Emerging targets in treating pain.

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Emerging targets in treating pain David S. Chang a, Rahul Raghavan a, Sandy Christiansen b, and Steven P. Cohen c

Purpose of review To provide an overview on drug targets and emerging pharmacological treatment options for chronic pain. Recent findings Chronic pain poses an enormous socioeconomic burden for the more than 30% of people who suffer from it, costing over $600 billion per year in the USA. In recent years, there has been a surge in preclinical and clinical research endeavors to try to stem this epidemic. Preclinical studies have identified a wide array of potential targets, with some of the most promising translational research being performed on novel opioid receptors, cannabinoid receptors, selective ion channel blockers, cytokine inhibitors, nerve growth factor inhibitors, N-methyl-D-aspartate receptor antagonists, glial cell inhibitors, and bisphosphonates. Summary There are many obstacles for the development of effective medications to treat chronic pain, including the inherent challenges in identifying pathophysiological mechanisms, the overlap and multiplicity of pain pathways, and off-target adverse effects stemming from the ubiquity of drug target receptor sites and the lack of highly selective receptor ligands. Despite these barriers, the number and diversity of potential therapies have continued to grow, to include disease-modifying and individualized drug treatments. Keywords analgesia, chronic pain, drug discovery, neuropathic pain, nociceptive pain

INTRODUCTION Economic burden The epidemic of chronic pain poses significant personal and economic ramifications that transcend geographic and cultural boundaries. Among the four leading causes of years lost to disability, three are chronic pain conditions: low back pain (LBP), which represents the leading cause of disability; musculoskeletal disorders which rank third, and neck pain, which is fourth [1]. In a 2010 report, the Institute of Medicine estimated that chronic pain afflicts one out of three Americans, costing between $560 and $635 billion [2]. Not surprisingly, the spectrum of LBP disorders comprises one of the principal health economic burdens worldwide, with an estimated in cost in the USA exceeding $100 billion per year. [3,4].

Classification Unlike acute pain, which is an evolutionary tool designed to warn the body of ongoing or impending injury, chronic pain is generally considered a disease unto itself. There are several other ways to categorize pain, the most useful being by type. Nociceptive pain, which includes inflammatory and mechanical

causes, is the pain that arises from injury to nonneural tissue, whereas neuropathic pain is defined as the pain that results from a disease or lesion affecting the somatosensory system [5 ]. Several instruments have been designed to facilitate classification of chronic pain into nociceptive (e.g. arthritis), neuropathic (neuropathy), or mixed (failed back surgery syndrome), with two of the most common being painDETECT and self-completed Leeds Assessment of Neuropathic Symptoms and Signs pain scale (s-LANSS) [6,7]; however, physician designation based on clinical presentation remains the reference standard. The distinction between different types of pain is important because it affects prescribing &&

a Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, bAnesthesiology, MedStar Georgetown University Hospital, Washington, District of Columbia and c Anesthesiology and Physical Medicine & Rehabilitation, Johns Hopkins School of Medicine and Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

Correspondence to Steven P. Cohen, 550 North Broadway, Suite 301, Baltimore, MD 21205, USA. Tel: +1 410 955 1822; fax: +1 410 614 7592; e-mail: [email protected] Curr Opin Anesthesiol 2015, 28:000–000 DOI:10.1097/ACO.0000000000000216

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www.co-anesthesiology.com

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.


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KEY POINTS Chronic pain is a disease unto itself with a tremendous worldwide economic impact. Currently available pain therapeutics suffer from a high incidence of adverse effects and limited efficacy. Our understanding of the pathophysiological mechanisms underlying chronic pain continues to evolve as does the identification of potential targets.

habits and other treatment decisions (Fig. 1) [5 ,8 ]. It is generally acknowledged that the mechanism-based treatment of pain results in better outcomes compared to disease or etiologic-based treatment, yet in clinical practice, this is extremely difficult to implement [9]. In patients with chronic pain, approximately 15–25% have a neuropathic cause [10–12] (Fig. 1). &&

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Medical need The pharmacological treatment of chronic pain is characterized by high failure rates and side-effects. For example, in neuropathic pain, the numberneeded-to-treat (NNT) for one person to obtain benefit ranges from around 3 for tricyclic antidepressants (TCA) to over 5 with gabapentinoids – both first-line treatments. For nociceptive pain, NSAIDs and antidepressants work in similar proportions of individuals. Calculating NNTs is confounded by the fact that a large proportion of negative trials, particularly those sponsored by industry, are never published [13]. The translation from animal models to clinical trials is characterized by failure rates that exceed 90%, and for many conditions such as mechanical LBP or herniated discs, there are no widely accepted pain models. Even in individuals who respond to treatment, there is often room for further improvement. Clinical studies have determined that 30% pain relief constitutes clinically meaningful benefit [14], and most drugs that receive US Food and Drug Administration (FDA) approval for chronic pain demonstrate differences of between 10 and 20% above placebo. This has led to increasing use of combination drug therapy for chronic pain, which may provide better relief than single-agent therapy, but is generally associated with more adverse effects [15].

TARGETS Opioid receptors In the effort to find opioid analgesics that are safer and better tolerated than classic mu opioid agonists, 2


drug research has focused on strategies to identify potential targets that provide a larger therapeutic index. Kappa agonism Preclinical studies of kappa opioid receptor activation have demonstrated a consistent analgesic effect, particularly in the treatment of visceral pain, as well as the absence of common mu-associated side-effects such as euphoria/addiction, respiratory depression, constipation, or withdrawal [16]. Despite promising clinical data in which the kappa agonist enadoline demonstrated equianalgesic efficacy compared to morphine for postoperative pain, systemic administration has been limited by a high incidence of neuropsychological effects such as sedation and dysphoria [16]. Therefore, focus has shifted to development of peripherally restricted kappa agonists. Kappa-mediated antinociception appears to be predominantly peripherally mediated since it is reversed by peripherally restricted opioid antagonists, and systemic and peripherally restricted kappa agonists demonstrate equivalent antinociceptive effects [17]. In terms of drug development, Cara Therapeutics has two peripherally selective kappa agonists in their drug development pipeline [18]. In a small double-blind study performed in healthy humans, the intravenous (i.v.) administration of compound CR665 demonstrated efficacy for visceral pain secondary to esophageal distension [19]. In a phase II trial performed following hysterectomy, i.v. CR845 was associated with a significant decrease in opioid consumption and pain scores for 24 h [20]. According to the company website, oral formulations of CR845 have completed phase I trials with plans to pursue phase II testing in 2015 [18]. Kappa antagonism The kappa receptor is implicated in mechanisms that decrease the analgesic efficacy of traditional mu-opioid agonists. Preclinical pain models involving sustained activation of spinal mu-opioid receptors demonstrate that opioid-induced hyperalgesia and opioid tolerance is a process mediated by the endogenous kappa receptor agonist, dynorphin, and reversed by kappa opioid antagonism [21]. Clinically, buprenorphine is a commercially available analgesic, described in literature as a kappa receptor antagonist with mu, delta, and opioid receptor-like receptor 1 (ORL-1) receptor agonist activity that may hold potential as a pain treatment for people with hyperalgesia and those on long-term opioid therapy. Despite earlier misconceptions regarding a ceiling effect for analgesia, buprenorphine acts clinically like a full mu opioid agonist in animal and human models of both cancer and neuropathic pain. Buprenorphine Volume 28 Number 00 Month 2015



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Emerging targets in treating pain Chang et al.

Cortex Pain perception and amplification Cognitive behavioral therapy Placebo Motor cortex stimulation

Brain

Thalamus

Brainstem

Periaqueductal gray

Midbrain

Medulla Rostroventral medulla Reticular formation

Descending modulation Spinal cord

Antidepressants Opioids, tramadol Muscle relaxants Acupuncture Cannabinoids Motor cortex stimulation Deep brain stimulation

Dorsal root ganglion Synaptic transmission and central sensitization Anticonvulsants Adrenagic agonists Opioids NMDA blockers (such as ketamine) Epidural/intrathecal analgesia Spinal cord stimulation Nerve growth factor inhibitors Cytokine inhibitors Muscle relaxants Cannabinoids

Patient with postherpetic neuralgia Peripheral stimulation, transduction, transmission, and amplification Topical agents Epidural steroids Anticonvulsants Antidepressants Cannabinoids Anti-inflammatory drugs Local anesthetic/nerve blocks Cytokine inhibitors Nerve growth factor inhibitors

FIGURE 1. Schematic drawing demonstrating the site(s) of action of different analgesics. Reproduced with permission from [4 ]. &&

activity is largely mediated at the level of the spinal cord, explaining its lower propensity of respiratory depression as well as its superior antihyperalgesic properties in experimental human pain models [22,23].

Opioid heteromers Studies of opioid receptor subtypes have revealed the formation of functional heteromers (associations between different receptor subtypes) with distinct ligand binding properties and intracellular



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signaling [24]. Among these, the mu-delta opioid receptor heteromer has generated the greatest interest as a potential pain therapeutic target [25 ]. Nascent studies have shown endogenous expression of heteromers in key areas of pain processing such as the dorsal root ganglia (DRG) and rostral ventral medulla (RVM). Despite evidence that prolonged opioid exposure stimulates the recruitment of delta opioid receptors to the cell surface and increases the level of opioid receptor heteromers [26], the precise role of heteromers in pain processing remains unknown [25 ]. Based on studies demonstrating the colocalization of the cannabinoid CB1 and mu opioid receptors, some researchers have hypothesized the existence of a CB1-mu opioid receptor heteromer [24]. &

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Opioid receptor-like receptor 1 Opioid receptor-like receptor 1, also known as nociceptin receptor (NOP), is a G-protein-coupled receptor (GPCR) that shares 60% sequence homology with classical opioid receptors (mu, delta, and kappa). Initially described as an orphan receptor without an endogenous ligand in 1994 [27], the following year, different investigative teams identified the endogenous ligand, nociception/orphanin FQ peptide (N/OFQ) in the first example of reverse pharmacology (deorphanization) [28,29]. Successive studies have revealed widespread central nervous system (CNS) expression, with receptor activation yielding a range of physiological effects, including analgesia, hyper or hypolocomotion, anxiolysis, circadian rhythm alterations, thermoregulatory disturbances, learning impairment, opioid withdrawal, and reward pathway alterations [30]. Despite structural similarities with classical opioid receptors, ORL-1 is insensitive to naloxone [31]. ORL-1 is coupled to inhibitory G-proteins, and activation by its endogenous ligand N/OFQ results in adenylyl cyclase inhibition and suppressed cAMP formation, as well as the closure of voltage-gated Ca2þ channels and opening of inward rectifying Kþ channels, ultimately reducing neuronal excitability [32–35]. In preclinical studies, N/OFQ-mediated ORL-1 activation has been demonstrated to modulate a range of neurotransmitter systems resulting in glutamate, catecholamine, and tachykinin inhibition [36–38]. Although the initial characterization demonstrated a hyperalgesic effect after intracerebroventricular administration [28], subsequent studies have highlighted a more complicated role in which the effect on pain processing is dependent on the site of administration, as well as the duration of nociceptive input [31,39]. For 4


example, supraspinal N/OFQ is pronociceptive [40,41], whereas spinal administration exerts an antinociceptive effect [42,43]. The supraspinal pronociceptive action is due to a net negative effect on descending inhibitory control. The analgesic spinal mechanism occurs via the inhibition of neurotransmitter release [31,40,43,44] and is naloxone-insensitive [45,46]. Rizzi et al. [39] studied the effects of systemic pharmacological antagonism in the formalin test, where both knockout mice and mice treated with systemic NOP receptor antagonists exhibited increased nociceptive behavior, indicating that NOP receptor’s spinal antinociceptive action has a relatively greater role in pain processing. Rizzi et al. [39] also demonstrated that endogenous NOP receptor signaling is only active and modifiable during tonic and not acute nociceptive input. Existence of a peripheral mechanism of action has also been demonstrated in animal models, with decreased nociception after peripheral NOP activation [47–49]. Additional studies have identified several potential adverse effects directly related to NOP activity including hypolocomotion, ataxia, memory impairment, and hypothermia [50]. Several knockout and NOP receptor antagonism models have demonstrated a decreased propensity to develop morphine tolerance [51–53], and supraspinal NOP receptor antagonism potentiated the analgesic effects of systemic morphine in opioidtolerant mice [54]. Therefore, the co-administration of an NOP receptor antagonist and a mu-opioid receptor agonist could potentially result in greater analgesic benefit and reduced tolerance and sideeffects [31]. Buprenorphine — a long-acting agonist– antagonist opioid analgesic that is used for moderate to severe pain – has been noted to possess an agonist effect at the ORL-1 receptor in addition to its mu and kappa effects [55,56]. At present, the development of NOP-selective ligands for pain is mostly preclinical. Nonetheless, at least two compounds have reached clinical stages of development, with each containing multiple receptor affinities. Lowselectivity NOP antagonist JTC-801 with overlapping mu-opioid activity (Japan Tobacco Inc., Tokyo, Japan) has been used in phase I and phase II trials for pain, but no published data are available [31]. Cebranopadol (GRT-6005; GRT-6005/06), also a low-selectivity NOP agonist with overlapping mu-activity, is under development by Gruenenthal. On the basis of available clinical trial databases, there are six completed and one ongoing phase II trials for postoperative pain, neuropathic pain, osteoarthritic pain, and chronic LBP, as well as one ongoing phase III trial for cancer pain [57 ]. &

