Study of Physicochemical Stability of Ziconotide in Medication Cassette Reservoir

ObjectiveTo determine the physicochemical stability of ziconotide solutions for intrathecal administration in the Medication Cassette Reservoir (MCR).Materials and MethodsA 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.ResultsThe 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.ConclusionThis 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.     

Stability of Morphine Sulfate-Clonidine and Sufentanil-Clonidine Mixtures

BackgroundSpinal analgesia is recommended for intractable cancer pain. Morphine-clonidine and sufentanil-clonidine are often used in association in intrathecal drug delivery systems, injected by intraabdominal pumps. To refill these pumps and to limit patient transport, it may be necessary to ship the mixtures in polypropylene syringes to peripheral establishments located near patient homes. The purpose of this study is to determine the stability of morphine-clonidine and sufentanil-clonidine mixtures in polypropylene syringes to ensure the best and safest transport conditions and in implantable pumps for intrathecal use.Materials and MethodsThe stability study method was conceived according to the International Council for Harmonization guidelines. For polypropylene syringes, four different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over seven days. Two storage temperatures were tested (5 ± 3 °C and 25 ± 2 °C). For implantable pumps, two different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over 28 days and stored at 37 °C.ResultsFor the morphine-clonidine mixtures in polypropylene syringes, all mixtures remained stable for five days in both storage conditions (5 ± 3 °C and 25 ± 2 °C) because of relative concentrations systematically positioned between 90% and 110% (95% CIs of the mean of three samples). The two mixtures in implantable pumps remained stable for 28 days.For the sufentanil-clonidine mixtures in polypropylene syringes, cold conservation kept all the preparations stable for seven days, whereas a quick degradation was observed after only two days for ambient storage conditions. This result is similar to that with an implantable pump, in which the concentration is <90% on day 7 for low concentration mixtures.No visual modification, no significant pH modification, and no changes in turbidity assays were observed in either study.ConclusionThis study shows the stability of the morphine-clonidine mixtures in syringes stored at 5 °C for five days and in implantable pumps stored at 37 °C for 28 days. For the sufentanil-clonidine mixtures, the results show stability in syringes for seven days at 5 °C. Pump results show stability of seven days for low concentrations and 28 days for high concentrations.     

Stability Study of Admixtures Combining Ziconotide With Morphine or Sufentanil in Polypropylene Syringes

BackgroundThe 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 MethodsA 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.ResultsThe 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.ConclusionThis 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.     

Chemical Stability of an Admixture Combining Ziconotide and Bupivacaine During Simulated Intrathecal Administration

Objective. To determine the stability of an admixture combining ziconotide with bupivacaine hydrochloride during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. An admixture containing ziconotide (25 µg/mL) and bupivacaine hydrochloride (5 mg/mL) was stored in SynchroMed® II pumps at 37° and in control vials at either 37° or 5°. Using high‐performance liquid chromatography, drug concentrations were determined from samples obtained at varying intervals during the 30‐day study. Results. After 30 days, pump ziconotide and bupivacaine hydrochloride concentrations measured an average of 86.9% and 99.4% of their initial concentrations, respectively. Control vials displayed similar degradation rates for both drugs. Statistical evaluation of the ziconotide 95% confidence interval indicated that the ziconotide concentration would meet or exceed 90% and 80% of initial concentration for 22 days and 45 days, respectively. Conclusions. An admixture containing 25 µg/mL ziconotide and 5 mg/mL bupivacaine hydrochloride was 90% stable for 22 days and 80% stable for 45 days (extrapolated) in SynchroMed® II infusion pumps.     

Chemical Stability of Admixtures Combining Ziconotide with Morphine or Hydromorphone During Simul ated Intrathecal Administration

Objective. To determine the stability of admixtures combining ziconotide with morphine or hydromorphone under simulated intrathecal infusions. Materials and Methods. Admixtures of ziconotide (25 µg/mL) with morphine or hydromorphone (both at 35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°C, and in control vials at 37°C and 5°C. Drug concentrations were determined using high‐performance liquid chromatography. Results. The ziconotide pump concentration with morphine declined to 79% of initial in 17 days, and to 88% of initial after 25 days with hydromorphone. Ziconotide concentrations in control vials stored at 37°C displayed similar rates of decay, but vials stored at 5°C exhibited no ziconotide loss. A statistical evaluation of the two combinations shows ziconotide–hydromorphone retaining 80% stability for 40 days (extrapolated), compared to 15 days for ziconotide–morphine. Morphine and hydromorphone were stable in the presence of ziconotide under all conditions. Conclusions. Ziconotide–hydromorphone admixtures were more stable than ziconotide–morphine admixtures.     

