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Complications of Intrathecal Drug Delivery Systems and Drugs Used

By Alyson M. Engle MD¹, Mark N. Malinowski DO², Jonathan M. Hagedorn MD³, and Timothy R. Deer MD⁴

¹University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
²Adena Regional Medical Center, Adena Spine Center, Chillicothe, OH, USA
³Mayo Clinic, Rochester, MN, USA
⁴The Spine and Nerve Center of The Virginias, Charleston, WV, USA

Introduction

Intrathecal drug delivery systems (IDDS) are devices used to provide continuous infusion of a drug into the intrathecal (IT) space via a sialastic catheter strategically placed in the cerebral spinal fluid (CSF) of the neuroaxis. The IDDS is comprised of a pump and a catheter. The IDDS pump can be programed as a constant flow device, with complex programing or with an ability to administer “dosing-on-demand”. IDDS offers a tool for physicians to provide personalized precision medicine by effectively delivering therapeutic drug levels for extended periods of time at a specified target. The delivery of medication into the IT space allows for targeted dosing at the spinal cord and reduces systemic side effects, and this is a key advantage for the use of IDDS in the pain care algorithm. The Polyanalgesic Consensus Conference (PACC) best practices and guidelines, in conjunction with the SAFE principles, help guide the decision-making process when considering IDDS for treatment [1, 2].

Indications

Spasticity and severe, refractory or chronic intractable dystonia unresponsive or intolerant of oral anti-spasticity agents (e.g., baclofen)
Malignant pain [3]
End of life care:
- – Painful disorders not amenable to care and require palliative comfort care.
Non-malignant, chronic intractable refractory pain
- – Failed back surgery syndrome
- – Compression fractures
- – Spondylosis
- – Spondylolisthesis
- – Spinal stenosis
- – Complex regional pain syndrome type I
- – Complex regional pain syndrome type II
- – Diabetic peripheral neuropathies
- – Facial pain syndromes
- – Abdominal pain
- – Pelvic pain
- – Plexopathies.

Refractory pain is considered to be intractable pain despite less aggressive evidence-based multi-modal treatment regimens for an appropriate duration of time.

Contraindications

Relative Contraindications

Impaired wound healing states (e.g., tobacco use, uncontrolled diabetes)
Uncontrolled co-morbidities that may be exacerbated in the setting of IDDS (e.g., cardiopulmonary disease states)
Lack of familial or social support.

Absolute Contraindications

Systemic infection or active infection at site of implantation
Allergy to potential drugs or implant materials
Patient refusal, not able to provide informed consent (or medical power of attorney)
Psychosis or dementia
Uncorrected coagulopathy
Patient refusal to have the device refilled
Active substance abuse.

Technique

The procedure can be performed under monitored anesthesia care or general anesthesia. The patient is placed in lateral decubitus position with attention to the pressure points. Sterile technique for preparing the lower spine and lower abdominal area is carried out. Fluoroscopic guidance is used to identify the appropriate landmarks for skin and dural insertion (e.g., the inferior aspect of the right L5 lamina and entry site of L3–L4 interspace). Entry below L1–2 is preferred to avoid direct contact with the conus medularis. Administration of local anesthetic with 7–10 mL of 0.25% bupivacaine with 1:100 000 epinephrine for areas of skin incision. A small skin incision is made.

A paramedian approach is used to advance the Tuohy needle under fluoroscopic guidance until CSF is obtained. Midline approach risks the catheter becoming compressed between the spinous processes, which could lead to catheter maceration.

The catheter is inserted through the Tuohy needle and advanced under fluoroscopic guidance to the appropriate level. Once there is confirmation of CSF from the catheter, the physician has confidence of placement, although some physicians may choose to flush the catheter with preservative free saline, or to perform a myelogram (Figures 50.1–50.3).

