Pulmonary

Preservative-free morphine and ziconotide are the only FDA-approved intrathecal analgesics²⁷. IT opioids can cause respiratory depression, especially in patients with underlying lung diseases. Monitoring and careful selection of IT drugs are necessary.

Intrathecal morphine may have an increased risk of deadly respiratory depression during initiation, or restarting, or when other CNS depressants such as sedatives or hypnotics are being used^28,29,30. Many patients treated with intrathecal infusion or oncology patients on systemic opioids may be opioid tolerant;³¹ but caution should be exercised in patients with chronic lung diseases or medical, radiation or surgical treatments affecting pulmonary function.

There is no evidence of increased respiratory depression risk with ziconotide²⁸.

Consensus Point 3. The PACC recommends consideration of pulmonary disease and status when choosing IT drugs and during both initial dosing and dosing adjustments with opioids. USPSTF Grade B; Level of certainty low; Quality of evidence II.

Cardiac

Limited data indicate that ziconotide, an intrathecal (IT) drug used for pain management, may be associated with dose-related cardiovascular side effects such as hypotension and postural hypotension. These adverse events are more likely at higher doses or with rapid dose escalation^32,33. To minimize risk, treatment should start at lower doses, with small dose increments and longer intervals between titrations.

The initial studies comparing fast versus slow titration protocols for ziconotide revealed a higher incidence of cardiovascular AEs in patients receiving higher daily doses. The current PACC guidelines recommend starting with lower doses and gradual titration to reduce the likelihood of these side effects.

The American College of Cardiology (ACC) and the American Heart Association (AHA) risk stratification guidelines can be applied to evaluate patients with a history of cardiovascular disease (CVD) who are being considered for intrathecal (IT) device implantation³⁴.

Chronic Kidney Disease (CKD) is a significant comorbidity that increases the risk of cardiovascular complications compared to the general population. Due to the close link between CKD and cardiovascular disease, patients with CKD should be evaluated using the same ACC/AHA criteria to assess their cardiovascular risk prior to IT device implantation³⁵.

Clonidine is often used intrathecally off-label²⁷ and can lead to hypotension when administered at lower doses, making it crucial to monitor blood pressure closely, especially in patients already prone to low blood pressure.

At higher doses, clonidine may cause hypertension. Abrupt discontinuation can result in rebound hypertension, which poses significant risks, such as hypertensive crisis and stress-induced cardiomyopathy^27,36,37,38. This emphasizes the importance of careful tapering and monitoring when discontinuing the medication.

Consensus Point 4. The PACC recommends that consideration be given to the choice of IT medications, with particular attention paid to clonidine, when treating patients with cardiovascular disease, with special consideration towards clinically significant hypotension and/or rebound hypertension. USPSTF Grade A; Level of certainty low; Quality of evidence 1-C.

Endocrine

Painful diabetic neuropathy may occur in close to 50% of diabetics with pain and neuromodulation with IDD is underutilized²⁹. Surgical site infections and poor wound healing may be seen in patients with poor glycemic control perioperatively^31,41,42,43. Long-term IT opioid use can lead to hypogonadism and bone loss^{44,45,46,47,48,49}. Diabetes management should be optimized before implant procedures.

Consensus Point 5. The PACC recommends optimization of diabetes management before implant. Other hormonal abnormalities should be considered if symptoms or signs develop, and proper assessment by an endocrinologist or primary care specialist should be considered.

USPSTF Grade B; Level of certainty low; Quality of evidence II.

Renal & Hepatic Function

Drug excretion and metabolism must be considered when selecting IT agents, particularly in patients with renal or hepatic dysfunction. Creatine kinase baseline lab work should be obtained and monitored when using ziconotide³⁰.

Coagulopathy, Chronic infection and Polypharmacy

The PACC and the American Society of Regional Anesthesia (ASRA) have established guidelines for discontinuing anticoagulants and antiplatelet agents before undergoing neuraxial procedures, such as intrathecal drug delivery system (IDDS) implantation^31,50,51,52. These recommendations help mitigate the risk of neurological complications, such as spinal hematomas. Discontinuation of anticoagulants may carry a higher risk in cancer patients compared to the non-cancer population, necessitating a thorough risk/benefit assessment for each patient³². Those with a low to moderate risk of thromboembolism may discontinue anticoagulants safely, whereas patients at high risk may not be suitable candidates for IDDS implantation due to the increased risk of perioperative complications.

In high-risk patients who cannot safely discontinue anticoagulants, some clinicians advocate for bridging therapy with low molecular weight heparin⁵³. However, this approach can increase the incidence of perioperative bleeding and should be used with caution^54,55,56. Neuraxial access is typically avoided in those unable to discontinue antithrombotic agents.

Consensus Point 6. The PACC recommends careful attention to hepatorenal function as well as bleeding risks of patients considered for IDD. Discussion with oncologic treatment providers is essential to determine surgical risk for patients undergoing IDDS placement during oncologic treatments. Additionally, adherence to evidence-based guidance in managing drugs impacting coagulation and comorbidities impacting bleeding risks is paramount. USPSTF Grade A; Level of certainty moderate; Quality of evidence II.

Uncontrolled current chronic infection is a contraindication for device implantation^32,57,58. When MRSA is common in the population it may be prudent to consider all patients high risk; screen with nasal swabs⁵⁷ and treat with proper antibiotic prophylaxis. Reviews of available data on immunocompromised cancer or acquired immunodeficiency syndrome (AIDS) patients does not indicate a higher risk of infection with implantation^13,32,42.

Consensus Point 7. The PACC recommends careful attention to comorbidities that may increase infection risks in the perioperative period. USPSTF Grade A; Level of certainty high; Quality of evidence I.

The need for polypharmacy in elderly cancer patients with preexisting comorbidities and cognitive impairment can affect treatment outcomes and opioid therapy should be used with caution and close monitoring^{59,60,61,63,63,64,65}. Age alone is not a contraindication for IDD, and individual patient health status should guide treatment decisions.

Consensus Point 8. The PACC recommends attention to polypharmacy, cognitive impairment and other issues that may impact pharmacokinetics and patient response. USPSTF Grade A; Level of certainty moderate; Quality of evidence 1-C.