Trialing

There are four main types of trialing methods for intrathecal drug delivery (IDD) systems: single-shot intrathecal bolus injection, multiple intrathecal bolus injections, continuous intrathecal infusion, and continuous epidural infusion. All methods demonstrate similar efficacy, and no one method has been proven to be superior for predicting long-term outcomes of IDD⁵⁹. The choice of trialing method is influenced by factors such as the patient’s clinical status, diagnosis, the type of medication used, and the capabilities of the facility and physician preferences¹¹. Currently, major insurance carriers in the USA (Medicare, UnitedHealthcare, and Anthem) and some European countries require a catheter trial for pump implant approval.

Single-Shot Bolus Method

The single-shot bolus method is relatively quick and has a theoretical reduced risk of infection. It can be conducted in an office or outpatient setting. However, this method may have an increased risk of side effects (e.g., nausea, vomiting, diaphoresis, urinary hesitancy), and repeated injections may be necessary to assess the appropriate dose, which can prolong the trial duration.

Continuous Infusion Trialing

Continuous infusion trialing allows for medication titration to achieve efficacy, while providing direct observation of side effects over hours to days. This method is typically conducted in an inpatient setting and may pose a higher risk of infection, but could reduce side effect risks and allow for trialing with multiple medications. It is particularly useful for patients on anticoagulants or with cancer.

Staged Trial

A staged trial involves placing a potentially permanent intrathecal catheter, attaching it to a tunneled extension, and using an external pump for trialing. If the trial is successful, the external extension can be removed, and the intrathecal catheter can be connected to an internal pump. This method is advantageous for patients who have a limited window for trialing and implant (e.g., cancer patients or those on anticoagulants).

Trialing Location and Site-of-Service Issues

Trials can be performed in the office, outpatient ambulatory surgery center (ASC), or hospital settings. Single-shot bolus injections can be safely conducted in outpatient settings, but catheter trials are typically conducted in an inpatient setting¹¹. Medications such as intrathecal fentanyl, ziconotide, bupivacaine, and baclofen may be considered for outpatient trials, if patient risk factors and adequate monitoring are managed appropriately. Inpatient settings are recommended for patients with significant comorbidities or difficulty accessing the intrathecal space¹¹.

Consensus Point 7: When performing an IDD trial, physicians should consider the medication(s) used and patient factors in deciding the setting: inpatient vs outpatient. For catheter trials, an inpatient setting is recommended. USPSTF grade B; level of certainty moderate; evidence level IB.

TRIAL STRATEGIES BASED ON MEDICATION CHOICE

Hydrophilic Medications

Hydrophilic opioids like morphine, hydromorphone, and baclofen diffuse farther in the cerebrospinal fluid (CSF) and have lower systemic uptake compared to lipophilic agents^64,65,66. Therefore, hydrophilic opioids are well-suited for single-shot bolus injections during trialing.

Lipophilic Medications

Lipophilic agents such as fentanyl and bupivacaine do not distribute widely in the CSF and are rapidly taken up systemically^67,68,69. Hence, intrathecal trials with these agents are best accomplished through continuous infusion with the catheter tip placed near the innervation segment of the pain target^70,71.

Consensus Point 8: Physicians should consider pharmacokinetic parameters affecting drug distribution in IDD, especially lipid solubility and systemic effects of drugs cleared from the intrathecal space, particularly for those which are highly lipophilic. USPSTF grade A; level of certainty moderate; evidence level IC.

Ziconotide

Ziconotide is a large hydrophilic peptide that must be administered intrathecally due to its restricted dural distribution¹¹. Continuous infusion trials with ziconotide carry high infection risks if maintained with percutaneous catheters for more than two weeks⁷⁴. Therefore, single-shot boluses may be preferred⁷⁵ and the PRIZM registry study suggests that ziconotide use first-in-pump may result in better analgesia, versus use as an add-on or rescue agent⁷⁹.

Consensus Point 9: Intrathecal trialing of ziconotide may be best performed using injections of small boluses as opposed to continuous infusion. USPSTF grade B; level of certainty moderate; evidence level IB.

UPDATES ON IMPLANTATION ISSUES

Catheter Location

The traditional understanding of CSF circulation has evolved to a more complex model involving oscillatory and pulsatile movements influenced by cardiac and respiratory cycles^80,81. Drug distribution in the CSF is limited to a few centimeters from the administration site, making the placement of the catheter tip critical for therapy success^60,64.

Pharmacokinetic Factors

• Hydrophilic Drugs: Display broader rostrocaudal movement in the CSF, resulting in lower systemic uptake and prolonged spinal analgesia⁶⁵.
• Lipophilic Drugs: Have limited spread in the CSF and are quickly reabsorbed in systemic circulation⁶⁵. Catheter placement near the targeted spinal segments is essential for these agents.

Bupivacaine has a limited distribution at low flow rates and should be administered with a dermatomal approach. For head and neck cancer pain or neuropathic facial pain, in combination with an opioid, catheter advancement as high as the C1 level has been reported^84,85.

For lumbar and leg pain, a classic lumbar approach with catheter tip placement around T9-T10 can minimize migration risks. Retrograde placement may be effective for pelvic cancer pain⁸³, and placement as high as C1 may be appropriate for head and neck pain.

