Analgesic Drugs in Development
Increasing understanding of the physiology and pharmacology of pain is making new therapeutic strategies accessible. This chapter deals with new developments in the discovery and clinical evaluation of analgesic drugs, as well as the mechanisms and utility of drugs introduced for other therapeutic targets but recently found empirically to have a place in the treatment of pain. Recent reviews (Graul 2003, Nitu et al 2003, Gilron and Coderre 2007, Kissin 2010) highlight drugs currently in development for the treatment of pain. These drugs, in the main, fall into known therapeutic classes such as opioid analgesics, cyclooxygenase (Cox) blockers, and local anesthetics, but some novel agents are mentioned (e.g., blockers of calcitonin gene–related peptide [CGRP] receptors and antibodies against nerve growth factor [NGF]) that constitute real therapeutic innovation. There is also a significant population of drugs previously introduced for other therapeutic indications (e.g., anticonvulsants) that are being developed for the additional indication of the treatment of pain. For example, Kissin (2010) points out that between 1960 and 2009, 59 drugs were introduced that are useful in the treatment of pain, 39 of which were specifically introduced for treating pain and 20 initially intended for non-pain indications. Drug discovery is still an imprecise discipline with no guarantee that agents discovered to be active in preclinical tests will, in fact, be clinically efficacious. In particular, the ratio of analgesic effects to unwanted adverse effects can be assessed only in the clinic. As yet we have incomplete understanding of the mechanisms underlying neuropathic pain (see Scadding 2003 and Chapters 61, 62 and 63), and this complicates the search for new drugs to treat it. Even acute pain is currently not well treated in all cases, and although some of the reasons for this are attributable to inappropriate or insufficient use of existing therapies (Bandolier 2003), there is clearly also a need here for effective, yet well-tolerated new analgesics. Early-stage discovery research on novel strategies to produce pain-relieving drugs is very active (Hill 2003, Woodcock et al 2007, Melzack 2008), but it will be some time before the benefits of this research are seen at the level of patient care. This chapter concentrates on novel chemical entities that are either in or close to clinical evaluation and does not attempt to provide an extensive discussion of all drugs at the research stage with the potential to be used for the treatment of pain.
A large number of potential targets for the discovery of novel analgesic drugs have emerged in the past 5 years or so (Boyce et al 2001, Hill 2003, Wesselmann et al 2009, Melnikova 2010), but because we have poor understanding of the pathophysiology of pain, few of them have a high probability of success until the drugs discovered have reached the stage of phase II clinical proof of concept. The targets fall into three main classes:
The first target has the highest chance of being successful but possibly the least chance of being a real therapeutic advance. The cost–benefit analysis for each of these strategies is different. Although refinement of existing drugs provides the greatest probability of success, there comes a time when the improvement is so small that the drug will not recoup its cost of development (see later).
Progress in molecular neurobiology has generated a stream of new putative targets. However, this approach has yet to deliver an analgesic to the clinic. Phenotyping of transgenic mice in pain and inflammation assays can provide early target validation, although adoption of such targets is a high-risk strategy. Identifying receptor or ion channel targets that show phenotypic changes related to the pathophysiology of human pain could provide treatments of pain syndromes that are refractory to existing analgesics. At the preclinical level, many potential novel targets have been identified directly as a result of genomic studies, including the use of gene subtraction methods to determine changes in gene expression in pathological tissue following injury or inflammation. A major challenge will be to predict the physiological and pathophysiological relevance of novel targets and the potential efficacy versus adverse effects of compounds that act on the final protein products of these genes. The importance of this cannot be underestimated since there are likely to be more targets than can be viably exploited, and success in developing novel analgesics is going to be increasingly dependent on judicious identification of the best targets. To achieve this, potential targets need to be strictly reviewed in the context of evidence from both clinical and preclinical sources, including data from transgenic animals, as well as evidence from the observed pharmacology of available analgesic compounds (Hill 2003, Woodcock et al 2007).
Information from genomic studies can help in the identification and evaluation of subtypes and/or splice variants of targets identified from clinical or preclinical studies. For example, some of the more effective treatments of neuropathic pain are compounds with sodium channel–blocking properties such as carbamazepine, phenytoin, mexiletine, and amitriptyline. The therapeutic utility of these compounds is, however, limited by their wide spectrum of pharmacological action and, importantly, the non-selective targeting of sodium channel subtypes, which together results in a small therapeutic window (see below).
One significant barrier is that the existing animal models of pain that are used to evaluate candidate analgesics are not always predictive of analgesic activity in human pain patients (for a discussion of this issue, see Hill 2004, Negus et al 2006, Woodcock et al 2007). This means that clinical testing is always necessary when a new analgesic hypothesis is to be evaluated following safety assessment of a new chemical entity. It also predicates testing in pain patients rather than in experimental medicine volunteers because although an experimental medicine approach can be helpful, even this approach has its drawbacks. Petersen and colleagues (2003) found that the clinical effectiveness of lamotrigine in patients with neuropathic pain could not be duplicated in a human volunteer model of neuropathic pain, although other analgesic drugs were effective in this paradigm. They explained this difference by suggesting that the physiological and biochemical changes consequent on neuropathy generated the lamotrigine sensitivity observed in patients with neuropathic pain but that similar changes in sensitivity could not readily be simulated in healthy volunteers.
Currently, only some 20% of drugs entering clinical evaluation become marketed medications, and for central nervous system (CNS) drugs (the category into which many analgesics fall), the success rate drops to about 14% (Dickson and Gagnon 2004). Clinical testing is both expensive and time-consuming; it costs up to $450 million (Rawlins 2004) and takes an average of 5 years (Dickson and Gagnon 2004) to establish the needed clinical efficacy, safety, and a suitable dose range for routine use (Rawlins 2004). The total cost of the whole process of discovery and development of a new drug may be as high as $800 million and takes, on average, 12.8 years (Dickson and Gagnon 2004). The introduction of increased regulatory and safety requirements and increased levels of competition in the pharmaceutical industry add to the difficulties of the process (Woodcock et al 2007, Melnikova 2010).
Non-steroidal anti-inflammatory drugs (NSAIDs) and selective Cox-2 blockers have been found useful in the treatment of pain, and this topic is dealt with in detail elsewhere in this volume (see Chapters 32 and 33). It is noteworthy that a systematic review and a recent comparative study concluded that selective Cox-2 blockers such as etoricoxib, valdecoxib, and rofecoxib are more effective in the treatment of pain than are weak opioids such as oxycodone, tramadol, or codeine combined with paracetamol (Chen et al 2004; see also Brattwall et al 2010). Overall, Cox-2 blockers have a similar analgesic efficacy and ceiling as non-selective NSAIDs, thus suggesting that it is blockade of Cox-2 and not Cox-1 that is the important property for pain relief. Increasing evidence suggests that the important locus of action for pain relief with Cox-2 blockers is in the CNS (for a review on Cox-blocking drugs, see Warner and Mitchell 2004).
There has been much interest in developing NSAIDs with a nitric oxide (NO) donor moiety attached as an alternative way of avoiding the irritant effects of NSAIDs on the gastrointestinal tract but allowing both Cox-1 and Cox-2 to be blocked (Ongini and Bolla 2006), although recently the Food and Drug Administration (FDA) refused to approve the registration of naproxcinod (Lowry 2010). In experiments in volunteers it was shown that the Cox-2 blocker celecoxib, when given together with low-dose aspirin, loses its gastrointestinal tract–sparing effect but that if NO–aspirin is co-administered, the gastric mucosa is protected in the presence of blockade of both Cox-1 and Cox-2 (Fiorucci et al 2003). It has also been suggested that drugs that block both Cox enzymes and 5-lipoxygenase (5-Lox)—and thereby reduce production of both prostanoids and leukotrienes—would constitute another useful class of anti-inflammatory analgesics that would have minimal irritant effects on the gastrointestinal tract. Licofelone, currently the most advanced drug claimed to work by this Cox/5-Lox blocking mechanism, is in phase III clinical trials (Martel-Pelletier et al 2003, Raynauld et al 2010) and has recently been shown to reduce cartilage loss in patients with osteoarthritis, in addition to its analgesic properties. The withdrawal of some of the Cox-2–selective agents from the market along with the introduction of more stringent monitoring of the remainder (see Psaty and Weiss 2007, Warner and Mitchell 2008) has shifted emphasis to alternative strategies such as specific 5-Lip inhibitors (Masferrer et al 2010), prostaglandin E synthase blockers (Trebino et al 2003), or prostaglandin receptor (EP receptor) blockers (Clark et al 2008).
New formulations of traditional opioids such as morphine continue to be introduced as advances in formulation technology are made (see Melnikova 2010). The morphine metabolite morphine-6-glucuronide is also being developed as an injectable analgesic (Graul 2003, Olofsen et al 2010). Although it remains to be demonstrated conclusively that it has significant clinical advantages over the parent compound or over other synthetic opioids that are already available, it is encouraging that in phase II and III postoperative pain studies, analgesia similar to that seen with morphine was achieved along with a lower incidence of nausea and vomiting. Phase III trials were completed in 2007 and a partner is being sought to commercialize this agent (Paion website, accessed October 29, 2010, http://www.paion.de). Tapentadol is a new agent with μ-opioid agonist and noradrenaline uptake blocking properties that has analgesic potency in acute pain states higher than would be predicted from its opioid receptor affinity alone (Afilalo et al 2010). There is still active research on the idea of a peripherally restricted μ-opioid that will produce analgesia (probably by way of modulation of the immune system) but without any potential for CNS side effects (Sehgal et al 2011, Stein and Machelska 2011). There is also continued interest in the sublingual and intranasal delivery of opioids, especially those related to fentanyl. In particular, it has been suggested that buprenorphine might be suitable for intranasal delivery, although studies on abuse potential have shown that the intranasal route is favored by those taking buprenorphine recreationally, so considerable regulatory hurdles may face the introduction of such a product (Middleton et al 2011).
It is noteworthy that some κ-opioid agonists are still in clinical evaluation even though earlier studies had shown that the CNS side effect–to-efficacy ratio of this class of compound was not favorable (see Vanderah 2009). Current developmental compounds are aimed at peripheral κ-opioid receptors and have minimal brain penetration so that unwanted central side effects such as sedation and dysphoria can be avoided. Eisenach and colleagues (2003) demonstrated in a small randomized, double-blind study that ADL 10-0101 reduced pain in chronic pancreatitis patients with ongoing abdominal pain that was resistant to concomitant μ-opioid therapy. Another peripheral κ-opioid, CR665, was found to attenuate experimental visceral pain but not cutaneous pain in volunteers (Arendt-Neilsen et al 2009). It has been suggested that co-administration of the opioid antagonist naloxone with the κ-opioid partial agonist nalbuphine (both in carefully defined doses) can optimize the κ-opioid analgesic effect in both men and women (Gear et al 2003). A small open trial has indicated that this regimen may be useful in treating neuropathic trigeminal pain (Schmidt et al 2003). It has been claimed that opioids that have mixed agonism at both μ- and δ-opioid receptors, such as DPI-3290 (Gengo et al 2003), can produce the full analgesic spectrum of a μ-agonist but with less respiratory depression (as estimated by hypercapnia) in animal experiments. SB-235863 and JNJ-20788560 are novel δ-opioid–selective agonists that were effective in animal models of inflammatory and neuropathic pain but with no effect on baseline nociception and reduced potential for respiratory depression, tolerance, and dependence (Petrillo et al 2003, Codd et al 2009). The utility of selective δ-opioid agonists has not yet been confirmed in published human clinical trials.
