A safety review of approved intrathecal analgesics for chronic pain management

ABSTRACT

Introduction: Intrathecal (IT) drug therapy is an effective treatment option for patients with chronic pain of malignant or nonmalignant origin, with an established safety profile and fewer adverse effects compared to oral or parenteral pain medications. Morphine (a μ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the U.S. Food and Drug Administration for the treatment of chronic pain. Although both are considered first-line IT therapies, each drug has unique properties and considerations.

Areas Covered: This review will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies.

Expert Opinion: Morphine and ziconotide are effective IT therapies for patients with chronic malignant or nonmalignant pain that is refractory to other interventions. IT ziconotide is recommended as a first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management.

KEYWORDS:

• Adverse effects
• cancer pain
• chronic pain
• intrathecal
• morphine
• safety
• ziconotide

Article highlights

• Intrathecal drug delivery for pain offers certain advantages over conventional oral and parenteral routes. As these medications are directly delivered to the central nervous system and bypass the blood-brain barrier, they are associated with fewer systemic adverse events and significantly lower doses needed to achieve pain relief.

• Only two intrathecal medications are approved by the Food and Drug Administration for the treatment of chronic pain: morphine (a µ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist). Both are recommended by the Polyanalgesic Consensus Conference as first-line treatment for patients with malignant or non-malignant pain.

• Intrathecally administered morphine is less likely to be associated with systemic adverse effects compared to oral opioids; however, one of the most dangerous and deadly complications common to both routes of administration is respiratory depression.

• Compared to morphine, ziconotide is not associated with the development of tolerance, dependence, respiratory depression, addiction, or withdrawal symptoms. It can also be rapidly weaned or discontinued if necessary.

• Ziconotide has a very narrow therapeutic window and requires a ‘low and slow’ titration. Its use is contraindicated in patients with a history of psychosis due to the risk of severe psychiatric symptoms and neurological impairment.

• The use of other intrathecal agents or combination therapy with other opioids (hydromorphone, fentanyl) and local anesthetics (bupivacaine) is common. This is considered an off-label therapy and the Food and Drug Administration does not regulate compounded formulations.

This box summarizes the key points contained in the article.

Declaration of interest

CE Argoff is a Speakers Bureau member for Allergan, Inc., AstraZeneca Pharmaceuticals LP, Depomed, Inc., Iroko Pharmaceuticals, LLC, Millennium Laboratories, LLC, Teva Pharmaceuticals Industries Ltd., and XenoPort, Inc.; Advisory Board member for AstraZeneca Pharmaceuticals LP, Collegium Pharmaceutical, Inc., Depomed, Inc., Endo Pharmaceuticals Inc., Pfizer Inc., Purdue Pharma L.P., Shionogi & Co. Ltd., Teva Pharmaceuticals Industries Ltd., Vertex, and XenoPort, Inc.; Research support from Eli Lilly and Company, Endo Pharmaceuticals Inc., and Forest Laboratories, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have served as a consultant for Flowonix and Tersera and have performed research for Medtronic, Flowonix, and Tersera. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.