Intrathecal Drug Delivery Devices Research Articles

Optimizing Preoperative Chronic Pain Management in Elective Spine Surgery Patients

» Chronic preoperative opioid use negatively affects outcomes after spine surgery, with increased complications and reoperations, longer hospital stays, decreased return-to-work rates, worse patient-reported outcomes, and a higher risk of continued opioid use postoperatively.» The definition of chronic opioid use is not consistent across studies, and a more specific and consistent definition will aid in stratifying patients and understanding their risk of inferior outcomes.» Preoperative weaning periods and maximum dose thresholds are being established, which may increase the likelihood of achieving a meaningful improvement after surgery, although higher level evidence studies are needed.» Spinal cord stimulators and intrathecal drug delivery devices are increasingly used to manage chronic back pain and are equivalent or perhaps even superior to opioid treatment, although few studies exist examining how patients with these devices do after subsequent spine surgery.» Further investigation is needed to determine whether a true mechanistic explanation exists for spine-related analgesia related to spinal cord stimulators and intrathecal drug delivery devices.

ID: 208161 Intrathecal Pump Refill With a Different Concentration - A Routine Thing or Is it?

Intrathecal drug delivery device is an FDA-approved therapy for chronic pain management. The therapy is generally safe, but few serious complications have been reported. The complications related to implantation, device mechanical failure, and during reservoir refill are well described but issues related to refill when drug concentration has changed is less well described. We described a case of potential drug overdose during reservoir refill despite following all safety protocol.

ID: 205492 A Clinical Evaluation of the Accuracy of an Intrathecal Drug Delivery System

Implantable intrathecal drug delivery (ITDD) devices are used to treat severe pain and spasticity refractory to conventional medical management. ITDD flow patterns can be continuous, flex, or patient controlled, and may be affected by changes in fluid volume, body temperature and atmospheric pressure.1 Manufacturer-approved medications are morphine sulphate, baclofen, or ziconotide as monotherapy.2 Although off-label medications and drug admixtures are commonly used in clinical practice and recommended by international guidelines 3-5 , manufacturers state that this practice can result in corrosion to the infusion system and device failure.2 The impact of off-label drugs and drug combinations on pump accuracy has hitherto never been assessed.

A Clinical Evaluation of the Accuracy of an Intrathecal Drug Delivery Device

IntroductionImplantable intrathecal drug delivery (ITDD) devices are used to treat severe pain and spasticity refractory to conventional medical management. Although off-label medications and drug admixtures are commonly used in clinical practice and recommended by international guidelines, manufacturers state that this practice can result in device failure. The impact of off-label drugs and drug combinations on pump accuracy has hitherto never been assessed. Materials and MethodsA multinational, three-center, retrospective review of patient records was undertaken. The inclusion criterion was the presence of an ITDD device implantation in adult patients, with the pump in situ for the expected battery lifespan. Residual drug volumes at each refill, drug mixtures and concentrations, and rate and flow pattern of the pump (simple or flex) were recorded. A normalized flow rate ratio was calculated (actual to theoretical flow rate). The impact of nonapproved drugs, battery life, pump size, and flow program on drug delivery accuracy was assessed. ResultsData from 1402 pump refills were collected (73 patients). The overall mean accuracy ratio was 0.995 (95% CI = 0.986–1.004). The ratio for approved drug status was 0.990 vs 0.997 in nonapproved, with a difference of −0.007 (−0.032 to 0.017). At the tenth centile for remaining battery life (14 months), the ratio was 0.983 vs 1.009 for the 90th centile (69 months), with a difference of −0.026 (−0.038 to −0.014). The ratio for flex administration was 0.982 vs 1.006 for simple, with a difference of −0.024 (−0.040 to −0.008). For pump size of 40 mL, the ratio was 0.975 vs 1.010 for 20 mL, with a difference of −0.035 (−0.063 to −0.008). The 95% prediction interval for individual refill ratios was ±0.15. ConclusionIn a clinical setting, the ITDD pumps retained high levels of accuracy and acceptable precision across their lifespan despite using unapproved drugs or admixtures and under various flow modes and rates.