Self-medication with cannabis is commonly used to relieve pain and other symptoms in patients with multiple sclerosis (Clark et al 2004), and it now appears that this will lead to a well-validated clinical application. There has been a resurgence in interest of late because of the initiation of a new sequence of clinical trials on pain conditions using standardized preparations of herbal extracts of cannabis containing defined amounts of the active chemical principles (Notcutt et al 2004). Some positive data have been reported (Notcutt et al 2004), but there are also negative studies on experimental pain in volunteers (Naef et al 2003) and on postoperative pain (Buggy et al 2003). It has recently been announced that a phase III trial with a standardized preparation of cannabis (Sativex) has shown a statistically significant reduction in pain, particularly in patients with neuropathic pain or cancer pain, when added to the patients’ existing pain control medication (GW Pharmaceuticals website, accessed October 23, 2010, http://www.gwpharm.com). Sativex is now licensed for the treatment of spasticity associated with multiple sclerosis in the United Kingdom and is in phase III clinical trials for the treatment of pain (Buggy et al 2003).
Preclinical research on cannabinoid pharmacology is active, and we now know that there are two G protein–coupled receptors (CB1 and CB2) sensitive to cannabis and endogenous cannabinoids (Sawynok 2003). The exclusive peripheral localization of the CB2 receptor raises the possibility of using agonists for this site as analgesics lacking the unwanted central psychotropic effects of cannabis (Guindon and Hohmann 2008). Selective agonists for the CB2 receptor have been claimed in the past, but many of these are partial agonists or have mixed pharmacology. A-796260 does appear to be a selective and efficacious CB2 agonist and is effective in a wide range of animal pain models (Yao et al 2008). There is an interesting overlap in the pharmacology of agents acting at cannabinoid receptors and those acting at VR1/transient receptor potential vanilloid 1 [TRPV1]) (see later). It is noteworthy that selective activation of CB2 receptors was found to suppress the hyperalgesia produced by intradermal capsaicin (Hohmann et al 2004), thus reinforcing the idea that CB2 agonists may have a role as analgesic drugs.
The effect of the endogenous purine adenosine on pain perception in humans is complex, with high intravenous doses evoking pain but low doses providing pain relief (Sawynok 2003, Sjolund et al 1999). Clinical analgesia has been observed in volunteer studies on cutaneous hyperalgesia following inflammatory pain when adenosine was given intravenously (Sjolund et al 1999) and in patients with neuropathic pain when adenosine was given intrathecally (Belfrage et al 1999). A recent clinical study on postoperative pain patients failed to show analgesia after administration of the selective A1 receptor agonist GR79236X, although the active control diclofenac was effective (Sneyd et al 2007). Recent animal experiments suggest that both A2A and A2B antagonists have potential in the treatment of inflammatory pain (Bilkei-Gorzo et al 2008).
The α2 adrenoceptor agonist clonidine has distinct analgesic properties when given either systemically or spinally that are separable from its other pharmacology. Use of this drug as an analgesic is limited by the sedative and vasodepressor properties that are produced by similar doses. The ratio of unwanted to wanted effects can be maximized by giving clonidine intrathecally, and it also works well when given epidurally. It has been claimed to be effective against acute and chronic pain, including cancer pain (Coombs et al 1985; Eisenach et al 1989, 1995), and may be effective in patients who have become tolerant to opioids or are suffering neuropathic pain. In a multicenter double-blind trial, epidural clonidine given concomitantly with epidural morphine improved pain relief in patients with severe cancer pain (Eisenach et al 1995). Only patients with neuropathic pain benefited from this treatment. Falls in systemic blood pressure after epidural clonidine were rated as severe in only 2 patients of 38 studied, and the incidence of dry mouth and sedation was similar to that seen with morphine alone. Clonidine has been shown to potentiate the action of opioids and local anesthetics. Related drugs (e.g., xylazine, dexmedetomidine, and tizanidine) have similar properties. Tizanidine, though initially introduced for the treatment of spasticity (Gelber et al 2001), has been suggested to be useful in treating a range of painful conditions, including myofascial and neuropathic pain (Gosy 2001). Arain and co-workers (2004) have found that intravenous infusion of dexmedetomidine before the end of major surgical procedures can reduce the early postoperative need for morphine by up to 66% and that this drug is well tolerated.
The analgesic mechanism of action of α2 agonists is similar to that of morphine and is exerted via activation of post-synaptic receptors that are coupled to increasing outward K+ conductance, which reduces cellular excitability. Studies using selective antibodies to identify localization of the A, B, and C subtypes of α2 receptors within the dorsal horn of the spinal cord suggest that activation of the α2A receptor is responsible for the analgesic properties (Stone et al 1998). This conclusion is supported by the observation that in mice with the gene for the α2A receptor mutated to substitute the aspartate residue at position 79 (which is obligatory for a functional receptor) with arginine, dexmedetomidine and clonidine are no longer capable of producing analgesia, anesthesia sparing, or hyperpolarization of locus coeruleus neurons (Lakhlani et al 1997). This is unfortunate because in these mutant mice impairment of Rotorod performance and loss of the righting reflex effects of clonidine are also lost, thus suggesting that the same receptor produces the analgesic, sedative, and vasodepressor effects and therefore it is unlikely that an improved α2 agonist analgesic will result from the introduction of more subtype-selective agonists.
It has been suggested that non-adrenoceptor imidazoline receptors exist and are responsible for some of the pharmacology of clonidine and its analogues, but these receptors have not yet been cloned and consequently cannot yet be considered as viable drug discovery targets. Additionally, the phenotype of the transgenic mice just referred to makes it probable that adrenoceptor agonism is a sufficient explanation for the analgesic actions of clonidine and related molecules.
Serotonin (5-hydroxytryptamine [5-HT]) has been implicated in the control of pain sensation as a result of physiological studies in laboratory animals on descending inhibition of dorsal horn nociception by stimulation of 5-HT–containing pathways originating in the vicinity of the midbrain raphe nuclei. The use of 5-HT receptor agonists as analgesics has been limited to date because of a lack of agents selective for the different receptor subtypes (14 of which have been cloned to date), but this situation is changing, and ligands that block or stimulate most of these receptors are now available (Jones and Blackburn 2002). When 5-HT1A agonists have been evaluated in human studies, limiting side effects (nausea, sedation, decreased blood pressure) have generally occurred at doses not easily separable from those producing analgesia. However, Colpaert and colleagues (2002) described a high-efficacy 5-HT1A receptor agonist, F13640 or befiradol, which is effective in reducing allodynia-like behavior in both rats with spinal cord injury and rats with ligatures around the infraorbital nerve. It remains to be established whether F13640 will relieve severe pain in humans with an acceptable window from 5-HT1A–related adverse effects (Lacivita et al 2008), and it is reported to be in a phase II clinical trial. Paradoxically, the highly selective 5-HT1A antagonist AZD7371 (robalzotan) failed to relieve pain in patients with inflammatory bowel disease, although it was effective in animal models of visceral pain (Lindstrom et al 2009).
The 5-HT1B/D agonists (e.g., sumatriptan, zolmitriptan, naratriptan, elitriptan, frovatriptan, and rizatriptan) are extremely effective in the treatment of migraine headache but do not appear to be generally analgesic. This is likely to be attributable to selective regional functional distribution of these receptors such that, for example, sensory input within the dorsal horn of the spinal cord originating in the occipital division of the trigeminal nerve can be attenuated by agents of this class but input from the lumbar dorsal roots cannot (Cumberbatch et al 1998). Clinical trials with the selective 5-HT1D agonist PNU-142633 (Gomez-Mancilla et al 2001) found it to be ineffective at relieving migraine headache. It should be noted that this agent has lower efficacy than sumatriptan does at human 5-HT1D receptors, and it is therefore possible that the hypothesis has not yet been adequately tested. However, in the guinea pig (which has a similar anatomical distribution of 5-HT1D receptors as humans), PNU-142633 was effective in reducing neurogenic dural vasodilatation (Williamson et al 2001). The prophylactic potential of this mechanism appears worthy of further study should suitable full agonists at the human 5-HT1D receptor become available.
A selective 5-HT1F receptor agonist, LY334370 (Lilly), was found to not contract cerebral or coronary arteries but was effective in blocking neurogenic extravasation, and it reduced c-fos expression in the trigeminal nucleus caudalis following application of a noxious stimulus to the head (Shepheard et al 1999, Goldstein et al 2001). In a detailed series of experiments, Shepheard and associates (1999) showed that LY334370 had no effect on neurogenic dural vasodilatation and had no general analgesic properties but that it was effective in reducing activation of trigeminal nucleus caudalis neurons following electrical stimulation of the dura mater in the anesthetized rat. Clinical data from a placebo-controlled double-blind study of oral dosing of LY334370 for acute migraine showed that the higher doses of 60 and 200 mg were effective against migraine headache. However, this was associated with a greater incidence of central side effects such as dizziness and somnolence than has been reported with the triptans (Goldstein et al 2001). The high doses needed make it possible that the antimigraine effects were due, at least in part, to 5-HT1B agonism, and likewise, the side effects may have been due in part to 5-HT1A agonism (Goldstein et al 2001). Lasmiditan (LY573144) is a more selective 5-HT1F agonist than LY334370 and is currently in clinical development (Ferrari et al 2010, Nelson et al 2010). In a phase IIA study, intravenous lasmiditan was effective in the treatment of acute migraine, but mild CNS adverse effects were observed in some patients (Ferrari et al 2010). It has been found effective when given orally in a phase IIB study and is planned to enter phase III in the fourth quarter of 2010 (Colucid Pharma website, accessed October 23, 2010, http://www.colucid.com/colucid_press_release_6_9_10.pdf).
It is unlikely that the analgesic properties of tricyclic antidepressants are due solely to effects on 5-HT since selective 5-HT uptake blockers such as fluoxetine and paroxetine appear to be less useful for the treatment of pain than do non-selective agents such as amitriptyline (McQuay et al 1996). It has been suggested, however, that the novel analgesic DUP-631 works by blocking uptake of both 5-HT and noradrenaline (norepinephrine) (Cook and Schmidt 1997), and this has also been suggested by one authority as the factor underlying the analgesic actions of tricyclic antidepressants (Godfrey 1996). Other mechanisms such as ion channel blockade have also been suggested (see below). The idea that combined blockade of 5-HT and noradrenaline (norepinephrine) uptake might be useful in the treatment of pain has gained credence from recent data on the antidepressants venlafaxine, duloxetine, and milnacipran, which share this mechanism (Briley 2003, Nitu et al 2003):
Bicifadine is a novel analgesic that has been shown to block noradrenaline (norepinephrine) and 5-HT uptake and to modulate the actions of glutamate at its receptors (Thomson Reuters Investigational Drug Database [IDDB] May 2004). In clinical trials, initial data analyses have indicated that it is effective against dental postoperative pain and is well tolerated (Scrip, No. 2886, September 19, 2003), but in a phase IIB trial of bicifadine for the pain of diabetic neuropathy, it failed to reach its primary end point of a reduction in pain score (XTL Pharma press release, November 18, 2008, http://www.fiercebiotech.com/node/41681/print).
Glutamate is the most widely distributed excitatory neurotransmitter in the CNS and is released by all primary afferent fibers synapsing with secondary sensory neurons in the dorsal horn of the spinal cord (for a historical review, see Salt and Hill 1983). It is now known that glutamate can act at two families of ionotropic receptors, for convenience referred to as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and at a group of G protein–coupled receptors known as the metabotropic glutamate receptors. The putative analgesic effects of metabotropic receptor ligands will not be considered here. The majority of studies in humans have used agents that act at NMDA receptors, and antagonism of activation of NMDA receptors by drugs as an analgesic strategy has recently been reviewed in book form (Sirinathsinghji and Hill 2002).
