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Intrathecal Drug Delivery Systems: A Problem-Based Learning Discussion

Dec 7, 2021

John William Mallett, MD; Gautam Sharma, MD; Muhammad A. Farooq Anwar, MD, MBA; Kevin Vorenkamp, MD, FASA
PBLDs for Residents

A 60-year-old patient who identifies as female arrives at your clinic with stage IV breast cancer and widespread metastasis, including to the thoracic spine. Her oncologists are reluctant to provide a prognosis, but they suggest she has approximately one year of life. She is currently on 60 mg of extended-release oxycodone every six hours, 30 mg of immediate-release oxycodone every four to six hours, 600 mg of ibuprofen every eight hours, and 60 mg of duloxetine daily. The patient reports moderate to severe pain for most of the day that limit her daily activities of living. She also reports side effects from the analgesic regimen, including nausea, vomiting, constipation, and drowsiness. Your patient has a robust family support system and is compliant with her medication regimen. She is seeking alternatives to her current pain control regimen for a better quality of life. 

1. What are the indications and contraindications for considering intrathecal drug delivery systems (IDDS)?

Indications:

Intrathecal drug delivery systems are indicated by the food and drug administration for the management of1:

  1. Severe spasticity
  2. Moderate to severe trunk or limb pain
  3. Intractable pain refractory to or accompanied by intolerable side effects to conservative medical management

IDDS should be considered for1:

  1. Patients with cancer pain and a life expectancy of more than three months
  2. Successful trial of neuraxial medications (with more than 50% reduction in pain)
  3. Functional improvement
  4. Failed conservative treatments and tolerable side effects to proposed IDDS pharmacotherapy
  5. Chronic noncancer pain, including axial pain (nonsurgical candidates), failed back surgery syndrome, complex regional pain syndrome, postherpetic neuralgia, phantom limb pain, pancreatitis, chronic abdominal or pelvic pain, and post-thoracotomy syndrome
  6. Spasticity, hypertonia, dystonia, or myoclonus 

Absolute contraindications for IDDS are1:

  1. Patient refusal
  2. Systemic infection
  3. Active drug abuse
  4. Severe coagulopathy
  5. Local infection at the surgical site(s)
  6. Allergy to device components or medications

Relative contraindications to IDDS include1:

  1. Atrophy or malnourishment
  2. Systemic anticoagulation that cannot be stopped for the perioperative period
  3. High opioid tolerance
  4. Spinal metastases with severe spinal stenosis
  5. Impaired wound healing (eg, uncontrolled diabetes mellitus)
  6. Disease process impairing drug clearance (eg, renal or hepatic disorders)
  7. Psychological dysfunction
  8. Comorbidities that impair respiratory drive (eg, sleep apnea, chronic obstructive pulmonary disease) or cardiac disease

2. Given her presentation, the patient is considered for placement of IDDS. The patient and her husband are curious to know about different types of IDDS and the procedure for implantation.

The three available IDDS configurations are characterized by the location of the catheter or the pump.2,3

A. Externalized system - both the catheter and pump are located externally. The system is generally for short term use (less than three months), such as for a trial of therapy or for patients with a minimal life expectancy. Although they are minimally invasive and less expensive, externalized systems involve the highest risk of infection and catheter migration.

B. Partial externalized systems - uses a tunneled catheter, but the pump is still externalized. The systems are used for an intermediate range of time (three to six months) and provide patients more mobility by reducing the risk of accidental catheter removal. They are associated with relatively lower infection rates than externalized systems. With some partial externalized systems, the catheter may be anchored to reduce migration risk.

C. Implanted (entirely internalized) systems - both the catheter and pump are surgically implanted in the patient. For long-term use (more than three months), the systems offer patients the greatest freedom of movement with lowest risk of dislodgement and infection. However, implantation and follow-up require multiple ambulatory visits for adjusting, reprogramming, and refilling. Programming options include fixed rate (eg, Codman 3000, Medtronic Isomed) and variable rate (eg, Flowonix Prometra II, Medtronic Synchromed II).

Placement

A. The trial:

  • Before placing any of the systems, patients may first have to undergo a trial of the desired therapy with either a single-shot approach, multiple boluses, or continuous infusion of the medication. The trial is considered successful if the patient does not experience significant adverse effects and their pain is reduced more than 50% from baseline (according to the Polyanalgesic Consensus Conference [PACC], pain reduction may be defined from 30%–70%).
  • For patients with cancer-related pain, the trial may be omitted because the dose and medications may need to be modified to achieve the desired effect (and other medical comorbidities and chemotherapy-related side effects may make a two-step process less achievable).

