Intrathecal Drug Delivery Research Articles

Refill Procedures of Intrathecal Drug Delivery Systems With a Recessed Fill Port on the Pump Surface: A Prospective Comparison Study of Ultrasound-Guided vs. Blind Refill Technique

Structural differences of implantable drug delivery systems (IDDSs) might have an impact on the efficiency of needle access to the reservoir fill port (RFP). The aim of this study was to assess the efficiency of RFP needle access with an ultrasound (US)-guided vs. a blind refill technique in IDDSs with a Recessed RFP (Recessed-RFP-IDDS). The primary outcome was the number of attempts needed to enter the RFP with a needle comparing the US-guided technique vs. the blind refill technique. The time to enter the RFP with the needle was a secondary outcome. We compared the amount of attempts between both techniques with the non-parametric Wilcoxon rank sum test. Fourteen adult patients underwent a total of 75 refills of their Recessed-RFP-IDDS during a period of 24 months. The median number of attempts to enter the RFP did not differ significantly between the US-guided technique and the blind refill technique (2.0 (IQR: 1-5) vs. 1.5 (IQR: 1-5.0), p = 0.572). The median time to enter the RFP with the needle did not differ significantly between both techniques (35.0 sec (IQR: 26.0-58.0) vs. 41.0 sec (IQR: 25.5-46.8), p = 0.878). The results of this study suggest that there is no difference in the RFP needle access efficiency between the US-guided and the blind refill technique in superficially located Recessed-RFP-IDDSs, if performed by experienced practitioners. However, the study did not address efficiency of the RFP needle access in IDDSs with aberrancy in pump location or refills performed by inexperienced staff.

Physician Guidance on the Use of Off-Labeled Drugs in Intrathecal Drug Delivery Systems for Chronic Pain

Physician Guidance on the Use of Off-Labeled Drugs in Intrathecal Drug Delivery Systems for Chronic Pain

Low-Dose Computed Tomography With Two- and Three-Dimensional Postprocessing as an Alternative to Plain Radiography for Intrathecal Catheter Visualization: A Phantom Pilot Study

ObjectivesIn intrathecal drug delivery, visualization of the device has been performed with plain radiography. However, the visibility of the related structures can be problematic. In troubleshooting, after the contrast material injection via the catheter access port, a computed tomography (CT) scan has been used. In troubleshooting, we also used a non‐contrast CT scan with 2D and 3D reconstructions. With the current phantom study, we aimed to obtain high‐resolution imaging of a poor opaque catheter with the use of a low‐dose single‐energy 2D and 3D CT scan with limited radiation exposure as a substitute for plain radiography.Materials and MethodsThe catheter was placed into a fatty substance and mounted on an anthropomorphic abdomen phantom followed by CT with varying kVp settings and with added tin beam filtering. Dose levels corrected based on the spinal catheter tip on T8 would result in a calculated effective dose in the range of the mSv's calculated for the plain x‐ray examination.ResultsUltimately, Sn100 kVp has the best trade‐off between visibility, artifacts, and noise for a fixed dose. Although 3D VRT imaging was challenging at this low dose level, we could make a full evaluation possible with complementary 2D projections.ConclusionsWe could correctly identify the catheter and related structures, which supports the investigation of this in vivo and side‐by‐side evaluation with plain radiography. If found superior, then this technique may be able to replace plain radiography, while providing better visualization and acceptable radiation exposure.Conflict of InterestDr. Delhaas reports personal fees from Medtronic Inc., as a previous consultant, outside the submitted work; Prof. van der Lugt reports grants from GE Healthcare, Siemens, Stryker, Medtronic, and Penumbra outside the submitted work.

Intrathecal Drug Delivery Systems for Cancer Pain: An Analysis of a Prospective, Multicenter Product Surveillance Registry.