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Serotonin, norepinephrine, and/or dopamine reuptake inhibition Preclinical studies have illuminated descending modulatory pain circuits stretching from the periaqueductal gray area (PAG) through the rostral ventromedial medulla (RVM) to the spinal cord [58]. Antidepressants are believed to potentiate these descending inhibitory pathways [59]. A recent Cochrane review on antidepressants concluded that they can be efficacious and well tolerated in a variety of neuropathic pain conditions. TCAs had the most robust data, with a calculated NNT of 3.6 [95% confidence interval (CI) 3–4.5] and a relative risk (RR) of 2.1 (95% CI 1.8–2.5) based on 17 studies. Serotonin and noradrenaline reuptake inhibitor, venlafaxine, had similar efficacy (NNT 3.1, 95% CI 2.2–5.1) across three studies, with an RR of 2.2 (95% CI 1.5–3.1). Additional studies performed in patients with diabetic neuropathy and postherpetic neuralgia demonstrated good efficacy, with NNTs of 1.3 and 2.7, respectively. The authors also concluded that there was limited evidence for the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in neuropathic pain [60]. A more recent guideline for the treatment of neuropathic pain included three randomized controlled trials evaluating the SNRI duloxetine, which demonstrated significant pain relief relative to placebo, with a combined NNT of 5.0 [61 ]. Of note, duloxetine was the only antidepressant effective in the management of chemotherapy-induced neuropathic pain, though it was ineffective in patients with central pain due to cord injury or stroke [61 ]. In general, antidepressants exhibit positive results in most peripheral neuropathic pain conditions, but have not consistently demonstrated efficacy in central pain disorders, phantom limb pain, HIV neuropathy, and chemotherapy-induced neuropathic pain [62]. For the treatment of chronic LBP, which often possesses both neuropathic and nociceptive components, the SSRIs paroxetine and trazodone failed to demonstrate efficacy compared to placebo, whereas TCAs exhibited slightly more efficacy than placebo in two out of three recent meta-analyses [63]. In three Eli Lilly-sponsored randomized controlled clinical trials performed in patients with chronic musculoskeletal LBP, duloxetine yielded significant reductions in pain compared to placebo [64–66]. In patients with osteoarthritis, three randomized controlled trials demonstrated significant pain reductions [67–69]. For fibromyalgia, 2012 guidelines coordinated by the German Interdisciplinary Association for Pain Therapy recommended the use of amitriptyline and duloxetine [70]. Similarly, a 2011 mixed treatment comparison meta-analysis &&

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supported the use of duloxetine and milnacipran, which along with pregabalin, are the only current US FDA-approved medications for fibromyalgia. This analysis also questioned previous metaanalyses which found amitriptyline to be superior to duloxetine and milnacipran in treating pain, sleep disturbance, and fatigue, on the basis of high risk for potential bias and poor methodological quality [71].

Histamine receptors Histamine receptors are found throughout the body including the nervous system, and histamine signaling can enhance the pain response [72,73]. The H3 receptor subtype (H3R) is an inhibitory autoreceptor located on both pre and postsynaptic neurons [74]. Activation of H3Rs in the skin via Ab fibers reduces calcitonin gene-related peptide (CGRP) and substance P release, leading to an anti-inflammatory response [75]. In the spinal cord, H3R activation reduces the nociceptive response to mechanical and inflammatory stimuli [76]. In the brain, histamine reduces nociceptive transmission via H1 and H2 receptors [77]. Supraspinal blockade of H3Rs increases neuronal histamine release and provides pain relief [78]. Several different H3R ligands have been used to study the receptor role in pain. Of special interest are immepip (an H3 agonist), and the H3 antagonists thioperamide and GSK189254 [79–81]. Immepip has been shown to attenuate tail pinch (mechanical) responses in rats, but neither tail flick nor hot plate reflexes were affected [73]. These responses are reversed by thioperamide [72]. Interestingly, intraventricular injection of thioperamide has been shown to increase the nociceptive threshold in a partial nerve-ligation model, whereas systemically administered H3R antagonists are pro-nociceptive [82]. In animals, GSK189254 was efficacious in reducing neuropathic pain induced by sciatic nerve chronic constriction injury and varicella-zoster [81]. Further study has revealed a dose-dependent reversal of mechanical allodynia induced by spinal nerve ligation that is comparable to gabapentin [83]. Future goals involve developing H3 antagonists that have good brain-penetrating properties and diminished systemic effects [84].

Alpha 2 receptor agonists Alpha 2 adrenergic receptors (a2-AR) are located on primary afferent nerves, dorsal horn neurons, and within pain processing brainstem nuclei; they possess both peripheral and central antinociceptive



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effects. Mechanistically, a2-ARs are G-proteincoupled and operate through a cAMP-mediated pathway. a2-AR activation is also linked to diminished neurotransmitter release through direct regulation of voltage-gated calcium ion channels [85]. a2-ARs are classified into three subtypes: a2a-AR, a2b-AR, and a2c-AR. Studies involving knockout models have demonstrated that a2a-AR is likely to be the dominant subtype in painprocessing pathways, as well as the primary mediator of cardiovascular and sedative effects. Due to a lack of selective pharmacological tools, more precise distinctions of the functions and/or contributions of each a2-AR subtype have yet to be delineated [86,87]. Proposed mechanisms for the peripheral and central antinociceptive effects include C-fiber hyperpolarization and blockade, and cross-reactivity and co-dependence between the a2-AR, mu-opioid receptor, and A1-adenosine receptor [88]. Spinal a2-AR-mediated analgesia comprises both pre and postsynaptic elements. Presynaptic receptor activation decreases the excitability of primary afferent nerve terminals and inhibits presynaptic C-fiber neurotransmitter release, whereas postsynaptic receptor activation leads to membrane hyperpolarization and a subsequent decrease in pain signal transmission [89]. Supraspinal antinociceptive mechanisms involved in a2-AR-mediated analgesia remain controversial, as direct stimulation of supraspinal brainstem loci have yielded both positive and negative results in preclinical pain models [86]. Preclinical models have demonstrated that periaqueductal gray area (PAG) descending inhibition of dorsal horn nociceptive transmission is at least partly mediated by a2-AR activation [89]. A small study involving the transdermal application of a clonidine patch in patients with sympathetically maintained neuropathic pain found that pain relief was confined to the skin region beneath the patch, suggesting a peripheral analgesic effect [90]. However, a number of findings point to the spinal cord as the primary locus of analgesic effects, including a strong correlation between analgesic effect and cerebral spinal fluid (CSF) agonist concentration in healthy human volunteers [91]. There are two US FDA-approved a2-AR agonists, clonidine and dexmedetomidine. Clonidine is a nonselective a2-AR agonist that has been studied in acute, chronic, nociceptive, and neuropathic pain populations, as well as across a variety of routes of administration, including intravenous, oral, transmucosal, intramuscular, and neuraxial [86]. In chronic pain populations, a number of small prospective studies with intrathecal clonidine have 6


been conducted [92]. A double-blind, placebocontrolled study by Siddall et al. in patients with spinal cord injury who received intrathecal clonidine and morphine found that both drugs in combination provided significantly better pain relief than placebo or either drug alone [93]. A number of other studies in patients with cancer pain and LBP involving the use of clonidine, typically with morphine, also demonstrated significant pain relief [92]. In an attempt to assess the long-term benefits of intrathecal clonidine for chronic pain states, a small retrospective study by Ackerman et al. [94], consisting of 15 patients with various chronic pain diagnoses, found limited therapeutic value, as the duration of relief typically lasted less than 18 months and included the presence of myriad side-effects including sedation and hypotension. Depression, insomnia and night terrors have also been reported with intrathecal clonidine use [95]. The most recent consensus statement regarding intraspinal therapy for chronic pain recommend intrathecal clonidine in combination with morphine, and clonidine alone as second and third-line therapies, respectively [95]. A review of clonidine in a 2014 review found the drug was beneficial in an array of neuropathic pain populations, including diabetic neuropathy and complex regional pain syndrome [96 ]. Dexmedetomidine is a newer a2-AR agonist with a shorter duration of action and eight times greater a2a-AR subtype selectivity. No studies have been conducted in chronic pain; however, a number of studies evaluating its systemic use in postoperative patients found no change in pain scores despite opioid-sparing effects [86]. Due to the possibility of neurotoxic effects, the neuraxial and perineural use of dexmedetomidine has been limited, though isolated studies evaluating it as an adjunct to epidural, spinal, and regional anesthesia have reported significant benefit [97–99]. &

Cannabinoid receptor Cannabis preparations have been used therapeutically in medicine for thousands of years [100,101], but clinical trials evaluating cannabis preparations and several synthetic analogs have yielded only modest success in the treatment of pain. For nociceptive pain, cannabinoids have shown limited effectiveness, and in some cases, elicited a hyperalgesic effect [102–105]. For neuropathic pain, a 2011 systematic review of 18 RCTs totaling 766 participants reported that cannabinoids were modestly effective in the treatment of neuropathic pain compared to placebo, with preliminary efficacy also shown for fibromyalgia and rheumatoid arthritis Volume 28 Number 00 Month 2015



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[106]. These results were tempered by a 2009 metaanalysis involving pooled data from 18 RCTs which expressed concern regarding odds ratios (ORs) greater than 4 for a number of adverse events including cognitive and motor function impairment, alterations in perception, and isolated reports of acute psychosis and addiction [107]. Additional studies also found a connection between chronic use and the subsequent development of schizophrenia and mood disorders [108,109]. Fortunately, advancements in our understanding of the endogenous cannabinoid system provide an opportunity to enhance the therapeutic index. The cannabinoid system has two principal receptor subtypes: CB1 and CB2. The CB1 receptor is abundant within the central and peripheral nervous system, whereas the CB2 cannabinoid receptor is primarily expressed by lymphatic immune cells, although neuroinflammation following injury to neurons can induce CB2 expression in both central and peripheral nervous systems [110–112]. Both CB1 and CB2 are GPCRs that inhibit adenylyl cyclase [113,114]. The two main ligands of the endogenous cannabinoid system are 2-arachidonoyl glycerol (2-AG) and anandamide (AEA), which are derivatives of arachidonic acid [115]. Their duration of action is generally short due to robust metabolic pathways in which both substances are catabolized to arachidonic acid [116]. AEA has also been shown to activate pro-nociceptive vanilloid 1 receptors present on primary afferent nociceptive fibers [117]. CB1 receptors found on presynaptic neurons are activated in the presence of excess neurotransmitter release, providing negative feedback. This signaling is present at both excitatory (glutamate) and inhibitory [gamma-aminobutyric acid (GABA) and glycine] nerve terminals and is implicated in hyperalgesia and antinociception [115,118]. Studies have indicated a state-dependent effect in which high levels of nociceptive input provoke pronociceptive actions of endocannabinoids, and low levels produce predominantly antinociceptive effects [119,120]. In preclinical studies, CB1 agonism has been shown to elicit a largely antinociceptive effect. CB1 receptors demonstrate significant analgesic effects at both spinal and peripheral sites, as well as in inflammatory, neuropathic, and cancer-related pain models [110,121]. Despite robust preclinical data, clinical introduction of CB1-targeted pain therapies has been limited by adverse effects including sedation and intoxication [122 ]. Peripherally restricted CB1 agonists have demonstrated antinociceptive properties in animal models of inflammatory and neuropathic pain; however, clinical trials have achieved only limited success [122 ]. A 2013 &