    B. Definitive placement:

    • Definitive placement is performed in the operating room under sterile conditions with local anesthesia with sedation, spinal anesthesia, or general anesthesia. Light sedation with monitored anesthesia care is preferred to allow for neurologic status assessment during the procedure.
    • The pump pocket typically should not lie below the belt mark and should avoid bony prominences. Occasionally, a patient’s abdomen cannot be easily used because of surgical alterations (eg, ostomy tubes), so the pump may be placed in the back or buttocks. Mark the placement site while the patient is sitting up rather than in a lateral position (common location is left or right lower quadrant of the abdomen). To decrease the risk of seroma, make sure the pocket size just fits the pump.
    • Access the intrathecal space via the paramedian approach around the L2–L4 level (below the conus, as verified with magnetic resonance imaging [MRI]), and advance the catheter under fluoroscopic guidance to the desired position. The American Society of Pain and Neuroscience Best Practices and Guidelines recommend appropriate placement levels based on the location of the pain.4 (See Table 1.) Anchor the catheter to the supraspinous ligament or fascia rather than adipose tissue.5

    Table 1. Appropriate placement position based on pain location

    Pain Location Vertebral Body Catheter Tip Location
    Brachial plexus C3–C5
    Arm C3–C5
    Breast T1–T2
    Upper chest wall T3–T4
    Visceral abdomen T5–T6
    Lower chest wall T6–T7
    Abdominal wall T6–T7
    Pelvis T9–T12
    Leg T10
    Sacral area Vertebral body at the level of conus

     

    IDDS Medications

    Using the case study presented at the beginning of this article, consider the following scenarios when selecting an IDDS agent for your patients.

    1. The patient has researched numerous online health websites and would like to be prescribed the most appropriate first-line agent based on randomized control trials. What medication would you recommend for her?

    Both morphine and ziconotide have indications as first-line agents for intrathecal administration for both localized and widespread cancer and noncancer pain. Most physicians start with morphine or hydromorphone in the clinical setting. However, some guidelines prefer ziconotide for noncancer pain because it has been assessed in randomized control trials, whereas morphine has not.6

    2. The patient returns with new-onset suicidal ideation (a potential side effect of ziconotide) and would like to try a medication with a broader therapeutic index that is still considered first line. What other first-line medications might you opt for, and what are their possible side effects?

    Ziconotide has several side effects, including thoughts of self-harm,7 and it is contraindicated in patients with a history of psychosis. Morphine is also considered a first-line agent, but it is associated with gastrointestinal upset, itching, constipation, urinary retention, and, less commonly, respiratory depression. However, the side effects can be reversed with naloxone.8

    3. Several months later, your patient’s pain becomes refractory to first-line agents. What other intrathecal medications do current consensus guidelines recommend?

    Several medications are considered reasonable monotherapies for IDDS based on current PACC guidelines, including morphine, hydromorphone, ziconotide, fentanyl, bupivacaine, clonidine, and sufentanil. Recommended initial dosages for infusions and intrathecal boluses can be found in tables 11 and 12, respectively, of the PACC guidelines. Ziconotide or local anesthetics are used for nociceptive or neuropathic pain, clonidine with or without opioids are appropriate for neuropathic pain, and opioids alone or combined with local anesthetics typically target nociceptive pain.9


    Perioperative IDDS Management

    The following problem-based learning discussion uses a new case study: A colleague had a family emergency, and you are asked to cover their general anesthesia shift. You first see a 64-year-old patient who identifies as female and is set to undergo a right total knee arthroplasty. Her past medical history includes hypertension, which is well-controlled with losartan, and she had an IDDS placed by another provider before she moved into town three months ago.

    1. What information do you need about the pump before proceeding?

    Recommended information includes the device age (IDDS typically last five to seven years), previous device evaluation, indication for implantation, medication being infused, date for refill or pump change, and dosing regimen (including flex or demand dosing). If you are unfamiliar with the specific device, you may decide to learn more from a device company representative before proceeding to surgery.10 Additionally, do not attempt spinal anesthesia unless you can perform it under fluoroscopic guidance, have a clear understanding of the catheter entry point, and have discussed risks and benefits with your patient.

    2. She reports receiving morphine 0.8 mg per day. What intraoperative concerns do you have?

    If your patient is already receiving intrathecal opioids, the risk of respiratory depression increases with the administration of additional opioids or intrathecal baclofen. Providers should note that patients with a lower body mass index often have the pump implanted in their lower abdomen. In contrast, obese patients are more likely to have the device implanted in their flank area. The surgery team should also be aware of the device placement to minimize the risk of damaging the device or catheter, particularly if the surgical field overlaps the device’s location.

    Drug delivery speed is directly correlated with patient temperature; as their temperature increases or decreases, so does the medication delivery. Most devices recommend maintaining a patient temperature under 39°C for this reason, although no lower limit is currently specified. MRI compatibility is dependent on the device, with some producers recommending pausing the pump to prevent fluctuations in medication dosing and others advising continuing the infusion. Lifesaving measures such as defibrillation or cardioversion should proceed without delay, but prevent currents from crossing the IDDS device as much as possible. If electrical shock is required, interrogate the device postoperatively.10

    3. The patient is petrified of having an airway device placed. Would it be reasonable to proceed without general anesthesia?