**Figure 50.1** Catheter is inserted through the Touhey needle. (*Source*: Courtesy of Serdar Erdine.)

**Figure 50.2** Free flow of CSF confirmed. (*Source*: Courtesy of Serdar Erdine.)

**Figure 50.3** Verify by fluoroscopy injecting dye. (*Source*: Courtesy of Serdar Erdine.)

After the needle is removed from the IT space, the stay suture for the anchor is placed through the supraspinous ligament and the anchor is placed over the IT catheter (Figure 50.4). Next, the pocket skin incision is made, and blunt dissection is used to make an appropriately sized pocket for the pump implant. Four sutures are positioned evenly to secure the pump at a later time to ensure that it does not move in the pocket. The pocket can be made in the abdominal wall or in the paravertebral region.

**Figure 50.4** Stay suture for anchor. (*Source*: Courtesy of Serdar Erdine.)

A tunneling tool is then used to pass the catheter from the spinal incision to the pocket (Figure 50.5). Once the tunneler is advanced to connect the incisions, and any stylet or handle has been removed, the catheter is then threaded through the tunneler into the pocket (Figure 50.6). Fill the reservoir of the pump (Figure 50.7).

**Figure 50.5** A tunneling tool to pass the catheter from the spinal incision to the pocket. (*Source:* Courtesy of Serdar Erdine.)

**Figure 50.6** Prepare the pocket for the DDS. (*Source*: Courtesy of Serdar Erdine.)

**Figure 50.7** Fill the reservoir of the pump. (*Source*: Courtesy of Serdar Erdine.)

At this point, the catheter is attached to the pump and the pump is then secured into the pocket using the four non-absorbable sutures previously positioned (Figure 50.8). The medication should be placed in the pump prior to implantation. After skin closure, the wound should be covered with a sterile dressing. The patient should then be observed in the PACU (Figure 50.9).

**Figure 50.8** Place the pump in the pocket. (*Source*: Courtesy of Serdar Erdine.)

**Figure 50.9** Pump in the pocket under fluoroscopy. (*Source*: Courtesy of Serdar Erdine.)

Complications

IDDS complications can be categorized as procedural, equipment, refill-related, pharmacologic and patient-specific complications. Table 50.1 lists potential IDDS complications by category. Table 50.2 outlines The PACC’s recommendations for IDDS. Table 50.3 provides the updated recommendations for prevention and management of complications published by The Center for Disease Control (CDC) and The Neuromodulation Appropriateness Consensus Committee (NACC).

Table 50.1 Complications associated with IDDS implantation.

Procedural complications

Bleeding
CSF leakage
Post-dural puncture headache
Seroma formation
Neurologic injury
Wound dehiscence
Skin erosion
Seroma
Neuroma
Infection
- – Surgical site
- – Deep infection
- – Discitis
- – Epidural abscess
- – Meningitis.

Equipment complications

Catheter malfunction
- – Dislodgement
- – Malposition
- – Migration
- – Kinking
- – Shearing
- – Puncture
- – Fracture
- – Leakage
- – Granuloma formation.
Pump malfunction
- – Pump failure
- – Battery failure
- – Pump rotation or flipping in the pocket
- – Overfilling.

Refill-related complications

Subcutaneous pocket
Medication error
Pump programming error.

Pharmacologic complications

Allergic reactions
Withdrawal
Overdose
Medication-specific side effects
- – Endocrinopathies (e.g., hypogonadism)
- – Low bone mineral density.

Patient-specific co-morbidities

Psychiatric co-morbidities
Cancer metastasis
Smoking
Diabetes
Immunosuppression Obstructive sleep apnea.

Table 50.2 Summary of the Polyanalgesic Consensus Conference recommendations on Intrathecal Drug Infusion Systems, 2017.¹

Psychology

Psychological assessment, counseling and after care are recommended in appropriate candidates. The use of an assessment is critical in all non-cancer patients receiving IDDS.
Psychological screening is not required for end-of-life patients, but psychological counseling should be considered.

