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Intrathecal Drug Delivery for Neuropathic Pain


which suggests that a lower starting dose and slower titration are better tolerated.


Long-term data are scarce given the fairly recent introduction of ziconotide. In a retrospective study by Raffaeli et al.58


conducted in 104


patients who received intrathecal ziconotide for both cancer and non-malignant pain, 54 % reported at least 50 % pain relief. Patients receiving ziconotide for one year obtained stable reductions in pain (mean VAS declined from 8.5 to 5.0), suggesting that tolerance does not prominently develop with prolonged administration. Doses ranged from 0.14 to 0.21 µg/hour, with higher doses associated with increased pain relief. Although there were no reported serious adverse effects, 63 % of patients reported at least one adverse effect, with the most common being psychomotor disorders (e.g. confusion and memory impairment), weakness, and balance impairment.


performed a multicenter trial to investigate whether the addition of ziconotide to patients already receiving intrathecal opioids improved their pain relief. Twenty-six patients with refractory chronic non-malignant pain (77 % FBSS) despite intrathecal morphine use had ziconotide added to their infusion. Twenty patients completed the titration phase and 18 proceeded to an extension phase lasting up to 72 weeks. At the end of the study, subjects experienced a 17 % decrease in pain at a mean ziconotide dose of 0.077 µg/hour. All patients reported at least one adverse effect, with confusion, dizziness, and hallucinations being among the most common. However, the enhanced benefit of co-administering opioids and ziconotide must be weighed against the decreased stability of ziconotide when mixed with opioids, which is accelerated at higher concentrations. In addition to the above studies, several case reports have documented good relief for refractory facial pain with intrathecal ziconotide.60–62


Table 3


summarizes common agent-specific adverse effects. Alpha-2 Agonists


Alpha-2 adrenergic receptors have been shown to play an important role in antinociceptive effects mediated at peripheral, spinal, and brainstem sites. These receptors are concentrated near sites of peripheral nerve injury or inflammation, and their activation reduces inflammation and hypersensitivity to tactile stimuli. Several subtypes of alpha-2 receptors have been identified, but evidence from recent studies suggests that the alpha-2A and alpha-2B receptors are primarily responsible for analgesia and sedation.63,64


Alpha-2 receptor agonists


produce their spinal analgesic effects via inhibitory interactions with pre- and post-synaptic primary afferent nociceptive projections onto secondary neurons in the dorsal horn. Pre-synaptically, the binding of alpha-2 agonists results in the inhibition of neurotransmitter release. Post-synaptically, alpha-2 agonists increase potassium conductance through G-coupled channels, hyperpolarizing the cell.


Several other mechanisms underlying alpha-2 agonist-induced analgesia have been proposed, including activation of spinal cholinergic neurons, which may potentiate their analgesic effects. It has also been postulated that the antinociceptive properties of this class of medication are


US NEUROLOGY


Intrathecal infusions are increasingly composed of mixed solutions to increase efficacy and minimize adverse effects. To assess the co-administration of ziconotide with other agents, Wallace and colleagues59


Table 3: Common Agent-specific Adverse Effects Opioids16,92,93


Adverse


Ziconotide56,57,59 Adverse


Clonidine69,70 Adverse


Bupivacaine51,97 Adverse


Baclofen38,98 Adverse


Effect % Effect % Effect % Effect % Effect % Constipation 57 Dizziness 39 Hypotension 53 Transient 17 Sedation 29 weakness


Sweating 47 Nystagmus 29 Nausea/ 40 Edema 2 Hypotonia 29 vomiting


Nausea 42 Confusion 26 Sedation 33 Urinary retention 37 Fever 25 Oxygen desaturation


Vomiting 33 Hypotension 24 Dry mouth 20 Insomnia/ 28 Sedation 24 nightmares


Impotence 21 Nausea 20 Confusion 15 Abnormal 18 gait


Pruritis Edema


14 Urinary 15 retention


7 Headache 12 enhanced through the inhibition of substance P release,65 while another


recent study suggests that the antihyperalgesic and antiallodynic effects of intrathecal alpha-2 agonists are associated with a significant reduction in spinal N-methyl-D-aspartate receptor phosphorylation.66


The most studied and only US Food and Drug Administration-approved alpha-2 agonist for intrathecal use is clonidine. Intrathecal clonidine has been studied extensively in animal models and has been shown to safely alleviate neuropathic pain in a dose-dependent manner.67


In


human subjects, clonidine has been used and studied as both a bolus administration and continuous infusion. While trials have shown promise using epidural clonidine infusion as monotherapy in treating CRPS, intrathecal clonidine infusions are typically combined with a local anesthetic or opioid.68


Some studies of intrathecal clonidine infusion


have yielded mixed results and recommend further study.69 Siddall and colleagues70


conducted a double-blind, placebo-controlled


study assessing the efficacy of intrathecal clonidine, alone or combined with morphine, in 15 patients with central pain attributable to SCI. A 17 % reduction in pain was observed in the group receiving intrathecal clonidine monotherapy compared with no change in the saline control group four hours post-administration. The group receiving combination intrathecal clonidine and morphine reported a 37 % reduction in pain scores. Eisenach and colleagues71


compared the effects of intrathecal


versus intravenous (IV) clonidine in normal volunteers in the setting of capsaicin injection, which produces pain, hyperalgesia, and allodynia. The IT but not IV injection of 150 µg clonidine reduced capsaicin-induced pain, pain to heat stimulation, and hyperalgesia. The groups did not differ in hemodynamic or sedative effects.


There is no evidence that intrathecal clonidine is neurotoxic, and it does not cause respiratory depression. The most common adverse effects of clonidine are hypotension, sedation, bradycardia, and nausea. The hypotension associated with clonidine administration may be more pronounced at lower doses, since at higher doses this effect


159


Hallucinations 5 Speech difficulty


3 33 Urinary retention Dysphagia 5 9


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