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 . In a 2010 report, the Institute of Medicine estimated that chronic pain afflicts one out of three Americans, costing between $560 and $635 billion . 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].
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 non-neural 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 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 . In patients with chronic pain, approximately 15–25% have a neuropathic cause [10–12] (Fig. 1).
The pharmacological treatment of chronic pain is characterized by high failure rates and side-effects. For example, in neuropathic pain, the number-needed-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 . 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 , 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 .
In the effort to find opioid analgesics that are safer and better tolerated than classic mu opioid agonists, drug research has focused on strategies to identify potential targets that provide a larger therapeutic index.
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 . 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 . 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 . In terms of drug development, Cara Therapeutics has two peripherally selective kappa agonists in their drug development pipeline . 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 . 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 . According to the company website, oral formulations of CR845 have completed phase I trials with plans to pursue phase II testing in 2015 .
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 . 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 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].
Studies of opioid receptor subtypes have revealed the formation of functional heteromers (associations between different receptor subtypes) with distinct ligand binding properties and intracellular signaling . 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 , the precise role of heteromers in pain processing remains unknown [25▪]. Based on studies demonstrating the co-localization of the cannabinoid CB1 and mu opioid receptors, some researchers have hypothesized the existence of a CB1-mu opioid receptor heteromer .
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 , 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 .
Despite structural similarities with classical opioid receptors, ORL-1 is insensitive to naloxone . 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 Ca2+ channels and opening of inward rectifying K+ 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 , 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 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. 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. 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 .
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 opioid-tolerant mice . 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 side-effects .
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. Low-selectivity 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 . 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▪].
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 . Antidepressants are believed to potentiate these descending inhibitory pathways .
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 . 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 . 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 . 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 . Similarly, a 2011 mixed treatment comparison meta-analysis 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 meta-analyses 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 .
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 . Activation of H3Rs in the skin via Aβ fibers reduces calcitonin gene-related peptide (CGRP) and substance P release, leading to an anti-inflammatory response . In the spinal cord, H3R activation reduces the nociceptive response to mechanical and inflammatory stimuli . In the brain, histamine reduces nociceptive transmission via H1 and H2 receptors . Supraspinal blockade of H3Rs increases neuronal histamine release and provides pain relief .
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 . These responses are reversed by thioperamide . 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 .
In animals, GSK189254 was efficacious in reducing neuropathic pain induced by sciatic nerve chronic constriction injury and varicella-zoster . Further study has revealed a dose-dependent reversal of mechanical allodynia induced by spinal nerve ligation that is comparable to gabapentin . Future goals involve developing H3 antagonists that have good brain-penetrating properties and diminished systemic effects .
Alpha 2 receptor agonists
Alpha 2 adrenergic receptors (α2-AR) are located on primary afferent nerves, dorsal horn neurons, and within pain processing brainstem nuclei; they possess both peripheral and central antinociceptive effects. Mechanistically, α2-ARs are G-protein-coupled and operate through a cAMP-mediated pathway. α2-AR activation is also linked to diminished neurotransmitter release through direct regulation of voltage-gated calcium ion channels . α2-ARs are classified into three subtypes: α2a-AR, α2b-AR, and α2c-AR. Studies involving knockout models have demonstrated that α2a-AR is likely to be the dominant subtype in pain-processing 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 α2-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 α2-AR, mu-opioid receptor, and A1-adenosine receptor .
Spinal α2-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 . Supraspinal antinociceptive mechanisms involved in α2-AR-mediated analgesia remain controversial, as direct stimulation of supraspinal brainstem loci have yielded both positive and negative results in preclinical pain models . Preclinical models have demonstrated that periaqueductal gray area (PAG) descending inhibition of dorsal horn nociceptive transmission is at least partly mediated by α2-AR activation . 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 . 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 .
There are two US FDA-approved α2-AR agonists, clonidine and dexmedetomidine. Clonidine is a nonselective α2-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 . In chronic pain populations, a number of small prospective studies with intrathecal clonidine have been conducted . A double-blind, placebo-controlled 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 . 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 . In an attempt to assess the long-term benefits of intrathecal clonidine for chronic pain states, a small retrospective study by Ackerman et al., 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 . 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 .
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 α2-AR agonist with a shorter duration of action and eight times greater α2a-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 . 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].
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 . These results were tempered by a 2009 meta-analysis 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 . 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 . Their duration of action is generally short due to robust metabolic pathways in which both substances are catabolized to arachidonic acid . AEA has also been shown to activate pro-nociceptive vanilloid 1 receptors present on primary afferent nociceptive fibers .