Training and techniques

Limited data exist as to appropriate and best catheter tip placement. The catheter should ideally be centered in the spinal dermatome associated with the pain generator. The consensus recommendation is that the doctor uses clinical judgement based on the clinical setting.
Each accredited facility should have the ability to evaluate an indwelling implanted device, including the pump and catheter system.
All patients admitted to a medical facility should have their IDDS documented as part of the medical record to include: IDDS type, manufacturer, medication(s), respective concentrations, daily dose, delivery modes and, if applicable, electronic pump interrogation.
Documentation of IDDS type and manufacturer of pump identification for drug delivery should be considered the standard of care prior to performing an MRI or pursuing elective surgery and is imperative for all patients admitted to hospital.
Training of all personnel for device evaluation and refilling is an important part of patient care. This training should be device specific and supervised carefully. The PACC recommends that 20 refills be supervised before independent practice is approved. Two or more trained individuals should check all reprogramming.
In order to offer IT therapies, regardless of primary specialty, the physician should be supervised in a minimum of 10 implant and/or explant cases.
In order to maintain skills, the implanter should be involved in five cases over the course of two years or should undergo additional hands-on certified educational training to refresh skills.
Training to manage an IT device is critical to the long-term success of the therapy. All pump management physicians should have ongoing educational training that includes knowledge of all current and FDA-approved devices and future devices approved by regulatory bodies for research and found to be clinically relevant.
Managing physicians who are not implanting physicians are expected to be trained to the same level as those who both implant and manage devices.

Pharmacology

First-line, FDA-approved medications to be used in the IT space:
- – Morphine
- – Ziconotide.
Off-label drug monotherapy or combination therapy is not recommended until FDA-approved drugs are tried and failed, or are contraindicated. In cancer pain, the on-label drugs can be used during the trial phase. If the results are not acceptable due to lack of efficacy or side effects, an admixture with bupivacaine of the primary use of fentanyl is supported by our consensus guidelines.
The PACC algorithms are based on improving safety and efficacy in clinical practice, which includes the use of off-label drugs.
Ziconotide has strong clinical evidence for efficacy.
There are no cases of death from ziconotide overdose and no granuloma formation has been reported.
Unless contraindicated, ziconotide should be the first drug selected in the population of non-cancer patients.
The initiating dose of IT opioids and ziconotide should be as low as reasonably expected to provide analgesia.
The initiating dose of IT opioids and ziconotide delivered continuously should be 50% or less of the dose used during bolus trialing.
The PACC recommends that the primary medication be weaned and discontinued when converting medications from one single medication to a different single medication in the algorithm.
The use of ziconotide and bupivacaine do not have the risk of withdrawal and weaning is not needed. The abrupt stopping of an opioid is not recommended.
The PACC recommends careful attention to side effects when adding any adjuvant drug to a primary drug.
Medications with significant withdrawal syndromes, including clonidine and baclofen, require rescue strategies in the event of abrupt cessation or interruption in IT delivery.
Before proceeding with aggressive dose titration above 1000 mcg per day of IT fentanyl, clinicians should closely monitor the outcome of each dose increase and, if efficacy is not being established, consider dose reduction with consideration of IT tolerance and hyperalgesia.

Patient-related factors

Patients with co-morbidities that negatively affect cardiopulmonary function need increased vigilance when instituting opioid therapy.
Localized, diffuse and global pain can be adequately treated with IT therapy. The evidence for global pain treatment is less well defined and should be approached cautiously.
The algorithms are based on evidence and consensus on safety. The patient’s physician and good clinical judgment should guide individual patient care.
The disease process should be considered when making decisions on algorithms for patient care.
IT therapies should be used at an appropriate time in the algorithm and not as a salvage treatment.
The stage of cancer and survival time should be considered when performing drug titration.
IT therapy should be considered within the same line as neurostimulation.
IT therapy should be considered after neurostimulation if the pain is isolated and unlikely to spread.
IT therapy should be considered before neurostimulation for active cancer-related pain that is mechanical and likely to spread.