ziconotide and Pain--Intractable

Ziconotide is a non-opioid analgesic for intrathecal (IT) administration. The aim of this review is to provide a comprehensive and clinically relevant summary of the literature on dosing and administration with IT ziconotide in the management of refractory chronic pain, and to describe novel dosing strategies intended to improve clinical outcomes.. A Medline search was conducted for "ziconotide," supplemented by manual searching of published bibliographies and abstracts from conferences.. Early experience with IT ziconotide in clinical trials combined with improved understanding of drug pharmacokinetics in the cerebrospinal fluid have led to a reappraisal of approaches to trialing and initiation of continuous-infusion therapy in an effort to improve tolerability. The traditional paradigm of trialing by inpatient continuous infusion may be shifting toward outpatient trialing by IT bolus, although definitions of success and specific protocols remain to be agreed upon. Expert consensus on IT continuous infusion with ziconotide suggests a starting dose of 0.5 to 1.2 mcg/day followed by dose titration of ≤0.5 mcg/day on a no more than weekly basis, according to individual patients' pain reductions and regimen tolerability.. Newer modalities that include patient-controlled analgesia and nocturnal flex dosing have been shown to hold promise of further improvements in ziconotide efficacy and tolerability.. Clinical trials and experience confirm the feasibility and usefulness of IT ziconotide in the management of refractory chronic pain. Emerging evidence suggests that additional IT delivery options may further expand the usefulness and benefits of ziconotide.

Topics: Analgesics, Non-Narcotic; Chronic Pain; Databases, Bibliographic; Dose-Response Relationship, Drug; Humans; Infusions, Spinal; omega-Conotoxins; Pain, Intractable; Treatment Outcome

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

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

For cancer and AIDS patients, 10-30% of pain is refractory to strong opioids, requiring intraspinal administration for pain management. Ziconotide is a selective N-type calcium channel blocker, which inhibits neurotransmitter release, and following intrathecal administration will affect primary nociceptive afferents. In 108 patients with previously unmanaged refractory pain despite the use of systemic or intrathecal opioids, in the initial titration phase, the mean Visual Analogue Scale of Pain Intensity scores improved more in the ziconotide group (53%) than the placebo group (18%). Serious adverse effects were more common in the ziconotide group (31%) than placebo group (10%) in the initial titration phase. In the 48 patients receiving ziconotide, who proceeded to the maintenance phase, the benefit of ziconotide was continued. Until a new approach with a better effectiveness/adverse effects profile than ziconotide for refractory pain emerges, further optimisation of ziconotide for use in the treatment of refractory pain should be undertaken.

Topics: Animals; Humans; Injections, Spinal; omega-Conotoxins; Pain, Intractable

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

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

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

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

For cancer and AIDS patients, 10-30% of pain is refractory to strong opioids, requiring intraspinal administration for pain management. Ziconotide is a selective N-type calcium channel blocker, which inhibits neurotransmitter release, and following intrathecal administration will affect primary nociceptive afferents. In 108 patients with previously unmanaged refractory pain despite the use of systemic or intrathecal opioids, in the initial titration phase, the mean Visual Analogue Scale of Pain Intensity scores improved more in the ziconotide group (53%) than the placebo group (18%). Serious adverse effects were more common in the ziconotide group (31%) than placebo group (10%) in the initial titration phase. In the 48 patients receiving ziconotide, who proceeded to the maintenance phase, the benefit of ziconotide was continued. Until a new approach with a better effectiveness/adverse effects profile than ziconotide for refractory pain emerges, further optimisation of ziconotide for use in the treatment of refractory pain should be undertaken.

