1. 2021;24;549-569Combination Intrathecal Drug Therapy Strategies for Pain Management
   Narrative Review
   Jay Karri, MD, Mani Singh, MD, Devas J. Modi, MD, Vwaire Orhurhu, MD, Caleb Seale, MD, Michael Saulino, MD, Anuj Marathe, BBA, Darrell Vydra, MD, Jonathan M. Hagedorn, MD, Brian Bruel, MD, and Alaa Abd-Elsayed, MD.

BACKGROUND: Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or medication alternation is deemed untenable or unfeasible. Unfortunately, the supportive evidence basis for the use of these strategies and specific drug combinations is generally lacking and unclear, with many medications being used for off-label indications.

OBJECTIVES In this manuscript, we provide a robust exploration and analysis of the literature to provide an evidence-based narrative for the use of CIDT strategies in regard to clinical indications, pharmacologic parameters, specific drug combinations, safety profiles, and future directions.

STUDY DESIGN: Narrative review.

METHODS: This was an evidence based narrative performed after extensive review of the literature.

RESULTS: Variances in intrathecal pharmacokinetics and pharmacodynamics are utilized advantageously with CIDT strategies to achieve improved analgesic benefit; however, appropriate use may be limited by increased or compounded risk of adverse effects. The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors, including a lack of standardized dosing. The most evidenced CIDT strategies include polyanalgesia with morphine-ziconotide, opioid-clonidine, and morphine-bupivacaine. Notably, in addition to pain relief, morphine-bupivacaine has been shown to decrease early opioid escalation requirements.

LIMITATIONS: The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors including a lack of standardized dosing.

CONCLUSIONS: CIDT strategies and polyanalgesia combinations can be effective for treating various patient populations with chronic pain. The appropriate use of these strategies may be limited by increased or compounded risk of adverse effects, both of which are highly patient and scenario dependent. Therefore, practitioners should maintain a particularly low threshold of suspicion for adverse effects in patients with CIDT such that safety profiles associated with this therapy can be favorably maintained.

KEY WORDS: Intrathecal, polyanalgesia, chronic pain, ziconotide, morphine, clonidine, bupivacaine