Intrathecal drug delivery for pain management: recent advances and future developments

Jain, Sameer; Malinowski, Mark N.; Chopra, Puneet; Varshney, Vishal; Deer, Timothy R.

doi:10.1080/17425247.2019.1642870

Cited by 36 publications

(34 citation statements)

References 60 publications

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“…Overall, our results suggest that low-intensity noninvasive transcranial ultrasound may be used to increase the whole-brain delivery of a variety of off-the-shelf small or large therapeutic agents, following the same intrathecal administration that is used routinely in clinics worldwide to administer therapeutic agents into the CSF (Burch et al, 1988;Calias et al, 2014;Edeklev et al, 2019;Eide et al, 2018;Jain et al, 2019;Leal et al, 2011;Liu et al, 2004;Mack et al, 2016). Further, this method provides a means to directly upregulate glymphatic transport, which could be used for causative evaluation of the role of the glymphatic system in the variety of physiological and disease processes to which the glymphatic system has been correlated (Abbott et al, 2018;Ahn et al, 2019;Aspelund et al, 2015;Benveniste et al, 2019;Gaberel et al, 2014;Gakuba et al, 2018;Iliff et al, 2014;Kress et al, 2014;Lundgaard et al, 2017;Mader and Brimberg, 2019;Mendelsohn and Larrick, 2013;Peng et al, 2016;Plog and Nedergaard, 2018;Pu et al, 2019;Simon and Iliff, 2016).…”

Section: Discussionmentioning

confidence: 76%

“…via intrathecal delivery during a spinal tap, the agent would already be across the BBB and therefore able to access the brain and spine parenchyma. Indeed, intrathecal delivery is already used in the treatment or prophylaxis of a variety of CSF-based diseases, including leptomeningeal metastatic cancer and infectious meningitis (Jain et al, 2019). However, drug penetration into the brain and spine parenchyma from the CSF is known to be severely limited (Burch et al, 1988;Calias et al, 2014;Leal et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Aryal

Zhou

Rosenthal

et al. 2020

Preprint

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Intrathecal drug delivery is routinely used to bypass the blood-brain barrier in treating varied central nervous system conditions. However, the utility of intrathecal delivery is limited by poor parenchymal uptake of agents from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol significantly increases the brain parenchymal uptake of intrathecally administered drugs and antibodies. Essentially, we show that our protocol of transcranial ultrasound can accelerate glymphatic fluid transport from the cisternal space into the parenchymal compartment. Specifically, we administered small (~1kDa) and large (~150 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using both real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of each agent into the brain parenchyma from the cisternal cerebrospinal fluid, notably with no brain parenchymal damage. The low intensity of the ultrasound and its noninvasiveness underscores the ready path to clinical translation of this technique for whole-brain delivery of a variety of agents. Furthermore, this technique can be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Aryal

Zhou

Rosenthal

et al. 2020

Preprint

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“…Similarly, although intrathecal administration has been applied to treat a broad range of brain disorders for many decades, it still suffers several disadvantages in clinical applications. It is arduous to forecast the percentage of an intrathecal dose reaching the brain, and treatment is dependent on reliable catheter placement and stability [76,77].…”

Section: Bypassing the Bbb With Invasive Approachesmentioning

confidence: 99%

Dendrimer-Based Drug Delivery Systems for Brain Targeting

2019

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Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. Therefore, a number of nanocarriers have been designed over the past few decades to deliver drugs to the brain. Among these nanomaterials, dendrimers have procured an enormous attention from scholars because of their nanoscale uniform size, ease of multi-functionalization, and available internal cavities. As hyper-branched 3D macromolecules, dendrimers can be maneuvered to transport diverse therapeutic agents, incorporating small molecules, peptides, and genes; diminishing their cytotoxicity; and improving their efficacy. Herein, the present review will give exhaustive details of extensive researches in the field of dendrimer-based vehicles to deliver drugs through the BBB in a secure and effectual manner. It is also a souvenir in commemorating Donald A. Tomalia on his 80th birthday.

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“…Choice of pharmacological agent and its route of administration are two of many components in a patient's individualized pain‐management strategy, but they are important aspects of care that have far‐reaching implications. Consequently, the development of new analgesics remains a focus of clinical research, a key aim of which is to reduce opioid use for severe and refractory pain (Jain et al., 2019). However, given the short‐term absence of novel, efficacious agents, it may be helpful to consider whether any licensed nonopioids could be better utilized; reflection on experience and evidence might identify practice adjustments that improve their clinical application.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal pain management with ziconotide: Time for consensus?

Matis

Negri²,

Dupoiron

et al. 2021

Brain and Behavior

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This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence‐based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under‐used in Europe, adding that ziconotide ITA has potential to be a first‐line alternative to morphine; both are already first‐line options in the USA. Ziconotide ITA (initiated using a low‐dose, slow‐titration approach) is suitable for many patients with noncancer‐ or cancer‐related chronic refractory pain and no history of psychosis. Adopting ziconotide as first‐line ITA could reduce opioid usage in these patient populations. The group advocated a risk‐reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US–European alignment of the licensed starting dose for ziconotide: the low‐and‐slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low‐and‐slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core.

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Intrathecal drug delivery for pain management: recent advances and future developments

Cited by 36 publications

References 60 publications

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Dendrimer-Based Drug Delivery Systems for Brain Targeting

Intrathecal pain management with ziconotide: Time for consensus?

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