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placebo-controlled study investigating the effects of AZD1940 – a peripherally restricted CB1/CB2 receptor agonist – demonstrated no analgesic efficacy for capsaicin-induced pain [123]. CB2 expression is inducible in pathologic states, and up-regulated in microglial cells and the spinal cords in neuropathic pain models [111,124,125]. CB2 receptors are also found on postsynaptic neurons in the setting of neural injury [126]. Peripheral administration of the endogenous cannabinoid AEA into the rat hindpaw was found to reverse inflammatory pain due to intraplantar injection of carrageenan – an effect abolished by peripheral CB2, but not CB1 receptor antagonism [117]. In animal models of neuropathic pain, AM1241, a highly selective CB2 agonist, reversed tactile and thermal hypersensitivity produced by spinal nerve ligation in rats. These effects were successfully antagonized by CB2, but not CB1 receptor antagonism, and preserved in mice lacking CB1, suggesting that neuropathic pain inhibition can be produced by the actions of AM1241 at CB2 receptors [127]. In addition to its ability to inhibit neuropathic hypersensitivity, AM1241 has been shown to be antiinflammatory and efficacious against acute pain [116,128–130]. However, despite large investment from the pharmaceutical industry in targeting CB2 receptors, with at least 50 patents published between 2009 and 2012, clinical efficacy has yet to be established [131]. Targeting metabolic inhibitors has also failed to deliver any clinically efficacious compounds. Confounding their analgesic effect is the observance of analgesic tolerance in the endogenous cannabinoid system following chronic administration of cannabinoid-hydrolyzing enzyme inhibitors, as well as the generation of pronociceptive compounds when accumulated endocannabinoids are diverted to other hydrolyzing enzymes [132,133]. Utilization of CB1 antagonists and inverse agonists in combination with CB1 and CB2 receptor agonists has the potential to improve their therapeutic index. CB1 antagonists themselves have shown analgesic effects in animal models of inflammatory arthritis and hyperalgesia, with a concomitant reduction in CNS side-effects [134,135 ]. Their mechanism of action is believed to be the diversion of endogenous cannabinoids away from CB1 receptors, leading to increased CB2 receptor activation and transient receptor potential vanilloid type 1 (TRPV1) receptor desensitization. However, with the removal of antiobesity CB1 receptor antagonist, Rimonabant, from market in 2008 due to a high incidence of psychiatric effects, enthusiasm surrounding this approach has waned [122 ].


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Ion channels

temperature have [156 ,158,162,163].

entered

preclinical

testing

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Vanilloid receptor 1 The vanilloid receptor or TRPV1 receptor is a homotetrameric, nonselective cation channel highly expressed on nociceptive C and A-delta fibers in dorsal root (DRG) and trigeminal ganglia [136–139]. TPRV1 responds to a variety of endogenous ligands, changes in pH (428C), and membrane depolarization. Receptor activation results in Naþ and Ca2þ ion movement into cells [140–142]. Transient receptor potential vanilloid type 1 is up-regulated during inflammation [143–146], and TRPV1 knockout mice display reduced thermal hypersensitivity after inflammation [147,148]. Agonists such as capsaicin – the active ingredient in hot chilli peppers – and the vanilloid analog, resiniferatoxin (RTX), desensitize TRPV1 channels, and are antinociceptive in animal models of inflammatory, neuropathic, and cancer pain [139,149,150]. However, systemic administration in humans is associated with a high incidence of side-effects (e.g. high blood pressure, respiratory effects). Therefore, TRPV1 agonist development has focused on local delivery mechanisms [151]. Topical formulations are available over the counter and are effective in treating peripheral neuropathic pain [5 ], but did not benefit patients with interstitial cystitis and painful bladder syndrome [151]. Alternatively, high-dose site-specific therapy has shown positive pain relief in human trials [150,151]. The compound 4975 (Adlea) demonstrated significant pain reduction for various orthopedic conditions after a single local injection [152–154]. Phase 2 and 3 trials are ongoing for orthopedic surgical procedures [151]. The evidence for efficacy in patients with chronic knee osteoarthritis receiving intra-articular injections and sufferers of cluster and migraine headache receiving intranasal formulations has been mixed [151,155]. Transient receptor potential vanilloid type 1 genetic knockouts exhibit reduced hyperalgesia [147,148], and a number of TRPV1 antagonist compounds are under development as novel pain therapeutics [156 ]. Small-molecule TRPV1 antagonists have reported efficacy in rodent models of inflammatory pain, osteoarthritis pain, neuropathic pain, and cancer pain [151]. Multiple TRPV1 antagonists have reached various stages of clinical development [151,157,158], but have been discontinued due to adverse effects including hyperthermia and elevated liver enzymes [157–161], raising concerns regarding the complexity of TRPV1 signaling and its role in thermoregulatory homeostasis. Consequently, a number of compounds that do not influence body &&

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N-Methyl-D-aspartate receptor The N-methyl-D-aspartate (NMDA) receptor has an established role in somatosensory pain processing and synaptic plasticity [164,165]. It is activated after repeated or intense somatosensory stimuli causing the continuous release of glutamate and prolonged membrane depolarization sufficient to relieve its tonic magnesium inhibition. The result is a positive feedback and logarithmic amplification of current flow through NMDA receptors in the setting of prolonged nociceptive stimuli and sustained membrane depolarization [165]. NMDA receptor recruitment and increase in the discharge of dorsal horn nociceptive neurons result in a short-term ‘wind-up’ effect, whereby successive stimuli progressively increase nociceptive responses. Additionally, NMDA receptors initiate Ca2þ-mediated intracellular signaling pathways resulting in long-term potentiation (dorsal horn neuron sensitization, increase in receptive field size, decreased activation threshold), opioid tolerance, and the development of chronic neuropathic pain [165,166]. The NMDA receptor ion channel is a heterotetrameric structure consisting of up to seven subunits [167]. Subunit composition is variable and includes NR-1, a pore forming subunit that binds an obligatory glycine co-agonist, NR-2, a glutamate-binding subunit, and in some cases, NR-3, an additional glycine binding subunit. Within the channel are binding sites for magnesium and uncompetitive NMDA antagonists such as ketamine and phencyclidine (PCP) [166]. Widely distributed throughout the CNS, NMDA receptors are involved in numerous physiologic (learning and memory) and pathologic processes (chronic pain, neurodegeneration, and dementia), making the development of useful pharmacological agents difficult [165,168]. Uncompetitive ion channel blockers including ketamine, dizocilpine (MK-801), and PCP, despite efficacy in preclinical inflammatory and neuropathic pain models as well as a number of clinical trials [postherpetic neuralgia (PHN), spinal cord injury central pain, and peripheral neuropathy], are limited by psychomimetic effects [165]. Attempts to decrease off-target effects have led to the development of low-affinity channel blockers [165], and preclinical studies of these compounds have demonstrated an ability to inhibit ‘wind-up’ without affecting physiologically appropriate responses to noxious stimuli [169–171]. The antiparkinsonian drug, amantadine, successfully relieved postsurgical neuropathic pain in cancer patients; however, its structurally related analog Volume 28 Number 00 Month 2015



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memantine exhibited no difference compared to placebo in patients with neuropathic pain [172–175]. Another compound, bicafadine – a serotonin-norepinephrine-dopamine reuptake inhibitor with low NMDA receptor affinity – demonstrated benefit in animal models of neuropathic pain and experimental studies involving dental and postsurgical pain [176–178], but failed to show an effect in patients with chronic LBP. However, a subsequent subgroup analysis that stratified patients based on compliance found a significant reduction in pain scores over placebo [179]. Nevertheless, the complexity of NMDA receptors provides a number of pharmaceutical targets with potentially improved side-effect profiles. One such target is the NR2B subunit which is expressed in DRG cells, as well as dorsal spinal horn [180]. Despite excellent selectivity, the early NR2B antagonists ifenprodil and eliprodil failed because of cross-reactivity with other molecular targets (serotonin receptors, alpha1-adrenergic receptors, and cardiac ion channels) [181]. Nonetheless, the development of even more selective compounds has met success in animal pain models of inflammatory and neuropathic pain [181,182]. Clinically, traxoprodil (CP-101 606) exhibited pain relief in patients with pain after spinal cord injury and radicular pain without psychomimetic effects [183]. However, another NR2B-selective compound, radiprodil (RGH-896), failed to show significant analgesic benefit in a phase II placebo-controlled study conducted in diabetic neuropathy [184]. A number of similar subunit selective NMDA receptor antagonists have been studied for nonpain indications but have yet to be tested in pain models or clinical trials [185]. Glycine is an obligatory co-agonist that binds to the NR-1 subunit and potentiates NMDA receptor action [166]. Thus, glycine B antagonists reduce NMDA response and promote desensitization. Glycine B antagonists do not display the psychomimetic and neurotoxic effects associated with NMDA receptor antagonism, though ataxia and motor relaxation have been reported [186]. Several glycine antagonists have shown positive results in preclinical neuropathic and inflammatory pain models [165]; however, clinical evidence is lacking as a single trial involving the oral administration of GV196771 reported reduced areas of allodynia, but without significant pain relief [187]. Voltage-gated sodium channels Voltage-gated sodium channels (NaV) are large transmembrane proteins responsible for the initiation and propagation of action potentials in excitable cells such as neurons, glial cells, and

cardiac myocytes. They comprise nine highly homologous sodium channel isoforms (NaV 1.1–NaV 1.9) [188,189 ]. NaV-blocking drugs such as local anesthetics, anticonvulsants, and tricyclic compounds have well established clinical efficacy in the treatment of neuropathic pain [190]; however, the current armamentarium of NaV-modulating drugs demonstrates poor selectivity between channel subtypes and is thus limited by adverse effects. Efforts to improve clinical effectiveness have focused on the study of isoform-specific therapeutics. Isoform NaV 1.3 demonstrates up-regulation in dorsal root neurons in animal models of neuropathic pain [188], but two subsequent neuropathic pain studies utilizing antisense oligonucleotides yielded contradictory data [191,192]. Another isoform – the NaV 1.8 receptor – increases in density after nerve injury [193]. NaV 1.8 antisense knockdown in rodent models of neuropathic pain demonstrates a pronociceptive role [194], and studies involving the use of inhibitory isoform-selective small molecules have demonstrated the ability to attenuate nociceptive behaviors in rodent models of neuropathic and inflammatory pain [195]. Human genetic studies reveal a critical role for isoform NaV 1.7 in pain processing, whereby individuals with loss-of-function mutations affecting NaV 1.7 are pain-free, but with preserved sensation to touch and temperature [196 ]. Alternatively, gain-of-function mutations have been shown to drive pain syndromes such as erythromyelalgia and paroxysmal extreme pain disorder [197,198]. The NaV 1.7-selective inhibitory antibody, SVmab1, is able to suppress both inflammatory and neuropathic pain in mouse models [189 ]. Although the study of selective inhibition of NaV isoforms remains mostly preclinical, new compounds continue to be developed [188]. &

&

&

Voltage-gated calcium channels (N, T, a2d subunits) Voltage-gated calcium channels (VGCCs) are multicomponent complexes with a central pore-forming a1 subunit surrounded by a2d, b and g subunits [199]. The a1 subunit largely determines channel function whereas additional subunits serve to regulate expression and trafficking of the VGCC complex [200]. VGCCs are classified into high-voltage activated (L, N, P/Q, and R-type Ca2þ channels), requiring strong depolarization for activation, and low-voltage activated (T-type Ca2þ channels). VGCCs are widely expressed in the peripheral and CNS and play important roles in the regulation of ion conductance, neurotransmitter release, and neuronal excitability [199]. In regards to pain processing, N and T-type calcium channels, as well as the a2d auxiliary subunit, have emerged as therapeutic