    IDDS is not an absolute contraindication to neuraxial anesthesia. Appropriate planning with radiographic imaging or ultrasound guidance prevents damage to the device and catheter. Aseptic technique is critical because central nervous system infection typically requires IDDS removal. If spinal anesthesia is necessary, it should be performed below the level of catheter entry and incision.


    IDDS Complications

    The following problem-based learning discussion uses a new case study with multiple choice questions: A 55-year-old patient with cancer presents to the emergency department for drowsiness. He visited his pain management provider earlier in the day for a refill of his intrathecal morphine pump. He has decreased responsiveness and constricted pupils.

    1. Which initial steps would you take to evaluate his condition?

    A. Review the clinic note
    B. Interrogate the pump
    C. Administer naloxone
    D. Order a brain MRI
    E. A, B, and C
    F. All of the above

    The correct answer is E. Reviewing patients’ records to learn about the pump contents, infusion rates, boluses, and recent refills is vital to troubleshooting pump issues. Consider consulting the pain service for pump interrogation to ensure that it functions as programmed. Conduct a bedside ultrasound examination and aspirate the drug volume to compare it with the previously injected volume.

    2. How would you manage your patient if you suspect a pump pocket fill?

    A. Provide hemodynamic monitoring and supportive care.
    B. Administer IV naloxone.
    C. Aspirate the pocket.
    D. All of the above

    The correct answer is D. Accidental pump pocket fills during a blind or image-guided pump refill can significantly harm a patient. Subcutaneous baclofen seems to pose minimal overdose risk (although patients may experience withdrawal, depending on the duration), but opioids can have significant systemic absorption and potential for overdose. Also, intrathecal opioids are highly concentrated to fit the maximum dose in 20–40 mL pumps. Patients should be closely monitored for possible side effects and overdose signs when a pocket fill is suspected. Have appropriate antidotes readily available, and consider aspirating the pocket with a specialist.11

    3. What is the most common cause of severe morbidity and mortality from IDDS?

    A. Procedural complications
    B. Spinal cord trauma
    C. Infections
    D. Medication-related issues

    The correct answer is D. Information from the Anesthesia Closed Claims Project Database shows that medication administration issues are the most common cause of death and severe permanent brain damage. Permanent spinal cord injury is most associated with delays in recognizing granuloma formation, procedural trauma, and hematoma.12

     

    References

    1. Shah N, Padalia D. Intrathecal delivery system. StatPearls. Treasure Island, FL: StatPearls Publishing; 2021. https://www.ncbi.nlm.nih.gov/books/NBK538237
    2. Hunter JP. Book reviews: practical management of pain by Honorio Benzon, James P. Rathmell, Christopher L. Wu, Dennis C. Turk, Charles E. Argoff, Robert W. Hurley. Physiother Can. 2016;68(2):208. https://doi.org/10.3138/ptc.68.2.rev 
    3. Bottros MM, Christo PJ. Current perspectives on intrathecal drug delivery. J Pain Res. 2014;7:615–26. https://doi.org/10.2147/JPR.S37591 
    4. Aman MM, Mahmoud A, Deer T, et al. The American Society of Pain and Neuroscience (ASPN) best practices and guidelines for the interventional management of cancer-associated pain. J Pain Res. 2021;14:2139–64. https://doi.org/10.2147/JPR.S315585 
    5. Deer TR, Hayek SM, Pope JE, et al. The Polyanalgesic Consensus Conference (PACC): recommendations for trialing of intrathecal drug delivery infusion therapy. Neuromodulation. 2017;20(2):133–54. https://doi.org/10.1111/ner.12543 
    6. Deer TR, Pope JE, Hanes MC, McDowell GC. Intrathecal therapy for chronic pain: a review of morphine and ziconotide as firstline options. Pain Med. 2019;20(4):784–98. https://doi.org/10.1093/pm/pny132 
    7. TerSera Therapeutics LLC. PRIALT (ziconotide) solution, intrathecal infusion. https://www.prialt.com/wp-content/uploads/prialt-prescribing-information.pdf. Updated May 2019. Accessed December 4, 2021.
    8. Ruan X. Drug-related side effects of long-term intrathecal morphine therapy. Pain Physician. 2007;10(2):357–66. PMID: 17387357.
    9. Deer TR, Pope JE, Hayek SM, Bux A, et al. The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines [published correction appears in Neuromodulation. 2017;20(4):405–6]. Neuromodulation. 2017;20(2):96–132. https://doi.org/10.1111/ner.12538 
    10. Nadherny W, Anderson B, Abd-Elsayed A. Perioperative and periprocedural care of patients with intrathecal pump therapy. Neuromodulation. 2019;22(7):775–80. https://doi.org/10.1111/ner.12880 
    11. Maino P, Perez RSGM, Koetsier E. Intrathecal pump refills, pocket fills, and symptoms of drug overdose: a prospective, observational study comparing the injected drug volume vs. the drug volume effectively measured inside the pump. Neuromodulation. 2017;20(7):733–9. https://doi.org/10.1111/ner.12597 

     


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