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 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.     

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.     

Stability and Analgesic Efficacy of Di‐acetyl Morphine (Diamorphine) Compared with Morphine in Implanted Intrathecal Pumps In Vivo

The objective of this study was to investigate di‐acetyl morphine as an alternative opioid analgesic for use in implanted intrathecal drug delivery systems because of its greater solubility through evaluation of its stability in vivo and analgesic efficacy in the period between pump refills. Contents of intrathecal drug delivery system reservoirs (SynchroMed, Medtronic, Inc., Minneapolis, MN) that had been filled with di‐acetyl morphine dissolved in saline (21), bupivacaine (9), or in both bupivacaine and clonidine (19) were sampled in vivo between 1 and 125 days after refill. The samples were assayed for di‐acetyl morphine and its breakdown products by micellar electrokinetic capillary chromatography. Prospective daily numerical pain scores between pump refills, using 11‐point Likert scales, on 24 patients with implanted SynchroMed pumps (12 delivering di‐acetyl morphine in saline, 12 were delivering morphine in saline) were collected. Results showed that di‐acetyl morphine immediately started to decay to mono‐acetyl morphine in implanted Synchromed pumps with half‐life of 50 days. Mono‐acetyl morphine decayed to morphine with a maxima estimated at 125 days. There was no clinically significant change in average weekly pain scores for up to ten weeks in either group (range, 2.5 to 2.8 for diamorphine and 2.7 to 3.1 for morphine) (2‐way repeated ANOVA, F(9,220) = 0.98, n.s.). We conclude that di‐acetyl morphine and its breakdown products, 6 mono‐acetyl morphine and morphine, provide similar analgesia to morphine alone when administered by intrathecal pump for a period of at least ten weeks and may be a useful alternative when a more soluble agent is favored.     

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

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

The Management of Pain From Collapse of Osteoporotic Vertebrae With Continuous Intrathecal Morphine Infusion

Objectives. Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from collapse of osteoporotic vertebrae affects quality of life (QoL) and autonomy of patients. The management of pain with oral or transdermal opiates can cause severe side‐effects. Continuous intrathecal administration of morphine through an implantable pump might represent an alternative therapy to conventional oral or transdermal administration of opioids and has some advantages and disadvantages for pain relief and improvement in QoL when compared to conventional opioid delivery. It is our objective to report our experience using intrathecal delivery of analgesics in a population of patients with refractory pain due to vertebral fractures. Materials and Methods. In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy. To test for efficacy and improvement in QoL, we administered the visual analog scale (VAS) for pain and the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Before patients were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side‐effects and responses to intrathecal therapy. Results. Significant pain relief was obtained in all implanted patients. Using the QUALEFFO, we observed significant improvement of all variables such as QDL (quality of daily life), DW (domestic work), ambulation, and PHS (perception of health status), before and after one year after pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic analgesic medication. The mean morphine dose during the spinal trial was 11.28 mg/day, 7.92 mg/day at pump implantation, and 16.32 mg/day at one‐year follow‐up. Conclusions. Our results show that intrathecal administration of morphine efficiently relieves the symptoms of pain and improves QoL. Continuous intrathecal administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery and has advantages in those patients who have severe side‐effects with systemic administration of analgesics.     

Intrathecal Morphine Infusion for Chronic Non‐Malignant Pain: A Multiple Center Retrospective Survey