Long-term open-label phase I/II extension study of intrathecal idursulfase-IT in the treatment of neuronopathic mucopolysaccharidosis II

Intrathecal (IT) idursulfase-IT for the treatment of cognitive impairment is being investigated in pediatric patients with neuronopathic mucopolysaccharidosis II (MPS II) in addition to intravenous idursulfase. In this article, we report the findings for 54 months of idursulfase-IT treatment in an ongoing phase I/II extension trial (NCT01506141). A total of 15 male participants with neuronopathic MPS II (aged 3-11 years at enrollment) who were previously treated with intravenous idursulfase entered the extension study. Idursulfase-IT 10 mg or 30 mg was administered monthly via an IT drug delivery device or lumbar puncture, if indicated. The primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics, cerebrospinal fluid glycosaminoglycan levels, and cognitive function. In total, 15 participants received a median (range) of 50 (18-55) idursulfase-IT doses. Idursulfase-IT was generally well tolerated; there were no life-threatening adverse events (AEs) or deaths. Most serious AEs were related to the IT drug delivery device; only 2 serious AEs were related solely to idursulfase-IT. After treatment with idursulfase-IT, cerebrospinal fluid glycosaminoglycans were decreased in all participants; these decreases were maintained. Cognitive function was stabilized in 3 of 4 testable participants at month55. These long-term results support the clinical development of idursulfase-IT for patients with MPS II with cognitive impairment.

Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A

IntroductionCurrently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study. MethodsPatients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging. ResultsIn the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: −17.97%, −18.99%, and −12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54. ConclusionsOverall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).

“Response to Letter to the Editor Regarding: Managing Intrathecal Drug Delivery Devices in a Global Pandemic”: A Correction

“Response to Letter to the Editor Regarding: Managing Intrathecal Drug Delivery Devices in a Global Pandemic”: A Correction

Neuromodulation techniques for cancer pain management.

Advanced pain management techniques may be indicated in 5-15% of cancer patients. Despite this, a recent review identified that, over the course of 1 year in England, only 458 patients received a procedure intended to provide analgesia and only 30 patients had intrathecal drug delivery (ITDD) devices implanted. This article describes the emerging evidence for ITDD in cancer pain and provides a narrative review of other neuromodulatory techniques (including spinal cord stimulation, peripheral nerve stimulation and acupuncture), approaches that might be employed to address this area of significant unmet clinical need. Numerous studies have been published within the last year reporting positive outcomes associated with ITDD in cancer pain management. Neuromodulation represents an important strategy in the management of persistent pain. Whilst the nonmalignant pain evidence-base is rapidly growing, it remains sparse for cancer pain management. The growing cohort of cancer survivors may significantly benefit from neuromodulatory techniques. ITDD and other neuromodulatory techniques for cancer pain management appear underutilised in the UK and offer the prospect of better treatment for cancer patients with refractory pain or intolerable side-effects from systemic analgesics.

Narrative review of intrathecal drug delivery (IDD): indications, devices and potential complications.

The management of chronic refractory pain (non-neoplastic and cancer-related pain) remains a therapeutic challenge. The continuous intrathecal (IT) administration of drugs may play an important role in the possible management options. Intrathecal drug delivery devices (IDDDs) may be effective for patients with refractory chronic pain. Therefore, they may be adopted for non-oncologic pain in patients with compression fractures, spondylolisthesis, spondylosis, back surgery failure syndrome and spinal stenosis. Oncologic patients can benefit from these treatments in a variable way according to tumor characteristics, prognosis, periprocedural imaging and risk of disease progression. In this review, we describe the most commonly used drugs (opioids and non-opioids), their pharmacokinetic and pharmacodynamic features and indications of use. The most used drugs are morphine, hydromorphone, fentanyl, methadone, bupivacaine, clonidine, and ketamine. Patient evaluation before the device implantation should be based on clinical examination, medical records assessment and psychometric evaluation. The infusion pumps available on the market are both non-programmable (with continuous IT deliver of drugs) and programmable (with variable deliver of drugs according to their flow rate). Moreover, we describe the procedure of implantation and the potential complications of IT drug delivery (such as bleeding, infection, loss of cerebrospinal fluid, wound seroma, loss of catheter pump propellant).

