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Intrathecal Drug Delivery for Neuropathic Pain


but higher doses were associated with partial or complete resolution of symptoms. Six of seven women went on to receive implantable baclofen infusion pumps and, at three months post-implant, marked reductions in pain were experienced such that three women had regained normal hand function and the ability to walk. These results were supported by Zuniga and colleagues,39


who reported two patients with refractory CRPS


who experienced dramatic reductions in spontaneous and evoked pain when treated with intrathecal baclofen.


Critics of baclofen analgesia argue that the pain reductions observed are merely the result of elimination of spasm-related pain, but a study conducted by Herman and colleagues40


be most effective in patients with neuropathic pain.48 cohort trial, Nitescu et al.49


In a prospective evaluated bupivacaine in combination with


morphine in 90 terminal cancer patients, 81 of whom endorsed either neuropathic or mixed pain. Eighty-six patients (96 %) obtained acceptable (60–100 %) pain relief, and sedative and rescue consumptions were significantly reduced (median follow-up 60 days).


demonstrated suppression of


neuropathic pain that was temporally distinct from spasm-related pain. In these patients, the suppression and reappearance of dysesthetic pain after a bolus of intrathecal baclofen occurred distinctly from that of spasm-related pain. No difference was noted in evoked pain in these patients. These results were supported by Taira et al.,41


who


found that nine of 14 patients with central pain secondary to stroke or SCI experienced significant reductions in spontaneous pain, allodynia, and hyperalgesia for up to 24 hours following intrathecal baclofen bolus.


In addition to alleviating central pain, intrathecal baclofen has shown efficacy when used to treat neuropathic pain secondary to failed back surgery syndrome (FBSS), amputation, and plexopathy.42 colleagues43


Lind and


published a case series in which they treated seven patients with refractory neuropathic pain with intrathecal baclofen infusion pumps and spinal cord stimulation, and four with baclofen alone. Both groups obtained significant pain relief, but a greater reduction in pain scores occurred in the combination group. The results were borne out over 67 months of follow-up. These results are further bolstered by a recent placebo-controlled trial conducted in 10 patients experiencing refractory neuropathic pain after spinal cord stimulation (SCS).44


Clonidine, baclofen,


and saline (control) were intrathecally administered by bolus injections in combination with SCS. Seven of 10 patients reported significant pain reduction when SCS was combined with active drugs. The most common adverse effects associated with intrathecal baclofen are somnolence, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.45


Local Anesthetics


Local anesthetics are sodium-channel-blocking agents that reversibly decrease the rate of depolarization and repolarization in neuromembranes, preventing action potential initiation and inhibiting signal conduction. Local anesthetics block the transmission of all neurons, not just the A-delta and C fibers responsible for the transmission of pain sensation. These agents have been the cornerstone of neuraxial analgesia for surgical pain for decades, but it was not until the 1990s that they were critically evaluated for chronic pain.46


Few studies to date have sought to isolate local anesthetic efficacy in neuropathic pain.


Most research evaluating intrathecal local anesthetics have used them in conjunction with opioids. Some authors have concluded that the combination provides synergistic effects after the observation that co-administration of bupivacaine diminishes morphine dose progression during long-term intrathecal administration.47


Bupivacaine, the most commonly studied intrathecal local anesthetic, appears to US NEUROLOGY


Similar results have been reported with opioid and bupivacaine combinations in non-cancer neuropathic pain. Krames and Lanning50 found that not only did the addition of bupivacaine enhance analgesia, but its opioid-sparing effects also resulted in decreased adverse effects (mean follow-up 28 months). In a retrospective cohort study conducted in 109 patients with FBSS or metastatic cancer of the spine, Deer et al.51 found that the combination of opioid and bupivacaine provided superior analgesia, lower (23 %) opioid and adjuvant requirements, and greater patient satisfaction than intrathecal opioids alone. In addition, those who received combination treatment required fewer doctor and emergency room visits.


In therapeutic concentrations, local anesthetics are relatively non-toxic and disrupt neurotransmission in a predictable fashion. The dose escalation of intrathecal local anesthetics is limited by adverse effects. Common adverse effects of intrathecal local anesthetics include numbness, paresthesias, weakness, and bowel/bladder dysfunction. High levels of systemic bupivacaine have been associated with cardiotoxicity, which is difficult to reverse. The incidence of adverse effects can be diminished by using combination therapy with opioids and other agents. In clinical practice, the typical range of intrathecal bupivacaine is less than 35 mg/day.


Table 2 summarizes the outcomes of prospective studies evaluating intrathecal medications for neuropathic pain.


Calcium Channel Blockers


Calcium plays a critical role in many intracellular processes, including the transmission of pain. The pro-nociceptive effects of calcium are likely attributable to several factors such as activation of second messenger systems and increased neurotransmitter release. The intracellular movement of calcium is pivotal to these processes and is regulated by several types of voltage-gated ion channels. Among the identified channel subtypes, the N-type voltage-gated calcium channel has been shown in both laboratory and animal models to have the most influence on pain transmission.52,53


Efforts to ameliorate the response to


calcium influx have centered around the intrathecal use of calcium channel blockers and have yielded the newest addition to the intrathecal armamentarium, ziconotide.


Derived from the venom of the predatory marine snail Conus magnus, ziconotide became the first calcium channel blocker approved for intrathecal use in 2004. It acts via the selective blockade of the N-type calcium channel, which is concentrated in the superficial layers of the dorsal horns, thereby downregulating the release of pro-nociceptive neurotransmitters.54


Ziconotide, marketed under the trade name Prialt® (Azur Pharma, Inc., Philadelphia, PA, US), has been shown to be effective in treating a variety of neuropathic pain conditions, including those associated with cancer, FBSS, AIDS, and trigeminal neuralgia.55


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