Challenges in Using Intrathecal Medications for the Treatment of Chronic Pain

PALM SPRINGS, CA—Small, sophisticated, reliable, and controllable implantable pumps, ongoing research, and clinical consensus with respect to the safe delivery of intrathecal medications for chronic pain was the focus of a presentation at the 2012 American Academy of Pain Medicine Annual Meeting.

“Choosing the appropriate medication to use for each patient can be a daunting task for most physicians,” said Tony L. Yaksh, PhD, of the University of California, San Diego, La Jolla, CA.

Implanted intrathecal drug delivery systems are widely used in the treatment of chronic pain when conservative therapies have failed and surgery is not a viable option, he said. Currently approved intrathecal medications are morphine, baclofen, and ziconotide; other agents used (but not approved by the FDA) are hydromorphone, fentanyl, sufentanil, buprenorphine, clonidine, ketamine, bupivacaine, ropivacaine, and midazolam.

Recently, a consensus panel was convened to determine a polyanalgesic algorithm for intrathecal therapies for both nociceptive and neuropathic pain. For nociceptive pain, the organizing principle is that single-agent opiates are used first-line; subsequent lines of therapy include a combination of two agents. For neuropathic pain, the organizing principle is that morphine/ziconotide should be used first-line; again, combination therapy is recommended for subsequent lines of therapy. Dr. Yaksh noted that these recommendations are in press and should be published this year.

Intrathecal morphine infusion, which is widely used clinically, has the potential to result in granuloma, he said. A 28-day study in dogs resulted in unexpected observations: tactile hypersensitivity and hind limb hypertonicity/paralysis.

One challenge currently being addressed is the question of tolerance: what mechanisms contribute to increased drug dose requirements? These can include disease progression, altered pain mechanisms, change in psychosocial status, altered kinetics/metabolism, pharmacodynamic changes, and system level changes, such as enhanced responsiveness to a noxious input (eg, latent hyperalgesia), he said.

Spinal drug safety considerations include lack of a blood-brain barrier, distinct structures from those affected systemically, high injectate concentrations, and poor CSF circulation. Intrathecal use of spinal drugs cannot be presumed to be safe because they are used systemically.

“Even for drugs with which there is extensive spinal experience, changes in concentration, combinations or delivery protocols may lead to deleterious outcome,” said Dr. Yaksh. For example, the extent and rate of redistribution of drug from lumbar spinal injection is a function of bolus vs infusion, volume, rate, baricity, local CSF dilution, and CSF pulsations, “changing variables changes drug movement, clearance, and action.”

He concluded by noting there is a need for neonatal preclinical models for spinal drug safety assessments.