Consensus Point 10: Intrathecal catheter placement should be targeted to the optimal vertebral level to cover spinal segments involved in the neuronal transmission of pain. USPSTF grade A; level of certainty moderate; evidence level IB.

CSF Dynamics and Infusion Strategies

Several studies failed to show any improvement in pain relief when increasing the continuous flow rate of drugs without changing the daily dose and switching from continuous to intermittent bolus administration has shown unpredictable results^94,95,96. This suggests that merely adjusting pump programming does not sufficiently improve drug distribution. Cardiovascular changes, such as heart rate and stroke volume, impact drug distribution in ways that are difficult to predict in clinical settings⁶². A slower infusion rate may reduce cardiovascular effects on drug spread.

There are fewer reported complications when using bolus administration compared to continuous flow at comparable total daily doses⁹⁷. However, bolus administration increases localized concentration (near the infusion site), but not overall spread.

Consensus Point 11: Switching modes of intrathecal catheter delivery from continuous to intermittent bolus may not produce improved outcomes. Impact on safety and efficacy both remain undetermined. USPSTF grade B; level of certainty moderate; evidence level IB.

Pump implantation sites

The standard practice involves placing the pump in the abdominal wall, as it avoids being in contact with clothing or daily movements^98,99. Improper implantation, such as placing the pump too superficially, can result in complications like skin erosion, pump malfunction, or damage from daily activities. Special considerations are necessary for patients with a lower or higher body mass index (BMI), who may face difficulty with placement.

Several studies have explored alternative implantation sites for patients where abdominal placement is not feasible, such as in those with high BMI or complex anatomy. Alternative locations like the flank or anterior thigh have been examined, but these sites are associated with their own set of challenges, including body posture affecting pump positioning and difficulty in maintaining consistent placement^100,101. It is also important to ensure that tubing is properly placed to avoid kinks or other issues, which could interfere with the functionality of the pump.

Consensus Point 12: The traditional implantation site for intrathecal pump placement remains in the abdominal wall. The PACC recognizes that the practice pattern is evolving and that for many practitioners, the buttock/posterior sites and other sites may be applicable and should be considered on a case-by-case basis. USPSTF grade B; level of certainty moderate; evidence level II.

Reducing Infection Rates

Infection prevention is a major concern during pump placement, catheterization, and post-operative care. The 2017 PACC^10,12 and NACC¹⁰² recommendations include adhering to protocols for skin antisepsis, sterilization of the pump site, and maintaining strict cleanliness preoperatively, intraoperatively, and postoperatively. The use of preoperative screening protocols ^105,107 and strict skin cleansing perioperatively is recommended. Evidence supports minimizing catheter manipulation and ensuring good wound care to reduce infection rates. Use of antibiotics before, during, and after the procedure, as well as the careful management of risk factors (like smoking or obesity), is advised to further reduce infection risks^10,12.

Consensus Point 13: IDDS implanters should follow published guidelines on perioperative management of implanted devices and time medication administration optimally to prevent infection. USPSTF grade B; level of certainty moderate; evidence level IB.

Perioperative and Postoperative Management of the New Device

Perioperative education regarding surgical risk, wound and device management is crucial. Occlusive wound dressings, office follow up within 2 weeks, and judicious use of systemic opioids with IDD infusion are recommended.

Consensus Point 14: Clinicians should educate patients and their caregivers perioperatively about IDDS, the medications being administered, and potential adverse events. Clinicians also should be aware that the initial postimplant phase can be complicated by concomitant administration of systemic opioids. USPSTF grade B; level of certainty moderate; evidence level II.

Initial Pump Flow Settings

Initial flow rates are often low to ensure patient safety and avoid complications. A screening trial may be required and may provide information regarding efficacy and potential starting dose, with ziconotide being an exception. In the context of intrathecal pumps, doses may be measured in micrograms or milliliters per hour. The specific medication being administered (e.g., morphine, baclofen) greatly influences the initial flow rate. After the initial dose, flow rate is gradually increased or decreased depending on how well the drug alleviates symptoms and whether there are any side effects.

Continuous infusion is steady, low-dose continuous infusion, or microboluses to maintain consistent drug levels and is the most common intial infusion protocol.. Slow flow rates with higher concentration morphine or hydromorphone may pose greater granuloma formation risk near the catheter tip^8,10,12,113.

Flex dosing and multiple flow rates, initially used for spasticity control with baclofen, has been used for analgesia during the day or nocturnal delivery^114,115,78.

Some pumps can deliver periodic single, or multiple, boluses without a continuous basal dose.

CSF velocity changes during drug bolus infusion depend on several factors, such as stroke volume, respiratory cycle, drug solution density, posture, and individual anatomical differences. These factors can alter drug dispersion and concentration^{116,117,118,119}.

Computational models suggest that low flow rates can affect CSF flow dynamics. Injection with higher latency may lead to a greater drug concentration and volume of contamination in the CSF ^97,120.

Patient activated boluses allow patients to moderate their pain management by using devices (like handheld controllers or mobile apps) to administer additional doses when needed. These doses can account for 5-20% of the total drug volume.

The use of patient activated boluses with ziconotide therapy was reported in 2010 and has become an accepted method to titrate this medication^121,122. The 2017 PACC recommendations based on the three pivotal ziconotide studies, and many years of post-FDA approval experience, suggest ziconotide dilution with preservative-free normal saline to allow dose initiation at 0.5 to 1.2 μg/d.