Management Of Severe Chronic Pain Research Articles

Intrathecal opioids: equally efficacious at any age.

Intrathecal opioid pumps have been used in the management of severe chronic pain for more than 40years. Numerous studies have shown significant therapeutic effects alongside tolerable side effects. In the last decades, life expectancy has increased in many countries in the world. With an aging population, the question arises whether effects equal to those in younger patients can also be achieved in elderly patients. This study is an in-depth re-analysis of data published previously. 36 patients were analyzed. The sample included 18 elderly patients (> 65years) and 18 younger patients. No differences between the two samples were found with regard to pain intensity under intrathecal opioid therapy and prior to implantation of the opioid pump. Likewise, there were no differences in anxiety/depression scores and pain-related disability. Side effects were reported at similar rates by the elderly patients and by the younger patients. Elderly patients showed a tendency towards lower opioid doses and slower dose increases. Our data hint at a consistent efficacy of intrathecal opioid therapy in elderly patients even after long-term treatment. Side effects of the treatment are relatively frequent but mild and no side effects were particularly frequent in elderly people.

Tapentadol Prolonged Release: A Review in Pain Management.

Tapentadol prolonged release (tapentadol PR) [Palexia® SR in EU] is a long-acting tablet formulation of the strong central analgesic tapentadol, which acts as both a μ-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor. Tapentadol PR is approved for chronic pain in various countries, with its EU indication (severe chronic pain manageable only with opioid analgesics) being the focus here. Well-designed trials and clinical practice data support tapentadol PR use in this setting. Short term, tapentadol PR was an effective and generally well tolerated analgesic for moderate to severe pain of varying aetiologies, including neuropathic pain. It provided analgesia at least as good as that of conventional strong opioids and appeared more favourable in terms of gastrointestinal tolerability, likely due to less potent MOR binding. Severe back pain with a neuropathic component responded well to moderate-dose tapentadol PR in some patients, while for others, an increase to the maximum recommended tapentadol PR dosage provided analgesia at least as good as that of moderate-dose tapentadol PR plus pregabalin and appeared to have some CNS tolerability benefits. Data also support the use of tapentadol PR in opioid rotation, including when conventional opioids are intolerable. Longer-term data in musculoskeletal pain conditions indicate continued benefit over up to 2 years’ treatment with tapentadol PR with no evidence of tolerance. Thus, tapentadol PR is a useful option for the management of severe chronic pain.

Management of severe chronic pain with methadone in pediatric patients with sickle cell disease

Vasocclusive pain crises are common among pediatric patients with sickle cell disease (SCD). Some patients with repeated pain crises develop chronic pain. We performed a retrospective cohort study of pediatric patients with SCD with chronic pain treated with methadone. We identified a significant reduction in pain hospitalizations following methadone treatment (0.35±0.19 vs. 0.19±0.17 hospitalizations/month, P=0.016). In addition, we did not observe overt organ toxicity nor symptoms of opioid withdrawal during methadone wean. We suggest that methadone is safe and has some clinical benefit, which should be proven in prospective randomized trials for pediatric patients with SCD and chronic pain.

Management of Severe Chronic Pain with Methadone in Pediatric Patients with Sickle Cell Disease