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targets. N-type channel expression is up-regulated in the spinal cord in rat models of peripheral nerve injury [201], and N-type blockade reduces ectopic activity in injured nerves [202]. Knockout mice lacking N-type VGCCs exhibit decreased painrelated responses in models of neuropathic and inflammatory pain [202]. Clinically, ziconotide, a peptide N-type selective antagonist approved by the US FDA for intractable pain, has demonstrated analgesic efficacy in at least two randomized controlled trials in patients with chronic pain from a variety of causes, including cancer and AIDS [203,204]. Due to its lack of specificity, including severe CNS and cardiovascular effects, the administration of ziconotide is restricted to intrathecal delivery [205]. The continued development of additional N-type selective compounds has led to orally administered drugs such as Z160, which have been shown to reduce thermal hyperalgesia and tactile allodynia in neuropathic pain models [206]. However, recent phase II clinical trials involving oral administration of Z160 in patient populations with neuropathic pain due to lumbosacral radiculopathy and postherpetic neuralgia failed to yield significant reductions in pain despite being well tolerated [207 ]. Phase II trials for N-type-selective compound, CNV2197944, are currently ongoing [207 ]. T-type channels also play a role in neuropathic pain processing, promoting neuronal excitability and neurotransmitter release, and T-type channel blockade reduces dorsal horn ectopic discharge activity following nerve injury. Preclinical studies involving T-channel antagonists such as ethosuximide and novel compound Z944 have demonstrated efficacy in a variety of pain models [202,208]. Z944 is currently undergoing phase II clinical trials [207 ]. The gabapentinoids (gabapentin, pregabalin, and enacarbil) bind to the a2d subunit of the VGCC complex. Although their precise mechanism of action remains uncertain, their analgesic effect is believed to be related to their ability to inhibit the trafficking of the a2d subunit to dorsal horn synaptic terminals in neuropathic pain [209]. Whereas gabapentin, pregabalin, and enacarbil are all US FDA-approved for a variety of neuropathic pain states, recent studies also suggest a potential role in the treatment of inflammatory pain [209]. &&

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Mas oncogene-related gene receptor Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in DRG and trigeminal ganglia [210]. Our current understanding of Mrg receptor function in pain processing is poor, but based on rodent models, it 10


is believed that MrgC receptor activation inhibits N-type calcium channels in DRG, leading to a reduction in postsynaptic currents in the substantia gelatinosa [211 ] There are several known MrgC agonists including bovine adrenal medulla peptide 8–22 (BAM8–22) and (Tyr6)-g2-MSH-6-12 [melanocytestimulating hormone (MSH)] [212]. Intrathecal administration of BAM8–22 in rodent models leads to attenuation of persistent inflammatory and neuropathic pain, an effect not seen in MrgC receptor knockout mice [213]. Animal models have also shown that mice injected with Complete Freund’s adjuvant (CFA) in the hindpaw exhibit MRC receptor up-regulation in the dorsal horn and DRG, and responded positively to treatment with BAM8–22 and MSH [214]. Furthermore, MrgC receptor activation also results in activation of the endogenous opioid system [215,216]. Mouse MrgC shares genetic overlap with the human protein MrgX1, suggesting the possibility of developing MrgX1 receptor agonists for human use [211 ]. It is believed that the endogenous mu-opioid agonists recruited by MrgC exhibit analgesic activity without the adverse effects associated with exogenous opioids [217]. Given the focal distribution and specificity of the Mrg receptor, it is hoped that pharmacologic treatment will have limited side-effects. &

&

Cytokine inhibition Tumor necrosis factor alpha antagonists Tumor necrosis factor a (TNF-a) is responsible for initiating the proinflammatory milieu of cytokines and growth factors implicated in pain. Multiple controlled trials have demonstrated the benefit of TNF-a antagonists for the treatment of rheumatologic diseases, including rheumatoid arthritis and spondyloarthropathies, either in combination or compared to other disease-modifying antirheumatic agents (DMARDs) [218–226]. These findings have led to the updated 2011 consensus statement on biological agents advocating TNF-a use in these patient populations either as a monotherapy, combination therapy, or second-line treatment depending on the disease [227]. More recently, the role of TNF-a antagonists has been examined for mechanical spine and neuropathic pain. In preclinical trials, TNF-a antagonists prevent pain behaviors in rodents; yet, clinical trials performed in patients with mechanical spine pain and radiculopathy have been equivocal [228]. Korhonen et al. [229] found a significant reduction in leg pain after a single intravenous infusion of Volume 28 Number 00 Month 2015



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infliximab (1–3 mg/kg) in a small open-label pilot study for lumbosacral radiculopathy; however, a subsequent placebo-controlled study performed in 40 patients with sciatica found no significant differences between groups. A later double-blind study evaluating two subcutaneous injections of adalimumab for radiculopathy (n ¼ 61) found a small benefit favoring adalimumab through a 6-month follow-up [230]. Evaluation of epidural TNF-a inhibitors for radicular pain has produced similarly mixed results [230]. Placebo-controlled studies by Kume et al. and Cohen et al. found no benefit for epidural etanercept; Freeman et al. demonstrated marginal improvements in leg pain compared to placebo through a 6-month follow-up, and Ohtori et al. found that epidural etanercept was superior to dexamethasone as a treatment for neurogenic claudication stemming from spinal stenosis up to 4 weeks after a single transforaminal injection [231–234]. Glial cell inhibitors Glial cells are an important element of the CNS, involved in the generation of chronic pain states. Both astrocytes and microglia are activated within hours of peripheral nerve injury, releasing a host of inflammatory mediators that sensitize nearby nociceptive neurons [235]. Microglias, in particular, have been implicated in chronic neuropathic pain due to their up-regulation of the P2X4R protein and stimulation of the complement pathway after nerve injury [236,237]. Mice deficient in the P2X4R gene demonstrate blunted pain behaviors following spinal nerve injury [238]. However, pharmacologic interventions targeting glial cells, such as minocycline, pentoxifylline, and propentofylline, have yielded disappointing results in clinical trials [239,240].

Nerve growth factor inhibitors Nerve growth factor (NGF) is part of a family of neurotrophins which include brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), which are essential to the development and maintenance of the mammalian nervous system. Neurotrophins act through two types of cell surface receptors – neurotrophin receptor (NGFR) and specific tyrosine kinase receptors (Trks or NTRKs). All neurotrophins bind to NGFR with similar affinity; however, BDNF, NT-4, NT-3, and particularly NGF preferentially bind to specific Trk receptor subtypes [241–243]. During embryonic development, TrkA is expressed in 70–80% of DRG small-fiber sensory neurons, and activation by NGF promotes neurite survival and growth. Postnatally, NGF sensitivity is

reduced and TrkA expression is down-regulated to a smaller subset of approximately 40% of DRG neurons [244]. Nevertheless, NGF–TrkA signaling appears to play a physiologic role in the trophic support and tonic regulation of small-fiber sensory neurons, as evidenced by the finding that NGF sequestration reduces sensitivity to noxious stimuli while preserving mechanical sensitivity [245]. This is consistent with animal models of both inflammation and peripheral nerve injury that demonstrate increased NGF levels. Clinically, there is strong evidence implicating a role in a variety of painful diseases such as interstitial cystitis, arthritis, and pancreatitis [246 ]. Nerve growth factor binds TrkA receptors at nociceptive nerve endings, inciting a series of intracellular events that increase TRPV1 and Nav 1.8 channel activity. NGF is transported in a retrograde fashion to the DRG, resulting in increased expression of TRPV1, substance P, and BDNF. Hypersensitivity occurs as a result of substance P and BDNF release in the spinal cord, combined with the antegrade transport of TRPV1 to nociceptive nerve endings [247 ]. Due to its role in both inflammatory and neuropathic pain, the NGF–TrkA complex represents a potential therapeutic target. Preclinical studies involving NGF inhibition and knockout models demonstrate reduced pain perception in the setting of acute local inflammation, arthritis, postoperative, visceral, and neuropathic pain [241,242]. Pharmacological innovations aiming to prevent the activation of TrkA by NGF have focused on three methodologies: sequestering free NGF; inhibiting NGF binding to TrkA; and inhibiting TrkA function [242]. Humanized anti-NGF antibodies hold an advantage over small-molecule antagonists in that they generally have higher specificity and fewer offtarget effects [243]. Anti-NGF antibodies such as tanezumab, fulranumab, fasinumab, REGN-475, and ABT-110 are the only therapeutics to date to reach clinical stages of development [243,246 ]. But despite multiple randomized trials demonstrating efficacy in a variety of pain conditions including osteoarthritis, interstitial cystitis and diabetic neuropathy [247 ], all clinical trials evaluating antiNGF antibodies were put on hold in 2010 due to concerns of rapidly progressive osteoarthritis and osteonecrosis leading to joint replacement. A subsequent 2012 US FDA arthritis advisory committee determined that there was no evidence directly linking anti-NGF antibodies to joint destruction and voted unanimously to resume clinical trials [246 ,248]. The development of ligands that inhibit NGF–TrkA binding lags behind the development


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of anti-NGF antibodies. ALE0540, which inhibits NGF binding to both TrkA and NGFR, has demonstrated an antinociceptive effect in animal models of neuropathic pain following intrathecal administration [249]. Inhibitors of TrkA function have also resulted in decreased pain-related behaviors in rodent models of pancreatitis. The targeting of TrkA suffers from an inherent lack of specificity that occurs with any drug that acts on a pervasive and versatile receptor class [250]. Nevertheless, future developments will likely result in compounds with greater specificity and tolerability.

antinociceptive effects in animal models of mechanical allodynia, visceral pain, and thermal nociception [255]. The utilization of bisphosphonate therapy may be associated with adverse effects such as osteopetrosis, chronic musculoskeletal pain, and osteonecrosis of the jaw [256]. Although rare, these serious side-effects may limit the widespread use of bisphosphonate therapy for pain. Reports of patients developing esophageal cancer have raised concerns regarding bisphosphonate therapy. However, a recent large-scale retrospective cohort study found a negative correlation between Barrett’s esophagus and bisphosphonate use [262].

Bisphosphonates Bisphosphonates are synthetic molecules with structural similarity to pyrophosphates – a naturally occurring component of bone. Bisphosphonates bind to calcium phosphate and inhibit the maturation and function of osteoclasts, thereby suppressing bone resorption [251]. They are used in the management of skeletal disorders associated with enhanced bone resorption and have been shown in several reviews to decrease both pain and morbidity related to bony metastases in a variety of cancers [252–254]. Additional studies have demonstrated analgesic effects in other conditions characterized by enhanced bone turnover such as Paget’s disease, fibrous dysplasia, and hypercalcemia of malignancy [255,256]. Complex regional pain syndrome (CRPS) is a condition with associated bony dystrophy. In several small randomized controlled trials, the use of bisphosponates has resulted in improvements in pain and function, suggesting a possible role in neuropathic pain [257,258]. However, a 2011 Cochrane review on the efficacy of bisphosphonates in CRPS concluded the treatment was promising, but not proven due to low-quality studies [259]. A small prospective study conducted in elderly postmenopausal women with osteoporosis and chronic LBP who were treated with oral risendronate therapy over 4 months found an improvement in pain in the absence of vertebral fractures, suggesting that bone resorption due to osteoporosis may be a cause of LBP [260]. A more recent placebo-controlled study evaluating intravenous pamidronate for mechanical chronic LBP found significant pain relief compared to placebo through a 6-month follow-up [261]. Although the analgesic mechanisms of action for bisphosphonates remain unclear, some authors attribute the effect on bone pain to osteoclast inhibition and possible anti-inflammatory properties, whereas others have proposed NGF, substance P, and/or CGRP inhibition [255]. In preclinical studies, bisphosphonates have demonstrated 12


Nitric oxide Nitric oxide is a ubiquitous signaling molecule involved in a wide range of biological processes. Nitric oxide is generated by the conversion of L-arginine to L-citrulline by nitric oxide synthase enzymes (NOS) – an enzyme present in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Nitric oxide activates soluble guanylyl cyclase, stimulating the conversion of guanosine triphosphate to second messenger cGMP which modulates a variety of intracellular targets including cGMP-dependent protein kinase (PKG), ion channels, and phosphodiesterases [263–265]. Early studies implicating nitric oxide in pain processing describe a pronociceptive role as inhibition of nitric oxide synthesis or synthesis of its second messenger cGMP reduced pain, and intrathecal administration of nitric oxide donors and cGMP analogs increased hyperalgesia [264]. Nevertheless, nitric oxide appears to have a dual effect on pain as it can promote both pro and antinociceptive effects [263]. In addition to its direct analgesic effects, nitric oxide has also been implicated in the potentiation of opioid analgesia [263]. Despite the complex effects on pain processing, the antinociceptive effect of nitric oxide signaling has emerged as a potential strategy in the development of pain therapies. One strategy involves the use of phosphodiesterase-5 (PDE5) inhibitors, which metabolize and terminate the intracellular effects of cGMP. Animal studies have demonstrated significant antinocieptive effects with local, systemic, and intrathecal administration of PDE5 inhibitors in nociceptive and neuropathic pain models [266–268]. Two studies have shown a synergistic effect when the PDE5 inhibitor sildenafil is used in combination with morphine [266]. Nevertheless, human studies have been lacking, with only a single phase 4 clinical trial conducted from 2005 to 2006 in patients with diabetic neuropathy that has no reported results [269]. Volume 28 Number 00 Month 2015