The dissociative anesthetics phencyclidine and ketamine have analgesic actions at subanesthetic doses; this is now known to be due to blockade of glutamate action at NMDA receptors. These agents produce hallucinations and ataxia at doses only slightly higher than those needed to produce analgesia, but nevertheless, ketamine in particular has been shown to have some utility in controlling pain that may not be sensitive to other analgesic agents. Post-surgically it has been shown that ketamine will suppress the central sensitization expressed as punctate hyperalgesia around a surgical incision (Stubhaug et al 1997) and the secondary hyperalgesia in humans following an experimental burn (Warnke et al 1997). Interestingly, in this latter study the wind-up of pain caused by repeated stimulation with a von Frey hair in the region of secondary analgesia was suppressed by ketamine but not by morphine. In patients with the usually intractable pain of post-herpetic neuralgia, subcutaneous ketamine was found to provide relief (Eide et al 1995). Ketamine, though usually administered by injection as part of anesthetic practice, has reasonable oral bioavailability and will relieve the pain of glossopharyngeal neuralgia (Eide and Stubhaug 1997) or postamputation stump pain (Nikolajsen et al 1997) when given by this route. In a double-blind, crossover comparison with alfentanil and placebo, intravenous ketamine was shown to be able to reduce cold hyperalgesia in patients with neuropathic pain without changing the heat pain threshold (Jorum et al 2003). Intranasal ketamine has been found to be effective in treating breakthrough pain in chronic pain patients (Carr et al 2004).
Other drugs with the same mechanism of action as ketamine (i.e., use-dependent block of the NMDA receptor ion channel) have been evaluated in clinical trials:
Sang (2002) concluded that, overall, clinical studies of these agents have failed to demonstrate an unequivocal clinical analgesic effect, although there is a theoretical argument that they might be able to do this with fewer side effects than ketamine because of a faster rate of blocking and unblocking of the receptor. In a recent study it was shown that oral amantadine could reduce morphine consumption in radical prostatectomy patients when co-administered and to also improve pain relief (Snijdelaar et al 2004), thus raising the possibility of using these agents concurrently even if they are not efficacious as monotherapy. A systematic review of published clinical studies concluded that there was evidence of a reduction in pain or consumption of other analgesics in more than half of the studies with dextromethorphan and ketamine but no evidence of analgesia in studies in which Mg2+ was used as the NMDA receptor antagonist (McCartney et al 2004).
There is evidence from experiments in animals that agents acting at the glycine–co-agonist site on the NMDA receptor complex may offer a better side effect profile than the ion channel blocking drugs referred to earlier. This may be most evident when a partial agonist for the receptor is used (Laird et al 1996, Sirinathsinghji and Hill 2002). In a randomized, double-blind, placebo-controlled trial of the efficacy of the glycine site antagonist GV196771 in relieving neuropathic pain (Wallace et al 2002) it was concluded that it had no significant effect overall, although a reduction in allodynia was noted at individual time points during the 14-day treatment period. Perhaps the most encouraging possibility for drugs acting at the NMDA receptor is the discovery of agents that have subtype selectivity, especially agents selective for receptors containing the NR2B subunit, which are abundant in sensory pathways but not in other parts of the CNS such as the cerebellum (for review, see Sirinathsinghji and Hill 2002). In animal experiments, agents of this type (e.g., CP101,606) have an impressive therapeutic ratio and produce antinociception at doses that have no effect on locomotor performance (Boyce et al 1999). It has been demonstrated that CP101,606 can reduce pain in patients with spinal cord injury or monoradiculopathy and that it is well tolerated (Sang et al 2003). However, another NR2B selective blocker, radiprodil (RGH-896), did not show a meaningful reduction in daily pain scores in a study of the pain associated with diabetic neuropathy (Pharma Letter, July 2, 2010, accessed October 19, 2010, http://www.thepharmaletter.com/file/96354).
Some opioid drugs (ketobemidone, methadone, dextropropoxyphene, and pethidine) have also been suggested to have actions at NMDA receptors that may contribute to their analgesic properties, but no controlled clinical studies have been conducted to explore this possibility (Sang 2002).
There are a large number of members of this family, but the receptor most clearly identified with a role in nociception, on the basis of experiments in laboratory animals, is the GluR5 receptor, which is preferentially sensitive to the agonist kainate (Simmons et al 1998). Selective antagonists for the GluR5 receptor are now available, and LY382884 was found to be antinociceptive in the rat formalin test at doses that did not produce locomotor ataxia, whereas agents selectively blocking GluR2 receptors produced ataxia but were not antinociceptive (Simmons et al 1998). Tezampanel, a mixed kainate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker (active at both GluR2 and GluR5 receptors), has been evaluated for analgesic activity in human volunteers (Sang et al 1998). Maximal tolerated intravenous doses were found to reduce capsaicin-induced hyperalgesia and allodynia but to have no effect on baseline nociception. The dose that could be tolerated was limited by hazy vision in most subjects and sedation in about 40% of the subjects tested. It has also been shown that this compound, again given intravenously, is effective in abortive treatment of migraine headache and that side effects at effective doses were mild (Sang et al 2004), in contrast to reports in earlier studies involving experimental pain in volunteers. In a phase IIB study, intravenous tezampanel was found to be more effective than placebo in relieving migraine, and an oral prodrug (NGX426) is in evaluation as treatment of neuropathic pain and migraine (Raptor Pharmaceuticals website, accessed October 27, 2010, http://www.raptorpharma.com/tezampanel_migraine.html). NS1209, another mixed kainate/AMPA receptor blocker, has been shown to be active against some aspects of nerve injury pain when given intravenously and was better tolerated than intravenous lidocaine (Gormsen et al 2009). The selective AMPA receptor blocker E2007 (perampanel) is in phase II clinical trials for neuropathic pain and migraine prophylaxis (Mackey 2010).
It is worth noting that the current classification of analgesic drugs according to mechanism of action is somewhat arbitrary since many agents have multiple actions. For example, the anticonvulsant topiramate, which has been effective in some experimental neuropathic pain studies in humans and is used prophylactically against migraine, is not just a voltage-gated ion channel blocker (see later) but has also been shown to block kainate-evoked neuronal responses (Sang 2002).
There has been interest in the role of substance P (SP) in nociception since the suggestion that this peptide was concentrated in the dorsal roots (for a historical review, see Salt and Hill 1983). Mice in which the gene for the neurokinin 1 (NK1) receptor had been deleted showed deficiencies in spinal wind-up and intensity coding of spinal reflexes, although baseline nociception was unaffected (De Felipe et al 1998). In mice in which the gene encoding the precursor for SP, preprotachykinin, had been deleted, responses to mildly painful stimuli were intact but the response to more intense stimuli was attenuated (Zimmer et al 1998). The discovery of non-peptide antagonists of the NK1 (SP) receptor allowed testing of the hypothesis that antagonism of the effects of SP might lead to analgesia. In animal experiments, convincing evidence of antinociceptive effects has been obtained with these compounds, especially for inflammatory hyperalgesia (Rupniak et al 1995) or hypersensitivity induced by experimental diabetes (Field et al 1998). Despite evidence from animal studies of the antinociceptive effects of NK1 antagonists, the long-acting orally active NK1 receptor antagonist aprepitant, at a dose established to be antiemetic in humans (Navari et al 1999), was ineffective in relieving postoperative dental pain and was also ineffective in patients with established pain associated with post-herpetic neuralgia (Boyce and Hill 2004). The orally active NK1 antagonist lanepitant (LY303870; 50, 100, or 200 mg orally twice daily for 8 weeks) had no significant effect on pain intensity (daytime or nighttime) when compared with placebo in patients with painful diabetic neuropathy (Goldstein et al 1999). Lanepitant also had no effect on pain in patients with moderate to severe osteoarthritis (Goldstein et al 1998). Finally, clinical trials of NK1 receptor antagonists for acute migraine and migraine prophylaxis have also been disappointing. L-758,298, an intravenous prodrug of aprepitant, failed to abort migraine pain as measured either by the time to meaningful relief or by the number of patients reporting pain relief within 4 hours (Boyce and Hill 2004). Similarly, GR205171 (Connor et al 1998) and lanepitant (Goldstein et al 1997) were ineffective as abortive treatment of migraine headache. Furthermore, prophylactic administration of lanepitant (200 mg/day orally) for 1 month had no effect on migraine frequency and severity when compared with placebo (Goldstein et al 1999).
The lack of clinical efficacy of aprepitant or GR205171 in pain or migraine trials is not due to an insufficient dose or lack of brain penetration. At the dose used in the analgesia trials, aprepitant was found to produce greater than 90% NK1 receptor occupancy on positron emission tomography (PET; Bergstrom et al 2004) and is antiemetic in cancer patients following chemotherapy (Navari et al 1999). Similarly, the dose of GR205171 used in the migraine trial was based on adequate NK1 receptor occupancy as calculated from PET studies (Connor et al 1998). In view of these negative findings, it has been concluded that NK1 receptor antagonists are not effective as analgesic agents in humans (for a detailed review, see Boyce and Hill 2004). In conclusion, although SP, acting at NK1 receptors, appears to play a role in pain transmission in animals, it is clear that NK1 receptor antagonists are not likely to be usable as simple analgesic drugs in the same way as, for example, opioids and NSAIDs.
Many other peptides in addition to SP have been found in primary afferent fibers and/or the dorsal horn of the spinal cord and have been suggested to have a role in pain perception or modulation. Only a small number of these peptides have been studied to the point of examining compounds interacting with their specific receptors or release mechanisms, and even fewer have advanced to preclinical or clinical development.
The most abundant peptide in mammalian primary afferent fibers is CGRP, and there is much evidence that it has a role in nociception. In particular, there is persuasive clinical evidence that this peptide has a causative function in migraine headache (Edvinsson 2003). A potent antagonist of the CGRP receptor, BIBN4096BS (olcegepant), has been found to be effective as an acute abortive treatment of migraine headache after intravenous administration in a phase II clinical trial (Olesen et al 2004). Its efficacy was similar to that of the triptans, and no serious adverse effects occurred in this 126-patient study. Subsequently, a volunteer study showed that infusion of CGRP in 6 of 10 subjects produced a headache that was prevented by pre-infusion of olcegepant (Petersen et al 2005). Orally active, small-molecule CGRP receptor antagonists have now been discovered (such as MK-0894 or telcagepant; Salvatore et al 2011). Telcagepant was found to abort migraine pain and relieve associated symptoms of nausea, photophobia, and phonophobia and has been shown to be effective in phase III clinical trials (Ho and Goadsby 2010), although recently this compound has been abandoned as a result of adverse effects on liver function (company communication, November 2011). CGRP antagonists have the potential to be effective agents for treating migraine headache without the vasoconstrictor effects seen with the triptans, and theory would predict wider utility in the treatment of pain.
Cizolirtine, a novel compound with antinociceptive activity in a variety of animal assays, has been shown to be able to inhibit spinal release of SP and CGRP in rats (Ballet et al 2001). If this is the basis of its analgesic properties, presumably it is due to attenuation of CGRP-operated transmission since SP antagonists are not reliably analgesic in humans (see above). Cizolirtine is able to attenuate allodynia in neuropathic pain patients (Shembalkar et al 2001), but at doses of up to 150 mg it was ineffective in relieving dental postoperative pain (Matthew et al 2000). This agent is currently in clinical development for the treatment of urinary incontinence (Zatura et al 2010).
Cholecystokinin (CCK) is a peptide found in the spinal cord and has been implicated on the basis of animal experiments in the modulation of endogenous opioid systems (for background, see McCleane 2003). Potent and selective antagonists of the two receptors (CCK1 and CCK2) for this peptide are now available and have been evaluated for their ability to enhance the effects of opioids such as morphine in human pain patients. The CCK2 receptor antagonist L-365260 has been found to be ineffective in enhancing the analgesic effects of morphine in humans (McCleane 2003). However, the CCK1-selective antagonist MK-329 (devazepide) does enhance morphine effects in human pain patients and was evaluated in phase II clinical trials (Simpson et al 2002). The prototype CCK receptor antagonist proglumide has been found to enhance the analgesic effects of morphine in chronic benign pain patients (McCleane 1998), and loxiglumide, which has some CCK1 selectivity, has been found to produce pain relief in patients with biliary colic (Malesci et al 2003). There does not appear to be any current research activity around this mechanism.
