage complications appropriately.