Intrathecal morphine (ITM) is commonly used for the treatment of cancer pain. There is reluctance for its use in France to treat chronic noncancer pain. In order to appreciate its popularity, efficacy, dose escalation with time, and long‐term tolerance, we carried out a retrospective study in the neurosurgery departments of university teaching hospitals in France involved in intrathecal drug therapy. Only 44 patients with chronic noncancer pain used implanted pumps for ITM treatment. Nineteen patients were available for detailed analysis. This survey concerns these 19 patients. There were 13 women and six men. Their average age was 48.8 years (range: 30–69 y). The mean duration of pain before pump implantation was 100 months (range: 12–240 m). The mean follow‐up since implantation was 54 m (range: 4–144 m). Thirteen patients were suffering from postsurgery lumbar and radicular pain. The average initial and final dose per day of morphine was 1.3 mg (range: 1–2 mg) and 2.5 mg (range: 1–6.7 mg) for patients with nociceptive pain and 1.2 mg (range: 0.7–2 mg) and 3 mg (range: 1–10 mg) for patients with mixed pain, respectively. Five (26.3%) of 19 patients returned to their initial jobs. Increase in activity level was reported as good in seven patients (36.8%). Patient satisfaction rate was 90%. The VAS rate was reduced to 49.2% of the initial values while the subjective pain relief was estimated at 67.8%. Two cases (10.5%) of late pump site infection and two patients (10.5%) with catheter displacements were recorded. Side effects imputable to morphine included; constipation, somnolence, decreased libido, weight gain, amenorrhoea, vomiting, nightmares, and itching. No development of tolerance or addiction were recorded. We conclude that in well selected cases ITM should be considered as a possible therapeutic option in the treatment of intractable chronic benign pain.     

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.     

Intrathecal Granuloma and Intramedullary Abscess Associated With an Intrathecal Morphine Pump

Objective and Importance. Several previous reports have documented cord compression resulting from the formation of an intrathecal inflammatory mass in patients using intrathecal drug delivery systems. We present the first reported case of an intramedullary abscess and intrathecal inflammatory mass associated with an intrathecal drug delivery system. Clinical Presentation. A 47‐year‐old man was transferred to our institution from an outside hospital with a 3‐week history of the inability to ambulate or move his legs. His medical history included multiple failed back surgeries for back pain that had been effectively managed after the implantation of an intrathecal drug delivery system eight years prior. Upon presentation to us, his examination showed no movement in his lower extremities with pinprick‐preserved sensation in his toes. Imaging showed an intrathecal mass at the catheter tip, at spinal level T10 and T11. Contrast‐enhanced imaging indicated an intramedullary abscess at T11 and T12 level. Intervention. The patient underwent T10–L1 laminectomies with complete resection of the inflammatory mass, catheter tip, and explantation of the intrathecal drug delivery pump. A midline myelotomy also was performed to aspirate the abscess and the cavity was profusely irrigated. Pathology studies demonstrated that the inflammatory mass contained chronic inflammatory markers and necrotic tissue. The abscess was linked to infection with Streptococcus anginosus. Conclusion. Generally, inflammatory masses forming along the catheter tip are not associated with infections. We report the first case of an intramedullary abscess associated with an intrathecal drug delivery pump.     

Intrathecal Administration of Different Drugs by Programmable Infusion Device in Chronic Pain. A Case Report.

Objective and Importance . The subarachnoid infusion of narcotics by programmable devices in patients with chronic non-malignant pain can be a useful therapeutic method. However, certain side-effects, opioid tolerance or changes in the nature of the pain can lead to failure of the therapy. Clinical Presentation . We present a case report of a woman with both chronic perineal pain and sciatic pain with radiation to her lower limbs caused by failed back surgery syndrome. The pain proved to be resistant to common medical therapy and to spinal cord stimulation. Technique . After surgical implantation of a programmable infusion pump, the patient's leg pain improved with an intrathecal infusion of morphine and bupivacaine. The perineal pain was treated with an infusion of clonidine. The patient therefore needed alternative infusions of both drugs with changes of infusional parameters. Conclusion . The possibility of varying the infusion method of mixed drugs or alternating the drugs is fundamental for successful therapy since neuropathic pain must be considered a dynamic state.     

Intrathecal Morphine Therapy‐Related Granulomas: Faster to Grow than Thought

Complications of intrathecal drug delivery are relatively rare. Of these, infections, cutaneous erosion, and granulomas account for the most common complications. The latter is often noticed when the patient shows signs of sedation and/or reduced pain relief. Granulomas have always been considered to develop over a long period of time, usually calculated in months. Here, we present a case where a catheter‐tip granuloma formed within 5 weeks of intrathecal morphine. The patient was carrying an intrathecal pump for 3 months when it was diagnosed. Probable causes of the formation are discussed.     

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.