Bradykinin and its des-Arg metabolite have been implicated in nociceptive processing on the basis of experiments with peptide antagonists of the receptors (B2 and B1) at which they act and, more recently, on the basis of the phenotypes of knockout mice in which either B2 or B1 receptors had been deleted (Ferreira et al 2002, Mason et al 2002). Studies on these knockout mice have also led to the conclusion that these kinins have an important spinal role in the nociceptive process (Ferreira et al 2002). In addition, it has been shown that nerve injury in the mouse (Rashid et al 2004) or the production of paw inflammation in the rabbit (Mason et al 2002) reveals a dominant role for the B1 receptor in nociception, which has led to the suggestion that B1 antagonists might be clinically useful analgesics with efficacy similar to that of the opioids. In the rabbit the B1 peptide antagonist B9858 will attenuate a nociceptive spinal reflex when paw inflammation is present but has little effect in the absence of inflammatory sensitization (Mason et al 2002). Non-peptide antagonists for the human B1 receptor are now becoming available, and some of them are orally bioavailable, low-molecular-weight compounds with the potential to be evaluated for relief of clinical pain once their safety is established (Su et al 2003, Wood et al 2003, Gougat et al 2004). A recent review summarized progress in this field, and although phase II trials have been conducted with at least two B1 antagonists, there is no evidence to date of clinical efficacy in relieving pain (Huang and Player 2010).
Ever since the introduction of local anesthetics, it has been common for clinicians to use drugs that block ion channels for control of pain. This approach has expanded recently with the use of membrane-stabilizing anticonvulsant drugs to treat various intractable pain conditions. The molecular biology of ion channels is now sufficiently well understood to allow the rational design of blockers for a single channel subtype. Many established drugs, such as morphine, exert their effects by influencing the activity of ion channels indirectly by activating receptors that are coupled to ion channels via second-messenger systems. This section is not concerned with such drugs but rather with those that directly influence the activity of voltage-gated ion channels. Reviews of this area can be found in articles by Kaczorowski and colleagues (2008) and Cregg and colleagues (2010).
Na channels are overexpressed in biopsy specimens taken from painful neuromas (England et al 1996). It has been suggested that the slow, tetrodotoxin (TTX)-resistant Na current carried by Nav1.8 is the best target for a drug that will relieve pain but have minimal side effects and that these channels are overexpressed in the presence of inflammation and are found on NGF-dependent unmyelinated nociceptive afferent fibers (Akopian et al 1996). Cloning and expression of the channels (Akopian et al 1996) make this an achievable objective. Genetic studies indicate that Nav1.7 may be the most logical target for a selective blocking drug because familial mutations in this channel have been shown to lead to congenital analgesia in some cases and spontaneous pain in others in human subjects (Kaczorowski et al 2008, Cregg et al 2010). Success has been achieved in discovering agents with selectivity for both Nav1.7 and Nav1.8 (Kaczorowski et al 2008), and efficacy has been shown in some animal pain models, although it remains to be demonstrated that these agents work in the clinical situation.
There is much room for improvement; for example, lidocaine (lignocaine) does not select between Na channels in neurons and those in other tissues, and in molar terms it is a rather weak blocker. It has higher affinity for the TTX-sensitive current in myelinated fibers than for the TTX-resistant current in nociceptors (Scholz et al 1998). Its use-dependent mechanism of action has allowed safe application as a local anesthetic (Murdoch Ritchie 1994), and this is likely to be an important property of any novel Na channel blockers. When given intravenously, lidocaine (lignocaine) has been found to be effective in the treatment of a number of neuropathic pain states, whereas efficacy against other types of pain is the subject of debate, with positive and negative studies being reported. If the infusion rate is limited to 5 mg/kg/hr (Field at al 1997), side effects are mild with minimal cardiovascular changes. Pain relief after a 1-hour infusion lasts several hours and on occasion very much longer. It has also been found to be effective against migraine headache when given intranasally (Maizels et al 1996). Patches containing 5% lidocaine (lignocaine) have been found to be effective and safe in treating the pain of post-herpetic neuralgia and are now being evaluated for the treatment of other pain conditions (Dworkin et al 2007). In particular, a study involving patients with diabetic neuropathy indicated significant improvement in pain and quality of life (Barbano et al 2004).
The anticonvulsants phenytoin and carbamazepine also inhibit both TTX-resistant and TTX-sensitive currents in rat dorsal root ganglion cells (Rush and Elliot 1997), and this may explain the clinical effectiveness of these agents in treating pain (McQuay et al 1995). Lamotrigine may prove useful in the treatment of neuropathic pain in patients infected with human immunodeficiency virus (Simpson et al 2003), and the recent demonstration that it reduces cold-induced pain in volunteer subjects may indicate wider utility in treating other types of pain (Webb and Kamali 1998). Lamotrigine has been evaluated in phase III clinical trials for the treatment of neuropathic pain, and despite the lack of universal agreement, there is published evidence from controlled trials in support of its efficacy (Pop-Busui 2007, Titlic et al 2008). The more recently introduced anticonvulsant topiramate has shown efficacy in animal experiments, which suggests that it should be useful against neuropathic pain (Tremont-Lukats et al 2000), and some clinical reports suggest that it may be effective against trigeminal neuralgia (e.g., Zvartau-Hind et al 2000) and other neuropathic pain (Chong and Libretto 2003). TTX, the invertebrate toxin Na+ channel blocker long used as an experimental tool, is in clinical development as an injectable therapy for neuropathic and cancer pain (Hagen et al 2008).
NW-1029 (ralfinamide) is a novel blocker of both TTX-sensitive and TTX-resistant Na channels and has antinociceptive properties in rat models of hyperalgesia associated with inflammation and nerve damage (Veneroni et al 2003). This orally bioavailable compound is well tolerated with no signs of neurological or cardiovascular effects at antinociceptive doses. It showed efficacy in a phase IIA study of patients with mixed neuropathic pain, but in a phase IIB/III clinical evaluation for neuropathic low back pain it failed to show analgesic efficacy in comparison to placebo (Newron website, accessed October 19, 2010, http://www.newron.com/Ralfinamide.html). It is also relevant to note that tricyclic antidepressants have been shown to block neuronal Na channels, and this may account for some of the analgesic activity of this class of compounds (Pancrazio et al 1998).
The neuronal voltage-gated Ca channels are a large and complex family with L-, N-, P-, Q-, R-, and T-type currents found in brain and other neuronal tissues. This diversity, though potentially confusing, provides a number of alternative targets for the design of new analgesic drugs. Blockers of L-type Ca currents are the most accessible since they have been used to treat cardiovascular disorders for many years. Although cardiovascular effects may limit their utility, it has recently been shown that nimodipine will reduce the daily dose of morphine needed to provide pain relief in a group of cancer patients (Santillan et al 1998) and that this effect is not due to a pharmacokinetic interaction of the drugs. Epidural verapamil has been shown to reduce analgesic consumption in patients after lower abdominal surgery (Choe et al 1998). In animal experiments it is readily demonstrable that L-channel blockers (e.g., nimodipine, verapamil, and diltiazem) have antinociceptive properties (Rupniak et al 1993, Neugebauer et al 1996), and it is important to consider the presence of this type of activity when evaluating a novel agent as an analgesic (Rupniak et al 1993).
N-, P-, and Q-type Ca currents have all been implicated in pain perception on the basis of anatomical location and animal experiments with invertebrate toxins that show some specificity for the individual channels. The best studied is the N channel, which has been located on the terminals of sensory nerve fibers, and blockade of this channel with the Conus ω-conotoxin GV1A has been shown to reduce sensory transmitter release and cause antinociception in experimental animals (Bowersox et al 1994). Because these toxins are peptides, it is necessary to apply them intrathecally (Malmberg and Yaksh 1995), but they produce striking effects at extremely low doses in a variety of tests, including the formalin and hot plate tests, and continuous infusion for 7 days results in maintained elevation of the nociceptive threshold. Spinal cord neuronal recordings in the presence and absence of inflammatory stimuli suggest that the N channel may be important in the development of spinal cord hyperexcitability and hyperalgesia (Neugebauer et al 1996, Nebe et al 1998). Well-controlled, intrathecal studies of ziconotide in humans have indicated that it produces pain relief in patients with severe refractory pain secondary to cancer or acquired immunodeficiency syndrome (Staats et al 2004). It is now approved for clinical use in the United States and the European Union for patients with severe pain refractory to other treatments (Schmitko et al 2010). Other related cone snail toxins are also in development for the treatment of pain, but no clinical data are yet available (Nelson 2004). Considerable progress has been made in the synthesis of selective, small-molecule N-type channel blockers (Zamponi et al 2009, Abbadie et al 2010), although initial attempts to show clinical efficacy in relieving pain have been unsuccessful.
Peptide blockers of P-type channels have also been studied for their antinociceptive effects in animals. They appear to be most effective in the presence of inflammation (Nebe et al 1997) and have a different effect from N-type channel blockers in that they attenuate the late but not the early phase of the formalin response (Diaz and Dickenson 1997). No information is yet available about the action of P-type channel blockers in humans, but it is important to note that mutation of P/Q-type calcium channels has been associated with the occurrence of familial hemiplegic migraine (Ophoff et al 1996), thus suggesting one logical therapeutic use for blockers of this channel, although the phenotype of knockout mice suggests that blockers of this channel may not be usable without serious side effects or even lethality.
Gabapentin is a chemically novel anticonvulsant agent that is proving useful for the treatment of neuropathic pain (Rosner et al 1996, Rosenberg et al 1997, Backonja and Glanzman 2003), especially post-herpetic neuralgia (Rice et al 2001, Scheinfeld 2003). It has become a drug of choice for neuropathic pain because of its improved separation between wanted and unwanted effects in comparison to other anticonvulsants and tricyclics (Tremont-Lukats et al 2000, Rice et al 2001). It has also been suggested to be useful in treating the pain of multiple sclerosis (Houtchens et al 1997) and that associated with Guillain-Barré syndrome (Pandey et al 2002). Gabapentin has been found to enhance the analgesic effects of morphine in healthy volunteers (Eckhardt et al 2000) and has been used successfully as part of a post-surgical analgesic regimen after breast cancer surgery (Fassoulaki et al 2002) and after total abdominal hysterectomy (Turan et al 2004). The mode of action of this drug is at least in part due to blocking the action of presynaptic Ca channels since it binds with high affinity to the α2δ calcium channel subunit (Gee et al 1996). A more potent analogue (pregabalin, S-(+)-3-isobutylgaba) has also been introduced and has now been registered in both the United States and the United Kingdom for the treatment of neuropathic pain and fibromyalgia (Dworkin et al 2007). This approval was based on studies in patients with post-herpetic neuralgia and diabetic neuropathy in which it was demonstrated that 47% of the patients had a 50% reduction in pain. The main dose-related side effects were dizziness and somnolence of mild to moderate intensity. It has been shown to be effective in a randomized double-blind study in patients with postoperative dental pain (Hill et al 2001) and, in a variety of animal tests, has a profile similar to that of gabapentin (Bryans and Wustrow 1999). Recent studies have shown it to be effective in treating the pain of post-herpetic neuralgia and, in particular, to improve sleep and mood disturbance (Dworkin et al 2007).
Cholinergic agonists have long been known to be antinociceptive in animals, but clinical exploitation has been limited by severe side effects produced by non-specific activation of cholinergic systems. Recent detailed knowledge of the molecular biology of cholinoceptors has made it possible to design agents that are receptor subtype selective and thus may have an improved ratio of wanted to unwanted effects.