BACKGROUND:The safety and efficacy of intrathecal drug delivery systems (IDDSs) for the treatment of cancer-related pain have been demonstrated in randomized controlled clinical trials (RCTs). Despite positive evidence for this therapy, IDDS remains underutilized to treat cancer pain. Real-world registry data augment existing safety and effectiveness data and are presented here to broaden awareness of this therapeutic option, needed for adequate cancer-related pain treatment, and as a viable tool addressing concerns with systemic opioid use.METHODS:This prospective, long-term, multicenter (United States, Western Europe, and Latin America) registry started in 2003 to monitor the performance of SynchroMed Infusion Systems. Patient-reported outcomes were added in 2013. Before data acquisition, all sites obtained Ethics Committee/Institutional Review Board approval and written patient consent. The study was registered (NCT01524276 at clinicaltrials.gov) before patients were enrolled. Patients who provided informed consent were enrolled in the registry at initial IDDS implant or replacement.RESULTS:Through July 2017, 1403 patients with cancer pain were enrolled and implanted. The average (minimum/maximum) age of patients was 59 years (13/93 years), with 56.6% female. The most frequent cancer types were lung, breast, colon/rectal, pancreatic, and prostate. The majority of patients whose registry follow-up ended (87%; 1141/1311) were followed through death, with 4.3% (n = 57) exiting due to device explant or therapy discontinuation; the remaining 113 (8.6%) discontinued for reasons such as transfer of care, lost to follow-up, and site closure. Pain scores within the cohort of patients providing baseline and follow-up data improved significantly at 6 (P = .0007; n = 103) and 12 (P = .0026; n = 55) months compared to baseline, with EuroQol with 5 dimensions (EuroQol-5D) scores showing significant improvement at 6 months (P = .0016; n = 41). Infection requiring surgical intervention (IDDS explant, replacement, pocket revision, irrigation and debridement, etc) was reported in 3.2% of patients.CONCLUSIONS:Adequate and improved pain control in patients with cancer, even in advanced stages, with concurrent quality of life maintenance is attainable. Results from this large-scale, multicenter, single-group cohort supplement existing RCT data that support IDDS as a safe and effective therapeutic option with a positive benefit–risk ratio in the treatment of cancer pain.

Intrathecal Drug Delivery.

Targeted intrathecal (IT) drug delivery systems (IDDS) are well established as an effective treatment of patients with chronic nonmalignant or malignant pain, and as a tool for management of patients with severe spasticity. The risk to benefit ratio of IDD makes it a relatively safe therapy for both cancer- and noncancer-related pain, but it is not free of risks, so it should be managed at specific centers. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up to date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up and pharmacological recommendations published during recent years that provide evidence-based decision-making process in the management of chronic pain and spasticity in patients.

In Vivo Intrathecal Tracer Dispersion in Cynomolgus Monkey Validates Wide Biodistribution Along Neuraxis.

It is commonly believed that in intrathecal (IT) drug delivery, agent distribution is confined to a narrow region close to the injection site, thereby undermining the efficacy of the method. To test the claim, multimodal in vivo imaging was used to experimentally observe the effects of IT infusion in cynomolgus monkey, looking at cerebrospinal fluid flow, anatomy, and dispersion of a radiolabeled tracer. At high infusion rates, the tracer reached the cervical region after only 2 h, demonstrating rapid and wide distribution. The same in vivo nonhuman primate imaging data also provided evidence in support of a computational fluid dynamic model for the prediction of drug distribution following IT injection. Tracer dispersion was predicted in two specimens matching the distribution acquired with positron emission tomography (PET). For the third specimen, tracer dispersion simulations were conducted as a blind study: predictions were made before in vivo biodistribution data was known. In all cases, the computational fluid dynamics (CFD) predictions of drug dispersion after IT administration showed close spatio-temporal agreement with tracer biodistribution in vivo. Validation by in vivo nonhuman primate data confirms our ability to predict the biodistribution of intrathecally administered agents in subject-specific models of the central nervous system from first principles. The experiments reinstate IT delivery as a viable administration method when targeting molecules to the whole spine or the brain. The proposed computational methodology enables rational design of novel therapies for neurological diseases that require reliable, efficient, and safe delivery of therapeutic agents to specific target sites in the central nervous system.

Managing Chronic Non-Malignant Pain in the Elderly: Intrathecal Therapy

Intrathecal drug delivery (IDD) was first described in 1981 by Onofrio, who used a pump for continuous and intrathecal delivery of morphine to treat cancer pain. Over the following four decades, many reports supported this treatment method with implanted pumps for cancer and non-cancer pain. To date, more than 300,000 pumps for pain therapy and spasticity have been implanted worldwide. This article reviews current knowledge regarding intrathecal opioid therapy, focusing particularly on the use of IDD in elderly patients. Current literature is presented, and the arguments in favor of and against this therapy in elderly patients are discussed.

Subject-Specific Studies of CSF Bulk Flow Patterns in the Spinal Canal: Implications for the Dispersion of Solute Particles in Intrathecal Drug Delivery.