Topics: Animals; Humans; Injections, Spinal; omega-Conotoxins; Pain, Intractable

Intracerebroventricular (ICV) administration of opioids for control of intractable cancer pain has been used since 1982. We present here our experience of intracerebroventricular administration of pain treatments including ziconotide associated with morphine and ropivacaine for patients resistant to a conventional approach, with nociceptive, neuropathic, or mixed pain. These clinical cases were conducted with patients suffering from refractory pain, more than 6/10 on a numerical pain rating scale (NPRS) while on high-dose medical treatment and/or intolerance with significant side effects from oral medication. The baseline study visit included a physical examination and an assessment of pain intensity on a NPRS. Under general anesthesia, a neuronavigation device was used to place the catheter on the floor of the third ventricle, supported by an endoscope. Then, drugs were injected in the cerebroventricular system, through a pump (external or subcutaneous). The primary objective was to measure pain evaluation with ICV treatment after a complete withdrawal of other medications.Four patients were enrolled: 3 with intractable cancer pain and one with central neuropathic pain. The median NPRS at baseline was 9.5 [8.5; 19]. The mean NPRS after one month was 3.5 [3; 4.5]. Ziconotide was initiated at 0.48 µg/d and up to a median of 1.2 µg/d [1.0; 1.56]. The median dose of morphine and ropivacaine used initially was respectively 0.36 mg/d [0.24; 0.66] up to 0.6 mg/d [0.45; 4.63] and 1.2 mg/d [0; 2.4] up to 2.23 mg/d [1.2; 3.35]. Minor side effects were initially observed but transiently. One psychiatric agitation required discontinuation of ziconotide infusion. For intractable pain, using ziconotide by intracerebroventricular infusion seems safe and efficient, specifically for chronic neoplastic pain of cervicocephalic, thoracic, or diffuse origin and also for pain arising from a central neuropathic mechanism.

Topics: Aged; Analgesics; Analgesics, Opioid; Humans; Male; Middle Aged; Morphine; omega-Conotoxins; Pain Management; Pain, Intractable

Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ≥ 70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90±7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39±13% (95% confidence interval [CI]=13.61-64.49, P<.001), 51±12% (95% CI=27.56-74.56, P<.001), and 62±13% (95% CI=36.03-87.89%, P<.001), respectively. Four patients experienced mild adverse events related to the study drugs. In conclusion, an IT combination of low doses of ziconotide and morphine allows safe and rapid control of oral opioid-refractory malignant pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Therapy, Combination; Female; Humans; Injections, Spinal; Male; Middle Aged; Morphine; Neoplasms; omega-Conotoxins; Pain Measurement; Pain, Intractable; Prospective Studies; Treatment Outcome

Pharmacological management of severe chronic pain is difficult to achieve with currently available analgesic drugs, and remains a large unmet therapeutic need. The synthetic peptide ziconotide has been approved by the US Food and Drug Administration and the European Medicines Agency for intrathecal treatment of patients with severe chronic pain that is refractory to other treatment modalities. Ziconotide is the first member in the new drug class of selective N-type voltage-sensitive calcium-channel blockers. The ziconotide-induced blockade of N-type calcium channels in the spinal cord inhibits release of pain-relevant neurotransmitters from central terminals of primary afferent neurons. By this mechanism, ziconotide can effectively reduce pain. However, ziconotide has a narrow therapeutic window because of substantial CNS side-effects, and thus treatment with ziconotide is appropriate for only a small subset of patients with severe chronic pain. We provide an overview of the benefits and limitations of intrathecal ziconotide treatment and review potential future developments in this new drug class.

Topics: Analgesics, Non-Narcotic; Catheterization; Creatine Kinase; Drug Interactions; Half-Life; Humans; Injections, Spinal; omega-Conotoxins; Pain, Intractable

Ziconotide, an intrathecal analgesic for the management of chronic intractable pain, binds with high affinity to N-type calcium channels in neuronal tissue and obstructs neurotransmission. In three pivotal, well designed trials of 5-6 or 21 days' duration, titrated ziconotide was significantly more effective than placebo in treating chronic malignant or nonmalignant pain as assessed by mean percentage improvements from baseline in Visual Analogue Scale Pain Intensity scores. Improvements in secondary endpoints (e.g. proportion of patients who responded or achieved pain relief and the change in opioid use) generally support the efficacy of ziconotide over placebo. Ziconotide maintains its analgesic efficacy in preliminary results from long-term, open-label trials (data available for up to 12 months). Most ziconotide-related adverse events are neurological, mild to moderate in severity, resolve over time and reverse without sequelae on drug discontinuation. Low initial doses of ziconotide and gradual titration to onset of analgesia reduces the incidence and severity of adverse events. No evidence of respiratory depression has been reported with intrathecal ziconotide.