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Emerging targets in treating pain Chang et al. Table 1. Molecular targets, mechanisms and summary of evidence Target

Mechanism

Summary of evidence

Kappa opioid receptor

Antinociceptive action is predominantly peripheral; spinal activation is associated with opioidinduced hyperalgesia

Peripherally restricted agonists reduce opioid consumption and pain scores in clinical trials for postoperative pain; antagonism associated with antihyperalgesic effect in human pain models

Opioid heteromers

Mu-delta opioid receptor heteromer expressed in DRG and RVM; CB1 and mu opioid receptors are colocalized Supraspinal activation is pronociceptive; spinal and peripheral activation is antinociceptive

Predevelopmental stages

Serotonin, norepinephrine, and dopamine

Enhanced descending inhibition

Strong evidence that TCAs and SNRIs are effective in peripheral neuropathic pain conditions; limited evidence supporting use of SSRIs; evidence supporting use of SNRIs for nociceptive pain

Histamine receptor

H3R activation inhibits histamine release; peripheral H3R activation reduces CRGP and substance P release; intracerebral histamine signaling reduces nociceptive transmission

Preclinical evidence for analgesia in nociceptive pain models with H3R activation; preclinical evidence in neuropathic pain models utilizing brain-penetrating H3R antagonists

Alpha 2 receptor

Antinociceptive action is predominantly spinal with pre and postsynaptic suppression of pain processing

Clinical evidence for limited long-term pain relief; intrathecal administration may be beneficial in mixed or neuropathic pain states

Cannabinoid receptors

Presynaptic CB1 receptors attenuate neurotransmitter release; CB2 receptors are upregulated in neuropathic pain models

Strong evidence for cannabinoids in neuropathic pain, some evidence for use in nociceptive pain, but high incidence of adverse effects; CB1 receptor agonists with preclinical evidence in nociceptive and neuropathic pain models, but negative evidence in clinical trials; CB2 receptor agonists with preclinical evidence in nociceptive and neuropathic pain models, but no clinical evidence

TRPV1

TRPV1 are ion channels sensitive to changes in pH (428C), membrane depolarization and a variety of ligands; Agonists desensitize TRPV1 channels

Strong evidence supporting topical agonists in neuropathic pain; evidence with site-specific agonists is mixed; antagonists in preclinical studies provide evidence for neuropathic and nociceptive pain; clinical trials are completed but no results have been reported; additional trials discontinued due to adverse effects

NMDA receptor

NMDA receptors are ionotropic glutamate receptors recruited by intense or prolonged nociceptive stimuli; involved in short- and long-term central sensitization

Clinical effectiveness for noncompetitive inhibitors is limited by psychomimetic effects; clinical evidence for lower affinity antagonists is mixed; NR2B antagonists have some preclinical evidence for analgesia; glycine B antagonists shown in preclinical studies to be efficacious for neuropathic pain, but clinical evidence is negative

Voltage-gated sodium channels

Responsible for the initiation and propagation of action potentials in neurons

NaV 1.8 inhibition shows preclinical evidence in nociceptive and neuropathic pain models; there is preclinical evidence for NaV 1.7 inhibition for nociceptive and neuropathic pain

Voltage-gated calcium channels

Regulate ion conductance, neurotransmitter release, and neuronal excitability in the central and peripheral nervous systems

Preclinical evidence for N-type channel blockade in neuropathic pain, but weak clinical evidence; preclinical evidence for T-type channel blockade in nociceptive and neuropathic pain models; ongoing clinical trials but no results reported

MRG receptor

MRG receptor activation inhibits N-type calcium channels in DRG, leading to a reduction in postsynaptic currents in the substantia gelatinosa

Preclinical evidence in nociceptive and neuropathic pain models

TNF-a inhibitors

TNF-a signaling initiates proinflammatory milieu of cytokines and growth factors implicated in pain.

Strong clinical evidence in rheumatologic disease; clinical evidence in nociceptive and neuropathic pain have been mixed

ORL-1


Completed and ongoing phase II and III clinical trials, but no published results


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Drugs in anesthesia Table 1 (Continued) Target

Mechanism

Summary of evidence

Glial cell inhibitors

Glial cells are activated by peripheral nerve injury and release inflammatory mediators that sensitize nearby nociceptive neurons

Preclinical evidence in neuropathic pain, but clinical studies have been negative

Nerve growth factor inhibitor

NGF binds to TrkA receptors at nociceptive nerve endings resulting in increased pain signaling and hypersensitivity Unclear analgesic mechanism. May exert its effects via osteoclast inhibition and possible anti-inflammatory properties

Strong clinical evidence for humanized anti-NGF antibodies in nociceptive and neuropathic pain

Bisphosphonates

Nitric oxide and phosphodiesterase inhibitors

Precise analgesic mechanism unclear, but may be dependent on activation of cGMP signaling pathway; Potentiates opioid and NSAID analgesia

Strong clinical evidence in conditions with enhanced bone turnover; Low quality evidence for treatment of CRPS Preclinical evidence when PDE5 inhibitors used in combination with morphine; NO-linked therapies associated with fewer gastric lesions in preclinical models, and equal analgesia in clinical studies

CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; cGMP, cyclic guanosine monophosphate; CRPS, complex regional pain syndrome; DRG, dorsal root ganglia; H3R, histamine H3 receptor; MRG, Mas oncogene-related gene; NaV, voltage-gated sodium channels; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NR2B, N-methyl-D-aspartate receptor subunit 2B; ORL-1, opioid receptor-like receptor 1; PDE5, phosphodiesterase type 5; RVM, rostral ventral medulla; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TNF, tumor necrosis factor; TrkA, tyrosine receptor kinase A; TRPV1, vanilloid receptor 1.

Another strategy for drug development has been the addition of nitric oxide-releasing moieties to existing pain therapies. This approach has generated a new class of analgesics, called cyclooxygenase inhibitor nitric oxide donors (CINODs), with reduced gastrointestinal toxicity and enhanced anti-inflammatory activity [270]. First in class drug, NCX-701 or nitroparacetamol, combines paracetamol (acetaminophen) and nitro-oxybutyroyl through ester linkage. The nitro-oxybutyroyl moiety releases low steady levels of nitric oxide, enhancing the analgesic potency of paracetamol in animal models of inflammatory and neuropathic pain [271]. A 2003 randomized, double-blind, placebo-controlled, phase II trial in 101 patients with moderate to severe postoperative dental pain demonstrated that NCX-701 was better than placebo, but no better than paracetamol alone, though based on a subanalysis, the authors concluded that NCX-701 was more effective than paracetamol on a mole-per-mole basis [271]. Within the CINOD class are also nitric oxide-NSAIDs, with nitric oxide linkage to aspirin (ASA), indomethacin, and diclofenac. These compounds demonstrate a cytoprotective effect in animal studies [270], though no human trials have been reported. Another combination therapy that has yielded preliminary success is combining nitric oxide donors with opioids in opioid-tolerant patients. In two small, randomized, double-blinded studies conducted in patients with cancer pain (n ¼ 36 and n ¼ 48), Loretti et al. found a significant reduction in opioid use after the addition of a nitroglycerin patch [272,273]. 14


CONCLUSION Many obstacles exist for the development of effective medications to treat chronic pain. These include challenges in identifying the mechanisms of pain and molecular targets, the overlap and multiplicity of pain pathways, and the avoidance of off-target adverse effects. Despite these barriers, novel and diverse therapies continue to be developed, providing the foundation for better and safer pain pharmacotherapy [Table 1]. Acknowledgements We would like to thank Dr Srinivasa Raja and Dr Eugene Hsu for their assistance with this article. Financial support and sponsorship This work was supported by the Centers for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. US Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. J Am Med Assoc 2013; 310:591–608. 2. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education. Relieving pain in America: a blueprint for transforming prevention, care, education and research. The National Academies Press; 2011. HYPERLINK ‘http://books.nap.edu/openbook.php? record_id=13172’ http://books.nap.edu/openbook.php?record_id=13172.




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Emerging targets in treating pain Chang et al. 3. Juniper M, Le T, Mladsi D. The epidemiology, economic burden, and pharmacological treatment of chronic low back pain in France, Germany, Italy, Spain and the UK: a literature-based review. Expert Opin Pharmacother 2009; 10:2581–2592. 4. Crow W, Willis D. Estimating cost of care for patients with acute low back pain: a retrospective review of patient records. J Am Osteopath Assoc 2009; 109:229–233. 5. Cohen SP, Mao J. Mechanisms of neuropathic pain and their clinical && implications. Br Med J 2014; 348:f7656. In-depth and detailed review of neuropathic pain mechanisms and potential pharmacologic targets. 6. Freynhagen R, Baron R, Gockel U, et al. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006; 22:1911–1920. 7. Bennett MI, Smith BH, Torrance N, et al. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain 2005; 6:149–158. 8. Hsu E, Murphy S, Chang D, Cohen S. Expert opinion on emerging drugs: && chronic low back pain. Expert Opin Emerg Drugs 2015; 20:103–127. Review of available and developmental pain therapeutic compounds, as well as discussion of barriers to market entry. 9. Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 2001; 95:241–249. 10. Bouhassira D, Lante´ri-Minet M, Attal N, et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008; 136:380– 387. 11. Harifi G, Amine M, Ait Ouazar M, et al. Prevalence of chronic pain with neuropathic characteristics in the Moroccan general population: a national survey. Pain Med 2013; 14:287–292. 12. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7:281–289. 13. Hopewell S, Loudon K, Clarke MJ, et al. Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database Syst Rev 2009; MR000006. 14. Farrar JT. What is clinically meaningful: outcome measures in pain clinical trials. Clin J Pain 2000; 16 (2 Suppl):S106–S112. 15. Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev 2012; 7:CD008943. 16. Pande AC, Pyke RE, Greiner M, et al. Analgesic efficacy of enadoline versus placebo or morphine in postsurgical pain. J Clin Neuropharm 1996; 19:451– 456. 17. Riviere PJM. Peripheral kappa-opioid agonists for visceral pain. Br J of Pharm 2004; 141:1331–1334. 18. Pipeline & Technologies (n.d.). Retrieved January 2015. http://www.cara therapeutics.com/pipeline-technologies.shtml. 19. Arendt-Nielsen L, Olesen AE, Staahl C, et al. Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multimodal, multitissue experimental human pain model: selective effect on visceral pain. Anesthesiology 2009; 111:616–624. 20. Gan TJ, Jones JB, Schuller R, et al. Analgesic and morphine-sparing effects of the peripherally-restricted kappa opioid agonist CR845 after intravenous administration in women undergoing a laparoscopic hysterectomy. Anesth Analg 2013; 116:S1. 21. Vanderah TW, Gardell LR, Burgess SE, et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 2000; 20:7074–7079. 22. Pergolizzi J, Aloisi AM, Dahan A, et al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract 2010; 10:428–450. 23. Koppert W, Ihmsen H, Korber N, et al. Different profiles of buprenorphineinduced analgesia and antihyperalgesia in a human pain model. Pain 2005; 118:15–22. 24. Constantino CM, Gomes I, Stockton SD, et al. Opioid receptor heteromers in analgesia. Exp Rev Mol Med 2012; 14:e9. 25. Ong EW, Cahill CM. Molecular perspectives for mu/delta opioid receptor & heteromers as distinct, functional receptors. Cells 2014; 3:152–179. Detailed overview of mu/delta opioid receptor heteromer as a functionally distinct receptor and potential analgesic target. 26. Cahill CM, Morinville A, Lee MC, et al. Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances deltamediated antinociception. J Neurosci 2001; 21:7598–7607. 27. Mollereau C, Parmentier M, Mailleux P, et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 1994; 341:33–38. 28. Reinscheid RK, Nothacker HP, Bourson A, et al. Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science 1995; 270:792–794. 29. Meunier JC, Mollereau C, Toll L, et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 1995; 377:532–535. 30. Mogil JS, Pasternak GW. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 2001; 53:381–415.