The cholinergic analgesia story was revived following the discovery (Spande et al 1992) that epibatidine, an alkaloid extracted from the skin of an Ecuadorian frog, was a more potent analgesic than morphine. This compound was subsequently shown to be a potent nicotinic agonist (Badio and Daley 1994) but was too toxic to be developed as a clinical analgesic (Rupniak et al 1994). A synthetic analogue of epibatidine, ABT-594, has been reported to be an analgesic development candidate with an improved therapeutic ratio. This agent, in contrast to epibatidine, does not act at neuromuscular junction nicotinic receptors and has low affinity at some CNS nicotinic sites (α7) but high affinity at others (α4α2). It has moderate affinity at autonomic and sensory ganglion (α3-containing) receptors (Donelly-Roberts et al 1998). In vivo, ABT-594 showed antinociceptive activity in thermal and chemical (formalin) tests that was reversed by the brain-penetrant nicotinic antagonist mecamylamine, and analgesia persisted after chronic dosing of the drug (Bannon et al 1998). Acute dosing caused a decrease in locomotor activity, a decrease in body temperature, and loss of balance, but these effects, unlike the antinociception, showed tolerance on repeated dosing. A part of the analgesia produced by ABT-594 may be due to activation of descending inhibitory pathways originating in the nucleus raphes magnus (Bitner et al 1998). One limitation may be the ability of such drugs to interact with brain reward systems and thus produce dependence (Epping-Jordan et al 1998). ABT-594 was investigated in two separate phase II studies of diabetic neuropathic pain and, although well tolerated, did not produce an adequate effect on pain scores in either study (Neurosearch press release, February 11, 2009, http://www.fiercebiotech.com/press-releases/neurosearch-announces-results-phaseii-studies-abt-594-diabetic-neuropathic-pain).
The use of capsaicin as a rubefacient for the treatment of painful disorders is traditional, but it is only in the past 20 years that the pharmacology of the active principal, capsaicin, has become well understood. Early work of the Janscos in Hungary (for background, see Salt and Hill 1983) showed that systemic administration to rodents would deplete peptides from small primary afferent fibers without affecting CNS neurons, large sensory fibers, or autonomic fibers. Such administration produced initial nociceptive behavior, consistent with the pain seen when capsaicin is injected or applied topically in humans, followed by prolonged elevation of nociceptive thresholds.
Preparations containing capsaicin for topical application are now widely available and are sometimes effective in relieving painful conditions involving unmyelinated fiber dysfunction. Such conditions include post-herpetic neuralgia, post-mastectomy pain, and diabetic neuropathy (Szallasi 1997). A systematic review of the use of topical capsaicin for pain concluded that it had only moderate or poor efficacy and was likely to be most useful in patients intolerant of other treatments (Mason et al 2004). Commercial preparations generally contain only low concentrations of capsaicin (<1%), and even at this dose compliance can be low because of the burning sensation experienced on application. In initial trials of high-dose (5–10%) topical capsaicin applied under regional anesthetic cover in patients with refractory pain (Robbins et al 1998), burning pain from the capsaicin was experienced by some patients and had to be treated with intravenous fentanyl. Marked temporary pain relief was obtained in 9 of 10 patients, with 7 of them achieving significant and prolonged pain relief on repeated application. Further development of this approach has led to the introduction of a patch (Qutenza) containing 8% capsaicin that was effective in relieving the pain of post-herpetic neuralgia in three phase III clinical trials and is now a licensed product in the United States and United Kingdom. A transient increase in pain can be seen before the pain-relieving effect becomes apparent, but the side effects are manageable (Backonja et al 2008, Horsley 2011). Capsaicin is not suitable for oral administration in humans because it is poorly absorbed from and highly irritant to the gastrointestinal tract. It is not yet clear whether it is necessary to first stimulate the receptor to desensitize it (causing the patient discomfort) or whether it might be possible to block the receptor painlessly with a silent antagonist or partial agonist and yet still provide clinical pain relief. A specific receptor (TRPV1, formerly VR1) for capsaicin-like compounds has been expression-cloned (Caterina et al 1997; see also Planells-Cases et al 2003) from a dorsal root ganglion–derived DNA library. Other members of the TRP family have been cloned and also suggested to have a role in nociception (Planells-Cases et al 2003). In particular, ANKTM1 has been found to be responsible for transducing the response to mustard oil, a pungent substance that does not activate TRPV1, and this receptor may also have a role in responses to noxious cold (Jordt et al 2004). TRPV4 has recently been suggested to be essential for the production of Taxol-induced neuropathy in the rat (Alessandri-Haber et al 2004). Workers at Novartis have produced analogues of capsaicin that are not pain producing yet still have antinociceptive properties in animals and are free of unwanted bronchoconstrictor activity. One of these drugs entered clinical development as a potential analgesic (Wrigglesworth et al 1996). Identification of TRPV1 as a molecular target amenable to high-throughput screening stimulated the search for novel ligands of this receptor. High-affinity partial agonists (Wang et al 2003) and full antagonists such as SB-366791 (Gunthorpe et al 2004) are now available and are being studied in clinical trials. One complication that has emerged is that blockade of TRPV1 receptors in human subjects with the antagonist AMG517 produces a hyperthermia that is larger in some individuals than others, thus suggesting heterogeneity in response. The hyperthermic response leads to body temperatures of 40°C in some subjects, and it may not respond well to paracetamol. A second TRPV1 blocker that was studied in human subjects, SB-70548, did not appear to produce hyperthermia, and there is evidence of different mechanisms in the block of TRPV1 produced by different agents (see Caterina 2008, Ayour et al 2009). Clinical trials on a number of different TRPV1 blockers as potential analgesics are continuing, and it is possible that more than one channel in this family will need to be blocked to produce clinical analgesia (Vay et al 2012).
The knowledge of basic pain mechanisms is increasing exponentially, and as a result we now have a plethora of potential pain targets against which to develop drugs. A number of novel mechanisms are being studied through compounds currently in clinical trials, and other novel approaches are in preclinical development. Progress in taking agents from discovery to clinical use has been disappointingly slow, and it is salutary that the NK1/SP receptor antagonists were seen by many experts as the strongest candidates for a novel class of analgesics until clinical trial data showed this view to be untenable.
A rich source of new drugs for treating pain continues to be the empirical observation of beneficial properties of drugs introduced for the treatment of other conditions, especially anticonvulsants. The latest in a long line of such drugs is levetiracetam, which was initially found to be useful in three cases of neuropathic pain (Price 2004) and has now been studied for neuropathy, radiculopathy, and headache, where addition to normal pain medication regimens was found to improve both pain and anxiety in about 80% of a group of 53 patients (Kaplan and Kaplan 2004). This drug was also of interest because it appears to have a unique mode of action in binding to the synaptic vesicle protein SV2A (Lynch et al 2004), but sadly, late-stage clinical trials did not support the use of this drug or its derivative brivaracetam in pain, and subsequent development will focus on epilepsy (UCB website, accessed October 19, 2010, http://www.ucb.com/rd/pipeline/new-development).
The use of biologicals for the treatment of pain is also being evaluated. For example, it is known that human mutations in either NGF or its receptor TrkA cause congenital insensitivity to pain, peripheral small-fiber neuropathy, and a variable degree of autonomic dysfunction (Einasdottir et al 2004). As a consequence, several antibodies to NGF are now in clinical evaluation, including tanezumab, SAR164877, JNJ42160443, and MEDI-578 (Melnikova 2010, AstraZeneca website, accessed October 19, 2010, http://www.astrazeneca.com_mshost3690701/content/resources/media/investors/10809118/AZN-Q2-2010-Pipeline-Summary.pdf). Tanezumab (previously known as PF-483119 or RN-624) has shown striking efficacy against the pain of osteoarthritis, even in patients with moderate to severe arthritis, and the effects of a single dose were maintained for up to 8 weeks (Lane et al 2010). However, some patients in subsequent phase III trials (16 of 6800 subjects) showed progressively worsening osteoarthritis with evidence of bone necrosis in the knee, hip, or shoulder that led to the need for complete joint replacement, and the FDA placed these trials on hold until more information on these effects is available (Lane et al 2010; Bloomberg News, September 29, 2010, http://www.bloomberg.com/news/print/2010-09-29/pfizer-arthritis-drug-cut-pain-too-well).
Our approach to all new hypotheses needs to be cautious until we have solid clinical evidence of efficacy and safety from randomized, double-blind, placebo-controlled trials. The recent failure of agents in clinical evaluation and the limited novelty of the approach taken in the recent past (Kissin 2010) underline the fact that there is still an urgent need for original basic research to underpin the discovery of further novel analgesics.
The references for this chapter can be found at www.expertconsult.com.
Abbadie C., McManus O.B., Sun S.-Y., et al. Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state dependent Cav2.2 calcium channel blocker. Journal of Pharmacology and Experimental Therapeutics. 2010;334:545–555.
Afilalo M., Stegmmann J.-U., Upmalis D. Tapentadol immediate release: a new treatment option for acute pain management. Journal of Pain Research. 2010;3:1–9.
Akopian A.N., Sivlotti L., Wood J.N. A tetrodotoxin resistant voltage gated sodium channel expressed by sensory neurones. Nature. 1996;379:257–262.
Alessandri-Haber N., Dina O.A., Yeh J.J., et al. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. Journal of Neuroscience. 2004;24:4444–4452.
Arain S.R., Ruehlow R.M., Uhrich T.D., et al. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesthesia and Analgesia. 2004;98:153–158.
Arendt-Nielsen L., Olesen A.E., Staahl C., et al. Analgesic efficacy of peripheral κ-opioid receptor agonist CR665 compared to oxycodone in a multimodal multi-tissue experimental human pain model. Anesthesiology. 2009;111:616–624.
Ayour S.S., Hunter J.C., Simmons D.L. Answering the burning question of how TRPV1 channel antagonists cause unwanted hyperthermia. Pharmacological Reviews. 2009;61:225–227.
Backonja M., Glanzman R.L. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clinical Therapy. 2003;25:81–104.
Backonja M., Wallace M.S., Blansky F.R., et al. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized double blind study. Lancet Neurology. 2008;7:1106–1112.
Badio B., Daley J.W. Epibatidine, a potent analgesic and nicotinic agonist. Molecular Pharmacology. 1994;45:563–569.
Ballet S., Aubel B., Mauborgne A., et al. The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats. Neuropharmacology. 2001;40:578–589.
Bandolier. Acute pain. Bandolier Extra, February. 2003:1–22.
Bannon A.W., Decker M.W., Curzon P., et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterisation. Journal of Pharmacology and Experimental Therapeutics. 1998;285:787–794.
Barbano R.L., Herrman D.N., Hart-Gouleau S., et al. Effectiveness, tolerability and impact on quality of life of the 5% lidocaine patch in diabetic poly neuropathy. Archives of Neurology. 2004;61:914–918.
Belfrage M., Segerdahl M., Arner S., et al. The safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain. Anesthesia and Analgesia. 1999;89:136–142.
Bergstrom M., Hargreaves R.J., Burns H.D., et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biological Psychiatry. 2004;55:1007–1012.
Bilkei-Gorzo A., Abo-Salem O.M., Hayallah A.M., et al. Adenosine receptor sub-type selective antagonists in inflammation and hyperalgesia. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2008;377:65–76.
Bitner R.S., Nikkel A.L., Curzon P., et al. Role of the nucleus raphe magnus in antinociception produced by ABT-594: immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotoninergic neurons. Journal of Neuroscience. 1998;18:5426–5432.
Bowersox S.S., Valentino K.L., Luther R.R. Neuronal voltage-sensitive calcium channels. Drug News and Perspectives. 1994;7:261–268.
Boyce S., Hill R.G., Substance P (NK1) receptor antagonists—analgesics or not?. Holzer P., ed. Handbook of experimental pharmacology, tachykinins, vol. 164. Berlin: Springer-Verlag; 2004:441–457.
Boyce S., Wyatt A., Webb J.K., et al. Selective NMDA receptor NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted distribution of NR2B subunit in dorsal horn. Neuropharmacology. 1999;38:611–623.