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys.

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.

Response to: Managing Intrathecal Drug Delivery Devices in a Global Pandemic

Response to: Managing Intrathecal Drug Delivery Devices in a Global Pandemic

Response to Letter to the Editor regarding: Managing Intrathecal Drug Delivery Devices in a Global Pandemic

Response to Letter to the Editor regarding: Managing Intrathecal Drug Delivery Devices in a Global Pandemic

The Unmet Need for Intrathecal Drug Delivery Pumps for the Treatment of Cancer Pain in England: An Assessment of the Hospital Episode Statistics Database

Intrathecal drug delivery (ITDD) devices have been shown to be a clinically effective and cost-effective option for the management of cancer pain and recommended for use in England. The aim of this study is to assess the impact of the 2015 NHS England Clinical Commissioning Policy on the uptake of ITDD pumps for the management of cancer pain or if there is an ongoing unmet need for this intervention in England. Hospital Episode Statistics (HES) were obtained for all patients undergoing ITDD for the management of cancer pain between 2014 and January 2020. In addition, HES were utilized to estimate the number of patients with cancer potentially eligible for ITDD pump during the same period. The number of patients with cancer and those potentially suitable to receive an ITDD for the management of cancer pain have increased year on year since 2014. This increase has not been matched by an uptake in the provision of ITDD. Conservative estimates suggest that at least 8000 people with cancer pain would be eligible for ITDD; 458 patients received an intervention for pain management between April 2018 and March 2019 and only 30 ITDD pumps were implanted in that same period. We observed a substantial gap between the need and provision of ITDD for patients with refractory cancer pain in England despite the recommendation for the use of ITDD for this patient population. In addition, we present suggestions for improvement of access to and provision of ITDD in England.

Managing Intrathecal Drug Delivery Devices in a Global Pandemic

Managing Intrathecal Drug Delivery Devices in a Global Pandemic

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.

Ease of Fill Port Access During the Ultrasound-Guided vs. the Blind Refill Technique of Intrathecal Drug Delivery Systems With a Raised Septum, a Prospective Comparison Study

The localization of the reservoir fill port of Intrathecal Drug Delivery Devices (IDDS) can be difficult. The purpose of this study was to assess the ease of fill port access during the ultrasound-guided refill technique compared to the blind refill technique in IDDSs with a raised septum on the pump surface. Written informed consent was obtained from 19 adult patients undergoing regular refills of their Raised Septum IDDSs (RS-IDDSs). The primary outcome of this single center prospective comparison study was the number of attempts to enter the reservoir fill port with the needle comparing the ultrasound-guided technique vs. the blind technique. The number of skin punctures per refill procedure and time to enter the reservoir fill port was secondary outcomes. For between group comparisons the Friedman test for repeated measures on ranks was used. One hundred and eleven refill procedures were assessed in 19 patients over a period of 24 months. The median number of attempts to enter the reservoir fill port with the needle differed significantly between the ultrasound-guided technique and the blind technique (4 [IQR: 1-6] vs. 1 [IQR: 1-3], p = 0.018), in favor of the blind technique. The median time to enter the reservoir fill port differed significantly between the ultrasound-guided technique and the blind technique (58 sec [IQR: 38-94] vs. 22 sec [IQR: 16-40], p < 0.001). The results of this study suggest that for a RS-IDDS the blind refill technique needs significantly less attempts to enter the reservoir fill port than the US-guided refill technique.