Chemical Stability of Admixtures Combining Ziconotide With Baclofen During Simulated Intrathecal Administration

Objective. To determine the stability of admixtures combining ziconotide with commercially formulated or powdered baclofen during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. Admixtures of ziconotide (25 µg/mL) with commercially formulated (1.5 mg/mL) or powdered (2.0 mg/mL) baclofen were stored in implantable intrathecal pumps at 37°. Drug concentrations were determined with high‐performance liquid chromatography, and the length of time that the concentrations of both drugs remained ≥90% and ≥80% of initial (ie, the 90% and 80% stability, respectively) was estimated based on lower 95% confidence bounds obtained via linear regression. Results. Baclofen was stable in both admixtures. In the commercially formulated baclofen admixture, the mean ziconotide concentration declined to 82.2% of initial in 30 days; the estimates for 90% and 80% stability were 12 and 29 days, respectively. In the powdered baclofen admixture, the mean ziconotide concentration declined to 87.4% of initial in 30 days; the estimates for 90% and 80% stability were 20 and 41 days, respectively. Conclusion. Ziconotide–baclofen admixtures were more stable when prepared using powdered baclofen rather than a commercial baclofen formulation.     

Chemical Stability of Ziconotide‐Clonidine Hydrochloride Admixtures With and Without Morphine Sulfate During Simulated Intrathecal Administration

Objective. To determine the stability of ziconotide–clonidine hydrochloride admixtures with and without morphine sulfate during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. Admixtures of ziconotide (25 µg/mL) and clonidine hydrochloride (2 mg/mL) with and without morphine sulfate (35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°. Pumps were sampled immediately after filling and at four additional time points over the course of 28 (ziconotide–clonidine hydrochloride admixture) or 20 (ziconotide–clonidine hydrochloride–morphine sulfate admixture) days. Drug concentrations were determined using high‐performance liquid chromatography. Results. Ziconotide concentration exceeded 97% of initial at all time points when combined with clonidine alone; statistical evaluation indicated that both ziconotide and clonidine concentrations would remain above 90% of initial for more than 60 days. When compounded with both clonidine and morphine, ziconotide and clonidine concentrations declined; statistical evaluation indicated that the ziconotide concentration was 70% of initial after 20 days, and that clonidine would remain 90% stable for 42 days. Morphine was stable in the presence of ziconotide and clonidine. Conclusions. A ziconotide‐clonidine admixture was 90% stable for 60 days (extrapolated), and a ziconotide‐clonidine‐morphine admixture was 70% stable for 20 days.     

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

Background and ObjectivesThere 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 MethodsA 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.ResultsIn 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.ConclusionsThe 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.     

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

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

Continuous Intrathecal Infusion of Ziconotide for Treatment of Chronic Malignant and Nonmalignant Pain Over 12 Months: A Prospective,Open‐label Study

Objectives. This study aims to assess the safety and efficacy of long‐term intrathecal (IT) ziconotide infusion. Materials and Methods. In this prospective study, 155 patients with severe chronic pain (48 with malignant pain, 107 with nonmalignant pain) who had been responsive to short‐term IT ziconotide in a double‐blind, placebo‐controlled study received long‐term, open‐label IT ziconotide monotherapy. Efficacy assessments included the mean percentage change on the visual analog scale of pain intensity from baseline in the study of origin; safety was monitored by adverse event (AE) reports, periodic laboratory tests, and vital sign measurements. Results. At the last available observation, the visual analog scale of pain intensity scores had decreased by a mean of 36.9% from baseline in the short‐term trial (N = 144; 95% CI: 30.1–43.7%; p < 0.0001). The mean IT ziconotide dose remained stable over 12 months in the 31 patients who participated in the study for ≥ one year. Ziconotide‐related AEs were reported in 147 out of 155 patients (94.8%); 39.4% of patients discontinued treatment because of AEs, the majority of which were considered ziconotide related. Conclusions. Ziconotide IT monotherapy provided patients with analgesia for 12 months in this open‐label study, with an acceptable benefit/risk profile and no evidence of tolerance.     

