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Study Protocol: Prospective, Observational, Study to Assess the Safety of a Novel Intrathecal Bolus-Only Delivery Strategy as Compared to Traditional Simple Continuous Delivery

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Randomized, Prospective Study to Assess the Safety of a Novel Intrathecal Bolus-Only Delivery Strategy as Compared to Traditional Simple Slow Continuous Delivery

 

BACKGROUND

Historically, low volume, slow continuous infusion has been employed for long-term medication delivery into the intrathecal (IT) space.  However, challenges with IT drug delivery have plagued the therapy, including:

• Failure of a good trialing strategy to predict success with long-term delivery

• Predictable dose escalation

• Challenges with cessation of therapy: opioid withdrawal or life-threatening reactions

• Combination therapy often used

• Tier 2 and 3 of PACC 2012

• Positioned as salvage therapy

• Variability with location of catheter positioning

• Regarding predictable dose escalation, studies have shown IT opioid doses to increase by as much as 600% from baseline in 12 months.1

 In a study of possible existing predictors that might impact ITDD dose escalation, neuropathic pain was the highest risk factor.2

 

RATIONALE

Failure with IT therapy may represent a pharmacokinetic failure instead of a pharmacodynamic one.  Pharmacokinetics of the intrathecal space (and subsequent drug spread) are contingent on:3-6

• Regional intrathecal bidirectional mixing by cranial and lumbar "motors"

• Residence time within the CSF (physiochemical properties of the drugs)

• Kinetic energy of the injectate

• Diffusion (Brownian motion)

Variables that are commonly manipulated to improve efficacy with IT drug delivery include:

• Concentration (dose)

• Choice of the intrathecal agent (hydrophilicity)

Variables that we propose manipulating in order to improve intrathecal spread include:

• Kinetic energy of the injectate

• Volume delivered

This represents a paradigm shift from long-term continuous to bolus delivery, which may result in the following:

• Emulation of the success of the bolus delivery trial and improve outcomes for long-term intrathecal delivery.

• Account for inter-individual pharmacokinetic and pharmacodynamic differences by relying on intermittent, patient controlled doses.

• Reduce the aforementioned dose escalation

• Reduce the presumed "headaches" with intrathecal therapy

 

STUDY DESIGN

This study is proposed as a prospective, randomized, pilot study of approximately 30 subjects with chronic, intractable pain of confined location of the trunk leg area for at least six months with failure of more conservative measures. The objective of this study is to evaluate the safety of bolus-only delivery as compared to traditional continuous flow delivery.  This study includes a prospective comparison of two dosing strategies:

• Low volume continuous rate (no bolus delivery)

• Patient-controlled bolus delivery (no continuous rate)

Subjects will be opioid naïve prior to implant and randomized to one of the two groups on day of implant.

Primary Hypothesis: Group receiving patient-controlled bolus-only dosing will not have statistically higher rates of pharmacologic-related adverse events compared to the group receiving standard continuous flow delivery.

Secondary variables will include pain and quality of life scores, systemic opioids, functional scores and patient satisfaction measurements.

Subjects will be followed once per month for the first three months and then on a quarterly basis for up to one year following pump implantation.

 

DISCUSSION

Globally, intrathecal therapy positioned as a salvage therapy will largely fail as best candidates for intrathecal pump therapy are not necessarily failures of other therapies. The intrathecal candidate positioned earlier in the pain care algorithm may have better sustainable outcomes. The selection would therefore move away from the candidate that failed high-dose systemic opioid regimens to more opioid naive patients.

Indications for pump delivery vary substantially, as do the medications employed, although only ziconotide and morphine are FDA approved to treat chronic pain. A variant of the bolus-only delivery strategy for ziconotide has been described in literature recently for intrathecal opioids, along with a decision tree for implementation of intrathecal therapy.7

Bolus only strategies may be extended to off-label medications like bupivacaine.

The proposed dosing paradigm may also reduce many of the physician reported challenges and frustrations with intrathecal management that have become a barrier for employing the therapy. Intermittent dosing may reduce the chance of withdrawal or overdose, reduction of the required dose, granuloma formation, and/or dose escalation. This may revitalize the renewed interest in intrathecal therapy to treat chronic pain.