IntroductionPatients with sickle cell disease (SCD) experience acute painful events; some patients develop chronic pain requiring daily short acting opioids, and frequent emergency department (ED) visits, and inpatient hospitalization. From the Cooperative Study of Sickle Disease (Platt, NEJM 1991), only 1% of patients with SCD experience more than 6 pain events per year. Methadone is a synthetic opioid used in chronic pain, but there is a paucity of data on its use and effectiveness in the pediatric SCD population. We hypothesized that methadone can be used safely in pediatric patients with SCD with severe chronic pain and would reduce ED visits and hospitalizations.MethodsWe conducted a retrospective cohort study (IRB approved) of 16 pediatric patients with SCD who received methadone for chronic pain management, indicating having more than 5 pain events per year. These patients were among 1100 total patients with SCD at our center. Primary SCD providers escalated doses to maximal effect and when clinically stable, doses were weaned. Follow-up started at time of methadone initiation and ended when a patient was weaned or transitioned to adult care; the 1 year period before treatment initiation was defined as the baseline period. We calculated descriptive statistics to characterize the study population. We compared clinical outcomes (ED visits or hospitalization for pain) for the baseline period and 1 year post methadone initiation using paired T test. To evaluate methadone dosing and dependency, we identified the mean dose, percentage of time at highest dose, and wean of methadone. We assessed withdrawal and safety by reviewing outpatient encounters, EKG screening for QTc > 450, eGFR by cystatin C to determine either a decrease in eGFR by 20% or an eGFR <80, and microalbumin/creatinine urinary excretion.ResultsAmong the 16 participants, 10 (62.5%) were male and the genotypes of each patient were: 14 SS, 1 S/β0-thalassemia, 1 SC. The mean age was 15.5 (±2.8) years at time of methadone initiation and there was a medium follow-up of 2.1 years. Clinically, 13 (81.3%) had previous cholecystectomy, 6 (37.5%) had previous splenectomy, 7 (43.8%) had radiographic evidence of infarction of a long bone within the year prior to initiation of methadone, 10 (62.5%) were receiving chronic transfusion during methadone, and 10 (62.5%) received psychosocial counseling for depression and/or anxiety. The average number of ED visits per month was 0.31 (±0.27) in the baseline period and were 0.28 (±0.28, p=0.658) and 0.31 (±0.25, p=0.921) in the 1 year post and entire follow-up periods. The rate of hospitalizations per month decreased from 0.35 (±0.19) in the baseline period to 0.19 (±0.17, p=0.016) and 0.22 (±0.21, p=0.05) in the 1 year post and entire follow-up periods. The average initial starting dose was 12.5 mg and the mean highest dose was 26.6 mg. In 14 (87.5%) patients the final dose was less than the highest dose and 4 (25.0%) patients were weaned completely off of methadone. For the entire cohort, each patient spent a median of 183 days at their highest dose, a mean of 34% of the total time treated with methadone. No patients experienced signs consistent with opioid withdrawal during the follow-up period. The most common subjective complaints were sedation (12%), nausea and/or vomiting (24%) and constipation (6%). We found no documented new abnormal QTc intervals, changes in eGFR, or new onset proteinuria during the follow up period.ConclusionMethadone use in pediatric patients with SCD is well-tolerated and may lead to improved pain control as evidence by significant reduction in hospitalizations. Additionally, when followed closely, methadone can be used safely without concern for physiologic dependency; this is supported by our ability to wean patients off methadone entirely or weaning to a lower dose than their highest dose in the majority of the cohort. Hematologists should consider methadone as a part of chronic pain management in patients with SCD and severe chronic pain. DisclosuresLebensburger:ASH: Research Funding; NHLBI K23: Research Funding.

Clinical Uses of Intrathecal Therapy and Its Placement in the Pain Care Algorithm.

Intrathecal drug delivery is an effective treatment option for patients with severe chronic pain who have not obtained adequate analgesia from more conservative therapies (eg, physical therapy, systemic opioids, nonsteroidal anti-inflammatory drugs, antidepressants, and anticonvulsants). This review focuses on, but is not limited to, the 2 agents currently approved by the U.S. Food and Drug Administration for intrathecal analgesia: preservative-free morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker). We describe the appropriate use of intrathecal therapy in the management of severe chronic pain, based on current best practices. Topics addressed here include patient selection, trialing, dosing and titration, adverse event profiles, long-term management, intrathecal therapy for cancer-related pain, and the placement of intrathecal therapy in the pain care algorithm. In appropriately selected patients with chronic pain, intrathecal therapy can provide substantial pain relief with improved functioning and quality of life. Successful long-term management requires ongoing patient monitoring for changes in efficacy and the occurrence of adverse events, with subsequent changes in intrathecal dosing and titration, the addition of adjuvant intrathecal agents, and the use of concomitant oral medications to address side effects, as needed. Based on an infrequent but clinically concerning risk of overdose, granuloma, and other opioid-induced complications, nonopioid therapy with ziconotide may be preferred as a first-line intrathecal therapy in patients without a history of psychosis or allergy.