31. Lambert DG. The nociception/orphanin FQ receptor: a target with broad therapeutic potential. Nature Rev 2008; 7:694–710. 32. Hawes BE, Graziano MP, Lambert DG. Cellular actions of nociceptin: transduction mechanisms. Peptides 2000; 21:961–967. 33. New DC, Wong YH. The ORL1 receptor: molecular pharmacology and signaling mechanisms. Neurosignals 2002; 11:197–212. 34. Knoflach F, Reinscheid RK, Civelli O, Kemp JA. Modulation of voltage-gated calcium channels by orphanin FQ in freshly dissociated hippocampal neurons. J Neurosci 1996; 16:6657–6664. 35. Vaughn CW, Christy MJ. Increase by the ORL1 receptor (opioid receptor-like 1) ligand, nociception of inwardly rectifying K conductance in dorsal raphe nucleus neurons. Br J Pharmacol 1996; 117:1609–1611. 36. Nicol B, Lambert DG, Rowbotham DJ, et al. Nociceptin induced inhibition of Kþ evoked glutamate release from rat cerebrocortical slices. Br J Pharmacol 1996; 119:1081–1083. 37. Marti M, Stocchi S, Paganini F, et al. Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex. Br J Pharmacol 2003; 138:91–98. 38. Giuliani S, Maggi CA. Inhibition of tachykinin release from peripheral endings of sensory nerves by nociceptin, a novel opioid peptide. Br J Pharmacol 1996; 118:1567–1569. 39. Rizzi A, Nazzaro C, Marzola GG, et al. Endogenous nociceptin/orphanin FQ signaling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: pharmacological and genetic evidences. Pain 2006; 124:100–108. 40. Zeilhofer HU, Calo G. Nociceptin/orphanin FQ and its receptor: potential targets for pain therapy? J Pharmacol Exp Ther 2003; 306:423–429. 41. Pan Z, Hirakawa N, Fields HL. A cellular mechanism for the bidirectional painmodulating actions of orphanin FQ/nociceptin. Neuron 2000; 26:515–522. 42. King MA, Rossi GC, Chang AH, et al. Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. Neurosci Lett 1997; 223:113–116. 43. Ko MC, Wei H, Woods JH, Kennedy RT. Effects of intrathecally administered nociceptin/orphanin FQ in monkeys: behavioral and mass spectrometric studies. J Pharmacol Exp Ther 2006; 318:1257–1264. 44. Inoue M, Kawashima T, Takeshima H, et al. In vivo pain-inhibitory role of nociceptin/orphanin FQ in spinal cord. J Pharmacol Exp Ther 2003; 305:495–501. 45. Erb K, Liebel JT, Tegeder I, et al. Spinally delivered nociception/orphanin FQ reduces flinching behaviour in the rat formalin test. Neuroreport 1997; 8:1967–1970. 46. Yamamoto T, Nozaki-Taguchi N, Kimura Sl. Analgesic effect of intrathecally administered nociception, an opioid receptor-like 1 receptor agonist, in the rat formalin test. Neuroscience 1997; 81:249–254. 47. Ko MC, Naughton NN, Traynor JR, et al. Orphanin FQ inhibits capsaicininduced thermal nociception in monkeys by activation of peripheral ORL1 receptors. Br J Pharmacol 2002; 135:943–950. 48. Obara I, Przewlocki R, Przewlocki B. Spinal and local peripheral antiallodynic activity of Ro64-6198 in neuropathic pain in the rat. Pain 2005; 116:17–25. 49. Kolesnikov YA, Pasternak GW. Peripheral orphanin FQ/nociceptin analgesia in the mouse. Life Sci 1999; 64:2021–2028. 50. Schoblock JR. The pharmacology of Ro 64-6198, a systemically active, nonpeptide NOP receptor (opiate receptor-like 1, ORL-1) agonist with diverse preclinical therapeutic activity. CNS Drug Rev 2007; 13:107–136. 51. Ueda H, Yamaguchi T, Tokuyama S, et al. Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci Lett 1997; 237:136–138. 52. Ueda H, Inoue M, Takeshima H, Iwasawa Y. Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 2000; 20:7640–7647. 53. Chung S, Pohl S, Zeng J, et al. Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 2006; 318:262–267. 54. Rizzi A, Bigoni R, Marzola G, et al. The nociceptin/orphanin FQ receptor antagonist, [Nphe1]NC(1-13)NH2, potentiates morphine analgesia. Neuroreport 2002; 11:2369–2372. 55. Bloms-Funke P, Gillen C, Schuettler AJ, et al. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 2000; 21:1141– 1146. 56. Yamamoto T, Shono K, Tanabe S. Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by m receptor activation in the rat formalin test. J Pharmacol Exp Ther 2006; 318:206–213. 57. Lambert DG, Bird MF, Rowbotham DJ. Cebranopadol: a first in-class & example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth 2015; 114:364–366. Concise overview of preclinical and clinical data regarding cebranopadol in the treatment of a variety of pain conditions. 58. Marks DM, Shah MJ, Patkar AA, et al. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol 2009; 7:331–336. 59. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Inv 2010; 120:3779–3787. 60. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry 2010; 81:1372–1373.



15



ACO 280408

Drugs in anesthesia 61. Moulin DE, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014; 19:328–335. Comprehensive review of randomized controlled trials and systematic reviews related to the pharmacological management of neuropathic pain. 62. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68:2611–2632. 63. Chou R. Low back pain (chronic). BMJ Clin Evid 2010; 2010:1116. 64. Skljarevski V, Ossanna M, Liu-Seifert H, et al. A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur J Neurol 2009; 16:1041–1048. 65. Skljarevski V, Desaiah D, Liu-Seifert H, et al. Efficacy and safety of duloxetine in patients with chronic low back pain. Spine 2010; 35:E578–E585. 66. Skljarevski V, Zhang S, Desaiah D, et al. Duloxetine versus placebo in patients with chronic low back pain: a 12-week, fixed-dose, randomized, double-blind trial. J Pain 2010; 11:1282–1290. 67. Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain 2009; 146:253– 260. 68. Chappell AS, Desaiah D, Liu-Seifert H, et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Pract 2011; 11:33–41. 69. Frakes EP, Risser RC, Ball TD, et al. Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin 2011; 27:2361–2372. 70. Sommer C, Hauser W, Alten R, et al. Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline. Schmerz 2012; 26:297– 310. 71. Choy E, Marshall D, Gabriel ZL, et al. A Systematic review and mixed treatment comparison of the efficacy of pharmacological treatments for fibromyalgia. Semin Arth Rheum 2011; 41:335–345. 72. Cannon KE, Chazot PL, Hann V, et al. Immunohistochemical localization of histamine H3 receptors in rodent skin, dorsal root ganglia, superior cervical ganglia, and spinal cord: potential antinociceptive targets. Pain 2007; 129:76–92. 73. Kajihara Y, Murakami M, Imagawa T, et al. Histamine potentiates acidinduced responses mediating transient receptor potential V1 in mouse primary sensory neurons. Neuroscience 2010; 166:292–304. 74. Cannon KE, Nalwalk JW, Stadel R, et al. Activation of spinal histamine H3 receptors inhibits mechanical nociception. Eur J Pharmacol 2003; 470:139–147. 75. Cannon KE, Leurs R, Hough LB. Activation of peripheral and spinal histamine H3 receptors inhibits formalin-induced inflammation and nociception, respectively. Pharmacol Biochem Behav 2007; 88:122–129. 76. Lindsay B, Hough, Frank L. Rice. H3 receptors and pain modulation: peripheral, spinal, and brain interactions. Center for Neuropharmacology and Neuroscience: Albany Medical College, Albany, New York; 2010. 77. Glick SD, Crane LA. Opiate-like and abstinence-like effects of intracerebral histamine administration in rats. Nature 1978; 273:547–549. 78. Gogas KR, Hough LB, Eberle NB, et al. A role for histamine and H2-receptors in opioid antinociception. J Pharmacol Exp Ther 1989; 250:476–484. 79. Vollinga RC, de Koning JP, Jansen FP, et al. A new potent and selective histamine H3 receptor agonist, 4-(1H-imidazol- 4-ylmethyl)piperidine. J Med Chem 1994; 37:332–333. 80. Arrang JM, Garbarg M, Lancelot JC, et al. Highly potent and selective ligands for histamine H3-receptors. Nature 1987; 327:117–123. 81. Medhurst SJ, Collins SD, Billinton A, et al. Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgicallyinduced and virally- induced rat models of neuropathic pain. Pain 2008; 138:61–69. 82. Huang L, Adachi N, Nagaro T, et al. Histaminergic involvement in neuropathic pain produced by partial ligation of the sciatic nerve in rats. Reg Anesth Pain Med 2007; 32:124–129. 83. Hsieh GC, Honore P, Pai M, et al. Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems. Brain Res 2010; 1354:74– 84. 84. Gemkow MJ, Davenport AJ, Harich S, et al. The histamine H3 receptor as a therapeutic drug target for CNS disorders. Drug Discov Today 2009; 14:509–515. 85. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia 1999; 54:146–165. 86. Chan AK, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother 2010; 11:2849–2868. 87. Loveridge R, Patel S. Systemic nonopioid adjuvant analgesics: their role in acute postoperative pain in adults. Trends Anaesth Crit Care 2014; 4:10– 18. 88. Aley KO, Levine JD. Multiple receptors involved in the peripheral alpha 2, mu and A1 antinociception, tolerance and withdrawal. Neurosci 1997; 17:735– 744. &&

16


89. Budai D, Harasawa I, Fields HL. Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through alpha2adrenergic receptors. J Neurophysiol 1998; 80:2244–2254. 90. Davis KD, Treede RD, Raja SN, et al. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 1991; 47:309–317. 91. Eisenach JC, De Kock M, Klimscha W. [alpha]2-adrenergic agonists for regional anesthesia: a clinical review of clonidine (1984–1995). Anesthesiology 1996; 85:655–674. 92. Cohen SP, Dragovich A. Intrathecal analgesia. Med Clin N Am 2007; 91:251–270. 93. Siddall PJ, Molloy AR, Walker S, et al. The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg 2000; 91:1493–1498. 94. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage 2003; 26:668–677. 95. Deer T, Krames ES, Hassenbusch SJ, et al. Polyanalgesic consensus conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 2007; 10:300–328. 96. Kumar A, Maitra S, Khanna P, Baidya DK. Clonidine for management of & chronic pain: a brief review of the current evidences. Saudi J Anaesth 2014; 8:92–96. Qualitative analysis of 30 clinical studies of clonidine use in the treatment of chronic neuropathic pain. 97. Elhakim M, Abdelhamid D, Abdelfattach H, et al. Effect if epidural dexmedetomidine on intraoperative awareness and postoperative pain after onelung ventilation. Acta Anaesth Scand 2010; 54:703–709. 98. Kanazi GE, Aouad MT, Jabbour-Khoury SI, et al. Effect of low-dose dexmedetomodine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesth Scand 2006; 50:222–227. 99. Esmaoglu A, Mizrak A, Akin A, et al. Addition of dexmedetomidine to lidocaine for intravenous regional anaesthesia. Eur J Anaesthesiol 2005; 22:447–451. 100. Adams IB. Cannabis pharmacology and toxicology in animals and humans. Addiction 1996; 91:1585–1614. 101. Geller T. Cannabinoids: a secret history. Chem Heritage News Magazine 2007; 25. 102. Naef M, Curatolo M, Petersen-Felix S, et al. The analgesic effect of oral delta9-tetrahydrocannabinol (THC), morphine and a THC-morphine combination in healthy patients under experimental pain conditions. Pain 2003; 105:78– 79. 103. Kraft B, Frickey NA, Kaufmann RM, et al. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology 2008; 109:101–110. 104. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007; 107:785–796. 105. Beaulieu P. Effects of nabilone, a synthetic cannabinoid on postoperative pain. Can J Anaesth 2006; 53:765–769. 106. Lynch ME, Campbell F. Cannabinoids for treatment of chronic noncancer pain; a systematic review of randomized trials. Br J Clin Pharm 2011; 72:735–744. 107. Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 2009; 10:101353–101368. 108. Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Br Med J 2005; 330:11. 109. Leweke FM, Koethe D. Cannabis and psychiatric disorders: it is not only addiction. Addict Biol 2008; 13:264–275. 110. Kraft B. Is there any clinically relevant cannabinoid-induced analgesia? Pharmacology 2012; 89:237–246. 111. Atwood BK, Wager-Miller J, Haskins C, et al. Functional selectivity in CB2 cannabinoid receptor signaling and regulation: implications for the therapeutic potential of CB2 ligands. Mol Pharmacol 2012; 81:250–263. 112. Maresz K, Pryce G, Ponomarev ED, et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 2007; 13:492–497. 113. Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharm 1995; 48:443–450. 114. Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54:161–220. 115. Kano M, Ohno-Shosaku T, Hashimotodani Y, et al. Endocannabinoidmediated control of synaptic transmission. Physiol Rev 2009; 89:309–380. 116. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev 2009; 60:255–266. 117. Sokal DM, Elmes SJ, Kendall DA, Chapman V. Intraplantar injection of anadamide inhibits mechanically-evoked responses of spinal neurons via activation of CB2 receptors in anaesthetised rats. Neurpharm 2003; 45:404–411.