Sacral Neuromodulation and Twiddler's Syndrome

Twiddler's syndrome is the deliberate, inadvertent, or subconscious manipulation of an implantable generator within its subcutaneous pocket that can lead to malposition and fracture of the associated lead. The syndrome is well recognized in patients with pacemakers, implantable cardioverter defibrillators, deep brain stimulators, and more recently in intrathecal drug delivery devices. Here we present an instance of Twiddler's syndrome after sacral neuromodulation.

Advancing Safety in Intrathecal Analgesia: A Novel Web-Based Pharmacologic Requisition Platform and Data Repository for Intrathecal Drug Delivery Devices.

Advancing Safety in Intrathecal Analgesia: A Novel Web-Based Pharmacologic Requisition Platform and Data Repository for Intrathecal Drug Delivery Devices.

Surgical Site Infections in Cancer Patients with Intrathecal Drug Delivery Devices.

Our purpose was to determine the incidence of surgical site infection (SSI) in cancer patients receiving an intrathecal drug delivery system (IDDS) and compare that rate with the incidence of SSI in the general population receiving an IDDS or spinal cord stimulator. We attempted to describe risk factors for SSIs in cancer patients treated with IDDS in terms of exposure to cancer treatments. Retrospective review. Large tertiary care center. Cancer patients receiving an IDDS in 2006-2013. The incidence of SSI was determined according to the US Centers for Disease Control and Prevention definition. Medication regimens and current cancer treatment were investigated to identify immunocompromised patients during IDDS placement. Microbacteriology, treatment, and overall outcomes were investigated. Sixty-four patients had an IDDS implanted in 2006-2013. SSI developed in four patients (6.2%). All four patients had received chemotherapy or radiotherapy within three months before implantation. Three of the three were receiving dexamethasone, and three of the four required explantation of the IDDS. The incidence of SSI was at the upper end of the published infection rates for IDDS. The risk of SSI may be increased in this population because of factors that alter the patient's immune status, including concomitant corticosteroid use, radiotherapy near the SSI, and presence of immunomodulators. The identification and mitigation of certain risk factors for this population may prevent infection in future patients.

348. Correction of CNS and Somatic Pathology by Intra-Cerebrospinal Fluid Gene Therapy for Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPSII), or Hunter Syndrome, is a X-linked recessive Lysosomal Storage Disease (LSD) caused by deficiency in Iduronate-2-sulfatase (IDS), an enzyme involved in the stepwise degradation of the glycosaminoglycans (GAGs) heparan sulfate (HS) and dermatan sulfate (DS). GAG storage builds up in the CNS and peripheral tissues causing severe neurologic and multisystemic somatic disease. Patients usually die during the second decade of life. Periodic intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier limits the efficacy of the approach in treating neurological symptoms. Alternatively, the periodic infusion of ERT to the cerebrospinal fluid is under clinical testing, but serious adverse events associated with the use of intrathecal drug delivery devices have been reported. Here we report a gene therapy approach directly addressing the CNS pathology of MPSII. Through a minimally invasive procedure we delivered adeno-associated virus vectors of serotype 9 encoding IDS (AAV9-Ids) to the CSF of MPSII mice with already established disease. Four months after vector administration, treated mice showed a significant increase in IDS activity throughout the encephalon, with full resolution of lysosomal storage lesions, reversal of lysosomal dysfunction, normalization of the brain transcriptomic signature and disappearance of neuroinflammation. Moreover, our approach not only resulted in widespread distribution of vector in the CNS but also in liver transduction, providing a peripheral source of therapeutic protein that corrected the storage disease in visceral organs, with evidence of cross-correction of non-transduced organs by circulating enzyme. Importantly, MPSII mice treated with AAV9-Ids also showed normalization of behavioural deficits. These results provide a strong proof of concept for the clinical translation of our approach for the treatment of Hunter patients with cognitive impairment.