Boyce S., Ali Z., Hill R.G. New developments in analgesia. Drug Discovery World. 2001;2:31–35.
Bradley R.H., Barkin R.L., Jerome J., et al. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. American Journal of Therapeutics. 2003;10:318–323.
Brattwall M., Turan I., Jakobsson J. Pain management after elective hallux valgus surgery: a prospective randomized double-blind study comparing etoricoxib and tramadol. Anesthesia and Analgesia. 2010;111:544–549.
Briley M. New hope in the treatment of painful symptoms in depression. Current Opinion in Investigational Drugs. 2003;4:42–45.
Bryans J.S., Wustrow D.J. 3-Substituted GABA analogs with central nervous system activity: a review. Medicinal Research Reviews. 1999;19:149–177.
Buggy D.J., Toogood L., Maric S., et al. Lack of analgesic efficacy of oral δ-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106:169–172.
Carr D.B., Goudas L.C., Denman W.T., et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain; a randomized, double-blind, placebo-controlled, crossover study. Pain. 2004;108:17–27.
Caterina M. On the thermoregulatory perils of TRPV1 antagonism. Pain. 2008;136:3–4.
Caterina M.J., Schumacher M.A., Tominaga M., et al. The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature. 1997;389:816–824.
Chen L.C., Elliott R.A., Ashcroft D.M. Systematic review of the analgesic efficacy and tolerability of COX-2 inhibitors in post-operative pain control. Journal of Clinical Pharmacy and Therapeutics. 2004;29:215–229.
Choe H., Kim J.-S., Ko S.-H., et al. Epidural verapamil reduces analgesic consumption after lower abdominal surgery. Anesthesia and Analgesia. 1998;86:786–790.
Chong M.S., Libretto S.E. The rationale and use of topiramate for treating neuropathic pain. Clinical Journal of Pain. 2003;19:59–68.
Clark A.J., Ware M.A., Yazer E., et al. Patterns of cannabis use among patients with multiple sclerosis. Neurology. 2004;62:2098–2100.
Clark P., Rowland S.E., Denis D., et al. MF498 a selective E prostanoid receptor 4 antagonist relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis. Journal of Pharmacology and Experimental Therapeutics. 2008;325:425–434.
Clauw D.J., Mease P., Palmer R.H., et al. Milnacipran for the treatment of fibromyalgia in adults: a 15 week multicenter randomized double blind placebo controlled multiple dose clinical trial. Clinical Therapeutics. 2008;30:1988–2004.
Codd E.E., Carson J.R., Colburn R.W., et al. JNJ-20788560 a selective delta-opioid receptor agonist is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance or physical dependence. Journal of Pharmacology and Experimental Therapeutics. 2009;329:241–251.
Colpaert F.C., Tarayre J.P., Koek W., et al. Large-amplitude 5-HT1A receptor activation: a new mechanism of profound central analgesia. Neuropharmacology. 2002;43:945–958.
Connor H.E., Bertin L., Gillies S., et al. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treatment of migraine. Cephalalgia. 1998;18:392.
Cook L., Schmidt W.K. DUP-631: unique analgesia and biochemical profile of a serotonin–norepinephrine uptake inhibitor [abstract]. Acapulco, Mexico: American College of Neuropsychopharmacology (ACNP) Meeting; 1997.
Coombs D.W., Saunders R.L., LaChance D., et al. Intrathecal morphine tolerance: use of intrathecal clonidine, DADLE and intraventricular morphine. Anesthesiology. 1985;62:357–363.
Cregg R., Momin A., Rugiero F., et al. Pain channelopathies. Journal of Physiology. 2010;588:1897–1904.
Cumberbatch M.J., Hill R.G., Hargreaves R.J. Differential effects of the 5-HT1D/1B receptor agonist naratriptan on trigeminal versus spinal nociceptive responses. Cephalalgia. 1998;18:659–663.
De Felipe C., Herrero J.F., O’Brien J.A., et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature. 1998;329:394–397.
Detke M.J., Lu Y., Goldstein D.J., et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. Journal of Clinical Psychiatry. 2002;63:308–315.
Diaz A., Dickenson A.H. Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation. Pain. 1997;69:93–100.
Dickson M., Gagnon J.P. Key factors in the rising cost of new drug discovery and development. Nature Reviews. Drug Discovery. 2004;3:417–429.
Donelly-Roberts D.L., Puttfarken P.S., Kuntzweiler T.A., et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterisation. Journal of Pharmacology and Experimental Therapeutics. 1998;285:777–786.
Dworkin R.H., Oconnor A.B., Backonja M., et al. Pharmacologic management of neuropathic pain: evidence based recommendations. Pain. 2007;132:237–251.
Eckhardt K., Ammon S., Hoffman U., et al. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesthesia and Analgesia. 2000;91:185–191.
Edvinsson L. New therapeutic target in primary headaches—blocking the CGRP receptor. Expert Opinion on Therapeutic Targets. 2003;7:377–383.
Eide P.K., Stubhaug A. Relief of glossopharyngeal neuralgia by ketamine-induced N-methyl aspartate receptor blockade. Neurosurgery. 1997;41:505–508.
Eide P.K., Stubhaug A., Oye I., et al. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain. 1995;61:221–228.
Einasdottir E., Carlsson A., Minde J., et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Human Molecular Genetics. 2004;13:799–805.
Eisenach J.C., Carpenter R., Curry R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain. 2003;101:89–95.
Eisenach J.C., DuPen S., Dubois M., et al. Epidural clonidine analgesia for intractable cancer pain. Pain. 1995;61:391–399.
Eisenach J.C., Rauck R.L., Buzzanell C., et al. Epidural clonidine analgesia for intractable cancer pain: phase I. Anesthesiology. 1989;71:647–652.
England J.D., Happel L.T., Kline D.G., et al. Sodium channel accumulation in humans with painful neuromas. Neurology. 1996;47:272–276.
Epping-Jordan M.P., Watkins S.S., Koob G.F., et al. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 1998;393:76–79.
Fassoulaki A., Patris K., Sarantopoulos C., et al. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesthesia and Analgesia. 2002;95:985–991.
Ferrari M.D., Farkkila M., Reuter U., et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan—a randomised proof of concept trial. Cephalalgia. 2010;30:1170–1178.
Ferreira J., Campos M.M., Araujo R., et al. The use of kinin B1 and B2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level. Neuropharmacology. 2002;43:1188–1197.
Field M.J., McLeary S., Boden P., et al. Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat. Journal of Pharmacology and Experimental Therapeutics. 1998;285:1226–1232.
Field M.J., Oles R.J., Lewis A.S., et al. Gabapentin (neurontin) and 3-(+)-isobutylgaba represent a novel class of selective antihyperalgesic agents. British Journal of Pharmacology. 1997;121:1513–1522.
Fiorucci S., Santucci L., Wallace J.L., et al. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:10937–10941.
Gear R.W., Gordon N.C., Miaskowski C., et al. Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans. Neuroscience Letters. 2003;351:5–8.
Gee N.S., Brown J.P., Dissanayake V.U.K., et al. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit of a calcium channel. Journal of Biological Chemistry. 1996;271:5768–5776.
Gelber D.A., Good D.C., Dromerick A., et al. Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke. Stroke. 2001;32:1841–1846.
Gengo P.J., Petit H.O., O’Neill S.J., et al. DPI-3290 [(+)-3-((α-R)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydoroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity. Journal of Pharmacology and Experimental Therapeutics. 2003;307:1221–1226.
Gilron I., Coderre T.J. Emerging drugs in neuropathic pain. Expert Opinion on Emerging Drugs. 2007;12:113–126.
Godfrey R.G. A guide to the understanding and use of tricyclic antidepressants in the overall management of fibromyalgia and other chronic pain syndromes. Archives of Internal Medicine. 1996;156:1047–1052.
Goldstein D.J., Offen W.W., Klein E.G. Lanepitant, an NK1 antagonist, in migraine prophylaxis. Clinical Pharmacology and Therapeutics. 65, 1999. (abstract)
Goldstein D.J., Roon K.I., Offen W.W., et al. Selective serotonin 1F(5-HT1F) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358:1230–1234.
Goldstein D.J., Wang O., Saper J.R., et al. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia. 1997;17:785–790.
Goldstein D.J., Wang O., Todd T.E. Lanepitant in osteoarthritis pain. Clinical Pharmacology and Therapeutics. 1998;63:168.
Gomez-Mancilla B., Cutler N.R., Leibowitz M.T., et al. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia. 2001;21:727–732.
Gormsen L., Finnerup N.B., Almquist P.M., et al. The efficacy of the AMPA-receptor antagonist NS1209 and lidocaine in nerve injury pain: a randomized double blind placebo controlled three way crossover study. Anesthesia and Analgesia. 2009;108:1311–1319.
Gosy E. Spectrum of the clinical use of Zanaflex (tizanidine) in pain management. In: Krames E., Reig E., eds. Practice of neurology and pain management. Bologna, Italy: Monduzzi Editore; 2001:385–389.
Gougat J., Ferrari B., Sarran L., et al. SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl) amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl] methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics. 2004;309:661–669.
Graul A.I. Annual update 2003: drugs for pain and anesthesia. Drugs of the Future. 2003;28:489–524.
Guindon J., Hohmann A.G. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. British Journal of Pharmacology. 2008;153:319–334.
Gunthorpe M.J., Rami H.K., Jerman J.C., et al. Identification and characterization of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology. 2004;46:133–149.
Hagen N.A., Du Souich P., Lapointe B., et al. Tetrodotoxin for moderate to severe cancer pain: a randomized double blind parallel design multicenter study. Journal of Pain and Symptom Management. 2008;35:420–429.
Hill C.M., Balkenohl M., Thomas D.W., et al. Pregabalin in patients with postoperative dental pain. European Journal of Pain. 2001;5:119–224.
Hill R.G., New targets for analgesic drugs. Dostrovsky J.O., Carr D.B., Koltzenburg M., eds. Proceedings of the 10th World Congress on Pain. Progress in pain research and management, vol. 24. Seattle: IASP Press; 2003:419–435.
Hill R.G., Can the evaluation of drugs in animal pain models reliably predict the ability to produce clinical analgesia?. Villaneuva L., Dickenson A., Ollat H., eds. The pain system in normal and pathological states: a primer for clinicians. Progress in pain research and management, vol. 31. Seattle: IASP Press; 2004:247–258.
Ho T.W., Goadsby P.J. CGRP and its receptors provide new insights into migraine pathophysiology. Nature Reviews. Neuroscience. 2010;6:573–582.
Hohmann A.G., Farthing J.N., Zvonok A.M., et al. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. Journal of Pharmacology and Experimental Therapeutics. 2004;308:446–453.
Horsley W. Qutenza capsaicin cutaneous patch for neuropathic pain. NHS North East Treatment Advisory Group. Sept. 2011:1–10.
Huang H., Player M.R. Bradykinin B1 receptor antagonists as therapeutic agents for pain. Journal of Medical Chemistry. 2010;53:5383–5399.
Houtchens M.K., Richert J.R., Sami A., et al. Open label gabapentin treatment for pain in multiple sclerosis. Multiple Sclerosis. 1997;3:250–253.
Jeffrey S., FDA approves milnacipran for fibromyalgia. Medscape Medical News 2009. Available at, http://www.medscape.com/viewarticle/586898
Jones B.J., Blackburn T.P. The medical benefit of 5-HT research. Pharmacology, Biochemistry, and Behavior. 2002;71:555–568.
Jordt S.-E., Bautista D.M., Chuang H.-H., et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004;427:260–265.
Jorum E., Warnke T., Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine—a double blind, cross over comparison with alfentanil and placebo. Pain. 2003;101:229–235.
Kaczorowski G.J., McManus O.B., Priest B.T., et al. Ion channels as drug targets: the next GPCRs. Journal of General Physiology. 2008;131:399–405.