Recent flow dynamics studies have shown that the eccentricity of the spinal cord affects the magnitude and characteristics of the slow bulk motion of CSF in the spinal subarachnoid space, which is an important variable in solute transport along the spinal canal. The goal of this study was to investigate how anatomic differences among subjects affect this bulk flow. T2-weighted spinal images were obtained in 4 subjects and repeated in 1 subject after repositioning. CSF velocity was calculated from phase-contrast MR images for 7 equally spaced levels along the length of the spine. This information was input into a 2-time-scale asymptotic analysis of the Navier-Stokes and concentration equations to calculate the short- and long-term CSF flow in the spinal subarachnoid space. Bulk flow streamlines were shown for each subject and position and inspected for differences in patterns. The 4 subjects had variable degrees of lordosis and kyphosis. Repositioning in 1 subject changed the degree of cervical lordosis and thoracic kyphosis. The streamlines of bulk flow show the existence of distinct regions where the fluid particles flow in circular patterns. The location and interconnectivity of these recirculating regions varied among individuals and different positions. Lordosis, kyphosis, and spinal cord eccentricity in the healthy human spine result in subject-specific patterns of bulk flow recirculating regions. The extent of the interconnectivity of the streamlines among these recirculating regions is fundamental in determining the long-term transport of solute particles along the spinal canal.

Intrathecal therapy for pain in cancer patients.

Intrathecal drug delivery systems (IDDS) for cancer pain remain little employed despite a high level of efficiency even though the technique is widely recommended. This review aims to summarize recent advances in IDDS for cancer patients. The respective roles of catheter positioning, volume and flow rate in diffusion of intrathecal treatments, as well as the individual roles of blood pressure, heart rate, and amplitude of the respiratory movements in cerebrospinal fluid (CSF) treatment dispersion, are now well established. Models are available using MRI data. Morphine has long been the gold standard in first line treatment, but recent publications conclude that ziconotide has largely proven its efficiency and that adverse effects are controllable. Four recent publications have evaluated cohorts of cancer patients treated by IDDS in 315 patients. All found a great efficiency of intrathecal treatment for cancer pain. Technical innovations include new catheters and anchorage devices for easier placement and a lower rate of complication. Three-dimensional (3D) CT scan appears to be a noninvasive technique for the diagnosis of catheter complications. Ultrasound should be used to locate pump septum for refill. All recent recommendations highlight the efficiency of IDDS and propose to use it sooner.

Bilateral, sub-acute subdural hematoma following intra-thecal baclofen pump insertion: case report and literature review

BackgroundIntra-thecal baclofen pump has been proven a safe and effective treatment of spasticity. Subdural hematoma has been rarely described following intra-thecal drug delivery device insertion.Case presentationWe report on the rare case of a 45-year-old male with multiple sclerosis who presented with symptoms of intra-cranial hypotension 1 month after insertion of an intra-thecal baclofen pump for severe spasticity. Non-contrast head computerized tomography scan revealed bilateral, sub-acute, subdural hematomas. Due to the nature of the patient’s symptoms suggesting intra-cranial hypotension, surgical repair of the cerebrospinal fluid leak only was initially performed. However, after an initial improvement, the patient experienced increasing in severity headache and worsening tetraparesis. Subsequently, the patient underwent burr hole evacuation of the subdural hematomas with improvement of his symptoms. On the 6-week follow-up, he reported no headache and he was able to walk with assistance.ConclusionSubdural hematomas should be considered in all patients presenting with new neurologic deficits or persistent headache following intra-thecal drug delivery device insertion. Early recognition and appropriate management of this rare but potentially life-threatening complication is of great importance to improve prognosis and patient outcomes.

Attitudes of Hospice Providers Regarding Intrathecal Targeted Drug Delivery for Patients With Cancer

Pain is one of the most commonly experienced and feared symptoms faced by patients with a serious illness. For these patients, intrathecal drug delivery systems (IDDSs) provide greater potency and/or few systemic side effects. However, despite these benefits, the integration and management of IDDS for patients receiving hospice care has not been previous studied. An electronic, 18-question survey was sent to 200 hospice practitioners (physicians, nurse practitioners and nurses) in the state of Minnesota to explore their experience, confidence, and the perceived barriers to caring for patients with IDDS while being cared for on hospice. Providers were identified though mailing lists from the Minnesota Network of Hospice and Palliative Care organization. The survey was administered by the Mayo Clinic Survey Research Center with institutional review board approval. Slightly more than 50% of respondents have ever cared for a patient with an intrathecal pump. If a patient had a pump in place, only 28% of providers expressed confidence in managing their pain. Additionally, only 3 of 10 respondents felt that adjusting an intrathecal pump should be the first option when a patient with an IDDS in place had increased pain. Indeed, the vast majority (over 80%) of respondents preferred the use of systemic therapies for primary pain management. Access to IDDS vendors for changes/refills in the home is identified as another barrier with over 50% of respondents either unaware of an available vendor or reporting no vendor available. There are numerous self-reported barriers to ongoing use of IDDS with patients receiving hospice care.