Pharmacokinetic Analysis of Ziconotide (SNX‐111), an Intrathecal N‐Type Calcium Channel Blocking Analgesic,Delivered by Bolus and Infusion in the Dog

Background and Purpose: Ziconotide is a peptide that blocks N‐type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and infused ziconotide in dog. Experimental Approach: Male beagle dogs (N= 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest‐mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi ³H‐inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T_1/2‐α/β= 0.14 and 1.77 hours, and inulin T_1/2‐α/β= 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48‐hour infusions. Terminal elimination T_1/2 after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48‐hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance. Conclusions and Implications: After IT bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.     

Heterogeneity and heterotypic continuity of emotional and behavioural profiles across development

Purpose

To identify emotional and behavioural symptoms profiles from early childhood to adolescence, their stability across development and associated factors.

Methods

Our sample included 17,216 children assessed at ages 3, 5, 7, 11 and 14 years from the UK Millennium Cohort Study. We used latent profile and latent transition analysis to study their emotional and behavioural profiles from early childhood to adolescence. We included sociodemographic, family and parenting variables to study the effect on latent profile membership and transitions.

Results

The number and specific profiles of emotional and behavioural symptoms changed with the developmental stage. We found a higher number of profiles for ages 3, 5, and 14, suggesting greater heterogeneity in the presentation of emotional and behavioural symptoms in early childhood and adolescence compared to late childhood. There was greater heterotypic continuity between ages 3 and 5, particularly in transitions from higher to lower severity profiles. Children exposed to socioeconomic disadvantages were more likely to belong or transition to any moderate or high emotional and behavioural symptoms profiles. Maternal psychological distress and harsh parenting were associated with internalizing and externalizing profiles, respectively. Higher levels of internalizing and externalizing symptoms across development were associated with lower mental wellbeing and higher rates of self-harm and substance use in adolescence.

Conclusion

Emotional and behavioural symptoms develop early in life, with levels of heterogeneity and heterotypic stability that change throughout development. These results call for interventions to prevent and treat paediatric mental illness that consider the heterogeneity and stability of symptoms across development.

     

A person-centered perspective on differential efficacy of early behavioral intervention in children with autism: A latent profile analysis

BackgroundIndividuals with autism spectrum disorder (ASD) present heterogeneous symptom manifestations and responses to intervention. Despite being well-established, early intensive behavioral intervention (EIBI) has produced inconsistent responding across studies. Investigating individual differences and identifying more homogenous subgroups in samples may lead to a better understanding of symptom heterogeneity in ASD and response to EIBI.MethodAdopting a person-centered perspective, we conducted latent profile analyses (LPA) to explore the presence of homogenous subgroups in our sample of 233 preschoolers with ASD receiving early behavioral intervention services. We investigated predictors of group membership using logistic multinomial regressions and outcomes of membership with the BCH approach available in Mplus.ResultsWe found four latent profiles in our sample: a mild impairment profile, a severe impairment profile, and two intermediate profiles with combinations of mild to moderate autistic symptoms, adaptive functioning, and intellectual functioning. Only the annual family income predicted profile membership. All profiles made progress during the intervention period, with varying magnitudes of change. During the follow-up period, the moderate impairment and the severe impairment profiles showed stability or improvement in adaptive functioning, while the two mild impairment profiles showed a slight decrease.ConclusionsOur study contributes to the literature by suggesting the presence of distinct profiles with differences in their response to EIBI. The profiles associated with better short-term outcomes were different than the profiles who maintain their gains more consistently over time. This finding may guide both practitioners and researchers assessing the effects of intervention.     

Wireless Subcutaneous Trigeminal Nerve Field Stimulation for Refractory Trigeminal Pain: A Single Center Experience

