Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Disclosures: T. Bundy, none. Patients or Programs: A 54-year-old man with a 5-year history of persistent groin pain. Program Description: The patient was initially seen in our outpatient clinic with a chief complaint of right groin pain localized to the perineum. His pain began 5 years earlier. He first noticed pain after doing lunge exercises at the gym. Pain was described as being a constant ache that radiated down into his right testicle and was sometimes associated with numbness. The pain was made worse by sitting, even just for a few minutes, and was relieved with standing up almost immediately. The patient had 2 previous magnetic resonance imaging, which were both negative for right hip pathology. He was diagnosed with possible pudendal nerve entrapment and was referred to pain management for pudendal nerve block. The patient continued to complain of pain after nerve block and was prescribed physical therapy and an anti-inflammatory medication. Patient experienced minimal relief with these interventions and ultimately was referred to orthopedics for further evaluation. Setting: Outpatient clinic at a university hospital. Results: Magnetic resonance arthrogram of the right hip was ordered by orthopedics, and it showed 2 tears of the anterior acetabular labrum and a single tear of the superior acetabular labrum. There also was a focal zone of articular cartilage delamination along the superior-lateral aspect of the acetabular labrum. The patient ultimately underwent arthroscopic resection of acetabular labrum and pain completely resolved for approximately 3 weeks. On follow-up in our clinic, the patient stated that his pain had returned but was much less intense. Discussion: Despite having 2 previous magnetic resonance images, which were unremarkable for right hip pathology and symptoms that were consistent with pudendal nerve entrapment, this patient's pain generator was found to be from an acetabular labral tear. Conclusions: Acetabular labral tears should be considered in the differential diagnosis in the patients who are experiencing groin pain. If clinical suspicion is high, despite negative hip magnetic resonance imaging, additional diagnostic studies may be warranted.

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