Spinal mechanisms of pain and analgesia.

Chronic pain--especially that which is refractory to conventional treatment--presents particular challenges to physicians and patients. Examination of the molecular and cellular mechanisms involved in this pathophysiology suggests that spinal instillation of therapeutic agents may offer an effective treatment option through the modification of the processing and sensation of chronic pain. Intrathecal therapy, used alone or in combination with other analgesic agents, may reduce chronic pain by attenuating both pre- and postsynaptic activities. This article reviews chronic pain pathophysiology and the mechanisms whereby spinally administered analgesics may modify chronic pain. Available treatment options are also considered, including recommendations from the 2007 Polyanalgesic Consensus Conference (PACC) guidelines on the use of intrathecal agents for nociceptive, neuropathic, and mixed pain.

Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog.

BACKGROUND AND PURPOSE: Ziconotide is a peptide that blocks N-type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and infused ziconotide in dog. EXPERIMENTAL APPROACH: Male beagle dogs (N= 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest-mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi (3) H-inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T(1/2-α/ß) = 0.14 and 1.77 hours, and inulin T(1/2-α/ß) = 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48-hour infusions. Terminal elimination T(1/2) after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48-hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance. CONCLUSIONS AND IMPLICATIONS: After IT bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.

Neuroprotective and cardioprotective conopeptides: an emerging class of drug leads.

The peptides in the venoms of predatory marine snails belonging to the genus Conus ('cone snails') have well-established therapeutic applications for the treatment of pain and epilepsy. This review discusses the neuroprotective and cardioprotective potential of four families of Conus peptides (conopeptides), including omega-conotoxins that target voltage-gated Ca2+ channels, conantokins that target NMDA receptors, mu-conotoxins that target voltage-gated Na+ channels, and kappa- and kappaM-conotoxins that target K+ channels. The diversity of Conus peptides that have already been shown to exhibit neuroprotective/cardioprotective activity suggests that marine snail venoms are a potentially rich source of drug leads with diverse mechanisms.