IntroductionSubcutaneous trigeminal nerve field stimulation (sTNFS) is a neuromodulatory treatment for neuropathic trigeminal pain with the ability to reduce the intensity and frequency of pain attacks. However, hardware issues including lead migration, skin erosion, infection, so-called pocket pain at the site of the implanted neurostimulator are reported. Implantable wireless neurostimulation technology promises not only an even less invasive sTNFS treatment and thinner and more flexible electrodes better suited for facial implants, but also provides further advantages such as lack of an implantable neurostimulator and 3T magnetic resonance imaging compatibility.Material and MethodsAll patients who had received trial stimulation with a partially implantable sTNFS system were analyzed for ICHD-3 (3rd edition of the International Classification of Headache Disorders) diagnosis, success of trial stimulation, pre- and postoperative pain intensity, frequency of attacks, complications, and side-effects of sTNFS.ResultsAll patients (N = 3) responded to sTNFS (≥50% pain reduction) during the trial period. According to ICHD-3, N = 2 of the patients were classified with trigeminal neuralgia (TN) with concomitant persistent facial pain and N = 1 patient with multiple sclerosis associated TN. The time of the test period was 44 ± 31.24 days (mean ± SD). The average daily duration of stimulation per patient amounted 2.5 ± 2.2 hours (range 1–5). The pain intensity (defined on a visual analog scale) was reduced by 80% ± 17% (mean ± SD). Reduction or cessation in pain medication was observed in all patients. No surgical complications occurred in the long-term follow-up period of 18.84 ± 6 (mean ± SD) months.ConclusionThe partially implantable sTNFS device seems to be safe, effective, and reliable. Compared to conventional devices, the equipment is not limited to the length of trial stimulation. Furthermore, the daily stimulation duration was much shorter compared to previous reports.     

Long‐Term Intrathecal Ziconotide Therapy: A Case Study and Discussion

This case study describes the therapeutic result of intrathecal administration of ziconotide, a new synthetic neurotoxin derived from the venom of the Philippine marine snail, Conus Magus, to a 48‐year‐old male with chronic, and previously untreatable, neuropathic pain of an undeterminable etiology. The patient suffered tactile allodynia and reported his baseline pain intensity to be 80 mm on the 100 mm Visual Analog Scale for Pain Intensity. After responding affirmatively to treatment in a blinded placebo‐controlled trial, the patient enrolled in a long‐term, open‐label trial. Currently, the patient rates his pain at 16 mm and enjoys an improved quality of life. This result suggests that treatment with ziconotide may provide outstanding relief to patients with chronic pain while sparing them the unpleasant side effects associated with other treatments.     

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized,Double‐Blind,Placebo‐Controlled Clinical Trial

Objective. The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial. Materials and Methods. Patients (169 ziconotide, 86 placebo) with severe chronic nonmalignant pain unresponsive to conventional therapy and a visual analog scale of pain intensity (VASPI score) ≥ 50 mm were treated over a 6‐day period in an inpatient hospital setting. Initial starting dose was 0.4 µg/hour and was titrated to analgesia or intolerance (maximum dose 7.0 µg/hour). The starting and maximum doses were reduced to 0.1 µg/hour and 2.4 µg/hour, respectively, due to adverse events (AEs). Results. The mean percent reduction in VASPI score from baseline was 31.2% and 6.0% for ziconotide‐ and placebo‐treated patients, respectively (p ≤ 0.001). During the initial titration phase, a significantly greater percentage of patients in the ziconotide group compared to the placebo group reported AEs, including abnormal gait, amblyopia, dizziness, nausea, nystagmus, pain, urinary retention, and vomiting. Conclusion. Ziconotide provided significant analgesia in patients for whom conventional therapy failed. However, there was a considerable incidence of ziconotide‐associated AEs due to the rapid titration and high doses administered.     

Dorsal Versus Ventral Intrathecal Catheter Tip Location and Effect on Dose Escalation and Opioid Use in Patients With Cancer Pain

ObjectivesIn the practice of intrathecal drug delivery, consensus exists regarding the cephalad to caudad location of the catheter tip relative to dermatomal distribution of pain. However, data are lacking on the importance of dorsal vs ventral tip location relative to the spinal cord. We hypothesize that a dorsally placed catheter tip improves efficacy because of closer proximity to nociceptive pathways.Materials and MethodsA retrospective review of 298 patients with cancer with intrathecal drug delivery systems implanted at the Huntsman Cancer Institute from May 2014 to June 2020 was performed. Patients were stratified by catheter tip location zones based on available radiographic studies. Patient-controlled intrathecal medication dose requirements and rate of change were compared with catheter zone and other variables, including the presence of adjuncts such as bupivacaine and ziconotide.ResultsA total of 158 patients were suitable for analysis demonstrating a dorsal tip in 63.9% (n = 101) and ventral tip in 36.1% (n = 57), with a median follow-up of 17 days (interquartile range [IQR], 10–24). There was no difference in daily dose change from implant to discharge between the dorsal group 8.2% (IQR, 0.0–41.5) and ventral group 20.8% (IQR, 0.0–66.7; p = 0.12). Daily dose change from discharge to follow-up was 2.6% (IQR, 0.0–7.1) in the dorsal group and 1.8% (IQR, 0.0–5.7) in the ventral group (p = 0.92). Catheter tip location had no impact on systemic opioid use.ConclusionsWe did not find significant associations between dorsal vs ventral catheter tip location and measures of pain relief, including change in intrathecal dose or systemic opioid use.     