Kamata M., Naito S., Takahashi H., Higuchi H. Milnacipran for the treatment of chronic pain. Human Psychopharmacology. 2003;18:575–576.
Kaplan M., Kaplan L. Levetiracetam as an adjunct to other AEDs in the treatment of stable, satisfied chronic pain. Journal of Pain. 2004;5(suppl 1):56.
Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesthesia and Analgesia. 2010;110:780–789.
Lacivita E., Leopoldo M., Berardi F., et al. 5HT1A receptor, an old target for new therapeutic age. Current topics in medicinal chemistry. 2008;8:1024–1034.
Laird J.M.A., Mason G.S., Webb J., et al. Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation-induced mechanical hyperalgesia in rats. British Journal of Pharmacology. 1996;117:1487–1492.
Lakhlani P.P., MacMillan L.B., Guo T.Z., et al. Substitution of a mutant α2A-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:9950–9955.
Lane N.E., Schnitzer T.J., Birbara C.A., et al. Tanezumab for the treatment of pain from osteoarthritis of the knee, New England Journal of Medicine. 2010;363:1521–1531.
Lindstrom E., Ravnefjord A., Brusberg M., et al. The selective 5-hydroxytryptamine 1A antagonist AZD7371 (robalzotan tartrate monohydrate) inhibits visceral pain related visceromotor but not autonomic cardiovascular responses to colorectal distension in rats. Journal of Pharmacology and Experimental Therapeutics. 2009;329:1048–1055.
Lowry F., FDA panel nixes naproxcinod for osteoarthritis. Medscape Medical News, May 12, 2010 2010. Available at, http://www.medscape.com/viewarticle/721737_print
Lynch B.A., Lamberg N., Nocka K., et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:9861–9866.
Mackey C. The anticonvulsants market. Nature Reviews. Drug Discovery. 2010;9:265–266.
Maizels M., Scott B., Cohen W., et al. Intranasal lidocaine for treatment of migraine. JAMA: Journal of the American Medical Association. 1996;276:319–321.
Malesci A., Pezzilli R., Damato M., et al. CCK-1 receptor blockade for treatment of biliary colic: a pilot study. Alimentary Pharmacology and Therapeutics. 2003;18:333–337.
Malmberg A.B., Yaksh T.L. Effect of continuous intrathecal infusion of ω-conopeptides, N-type calcium channel blockers, on behaviour and antinociception in the formalin and hotplate tests in rats. Pain. 1995;60:83–90.
Martel-Pelletier J., Lajeunesse D., Reboul P., et al. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Annals of the Rheumatic Diseases. 2003;62:501–509.
Masferrer J.L., Zweifel B.S., Hardy M., et al. Pharmacology of PF-4191834 a novel selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. Journal of Pharmacology and Experimental Therapeutics. 2010;334:294–301.
Mason G.S., Cumberbatch M.J., Hill R.G., et al. The bradykinin B1 receptor antagonist B9858 inhibits a nociceptive spinal reflex in rabbits. Canadian Journal of Physiology and Pharmacology. 2002;80:264–268.
Mason L., Moore A., Derry S., et al. Systematic review of topical capsaicin for the treatment of chronic pain. British Medical Journal. 2004;328:991–995.
Mathiesen O., Imbimbo B.P., Hilsted K.L., et al. CHF3381 a NMDA receptor antagonist and MOA-A inhibitor attenuates secondary hyperalgesia in a human pain model. Journal of Pain. 2006;7:565–574.
Matthew I.R., Ogden G.R., Frame J.W., et al. Dose response and safety of cizolirtine citrate (E-4018) in patients with pain following extraction of third molars. Current Medical Research and Opinion. 2000;16:107–114.
McCartney C.J.L., Sinha A., Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesthesia and Analgesia. 2004;98:1385–1400.
McCleane G.J.M. The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. Anesthesia and Analgesia. 1998;87:1117–1120.
McCleane G.J.M. A randomized, double-blind, placebo-controlled crossover study of the cholecystokinin 2 antagonist L-365260 as an adjunct to strong opioids in chronic human neuropathic pain. Neuroscience Letters. 2003;338:151–154.
McQuay H., Carroll D., Jadad A.R., et al. Anticonvulsant drugs for management of pain: a systematic review. British Medical Journal. 1995;311:1047–1052.
McQuay H.J., Tramer M., Nye B.A., et al. Systematic review of antidepressants in neuropathic pain. Pain. 1996;68:217–227.
Melnikova I. Pain market. Nature Reviews. Drug Discovery. 2010;9:589–590.
Melzack R. The future of pain. Nature Reviews. Drug Discovery. 2008;7:629.
Middleton L.S., Nuzzo P.A., Lofwall M.R., et al. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction. 2011;106:1460–1473.
Murdoch Ritchie J.M. Mechanism of action of local anaesthetics. In: Fields H.L., Liebeskind J.C., eds. Progress in pain research and management. Seattle: IASP Press; 1994:189–204.
Naef M., Curatolo M., Petersen-Felix S., et al. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC) and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. 2003;105:79–88.
Navari R.M., Reinhardt R.R., Gralla R.J., et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group. New England Journal of Medicine. 1999;340:190–195.
Nebe J., Vanegas H., Neugebauer V., et al. ω-Agatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive processing in spinal cord neurons with input from the inflamed but not from the normal knee joint—an electrophysiological study in the rat in vivo. European Journal of Neuroscience. 1997;9:2193–2201.
Nebe J., Vanegas H., Scaible H- G. Spinal application of ω-conotoxin GIVA, an N-type calcium channel antagonist, attenuates enhancement of dorsal spinal neuronal responses caused by intra-articular injection of mustard oil in the rat. Experimental Brain Research. 1998;120:61–69.
Negus S.S., Vanderah T.W., Brandt M.R., et al. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. Journal of Pharmacology and Experimental Therapeutics. 2006;319:507–514.
Nelson D.L., Phebus L.A., Johnson K.W., et al. Preclinical pharmacology profile of the selective 5HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30:1159–1169.
Nelson L. One slip and you`re dead. Nature. 2004;429:798–799.
Neugebauer V., Vanegas H., Nebe J., et al. Effects of N-, L-type calcium channel antagonists on the responses of spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. Journal of Neurophysiology. 1996;76:3740–3749.
Nikolajsen L., Hansen P.O., Jensen T.S. Oral ketamine therapy in the treatment of postamputation stump pain. Acta Anaesthesiologica Scandinavica. 1997;41:427–429.
Nitu A.N., Wallihan R., Skljarevski V., et al. Emerging trends in the pharmacotherapy of chronic pain. Expert Opinion on Investigational Drugs. 2003;12:545–559.
Notcutt W., Price M., Miller R., et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “n of 1” studies. Anesthesia. 2004;59:440–452.
Olesen J., Diener H.-C., Husstedt I.W., et al. Calcitonin gene–related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. New England Journal of Medicine. 2004;350:1104–1110.
Olofsen E., Van Dorp E., Tepperna L., et al. Naloxone reversal of morphine and morphine-6-glucuronide induced respiratory depression in healthy volunteers. Anesthesiology. 2010;112:1417–1427.
Ongini E., Bolla M. Nitric-oxide based nonsteroidal anti-inflammatory agents. Drug Discovery Today. Therapeutic Strategies. 2006;3:395–400.
Ophoff R.A., Terwindt G.M., Vergouwe M.N., et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca++ channel gene CACNL1A4. Cell. 1996;87:543–552.
Pancrazio J.J., Kamatchi G.L., Roscoe A.K., et al. Inhibition of neuronal Na+ channels by antidepressant drugs? Journal of Pharmacology and Experimental Therapeutics. 1998;284:208–214.
Pandey C.K., Bose N., Garg G., et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesthesia and Analgesia. 2002;95:1719–1723.
Petersen K.A., Lassen L.H., Birk S., et al. BIBN4096BS antagonizes human CGRP induced headache and extracerebral artery dilatation. Clinical Pharmacology and Therapeutics. 2005;77:202–213.
Petersen K.L., Maloney A., Hoke F., et al. A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. Journal of Pain. 2003;4:400–406.
Petrillo P., Angelici O., Bingham S., et al. Evidence for a selective role of the δ-opioid agonist (8R-(4bS*,8aα,8aβ,12bβ)7,10-dimethyl-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-9H)-4,8-methanobenzofurol(3,2-e)pyrrolo(2,3-g)isoquinoline HCl (SB-235863) in blocking hyperalgesia associated with inflammatory and neuropathic pain responses. Journal of Pharmacology and Experimental Therapeutics. 2003;307:1079–1089.
Planells-Cases R., Garcia-Martinez C., Royo M., et al. Small molecules targeting the vanilloid receptor complex as drugs for inflammatory pain. Drugs of the Future. 2003;28:787–795.
Pop-Busui R. Does lamotrigine alleviate the pain in diabetic neuropathy? Nature Clinical Practice. Neurology. 2007;3:424–425.
Price M.J. Levetiracetam in the treatment of neuropathic pain: three case studies. Clinical Journal of Pain. 2004;20:33–36.
Psaty B.M., Weiss N.S. NSAID trials and the choice of comparators—questions of public health importance. New England Journal of Medicine. 2007;356:328–330.
Pud D., Eisenberg E., Spitzer A., et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain. 1998;75:349–354.
Rashid M.D.H., Inoue M., Matsumoto M., et al. Switching of bradykinin-mediated nociception following partial sciatic nerve injury in mice. Journal of Pharmacology and Experimental Therapeutics. 2004;308:1158–1164.
Raynauld J.-P., Martel-Pelletier J., Bias P., et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis; a first multicentre clinical trial using quantitative MRI. Annals of the Rheumatic Diseases. 2010;68:938–947.
Rawlins M.D. Cutting the cost of drug development? Nature Reviews. Drug Discovery. 2004;3:360–364.
Rice A.S.C., Maton S., Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
Robbins W.R., Staats P.S., Levine J., et al. Treatment of intractable pain with topical large-dose capsaicin; preliminary report. Anesthesia and Analgesia. 1998;86:579–583.
Rosenberg J.M., Harrell C., Ristic H., et al. The effect of gabapentin on neuropathic pain. Clinical Journal of Pain. 1997;13:251–255.
Rosner H., Rubin L., Kestenbaum A. Gabapentin adjunctive therapy in neuropathic pain states. Clinical Journal of Pain. 1996;12:56–58.
Rupniak N.M.J., Boyce S., Williams A.R., et al. Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP-67580. British Journal of Pharmacology. 1993;110:1607–1613.
Rupniak N.M.J., Carlson E., Boyce S., et al. Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils. Pain. 1995;67:188–195.
Rupniak N.M.J., Patel S., Marwood R., et al. Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity. British Journal of Pharmacology. 1994;113:1487–1493.
Rush A.M., Elliot J.R. Phenytoin and carbamazepine: differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia. Neuroscience Letters. 1997;226:95–98.
Salt T.E., Hill R.G. Transmitter candidates of somatosensory primary afferent fibres. Neuroscience. 1983;10:1083–1103.
Salvatore C.A., Kane S. CGRP receptor antagonists: toward a novel migraine therapy. Curr Pharm Biotechnol. 2011;12(10):1671–1680.
Sang C.M. Clinically available glutamate receptor antagonists in neuropathic pain states. In: Sirinathsinghji D.J.S., Hill R.G., eds. NMDA antagonists as potential analgesic drugs. Basel: Birkhauser; 2002:165–180.
Sang C.N., Hostetter M.P., Gracely R.H., et al. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology. 1998;89:1060–1067.
Sang C.N., Ramadan N.M., Wallihan R.G., et al. LY-293558, a novel AMPA/GluR5 antagonist, is efficacious and well tolerated in acute migraine. Cephalalgia. 2004;24:596–602.
