The search for novel analgesics: targets and mechanisms

Yaksh, Tony L.; Woller, Sarah A.; Ramachandran, Roshni; Sorkin, Linda S.

doi:10.12703/p7-56

Cited by 92 publications

(76 citation statements)

References 423 publications

(393 reference statements)

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“…5) Opioid analgesics, antidepressants, anti-arrhythmic agents, or antiepileptic drugs may be used for the treatment of neuropathic pain. [6][7][8][9] In the present case, the major painful site was the right dorsal region and consistent with that of the treated collaterals. We first thought the category of the present patient's pain might be vascular pain because the characteristics of the pain (pulsatile, dull, and worsened with breath) seemed to be that of visceral pain belonging to nociceptive pain rather than neuropathic pain.…”

Section: Discussionsupporting

confidence: 87%

“…6,7) Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system (eg, disk herniation, carpal canal syndrome, trigeminal neuralgia, or diabetic neuropathy). 5) Opioid analgesics, antidepressants, anti-arrhythmic agents, or antiepileptic drugs may be used for the treatment of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

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Intractable Back Pain After Coil Embolization of Giant Veno-Venous Collaterals in a Patient With Fontan Circulation

et al. 2017

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SummaryVeno-venous collaterals are sometimes seen in patients after the Fontan procedure. A 28-year-old female with tricuspid atresia who underwent the Fontan procedure had oxygen desaturation due to a giant veno-venous collateral. Coil embolization was performed for the collateral. After the procedure, she complained of severe back pain. Anti-inflammatory analgesics and steroids were not effective, although carbamazepine promptly relieved the intractable pain. Treatment-related pain after coil embolization for veno-venous collaterals in patients with Fontan physiology is quite rare, although cardiologists must recognize a critical condition to be differentiated from vascular occlusion. (Int Heart J 2017; 58: 298-301) Key words: Cardiac catheterization, Complication, Neuropathic pain, Total cavopulmonary connection T he complete caval-pulmonary repair of single ventricle lesions has created a whole new spectrum of systemic artery to pulmonary artery and systemic vein to pulmonary vein collaterals/fistulae. 1) These collaterals provide competition to the already precarious forward pulmonary blood flow, produce extra volume on the single ventricle, and/ or create a right to left shunt with systemic desaturation of the patient. 1) Therefore, when "Fontan" type patients undergo catheterization, cardiologists should check these lesions carefully and occlude if they exist. 1,2)Occlusion of vital structures/organs, embolization of unwanted areas, migration of devices, and hemolysis are wellknown complications of vascular occlusions.1) To the best of our knowledge, there are no previous reports regarding the refractory pain associated with the procedures of coil embolization for veno-venous collaterals in patients who underwent the Fontan operation.Here, we describe a 28-year-old female with Fontan physiology who developed intractable severe back pain after undergoing coil embolization for giant veno-venous collaterals. Carbamazepine successfully controlled the intractable pain although many other analgesic drugs failed to relieve it. Case ReportA female patient with tricuspid atresia (type Ic) initially underwent banding of the pulmonary arterial trunk at 6 months of age. The second operation had not been carried out until she was 5 years old, when the total cavopulmonary connection (lateral tunnel) was completed. She received coil embolization of a veno-venous collateral from the innominate vein to the left atrium for the first time when she was 12 years old. At that time, her peripheral oxygen saturation was at around 90%. She was referred to our hospital when she moved to our city at 26 years of age. Two years after the first visit to our hospital, a follow-up enhanced computed tomography (CT) revealed many veno-venous collaterals ( Figure 1A). Her peripheral oxygen saturation was 86% under room air. Hence, she was admitted to our hospital for embolization of the collaterals. On admission, she was well and her vital signs were as follows; blood pressure 110/70 mmHg; pulse rate 78/min; body temperature 36.5°C; an...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Intractable Back Pain After Coil Embolization of Giant Veno-Venous Collaterals in a Patient With Fontan Circulation

et al. 2017

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“…The resident glial and migrating cells (T cells, macrophages and neutrophils) in the spinal cord along with the second-order neurons are activated by the release of these substances, which in turn release a collection of pro-inflammatory and anti-inflammatory molecules to further act on the secondorder neurons activating several protein kinases responsible for the phosphorylation of several membrane bound receptors, thus initiating and maintaining the hyperexcitable state of these neurons, and further sending the nociceptive signals to higher brain centres. The second-order neurons facilitate the excitability of dorsal horn projection neurons and scheme onto raphespinal serotonergic neurons through the bulbospinal pathway which dismiss in dorsal horn neurons [24]. In Table 2, central and peripheral pain targets are shown along with their source of cell insult/stimuli and inflammatory mediators and receptors which are and may be the future targets for pain alleviation.…”

Section: Central Targetsmentioning

confidence: 99%

Analgesics: New Target and Sources

Saleem¹,

Naz²

2017

Pain Relief - From Analgesics to Alternative Therapies

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The aim of this chapter is to describe targets for analgesic drugs, including currently available target sites and possible future target sites for pain and information regarding analgesia for complete understanding of pain originating mechanism, pathways and related theories to recognize. This chapter fully describes methods for determination of analgesic effects of synthetic and natural substances by inducing pain in different models and methods of pain induction.

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“…Although the source of the pain state may be distinguishable, many clinical pain states likely reflect a combination of mechanisms; and, increasing evidence has pointed to overlapping components at the level of the primary afferent and spinal dorsal horn. These mechanisms and their associated pharmacology and biology have been extensively reviewed elsewhere [10,11]. In this discussion we will focus on the lumbar intrathecal route of drug delivery and consider: i) ongoing developments in the pharmacology of spinal therapeutics focusing on agents/targets that have been employed and shown to a varying degree to have efficacy in humans, ii) novel targeting methodologies and iii) several issues relevant to intrathecal drug delivery.…”

Section: A R T I C L E H I S T O R Ymentioning

confidence: 99%

“…It should be stressed that virtually all of the mechanistic studies defining pain processing have shown the importance of spinal systems. Accordingly, future pharmaceutical targets may likely arise from one or more of systems that have been shown to have actions on the behaviorally defined pain end point after intrathecal delivery in one of more preclinical models (see [10][11]). Several of these will be summarized below.…”

Section: Other Potential Pharmacological Spinal Targetsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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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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The search for novel analgesics: targets and mechanisms

Cited by 92 publications

References 423 publications

Intractable Back Pain After Coil Embolization of Giant Veno-Venous Collaterals in a Patient With Fontan Circulation

Intractable Back Pain After Coil Embolization of Giant Veno-Venous Collaterals in a Patient With Fontan Circulation

Analgesics: New Target and Sources

Current and Future Issues in the development of spinal agents for the management of pain

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