ACO 280408

Emerging targets in treating pain Chang et al. 118. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nature Med 2008; 14:923–930. 119. Piet R, Garenne A, Farrugia F, et al. State-dependent, bidirectional modulation of neural network activity by endocannabinoids. J Neurosci 2011; 31:16591–16596. 120. Kato A, Punnakkal P, Pernı´a-Andrade AJ, et al. Endocannabinoid-dependent plasticity at spinal nociceptor synapses. J Physiol 2012; 590:4717–4733. 121. Lim G, Sung B, Ji RR, Mao J. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain 2003; 105:275–283. 122. Davis MP. Cannabinoids in pain management: CB1, CB2 and nonclassic & receptor ligands. Expert Opin Investig Drugs 2014; 23:1123–1140. Overview of the endogenous cannabinoid system and its potential therapeutic targets. 123. Kalliomaki J, Annas P, Huizar K, et al. Evaluation of the analgesic efficacy and psychoactive effects of AZD1940, a novel peripherally acting cannabinoid agonist, in human capsaicin-induced pain and hyperalgesia. Clin Exp Pharmacol Physiol 2013; 40:212–218. 124. Maresz K, Carrier EJ, Ponomarev ED, et al. Modulation of the cannabinoids CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem 2005; 95:437–445. 125. Zhang J, Hoffert C, Vu HK, et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 2003; 17:2750–2754. 126. den Boon FS, Chameau P, Schaafsma-Zhao Q, et al. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci USA 2012; 109:3534–3539. 127. Ibrahim MM, Deng H, Zvonok A, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci 2003; 100:10529– 10533. 128. Ibrahim MM, Rude ML, Stagg NJ, et al. CB2 cannabinoid receptor mediation of antinociception. Pain 2006; 122:36–42. 129. Elmes SJ, Jhaveri MD, Smart D, et al. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naı¨ve rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci 2004; 20:2311–2320. 130. Sagar DR, Kelly S, Millns PJ, et al. Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur J Neurosci 2005; 22:371–379. 131. Riether D. Selective cannabinoid receptor 2 modulators: a patent review 2009-present. Expert Opin Ther Pat 2012; 22:495–510. 132. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonylglycerol. Chem Biol 2007; 14:1347–1356. 133. Long JZ, Li W, Booker L, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 2009; 5:37–44. 134. Croci T, Zarini E. Effect of the cannabinoid CB1 receptor antagonist rimonabant on nociceptive responses and adjuvant-induced arthritis in obese and lean rats. Br J Pharmacol 2007; 150:559–566. 135. Ueda M, Iwasaki H, Wang S, et al. Cannabinoid receptor type 1 antagonist, & AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury. Anesthesiology 2014; 121:1311–1319. Describes a possible role of CB1 antagonism in treating burn injury induced allodynia and hyperalgesia. 136. Szallasi A, Blumberg PM. [3H]resiniferatoxin binding by the vanilloid receptor species-related differences, effects of temperature and sulhydryl reagents. Naunyn-Schmiedebergs Arch Pharmacol 1993; 347:84–91. 137. Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51:159–212. 138. Immke DC, Gavva NR. The TRPV1 receptor and nociception. Semin Cell Dev Biol 2006; 17:582–591. 139. Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nature Rev Drug Discov 2007; 6:357–372. 140. Cortright DN, Szallasi A. Biochemical pharmacology of the vaniloid receptor TPRV1. An update. Eur J Biochem 2004; 271:1814–1819. 141. Gunthorpe MJ, Benham CD, Randall A, Davis JB. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 2002; 23:183–191. 142. Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 2007; 114:13–33. 143. Holzer P. TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia. Eur J Pharmacol 2004; 500:231–234. 144. Ji RR, Samad TA, Jin SX, et al. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002; 36:57–68. 145. Keeble J, Russell F, Curtis B, et al. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthr Rheumatol 2005; 52:3248–3256. 146. Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuopeptides 2004; 32:377–384.

147. Caterina MJ. Transient receptor potential ion channels as participants in thermosensation and thermoregulation. Am J Physiol Regulat Integr Comparat Physiol 2000; 292:R64–R76. 148. Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405:183–187. 149. Menendez L, Jua´rez L, Garcı´a E, et al. Analgesic effects of capasazepine and resiniferatoxin on bone cancer pain in mice. Neurosci Lett 2006; 393:70–73. 150. Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival? Clin J Pain 2008; 24:142–154. 151. Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev 2009; 60:267–277. 152. Cantillon M, Tagoe M, Vause E, et al. Safety, tolerability and efficacy of intraoperative ALGRX 4975 in a randomized, double-blind, placebo-controlled study of subjects undergoing bunionectomy. J Pain 2005; 6:S48. 153. Diamond E, Miller T. ALGRX 4975 reduces pain of intermetatarsal neuroma: preliminary results from a randomized, double-blind, placebo-controlled, phase II multicenter clinical trial. J Pain 2006; 7:S41. 154. Richards P, Stasko VG, Lacko I, et al. ALGRX 4975 reduces pain of acute lateral epicondylitis: preliminary results from a randomized, double-blind, placebo-controlled, phase II multicenter clinical trial. J Pain 2006; 7:S3. 155. Cantillon M, Vause E, Sykes D, et al. Safety, tolerability and efficacy of ALGRX 4975 in osteoarthritis (OA) of the knee. J Pain 2005; 6:S39. 156. Lee Y, Hong S, Cui M, et al. Transient receptor potential vanilloid type 1 & antagonists: a patent review (2011–2014). Expert Opin Ther Pat 2015; 25:291–318. Review of TRPV1 antagonists in development, includes preclinical and clinical data. 157. Gunthrope MJ, Chizh BA. Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov Today 2009; 14:56–67. 158. Treviasani M, Gatti R. TRPV1 antagonists as analgesic agents. Open Pain J 2013; 6 (S1):108–118. 159. Gavva NR, Treanor JJ, Garami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008; 136:202–210. 160. Othman AA, Nothaft W, Awni WM, Dutta S. Pharmacokinetics of the TRPV1 antagonist ABT-102 in healthy human volunteers: population analysis of data from 3 phase 1 trials. J Clin Pharmacol 2012; 52:1028–1041. 161. Rowbotham MC, Nothaft W, Duan WR, et al. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 2011; 152:1192–1200. 162. Nash MS, McIntyre P, Groarke A, et al. BCTP, a classic polymodal inhibitor of TRPV1 with a reduced liability for hyperthermia, is analgesic and ameliorates visceral hypersensitivity. J Pharmacol Exp Ther 2012; 342:389–398. 163. Watabiki T, Kiso T, Kuramochi T, et al. Amerljoiration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. J Pharmacol Exp Ther 2011; 336:743–750. 164. Benzon HT, Raja SN, Liu SS, et al. Essentials of pain medicine, 3rd ed. Philadelphia: Elsevier; 2011. 165. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain: multiple drug targets and multiple uses. Curr Pharm Des 2005; 11:2977–2994. 166. Childers WE, Baudy RB. N-Methyl-D-aspartate antagonists and neuropathic pain: the search for relief. J Med Chem 2007; 50:2557–2566. 167. Laube B, Kuhse J, Betz H. Evidence for a tetrameric structure of recombinant NMDA receptors. J Neurosci 1998; 18:2954–2961. 168. Kristensen JD, Svensson B, Gordh T Jr. The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans. Pain 1992; 51:249–253. 169. Jones MW, McClean M, Parsons CG, Headley PM. The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurons. Neuropharmacology 2001; 41:50–61. 170. McQuay HJ, Carroll D, Jadad AR, et al. Dextramethorphan for the treatment of neuropathic pain: a double-blind randomized controlled crossover trial with integral n-of-1 design. Pain 1994; 59:127–133. 171. Nelson KA, Park KM, Robinovitz E, et al. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997; 48:1212–1218. 172. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methylD-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized double-blinded, cross-over study. Anesth Analg 2000; 91:960–966. 173. Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and doseresponse trials. Anesthesiology 2002; 96:1053–1061. 174. Eisenberg E, Kleiser A, Dortort A, et al. The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study. Eur J Pain 1998; 2:321–327. 175. Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain: results of a randomized double-blinded, placebo-controlled trial. Pain 2003; 103:277– 283.



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Drugs in anesthesia 176. Basile AS, Janowsky A, Golembiowska K, et al. Characterization of the antinociceptive actions of bicifadine in models of acute, persistent and chronic pain. J Pharmacol Exp Ther 2007; 321:1208–1225. 177. Riff D, Huang N, Czobor P, Stern W. A five-day, multicenter, randomized, placebo-controlled, double-blind, efficacy and safety study of bicifadine and tramadol versus placebo in the treatment of postoperative bunionectomy pain. J Pain 2006; 7:S40. 178. Krieter PA, Gohdes M, Musick TJ, et al. Pharmacokinetics, disposition, and metabolism of bicifadine in humans. Drug Metab Dispos 2008; 36:252– 259. 179. Czobor P, Skolnick P. The secrets of a successful clinical trial: compliance, compliance, compliance. Mol Intervent 2011; 11:107–110. 180. Parsons CG. NMDA receptors as targets for drug action in neuropathic pain. Eur J Pharmacol 2001; 429:71–78. 181. Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmcol Sci 2001; 22:636–642. 182. Boyce S, Wyatt A, Webb JK, et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localization of NR2B subunit in dorsal horn. Neuropharmacology 1999; 38:611–638. 183. Sang CN, Weaver JJ, Jinga L, Wouden J, Saltarelli MD (2003). The NR2B subunit-selective NMDA receptor antagonist, CP-101,606, reduces pain intensity in patients with central and peripheral neuropathic pain. Program No. 814.9. 2003 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience. 184. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-spartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol 2011; 4:379– 388. 185. Koller M, Urwyler S. Novel N-methyl-D-aspartate receptor antagonists: a review of compounds patented since 2006. Expert Opin Therapeut Patents 2010; 20:1683–1702. 186. Danysz W, Parsons AC. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 1998; 50:597–664. 187. Wallace MS, Rowbotham MC, Katz NP, et al. A randomized, double-blind, placebo controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002; 59:1694–1700. 188. Jarvis MF, Honore P, Shieh CC, et al. A-83467, a potent and selective Na v 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. PNAS 2007; 104:8520–8525. 189. Lee JH, Park CK, Chen G, et al. A monoclonal antibody that targets a NaV1.7 & channel voltage sensor for pain and itch relief. Cell 2014; 6:1393–1404. Example of a monoclonal antibody approach for the study and targeting of sodium channel isoform NaV1.7. 190. Liu M, Wood JN. The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med 2011; 12:S93–S99. 191. Hains BC, Klein JP, Saab CY, et al. Upregulation of sodium channel Na v 1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 2003; 23:8881–8892. 192. Lindia JA, Ko¨hler MG, Martin WJ, Abbadie C. Relationship between sodium channel Nav1.3 expression and neuropathic pain behavior in rats. Pain 2005; 117:145–153. 193. Gold MS, Weinreich D, Kim CS, et al. Redistribution of Nav1.8 in uninjured axons enables neuropathic pain. J Neurosci 2003; 23:158–166. 194. Dong XW, Goregoaker S, Engler H, et al. Small interfering RNA-mediated selective knockdown of Nav1.8 tetrodotoxin resistant sodium channel reverses mechanical allodynua in neuropathic rats. Neurosci 2007; 146:812– 821. 195. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006; 444:894–898. 196. Jukic M, Kikelj D, Anderluh M. Isoform selective voltage-gated sodium & channel modulators and the therapy of pain. Curr Med Chem 2014; 21:164–186. Small-molecule approach for the study and targeting of specific sodium channel isoforms. 197. Drenth JP, Finley WH, Breedveld GJ, et al. The primary erythermyalgiasusceptibility gene is located on chromosome 2q31-32. Am J Hum Genet 2001; 68:1277–1282. 198. Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 2006; 52:767–774. 199. Catteral WA. Structure and regulation of voltage gated Ca2þ channels. Annu Rev Cell Dev Biol 2000; 16:521–555. 200. Cao YQ. Voltage-gated calcium channels and pain. Pain 2006; 126:5–9. 201. Cizkova D, Marsala J, Lukacova N, et al. Localization of N-type Ca2þ channels in the rat spinal cord following chronic constriction nerve injury. Exp Brain Res 2002; 147:456–463. 202. Yaksh TL. Calcium channels as therapeutic targets in neuropathic pain. J Pain 2006; 7:S13–30. 203. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 2006; 31:393–406.