Indented intrathecal drug delivery system with loss of reservoir volume

ObjectivesWe report two patients who underwent elective revision surgery were found to have reduced reservoir volumes and indented bottom shield of intrathecal drug delivery system (IDDS).Case reportsCase #1: A 59-year-old...

Optimizing Initial Intrathecal Drug Ratio for Refractory Cancer-Related Pain for Early Pain Relief. A Retrospective Monocentric Study.

Intrathecal (IT) drug delivery has shown its efficiency in treating refractory cancer pain, but switching opioids from the systemic to the intrathecal route is a challenging phase. Moreover, associations are widely used and recommended. Few data deal with the initial dosage of each drug. Analyzing conversion factors and initial dosages used in intrathecal therapy seems essential to decreasing the length of titration and to delivering quick pain relief to patients. We retrospectively analyzed data from consecutive adult patients implanted with an intrathecal device for cancer pain and treated at the Institut de Cancérologie de l'Ouest, in Angers, France, for four years. The main goal was to identify factors associated with early pain relief after intrathecal drug delivery system (IDDS) implantation. Of the 220 IDDS-treated patients, 70 (32%) experienced early pain relief (EaPR) and 150 (68%) delayed pain relief (DePR). Performance Status stage and initial IT ropivacaine:IT morphine ratio were the variables independently associated with EaPR. The best IT ropivacaine:IT morphine ratio to predict EaPR was 5:1, with a 73% (95% confidence interval [CI] = 64.8% to 79.6%) sensitivity and a 67.1% (95% CI = 54.9% to 77.9%) specificity. EaPR subjects experienced better pain relief (-84% vs -60% from baseline pain score, P < 0.0001), shorter length of hospitalization (7 vs 10 days, P < 0.0001), and longer survival (155 vs 82 days, P = 0.004). Local anesthetic:morphine ratio should be considered when starting IDDS treatment. EaPR during the IT analgesia titration phase was associated with better pain relief and outcomes in patients with refractory cancer-related pain.

Multiple Fibrin Glue Use in a Complicated Case of Postdural Puncture Headache Following Intrathecal Drug Delivery System Placement: A Case Report

A postdural puncture headache (PDPH) is a well-described complication after implantation of an intrathecal drug delivery system (IDDS). Treatment is typically with supportive management with the occasional need for an epidural blood patch. We describe a case of a patient with refractory muscle spasticity secondary to cerebral palsy that required a baclofen IDDS implantation and subsequently developed a PDPH. After failing conservative therapy as well as an epidural blood patch, the decision was made to attempt an epidural fibrin patch, which transiently improved her headache. Upon return of the patient’s symptoms, computed tomography myelogram demonstrated an extensive cerebrospinal fluid leak with ventral spread into the retroperitoneal space. Using a novel technique, a second epidural fibrin glue patch was administered just adjacent to the IDDS catheter insertion point, which was then successful in resolving her symptoms. Key words: Intrathecal drug delivery system, postdural puncture headache, dural tear, cerebrospinal fluid (CSF) leak, fibrin glue, epidural blood patch

Suspected transcutaneous cerebral spinal fluid leakage without postural headache after implantable intrathecal drug delivery system removal - A case report -

Suspected transcutaneous cerebral spinal fluid leakage without postural headache after implantable intrathecal drug delivery system removal - A case report -

Transitioning to a Valve -Gated Intrathecal Drug Delivery System (IDDS)

Transitioning to a Valve -Gated Intrathecal Drug Delivery System (IDDS)

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI.

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross‐sectional study comparing people with early stage Huntington's disease with age‐ and gender‐matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTT CAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease.

Intrathecal Pump Exposure to Electromagnetic Interference: A Report of Device Interrogation following Multiple ECT Sessions

