Spinal Drug Delivery

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During the past 15 years, the use of intraspinal drug delivery to treat chronic and cancer-related pain has increased. The use of implanted pumps for long-term subarachnoid delivery of drugs is safe and efficacious. Compared with an oral medical regime, selective spinal analgesia offers specific benefits, such as improved pain relief, improved lifestyle, and reduced side-effect profile. Patients currently receiving oral medication who experience dose-limiting side effects or uncontrolled pain, for example, may be good candidates for intraspinal drug delivery. This could indicate acute injections of steroids or chronic infusions of analgesics via an implanted pump.

Epidural Steroids

The epidural injection of corticosteroids has been used successfully to reduce nerve root irritation and inflammation. This injection can be performed in the neuraxis, where the injection bathes the spinal cord and neighboring nerve roots in the pathological area. Another approach is the transforaminal epidural injection (see Fig. 7). Here, the responsible nerve roots are identified and selectively targeted to receive epidural steroids.

Patients with symptoms limited to specific nerve roots benefit from transforaminal epidural injections. One prospective, randomized study found a success rate of 84% after 1.4 years of treatment with transforaminal epidural steroid injections vs 48% after treatment with saline trigger point injections for lumbosacral radiculopathy arising from a herniated nucleus pulposus (39). Similarly good results were reported for degenerative lumbar spinal stenosis; 75% of 34 patients reported a 50% reduction in pain scores after an average of 1.9 injections (40).

Many studies have been performed to delineate the population best treated with epidural steroid therapy. Hopwood and Abram, for example, have shown that treatment of nonradicular pain that had persisted longer than 24 months had a threefold increase in treatment failure. Factors that enhanced the possibility of a favorable outcome included pain for less than 6 months, radiculopathy, and advanced patient education. Failure factors consisted of sleep disturbance, constant pain, and unemployment (secondary to the pain symptoms) (41,42). Sandrock and Warfield found that the positive outcome of epidural steroid injections is determined by successful diagnoses of nerve root inflammation, no history of surgery in the area, symptoms of short duration, younger patient age, and needle placement at the level of pathology (43).

Fig. 7. Lateral view of transforaminal block.

There is obviously no consensus, but these results do indicate that outcome is related to nerve root irritation, recent onset of symptoms, and absence of psychological factors. Patients with herniated discs, spondy-lolisthesis, scoliosis, spinal stenosis (to a limited degree), and degenerative disc disease also seem to benefit.

Intrathecal Therapy

Multiple spinal cord receptors and compounds play a role in the transmission of pain along various pathways to the brain. Pharmaceuticals can be administered to alter the behavior of some of these neurotransmitters, but the ideal agent or combination of agents for use in intrathecal pain therapy has not been discovered.

Preservative-free morphine is the only analgesic approved for the intrathecal treatment of chronic pain by the US Food and Drug Administration (FDA). Thus, morphine is the agent most widely used intrathecally, but it might not be suitable for long-term use because patients may become tolerant of the effects of the drug and require escalated doses, which in turn could increase side effects to intolerable levels.

In a series of 120 patients treated with intrathecal morphine for non-malignant pain, Winkelmüller and Winkelmüller found that 92% of the patients were satisfied, 81% reported improved quality of life, and 67% had pain reduction at 6-month follow-up (44). In another large series, Paice et al. conducted a multicenter investigation involving 35 physicians and found that 95% of 429 patients (289 with nonmalignant pain) had good-to-excellent results (45).

Physicians have begun to use many other drugs intrathecally despite a lack of data on neurotoxicity, effect on pump stability, or efficacy (46). Agents used for cancer pain include hydromorphone, methadone, fenta-nyl, P-endorphine, D-ala2-D-leu5-enkephalin, dynorphin, midazolam, clonidine, bupivacaine, ketamine, octreotide, neostigmine, and aspirin. The drugs commonly used for chronic noncancer pain are meperidine, midazolam, clonidine, bupivacaine, octreotide, and aspirin. Neuropathic pain is treated with sufentanil, baclofen, clonidine, 3-(2-carboxy-piperazin-4-yl)-propyl-L-phosphonic acid, and ^-phenyl isopropyl adenosine. Adding bupivacaine or clonidine to intrathecal opioids can reduce pain and prevent the necessity of increasing the opioid dose.

Although morphine is the only drug approved by the FDA for intrathecal administration for pain, multiple agents are considered safe and are used when morphine fails (47) (see Fig. 8). Some new agents (e.g., ziconotide, a synthetic neurotoxin based on the venom of a marine snail) may prove administrable only via intrathecally (48). Studies are under way to determine the effectiveness and safety of using ziconotide to treat cancer pain and neuropathic pain.

Investigators are trying to determine the degree that pain treatment with intrathecal opioids enhances comprehensive medical management. In one randomized study, intrathecal therapy unexpectedly improved the survival of terminal cancer patients significantly, possibly by diminishing pain or by reducing the occurrence of drug toxicity. Patients with cancer pain randomly assigned to intrathecal therapy had marked reduction in pain, toxicities, and, in fact, survival. Patients and family members (caregivers) reported improved quality of life.

Intrathecal drugs may be delivered using a programmable pump or a constant-rate spinal infusion pump, which is not programmable. The constant-rate pump has only two basic variables: the size of the reservoir (which must be chosen before implantation) and the concentration of drug administered (which can be varied after implantation) (see Fig. 9A,B). The programmable pump, in contrast, allows clinicians to alter flow rate (see Fig. 9C). Unlike the programmable pump, in which batteries must

Fig. 8. Treatment algorithm for intrathecal medications.
Fig. 9. (A) Advanced Neuromodulation Systems AccuRx constant rate intrathecal pump. (Image courtesy of Advanced Neuromodulation Systems, Inc., used with permission.) (B) Arrow International constant rate intrathecal pump. (Image courtesy of Arrow International, used with permission).

be replaced every 5 to 7 years, the constant-rate spinal infusion pump does not require a battery. The larger reservoirs in constant-rate pumps can lead to longer intervals between refills.

Under investigation are ways of delivering drugs intrathecally without using a pump. These methods include injecting a sustained-release formulation, allografting catecholamine-producing cells intrathecally, and

Fig. 9. (C) Medtronic SynchroMed EL programmable intrathecal pump. (Image courtesy of Medtronic, Inc., used with permission.)

delivering a P-endorphin gene to the spinal cord using an adenovirus as the vehicle.

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