Patient Selection and Trial Methods for Intraspinal Drug Delivery for Chronic Pain: A National Survey

Objectives Intraspinal drug delivery via indwelling pump is an effective means of treating refractory pain. Before a patient is selected for pump implantation, an intraspinal drug delivery trial must be performed to establish side‐effects and efficacy profiles. No consensus protocol currently exists for such trials. As a preliminary step in this process, we surveyed a group of interventional pain physicians to explore attitudes on patient selection criteria, drug choice, trial techniques, and efficacy assessment. Methods The questionnaire was sent for self‐administration to 1500 interventional pain physicians, each of whom had implanted one or more Medtronic^® implantable infusion pumps. Results We received 205 completed surveys. Among the respondents, most were anesthesiologists (76%) and in private practice (82%). Nearly half (45%) of the respondents use the continuous intrathecal infusion technique to select patients for permanent implants. Conclusions Trial practices vary widely in terms of patient selection, medication choice, technique, and efficacy evaluation. We hope that our findings will encourage a concerted effort to evaluate existing trial protocols in order to establish a reliable standard of care.     

Management of Cancer-Related Pain With Intrathecal Drug Delivery: A Systematic Review and Meta-Analysis of Clinical Studies

BackgroundDespite increased attention paid to assessment and management, pain continues to be a prevalent and undertreated symptom in patients with cancer. Intrathecal drug delivery (IDD) is a therapeutic option that allows targeted delivery of analgesics to the intrathecal space.ObjectiveThe aim of this review was to examine the efficacy of managing cancer-related pain with IDD. Secondary objectives included the effects of IDD on systemic opioid use and infection rates.Evidence ReviewA systematic search of the literature published between 1990 and 2019 was performed to identify studies evaluating the efficacy and/or safety of IDD with external or implanted pumps in patients with cancer-related pain. Data were extracted and meta-analyses performed to determine the mean changes in pain levels at short-, mid-, and long-term intervals; changes in opioid (oral morphine equivalent [OME]) daily dose; and infection rates. Changes were assessed compared with baseline.FindingsPain levels were decreased from baseline: On a 0 to 10 scale, mean differences were −4.34 (95% CI [−4.93 to −3.75], p < 0.001) at 4 to 5 weeks; −4.34 (95% CI [−5.07 to −3.62], p < 0.001) at 6 to 12 weeks; and −3.32 (95% CI [−4.60 to −2.04], p < 0.001) at >6 months. Weighted mean OME consumption was reduced by 308.24 (SE = 22.72) mg/d. Weighted mean infection rates were ∼3% for external and implanted pumps.ConclusionsMeta-analyses show a statistically significant and sustained decrease in cancer pain with IDD, compared with baseline. Systemic opioid consumption was reduced on average by >50% after IDD. Infection rates were comparable with other indications.     

Effect of Co-Morbid Conditions on Persistent Neuropathic Pain after Brachial Plexus Injury in Adult Patients

MethodsThe medical records of patients diagnosed with BPI referred to a pain center between 2006 and 2010 were reviewed for 2 years retrospectively. Data regarding patient demographics, injury and surgical profiles, characteristics of NeuP and its severity, and treatment received were compared between patients with and without manifesting co-morbid conditions. The NeuP and pain intensity assessments were based on the DN4 questionnaire and a numerical rating scale, respectively.ResultsOf the 45 patients studied, 24 patients presented with one of the following co-morbid conditions: myofascial pain (21%), psychiatric disorder (17%), phantom limb pain (4%), complex regional pain syndrome (21%), and insomnia (37%). Tramadol was required by 20 patients with co-morbidity and, 9 patients without co-morbidity (p<0.001). The mean pain score after 2 years was higher in patients with co-morbidity than in those without co-morbidity (p<0.05).ConclusionsPersistent pain following BPI was more common in patients manifesting other painful conditions or psychiatric co-morbidity. A higher proportion of the patients in the co-morbid group required tramadol as a second-line of agent for pain relief.