Intrathecal drug delivery systems represent an increasingly common treatment modality for patients with a variety of conditions, including chronic pain and spasticity. Pumps rely on electronic programming to properly control and administer highly concentrated medications. Electromagnetic interference (EMI) is a known exposure that may cause a potential patient safety issue stemming from direct patient injury, pump damage, or changes to pump operation or flow rate. The objective of our case report was to describe an approach to evaluating a patient with a pump prior to and following exposure to EMI from electroconvulsive therapy (ECT), as well as to document findings from device interrogations associated with this event. Case report. Academic university-based pain management center. We present the case of a patient with an intrathecal pump who underwent multiple exposures to EMI in the form of 42 ECT sessions. Interrogation of the intrathecal drug delivery system revealed no safety issues following ECT sessions. At no time were error messages, unintentional changes in event logs, unintentional changes in pump settings, or evidence of pump stall or over-infusion noted. Communication with multiple entities (patient, family, consulting physicians, and device manufacturer) and maintaining vigilance through device interrogation both before and after EMI exposure are appropriate safeguards to mitigate the risk and detect potential adverse events of EMI with intrathecal drug delivery systems. Given the infrequent reports of device exposure to ECT, best practices may be derived from experience with EMI exposure from magnetic resonance imaging (MRI). Although routine EMI exposure to intrathecal drug delivery systems should be avoided, we describe one patient with repeated exposure to ECT without apparent complication.

Refill Port Identification of Intrathecal Drug Delivery System Devices With a Raised Fill Port

The aim of this study was to assess the accuracy of the manual identification of the reservoir fill port (RFP) for refill of intrathecal drug delivery systems (IDDSs) with a raised RFP on the pump surface (raised-RFP-IDDSs), and compare this to previously reported data of patients with IDDSs with a recessed RFP (recessed-RFP-IDDSs). Nineteen patients underwent 2 IDDS refills for the treatment of noncancer pain or spasticity. The primary endpoint of this prospective observational study was the deviation between the needle insertion point and the RFP center, quantified by fluoroscopic visualization. A distance surpassing that between the center and the margin of the RFP of 4mm was considered a clinically relevant deviation. The results were compared with previously reported data of a patient cohort with recessed-RFP-IDDSs, and the differences were tested using Student's t-test. The mean deviation from the RFP center was 4.9mm (standard deviation=3.7). The RFP identification accuracy deviated more than the clinically relevant difference in 17 out of 35 instances (48.6%). The number of attempts and median procedural time was significantly correlated to the needle deviation. The mean deviations in the raised-RFP-IDDS cohort were consistently lower compared to the recessed-RFP-IDDS cohort (first refill procedure 4.0 vs. 8.5, P<0.001; second procedure 5.9 vs. 8.1, P=0.074). The results of this study suggest that the manual localization of the RFP for raised-RFP-IDDSs is moderately accurate, and more accurate if compared to previously published accuracy of the template-guided technique for recessed-RFP-IDDSs.

On the dispersion of a drug delivered intrathecally in the spinal canal

This paper investigates the transport of a solute carried by the cerebrospinal fluid (CSF) in the spinal canal. The analysis is motivated by the need for a better understanding of drug dispersion in connection with intrathecal drug delivery (ITDD), a medical procedure used for treatment of some cancers, infections and pain, involving the delivery of the drug to the central nervous system by direct injection into the CSF via the lumbar route. The description accounts for the CSF motion in the spinal canal, described in our recent publication (Sánchez et al., J. Fluid Mech., vol. 841, 2018, pp. 203–227). The Eulerian velocity field includes an oscillatory component with angular frequency $\unicode[STIX]{x1D714}$, equal to that of the cardiac cycle, and associated tidal volumes that are a factor $\unicode[STIX]{x1D700}\ll 1$ smaller than the total CSF volume in the spinal canal, with the small velocity corrections resulting from convective acceleration providing a steady-streaming component with characteristic residence times of order $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}\gg \unicode[STIX]{x1D714}^{-1}$. An asymptotic analysis for $\unicode[STIX]{x1D700}\ll 1$ accounting for the two time scales $\unicode[STIX]{x1D714}^{-1}$ and $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}$ is used to investigate the prevailing drug-dispersion mechanisms and their dependence on the solute diffusivity, measured by the Schmidt number $S$. Convective transport driven by the time-averaged Lagrangian velocity, obtained as the sum of the Eulerian steady-streaming velocity and the Stokes-drift velocity associated with the non-uniform pulsating flow, is found to be important for all values of $S$. By way of contrast, shear-enhanced Taylor dispersion, which is important for values of $S$ of order unity, is shown to be negligibly small for the large values $S\sim \unicode[STIX]{x1D700}^{-2}\gg 1$ corresponding to the molecular diffusivities of all ITDD drugs. Results for a model geometry indicate that a simplified equation derived in the intermediate limit $1\ll S\ll \unicode[STIX]{x1D700}^{-2}$ provides sufficient accuracy under most conditions, and therefore could constitute an attractive reduced model for future quantitative analyses of drug dispersion in the spinal canal. The results can be used to quantify dependences of the drug-dispersion rate on the frequency and amplitude of the pulsation of the intracranial pressure, the compliance and specific geometry of the spinal canal and the molecular diffusivity of the drug.