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 placebo-controlled study investigating the effects of AZD1940 – a peripherally restricted CB1/CB2 receptor agonist – demonstrated no analgesic efficacy for capsaicin-induced pain .
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 . 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 . 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 . In addition to its ability to inhibit neuropathic hypersensitivity, AM1241 has been shown to be anti-inflammatory 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 .
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▪].
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 (<6), temperature (>42°C), and membrane depolarization. Receptor activation results in Na+ and Ca2+ 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 . 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 . 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 . 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 . 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 temperature have entered preclinical testing [156▪,158,162,163].
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 . 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 Ca2+-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 . 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) .
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 . Attempts to decrease off-target effects have led to the development of low-affinity channel blockers , 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 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 .
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 . 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) . 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 . 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 . 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 .
Glycine is an obligatory co-agonist that binds to the NR-1 subunit and potentiates NMDA receptor action . 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 . Several glycine antagonists have shown positive results in preclinical neuropathic and inflammatory pain models ; 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 .
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 ; 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 , 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 . NaV 1.8 antisense knockdown in rodent models of neuropathic pain demonstrates a pronociceptive role , 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 . 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 .
Voltage-gated calcium channels (N, T, α2δ subunits)
Voltage-gated calcium channels (VGCCs) are multicomponent complexes with a central pore-forming α1 subunit surrounded by α2δ, β and γ subunits . The α1 subunit largely determines channel function whereas additional subunits serve to regulate expression and trafficking of the VGCC complex . VGCCs are classified into high-voltage activated (L, N, P/Q, and R-type Ca2+ channels), requiring strong depolarization for activation, and low-voltage activated (T-type Ca2+ 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 . In regards to pain processing, N and T-type calcium channels, as well as the α2δ auxiliary subunit, have emerged as therapeutic targets. N-type channel expression is up-regulated in the spinal cord in rat models of peripheral nerve injury , and N-type blockade reduces ectopic activity in injured nerves . Knockout mice lacking N-type VGCCs exhibit decreased pain-related responses in models of neuropathic and inflammatory pain . 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 . 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 . 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 α2δ 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 α2δ subunit to dorsal horn synaptic terminals in neuropathic pain . 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 .
Mas oncogene-related gene receptor
Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in DRG and trigeminal ganglia . Our current understanding of Mrg receptor function in pain processing is poor, but based on rodent models, it 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)-γ2-MSH-6-12 [melanocyte-stimulating hormone (MSH)] . 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 . 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 . 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 . Given the focal distribution and specificity of the Mrg receptor, it is hoped that pharmacologic treatment will have limited side-effects.
Tumor necrosis factor alpha antagonists
Tumor necrosis factor α (TNF-α) is responsible for initiating the proinflammatory milieu of cytokines and growth factors implicated in pain. Multiple controlled trials have demonstrated the benefit of TNF-α 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-α use in these patient populations either as a monotherapy, combination therapy, or second-line treatment depending on the disease .
More recently, the role of TNF-α antagonists has been examined for mechanical spine and neuropathic pain. In preclinical trials, TNF-α antagonists prevent pain behaviors in rodents; yet, clinical trials performed in patients with mechanical spine pain and radiculopathy have been equivocal . Korhonen et al. found a significant reduction in leg pain after a single intravenous infusion of 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 = 61) found a small benefit favoring adalimumab through a 6-month follow-up . Evaluation of epidural TNF-α inhibitors for radicular pain has produced similarly mixed results . 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 . 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 . 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 . 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 . 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 . Humanized anti-NGF antibodies hold an advantage over small-molecule antagonists in that they generally have higher specificity and fewer off-target effects . 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 anti-NGF 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 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 . 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 . Nevertheless, future developments will likely result in compounds with greater specificity and tolerability.
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 . 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 . 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 . 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 .
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 . In preclinical studies, bisphosphonates have demonstrated antinociceptive effects in animal models of mechanical allodynia, visceral pain, and thermal nociception . The utilization of bisphosphonate therapy may be associated with adverse effects such as osteopetrosis, chronic musculoskeletal pain, and osteonecrosis of the jaw . 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 .
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 . Nevertheless, nitric oxide appears to have a dual effect on pain as it can promote both pro and antinociceptive effects . In addition to its direct analgesic effects, nitric oxide has also been implicated in the potentiation of opioid analgesia .
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 . 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 .
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 . 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 . 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 . 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 , 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 = 36 and n = 48), Loretti et al. found a significant reduction in opioid use after the addition of a nitroglycerin patch [272,273].
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].
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.
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