Properties and use of transdermal fentanyl

Steve Chaplin and Dr Austin Leach provide an overview of the properties of transdermal fentanyl preparations in the management of severe chronic pain in adults and opioid‐tolerant children.

Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists

Background and objective:Clinical trials have documented the efficacy and good tolerability of tapentadol prolonged released (PR) for severe chronic pain. This study investigated routine long-term administration by pain specialists.Methods:The effectiveness analysis included prospective data collected over a 3 month period (cohort I, n = 1457, mean age 61.2 ± 13 years) and over a 12 month period (cohort II, n = 588, 60.1 ± 13.2 years) regarding previous and concomitant analgesic treatment, tapentadol dosage, pain intensity, sleep and quality of life parameters, and tolerability.Results:Most patients (>77%) had suffered from severe chronic pain for ≥2 years with low back pain the main pain diagnosis (82%); 91% had already received analgesic long-term treatment prior to initiation of tapentadol therapy (42% of those received strong opioids). After 3 month tapentadol treatment, cohort I had experienced a mean pain reduction of 2.4 points (from 6.8 ± 1.6 at baseline) and improvements of 2.1 points in quality of sleep (from 5.8 ± 2.5) and quality of life (from 6.5 ± 2; all p ≤ 0.001). The 12 month tapentadol treatment (cohort II) reduced the mean pain intensity by 3.2 points from 6.7 ± 1.6 at baseline (NRS-11; p ≤ 0.001); 57% of the patients experienced clinically relevant pain relief of ≥50%. At end of observation, 92% attained either their intended pain reduction and/or an additional individual treatment target, both predefined at start of tapentadol therapy. This was accompanied by a significant reduction in pain-related impairments in daily activities and an improvement in quality of life (all p ≤ 0.001). Most frequent side-effects were nausea (6.3% of patients) and dizziness (3.8%) for cohort I, and nausea (1.5%) and constipation (1.2%) for cohort II.Conclusion:Tapentadol PR is effective and well tolerated and can be considered an alternative to classical strong opioids in long-term chronic pain therapy.Limitations:The study lacks a control group; assessment under routine practice conditions, however, reflects daily practice clinical management conditions.

Reviews The place of oxycodone/naloxone in chronic pain management

Opioid analgesics are usually effective in the management of severe chronic pain. However, symptoms of opioid-induced bowel dysfunction (OIBD) are common during opioid therapy. Opioid-induced bowel dysfunction is often unsuccessfully managed due to limited effectiveness and numerous adverse effects of traditional laxatives. Newer treatment possibilities directed at the pathomechanism of OIBD comprise combined prolonged-release oxycodone with prolonged-release naloxone (oxycodone/naloxone) tablets. Oxycodone/naloxone provides effective analgesia with limited impact on bowel function as oxycodone displays high oral bioavailability and naloxone act as local antagonist on opioid receptors in the gastrointestinal tract due to nearly complete inactivation in the liver. Oxycodone/naloxone is administered to opioid-naive patients with severe pain and those unsuccessfully treated with weak opioids. Oxycodone/naloxone may be also administered to patients treated with strong opioids who experience intense symptoms of OIBD. Studies conducted to date indicate that oxycodone/naloxone is an important drug in chronic pain management, prevention and treatment of OIBD.

Results of the CHANGE PAIN ® survey on physician's perception about the management of severe chronic non-cancer pain

Results of the CHANGE PAIN ® survey on physician's perception about the management of severe chronic non-cancer pain

Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today’s understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt®, Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of VGSC and their potential as novel lead compounds in drug development.

Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.Areas covered in this review: A MEDLINE search was done (January 2002 – July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials.What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy – it is a strong analgesic that is well tolerated.

Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain

Ziconotide is a conopeptide intrathecal (IT) analgesic which is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain. It is a synthetic equivalent of a naturally occurring conopeptide found in the venom of the fish-eating marine cone snail and provides analgesia via binding to N-type voltage-sensitive calcium channels in the spinal cord. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, IT administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Side effects of ziconotide which tend to occur more commonly at higher doses may include: nausea, vomiting, confusion, postural hypotension, abnormal gait, urinary retention, nystagmus/amblyopia, drowsiness/somnolence (reduced level of consciousness), dizziness or lightheadedness, weakness, visual problems (eg, double vision), elevation of serum creatine kinase, or vestibular side effects. Initially, when ziconotide was first administered to human subjects, titration schedules were overly aggressive and led to an abundance of adverse effects. Subsequently, clinicians have gained appreciation for ziconotide's relatively narrow therapeutic window. With appropriate usage multiple studies have shown ziconotide to be a safe and effective intrathecal analgesic alone or in combination with other intrathecal analgesics.

Intrathecal Ziconotide for Complex Regional Pain Syndrome: Seven Case Reports

Ziconotide is a nonopioid analgesic currently indicated as monotherapy, but frequently used in combination with opioids, for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of, or whose pain is, refractory to other treatments. There is a paucity of information regarding ziconotide use in patients with complex regional pain syndrome (CRPS). Seven cases in which IT ziconotide was used in patients with CRPS were analyzed. All patients (4 male, 3 female; age range, 14 to 52 years) had experienced inadequate pain relief with multiple conventional and interventional treatments. Three patients received ziconotide monotherapy exclusively; 4 patients received ziconotide monotherapy initially, then combination IT therapy. The mean ziconotide dose was 5.2 mcg/d (range, 0.5 to 13 mcg/d) at initiation and 24.7 mcg/d (range, 0.06 to 146 mcg/d) at the last available assessment. The mean duration of ziconotide therapy was 3.1 years (range, 26 days to 8 years). At ziconotide initiation, the mean visual analog scale (VAS) score was 89.3 mm (range, 75 to 100 mm); VAS scores decreased by a mean of 47.5% (range, 5% to 100%) at last assessment. Of the 5 patients who experienced substantial improvement in pain, edema, skin abnormalities, and/or mobility with ziconotide therapy, 2 have discontinued ziconotide and are pain free. Another patient experienced marked reversal of both edema and advanced skin trophic changes. Adverse events included urinary retention, depression, anxiety, and hallucinations. Adverse events generally resolved spontaneously, with treatment, or with ziconotide discontinuation/dose reduction. Although further studies are required, ziconotide holds promise as an effective treatment for CRPS.

A renaissance in marine pharmacology: From preclinical curiosity to clinical reality

Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt® (ziconotide, ω-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis® (trabectedin, ET-743) an antitumor agent discovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.

Ziconotide: an update and review

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

Intrathecal Ziconotide for Severe Chronic Pain: Safety and Tolerability Results of an Open-Label, Long-Term Trial

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

Nonclinical Safety of Ziconotide: An Intrathecal Analgesic of a New Pharmaceutical Class

Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended.

Optimizing use of opiates in the management of cancer pain.

Cancer pain is often suboptimally managed. The underestimation and undertreatment continues to be a problem despite the availability of consensus-based guidelines. Most patients with cancer develop pain. The prevalence and severity of pain among cancer patients varies according to primary and metastatic sites and stage of disease. Opioid therapy is the cornerstone of management of severe chronic pain in the field of cancer patients and in general in palliative care medicine. Since this class of drugs is the cornerstone of the treatment, optimizing its use may be useful in clinical practice. For this purpose we focused on 4 distinct issues: 1) How to implement the use the opioids in cancer patients; 2) How to optimise the use of morphine in cancer patients; 3) The management of side effects and opioid switching; 4) What is the role of other potent opioids. A holistic approach including an appropriate use of opioids may improve pain control in most cancer patients, particularly for those with advanced disease.

Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain

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

A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain

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