Topics: Animals; Clinical Trials as Topic; Humans; Neuroprotective Agents; omega-Conotoxins; Pain Measurement; Pain, Intractable

The U.S. Food and Drug Administration (FDA) recently approved Ziconotide intrathecal infusion for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of, or refractory to, other methods of treatment, including intrathecal morphine. Ziconotide is approved as a monotherapy, but there are challenges associated with the decision to wean intrathecal opioids for Ziconotide alone. Maintaining adequate analgesia and managing opioid withdrawal symptoms may be difficult. Additionally, a variety of adverse physiological, cognitive and psychiatric events may be associated with this new drug. Patients with pretreatment psychiatric disorders may be at increased risk for treatment complications.. To present a report of a case series describing treatment challenges and complications associated with the decision to convert established pump patients from intrathecal opioid therapy to Ziconotide monotherapy.. Three established pump patients, refractory to intrathecal opioid therapy, were converted to Ziconotide monotherapy. All of these patients experienced significant emotional distress or psychological symptoms that threatened the success of the treatment. Achieving adequate analgesia, reducing Ziconotide to mitigate adverse physiological effects, managing opioid withdrawal symptoms, and supportive psychological consultation were combined to achieve successful outcomes in two of our three patients.. This report describes challenges associated with the decision to convert established pump patients from intrathecal opioid therapy to Ziconotide monotherapy. Inadequate analgesia, adverse medication effects, and opioid withdrawal symptoms can precipitate a stressful situation that may be perceived as dangerous or threatening by patients who are predisposed to anxiety. Screening patients for psychiatric disorders, anxiety-proneness and/or vulnerability to stress should be considered to reduce the risk of treatment complications. A multimodal approach is strongly advocated, including rapid responses of treating physicians and nurses along with strong psychological support.

Topics: Calcium Channel Blockers; Chronic Disease; Female; Humans; Infusion Pumps, Implantable; Male; Middle Aged; Models, Biological; omega-Conotoxins; Pain Measurement; Pain, Intractable; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Analgesics; Humans; Infusion Pumps; Injections, Spinal; Neoplasms; omega-Conotoxins; Pain, Intractable

The objective was to assess the analgesic, antihyperesthesic, and anti-allodynic properties of SNX-111 in neuropathic pain.. We describe a patient with refractory, severe deafferentation pain successfully treated with SNX-111 in an open-label, baseline-controlled Phase I/II trial.. The patient was hospitalized for treatment and observation.. The patient was a 43-year-old man with intractable deafferentation pain of 23 years' duration secondary to brachial plexus avulsion.. SNX-111, the first neuron-specific, N-type, voltage-sensitive calcium channel blocker developed for clinical use, was administered by continuous, constant-rate, intrathecal infusion via an indwelling cervical catheter.. The primary outcome measures were the Visual Analog Scales of Pain Intensity (VASPI) and Pain Relief (VASPR).. The patient experienced complete pain relief (VASPI = 0.0 cm and VASPR = 10.0 cm) with elimination of hyperesthesia and allodynia.. SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

Topics: Adult; Brachial Plexus; Calcium Channel Blockers; Dose-Response Relationship, Drug; Humans; Injections, Spinal; Male; omega-Conotoxins; Pain Measurement; Pain, Intractable; Peptides; Phantom Limb

Topics: Acquired Immunodeficiency Syndrome; Calcium Channel Blockers; Clinical Trials, Phase III as Topic; Humans; Neoplasms; omega-Conotoxins; Pain, Intractable; Peptides