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204. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. J Am Med Assoc 2004; 291:63–70. 205. Maier C, Gockel HH, Gruhn K, et al. Increased risk of suicide under intrathecal ziconotide tredatment? A warning. Pain 2010; 152:235–237. 206. Lee M, Snutch T. Z160: a potent and state-dependent, small molecule blocker of N-type calcium channels effective in nonclinical models of neuropathic pain. J Pain 2013; 14:S71. 207. Gilron I, Dickenson AH. Emerging drugs for neuropathic pain. Expert Opin && Emerg Drugs 2014; 19:329–341. Comprehensive literature search of drugs in development for treatment of neuropathic pain. 208. Short G, Lee M, Snutch T. Z944: a first in-class T-type calcium channel blocker effective in nonclinical models of acute and inflammatory pain. J Pain 2013; 14:S71. 209. Rahman W, Dickenson AH. Voltage gated sodium and calcium channel blockers for the treatment of chronic inflammatory pain. Neurosci Lett 2013; 557:19–26. 210. Lembo PM, Grazzini E, Groblewski T, et al. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 2002; 5:201–209. 211. Li Z, He SQ, Xu Q, et al. Activation of MrgC receptor inhibits N-type calcium & channels in small-diameter primary sensory neurons in mice. Pain 2014; 155:1613–1621. Describes potential role of Mrg receptor in pain processing. 212. Dong X, Han S, Zylka MJ, et al. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 2001; 106:619– 632. 213. Guan Y, Liu Q, Tang Z, et al. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Proc Natl Acad Sci USA 2010; 107:15933– 15938. 214. Cai M, Chen T, Quirion R, Hong Y. The involvement of spinal bovine adrenal medulla 22-like peptide, the proenkephalin derivative, in modulation of nociceptive processing. Eur J Neurosci 2007; 26:1128–1138. 215. Jiang J, Wang D, Zhou X, et al. Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms. Br J Pharmacol 2013; 170:1027–1040. 216. Grazzini E, Puma C, Roy MO, et al. Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc Natl Acad Sci USA 2004; 101:7175–7180. 217. Viet CT, Schmidt BL. Biologic mechanisms of oral cancer pain and implications for clinical therapy. J Dent Res 2012; 91:447–453. 218. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human antitumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48:35–45. 219. Furst DE, Schiff MH, Fleischmann RM, et al. Adalimumab, a fully human anti tumor necrosis factor-a monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003; 30:2563–2571. 220. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human antitumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004; 50:1400–1411. 221. van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004; 63:508–516. 222. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340:253– 259. 223. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130:478–486. 224. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 50:353–363. 225. Callhoff J, Sieper J, Weib A, et al. Efficacy of TNF a blockers in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis: a metaanalysis. Ann Rheum Dis 2014; 0:1–8. 226. Goulabchand R, Mouterde G, Barnetche T, et al. Effect of tumour necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 2014; 73:414–419. 227. Furst DE, Keystone EC, Braun J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2011. Ann Rheum Dis 2012; 71 (Suppl II):i2–i45. 228. Olmarker K, Nutu M, Storkson R. Changes in spontaneous behavior in rates exposed to experimental disc herniation are blocked by selective TNF-a inhibition. Spine 2003; 28:1635–1642.




ACO 280408

Emerging targets in treating pain Chang et al. 229. Korhonen T, Karppinen J, Paimela L, et al. The treatment of disc-herniation induced sciatica with infliximab: one year follow-up results of FIRST II, a randomized controlled trial. Spine 2006; 31:2759–2766. 230. Genevay S, Viatte S, Finckh A, et al. Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62:2339–2346. 231. Cohen SP, White RL, Kurihara C, et al. Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann Intern Med 2012; 156:551–559. 232. Kume K, Amano S, Yamada S. The efficacy and safety of caudal epidural injection with the TNF-alpha antagonist, etanercept, in patients with disc herniation-induced sciatica. Results of a randomized, controlled, 1-month follow-up study. Ann Rheum Dis 2008; 67 (Suppl II):131. 233. Freeman BJ, Ludbrook GL, Hall S, et al. Randomized, double-blind, placebocontrolled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. Spine (Phila Pa 1976) 2013; 38:1986–1994. 234. Ohtori S, Miyagi M, Eguchi Y, et al. Epidural administration of spinal nerves with the tumor necrosis factor-a inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine (Phila Pa 1976) 2012; 15:439– 444. 235. Gosselin RD, Suter MR, Ru-Rong Ji RR, et al. Glial cells and chronic pain. Neuroscientist 2010; 16:519–531. 236. Toyomitsu E, Tsuda M, Yamashita T, et al. CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signal 2012; 8:301– 310. 237. Mika J, Zychowska M, Popiolk-Barczyk K, et al. Importance of glial activation in neuropathic pain. Eur J Pharmacol 2013; 716:106–119. 238. Tsuda M, Kuboyama K, Inoue T, et al. Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol Pain 2009; 5:28. 239. Landry RP, Jacobs VL, Romero-Sandoval EA, et al. Propentoflylline, a CNS glial modulator does not decrease pain in postherpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp Neurol 2012; 234:340–350. 240. Martinez V, Szekely B, Lemarie J, et al. The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain 2013; 154:1197–1203. 241. Siedel MF, Herguijuela M, Forkert R, et al. Nerve growth factor in rheumatic diseases. Semin Arthritis Rheum 2010; 40:109–126. 242. Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of nerve growth factor. Trends Pharm Sci 2006; 27:85–91. 243. Watson JJ, Allen SJ, Dawbarn DD, et al. Targeting nerve growth factor in pain. Biodrugs 2008; 22:349–359. 244. Bennett DL, Averill S, Clary DO, et al. Postnatal changes in the expression of the trkA high-affinity NGF receptor in primary sensory neurons. Eur J Neurosci 1996; 8:2204–2208. 245. Bennett DL. Neurotrophic factors: important regulators of nociceptive function. Neuroscientist 2001; 7:13–17. 246. Bannwarth B, Kostine M. Targeting Nerve Growth Factor (NGF) for Pain && Management: What Does the Future Hold for NGF Antagonists? Drugs 2014; 74:619–626. Detailed account of the clinical development of NGF antagonists including the 2010 FDA hold and subsequent 2012 FDA Arthritis Advisory Committee ruling. 247. Lewin GR, Lechner SG, Smith ES. Nerve growth factor and nociception: && from experimental embryology to new analgesic therapy. Handb Exp Pharmacol 2014; 220:251–282. Extensive and detailed overview of NGF physiology. 248. Holmes D. Anti-NGF painkillers back on track? Nat Rev Drug Disc 2012; 11:337–338. 249. Owolabi JB, Rizkalla G, Tehim A, et al. Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat. J Pharm Exp Ther 1999; 289:1271–1276.

250. Winston JH, Toma H, Shenoy M, et al. Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a. J Pain 2003; 4:329–337. 251. Wong RKS, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Syst Rev 2002; 2:CD002068. 252. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; 2:CD003474. 253. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 2012; 5:CD003188. 254. Yuen KK, Shelley M, Sze WM, et al. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 2006; CD006250. 255. Bonabello A, Galmozzi MR, Canaparo R, et al. Long-term analgesic effect of clodronate in rodents. Bone 2003; 33:567–574. 256. Winston MJ, Srivastava T, Jarka D, Alon US. Bisphosphonates for pain management in children with benign cartilage tumors. Clin J Pain 2012; 28:268–272. 257. Yanow J, Pappagallo M, Pillai L. Complex regional pain syndrome (CRPS/ RSD) and neuropathic pain: role of intravenous bisphosphonates as analgesics. ScientificWorldJournal 2008; 8:229–236. 258. Tran DQ, Duong S, Bertini P, Finlayson RJ. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anaesth 2010; 57:149–166. 259. O’Connell NE, Wand BM, McAuley J, et al. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev 2011; CD009416. 260. Ohtori S, Akazawa T, Murata Y, et al. Risedronate decreases bone resorption and improves low back pain in postmenopausal osteoporosis patients without vertebral fractures. J Clin Neurosci 2010; 17:209–213. 261. Pappagallo M, Breuer B, Lin HM, et al. A pilot trial of intravenous pamidronate for chronic low back pain. Pain 2014; 155:108–117. 262. Morden NE, Munson JC, Smith J, et al. Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury. Osteoporos Int 2015; 26:663–672. 263. Cury Y, Picolo G, Gutierrez VP, Ferreira SH. Pain and analgesia: the dual effect of nitric oxide in the nociceptive system. Nitric Oxide 2011; 25:245– 254. 264. Schmidtko A, Tegeder I, Geisslinger G. No NO, no pain? The role of nitric oxide and cGMP in spinal pain processing. Trends Neurosci 2009; 32:339– 346. 265. Miclescu A, Gordh T. Nitric oxide and pain: ‘something old, something new’. Acta Anaesth Scand 2009; 53:1107–1120. 266. Jain NK, Patil CS, Singh A, Kulkarni SK. Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine. Pharmacology 2003; 67:150–156. 267. Rocha FA, Silva FS Jr, Leite AC, et al. Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release. Br J Pharmacol 2011; 164 (2b):828–835. 268. Huang LJ, Yoon MH, Choi JI, et al. Effect of sildenafil on neuropathic pain and hemodynamics in rats. Yonsei Med J 2010; 51:82–87. 269. An open label, dose finding trial of viagra for the treatment of neuropathic pain (in diabetes mellitus). Bethesda, MD: National Library of Medicine (US)/ClinicalTrials.gov, 2015. https://clinicaltrials.gov/ct2/show/NCT 00194909? term¼sildenafilþpain&rank¼2. [Accessed 1 Feb 2015] 270. Serafim RA, Primi MC, Trossini GH, Ferreira EI. Nitric oxide: state of the art in drug design. Curr Med Chem 2012; 19:386–405. 271. Romero-Sandoval EA, Curros-Criado MM, Gaitan G, et al. Nitroparacetamol (NCX-701) and pain: first in a series of novel analgesics. CNS Drug Rev 2007; 13:279–295. 272. Lauretti GR, Perez MV, Reis MP, Pereira NL. Double-blind evaluation of transdermal nitroglycerine as adjuvant to oral morphine for cancer pain management. J Clin Anesth 2002; 14:83–86. 273. Lauretti GR, Lima IC, Reis MP, et al. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999; 90:1528–1533.



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Emerging targets in neuroinflammation-driven chronic pain.

Emerging targets for treating sulfur mustard-induced injuries.

Emerging potassium channel targets for the treatment of pain.

Emerging targets in migraine.

Emerging targets in osteoarthritis therapy.

Tamoxifen Resistance: Emerging Molecular Targets.

Emerging therapeutic targets in esophageal adenocarcinoma.

Emerging therapeutic targets in bladder cancer.

Emerging microtubule targets in glioma therapy.

Emerging targets and therapeutic approaches for the treatment of osteoarthritis pain.

Treating femoropopliteal disease: established and emerging technologies.

Therapeutic targets for treating fibrotic kidney diseases.

Editorial: Orphan GPCRs As Emerging Drug Targets.

Emerging targets for glioblastoma stem cell therapy.

MicroRNAs: emerging novel targets of cancer therapies.

Molecular pathophysiology of priapism: emerging targets.

Tuberculosis drug discovery and emerging targets.

Extracellular vesicles: emerging targets for cancer therapy.

Emerging molecular targets and therapy for cholangiocarcinoma.

Treating acute pain in light of the chronification of pain.

Buprenorphine for treating cancer pain.

Treating pain in patients with impaired cognition.

Treating abdominal pain in young people.

Sodium channel β subunits: emerging targets in channelopathies.