Sang C.N., Weaver J.J., Jinga L., et al. The NR2B subunit-selective NMDA receptor antagonist CP-101,606 reduces pain intensity in patients with central and peripheral neuropathic pain. Society of Neuroscience Abstract. 2003. 814.9
Santillan R., Hurle M.A., Armijo J.A., et al. Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double blind placebo-controlled study. Pain. 1998;76:17–26.
Sawynok J. Topical and peripherally acting analgesics. Pharmacological Reviews. 2003;55:1–20.
Scadding J.W. Neuropathic pain. Advances in Clinical Neuroscience and Rehabilitation. 2003;3:8–14.
Scheinfeld N. The role of gabapentin in treating diseases with cutaneous manifestations and pain. International Journal of Dermatology. 2003;42:491–495.
Schmidt B.L., Gear R.W., Levine J.D. Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans. Neuroscience Letters. 2003;343:144–146.
Schmidtko A., Lotsch J., Freynhagen R., et al. Ziconotide for treatment of severe chronic pain. Lancet. 2010;375:1569–1577.
Scholz A., Kuboyama N., Hempelmann G., et al. Complex block of TTX-resistant Na+ currents by lidocaine and bupivacaine reduce firing frequency in DRG neurons. Journal of Neurophysiology. 1998;79:1746–1754.
Seghal N., Smith H., Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14:249–258.
Shembalkar P., Taubel J., Abadias R., et al. Cizolirtine citrate (E-4018) in the treatment of chronic neuropathic pain. Current Medical Research and Opinion. 2001;17:262–266.
Shepheard S., Edvinsson L., Cumberbatch M., et al. Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. Cephalalgia. 1999;19:851–858.
Simmons R.M.A., Li D.L., Hoo K.H., et al. Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat. Neuropharmacology. 1998;37:25–36.
Simpson D.M., McArthur J.C., Olney R., et al. Lamotrigine for HIV-associated painful sensory neuropathies. A placebo-controlled trial. Neurology. 2003;60:1508–1514.
Simpson K., Serpell M., McCubbins T.D., et al, Neuropathic pain in patients using a CCK-antagonist devazepide (DEVACADE) as an adjunct to strong opioids: a multidose study. The 10th World Congress on Pain, Abstract 1443, 2002.
Sindrup S.H., Bach F.W., Madsen C., et al. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60:1284–1289.
Sirinathsinghji D.J.S., Hill R.G., eds. NMDA antagonists as potential analgesic drugs. Basel: Birhauser, 2002.
Sjolund K.-F., Segerdahl M., Sollevi A. Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain. Anesthesia and Analgesia. 1999;88:605–610.
Sneyd J.R., Langton J.A., Allan L.G., et al. Multicentre evaluation of the adenosine agonist GR79236X in patients with dental pain after third molar extraction. British Journal of Anaesthesia. 2007;98:672–676.
Snijdelaar D.G., Koren G., Katz J. Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study. Anesthesiology. 2004;100:134–141.
Spande T.F., Garraffo H.M., Edwards M.W., et al. Epibatidine: a novel (chloropyridyl) azabicycloheptane with potent analgesic activity from an Ecuadorian poison frog. Journal of the American Chemical Society. 1992;114:3475–3478.
Staats P.S., Yearwood T., Charapata S.G., et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized, controlled trial. JAMA: Journal of the American Medical Association. 2004;291:63–70.
Stein C., Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacological Reviews. 2011;63:860–881.
Stone L.S., Broberger C., Vulchanova L., et al. Differential distribution of α2A and α2C adrenergic receptor immunoreactivity in the rat spinal cord. Journal of Neuroscience. 1998;18:5928–5937.
Stubhaug A., Breivik H., Eide P.K., et al. Mapping of punctate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiologica Scandinavica. 1997;41:1124–1132.
Su D.-S., Markowitz M.K., DiPardo R.M., et al. Discovery of a potent, non-peptide bradykinin B1 receptor antagonist. Journal of the American Chemical Society. 2003;125:7516–7517.
Szallasi A. Perspectives on vanilloids in clinical practice. Drug News and Perspectives. 1997;10:522–527.
Titlic M., Jukic I., Tonkic A., et al. Lamotrigine in the treatment of pain syndromes and neuropathic pain. Bratislavske Lekarske Listy. 2008;109:421–424.
Trebino C.E., Stock J.L., Gibbons C.P., et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:9044–9049.
Tremont-Lukats L.W., Megeff C., Backonja M.M. Anticonvulsants for neuropathic pain syndromes: mechanism of action and place in therapy. Drugs. 2000;60:1029–1052.
Turan A., Karamanhoglu B., Memis D., et al. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesthesia and Analgesia. 2004;98:1370–1373.
Vanderah T. Delta and kappa opioid receptors as suitable drug targets for pain. Clinical Journal of Pain. 2009;26:S10–S15.
Vay L., Gu C., McNaughton P.A. The thermo-TRP ion channel family. properties and therapeutic implications, British Journal of Pharmacology. 2012;165:787–801.
Veneroni O., Maj R., Calabresi M., et al. Anti-allodynic effect of NW-1029, a novel Na+ channel blocker, in experimental animal models of inflammatory and neuropathic pain. Pain. 2003;102:17–25.
Villetti G., Bergamaschi M., Bassani F., et al. Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. Journal of Pharmacology and Experimental Therapeutics. 2003;306:804–814.
Wallace M.S., Rowbotham M.C., Katz N.P., et al. A randomized, double-blind, placebo controlled trial of a glycine antagonist in neuropathic pain. Neurology. 2002;59:1694–1700.
Wang Y., Toth A., Tran R., et al. High-affinity partial agonists of the vanilloid receptor. Molecular Pharmacology. 2003;64:325–333.
Warner T.D., Mitchell J.A. Cyclooxygenases: new forms, new inhibitors and lessons from the clinic. FASEB Journal. 2004;18:790–804.
Warner T.D., Mitchell J.A. Cox-2 selectivity alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet. 2008;371:270–273.
Warnke T., Stubhaug A., Jorum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced hyperalgesia in man: a double blind, crossover comparison with morphine and placebo. Pain. 1997;72:99–106.
Webb J., Kamali F. Analgesic effects of lamotrigine and phenytoin on cold induced pain: a cross over, placebo controlled study in healthy volunteers. Pain. 1998;76:357–363.
Wesselmann U., Baranowski A.P., Börjesson M., et al. Emerging therapies and novel approaches to visceral pain. Drug Discovery Today. Therapeutic Strategies. 2009;6(3):89–95.
Williamson D.J., Hill R.G., Shepheard S.L., et al. The anti-migraine 5-HT1B/1D agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs. British Journal of Pharmacology. 2001;133:1029–1034.
Wood M.R., Kim J.J., Han W., et al. Benzodiazepines as potent and selective bradykinin B1 antagonists. Journal of Medicinal Chemistry. 2003;46:1803–1806.
Woodcock J., Witter J., Dionne R.A. Stimulating the development of mechanism-based individualized pain therapies. Nature Reviews. Drug Discovery. 2007;6:703–710.
Wrigglesworth R., Walpole C.S.J., Bevan S., et al. Analogues of capsaicin with agonist activity as novel analgesic agents: structure activity studies. 4. Potent, orally active analgesics. Journal of Medicinal Chemistry. 1996;39:4942–4951.
Yao B.B., Hiseh G.C., Frost J.M., et al. In vitro and in vivo characterisation of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. British Journal of Pharmacology. 2008;153:390–401.
Zamponi G.W., Feng Z.-P., Zhang L., et al. Scaffold based designs and synthesis of potent N-type calcium channel blockers. Bioorganic & Medicinal Chemistry Letters. 2009;19:6467–6472.
Zatura F., Vsetica J., Abadias M., et al. Cizolirtine citrate is safe and effective for treating urinary incontinence secondary to overactive bladder: a phase II proof of concept study. European Urology. 2010;57:145–153.
Zimmer A., Zimmer A.M., Baffi J., et al. Hypoalgesia in mice with a targeted deletion of the tachykinin I gene. Proceedings of the National Academy of Sciences of the United States of America. 1998;95:2630–2635.
Zvartau-Hind M., Din M.U., Gilani A., et al. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology. 2000;55:1587–1588.
Abbadie C., McManus O.B., Sun S.-Y., et al. Analgesic effects of a substituted N-triazole oxindole (TROX-1) a state dependent Cav2.2 calcium channel blocker. Journal of Pharmacology and Experimental Therapeutics. 2010;334:545–555.
Afilalo M., Stegmmann J.-U., Upmalis D. Tapentadol immediate release: a new treatment option for acute pain management. Journal of Pain Research. 2010;3:1–9.
Backonja M., Wallace M.S., Blansky F.R., et al. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized double blind study. Lancet Neurology. 2008;7:1106–1112.
Barbano R.L., Herrman D.N., Hart-Gouleau S., et al. Effectiveness tolerability and impact on quality of life of the 5% lidocaine patch in diabetic poly neuropathy. Archives of Neurology. 2004;61:914–918.
Boyce S., Hill R.G., Substance P (NK1) receptor antagonists—analgesics or not?. Holzer P., ed. Handbook of experimental pharmacology, tachykinins, vol 164. Berlin: Springer-Verlag; 2004:441–457.
Chen L.C., Elliott R.A., Ashcroft D.M. Systematic review of the analgesic efficacy and tolerability of COX-2 inhibitors in post-operative pain control. Journal of Clinical Pharmacy and Therapeutics. 2004;29:215–229.
Dickson M., Gagnon J.P. Key factors in the rising cost of new drug discovery and development. Nature Reviews. Drug Discovery. 2004;3:417–429.
Dworkin R.H., Oconnor A.B., Backonja M., et al. Pharmacologic management of neuropathic pain: evidence based recommendations. Pain. 2007;132:237–251.
Garry E.M., Fleetwood-Walker S.M. Organizing pains. Trends in Neurosciences. 2004;27:292–294.
Gilron I., Coderre T.J. Emerging drugs in neuropathic pain. Expert Opinion on Emerging Drugs. 2007;12:113–126.
Gormsen L., Finnerup N.B., Almquist P.M., et al. The efficacy of the AMPA-receptor antagonist NS1209 and lidocaine in nerve injury pain: a randomized double blind placebo controlled three way crossover study. Anesthesia and Analgesia. 2009;108:1311–1319.
Graul A.I. Annual update 2003: drugs for pain and anesthesia. Drugs of the Future. 2003;28:489–524.
Guindon J., Walczak J.-S., Beaulieu P. Recent advances in the pharmacological management of pain. Drugs. 2007;67:2121–2133.
Proceedings of the 10th World Congress on Pain. Progress in pain research and management, vol 24. IASP Press, Seattle, pp 419–435.
Hill R.G., Can the evaluation of drugs in animal pain models reliably predict the ability to produce clinical analgesia?. Villaneuva L., Dickenson A., Ollat H., eds. The pain system in normal and pathological states: a primer for clinicians. Progress in pain research and management, vol 31. Seattle: IASP Press; 2004:247–258.
Ho T.W., Goadsby P.J. CGRP and its receptors provide new insights into migraine pathophysiology. Nature Reviews. Neuroscience. 2010;6:573–582.
Horsley W. Qutenza capsaicin cutaneous patch for neuropathic pain. NHS North East Treatment Advisory Group, Sept.. 2011:1–10.
Huang H., Player M.R. Bradykinin B1 receptor antagonists as therapeutic agents for pain. Journal of Medical Chemistry. 2010;53:5383–5399.
Kaczorowski G.J., McManus O.B., Priest B.T., et al. Ion channels as drug targets: the next GPCRs, Journal of General Physiology. 2008;131:399–405.
Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesthesia and Analgesia. 2010;110:780–789.
Lane N.E., Schnitzer T.J., Birbara C.A., et al. Tanezumab for the treatment of pain from osteoarthritis of the knee, New England. Journal of Medicine. 2010;363:1521–1531.
Melnikova I. Pain market. Nature Reviews. Drug Discovery. 2010;9:589–590.
Melzack R. The future of pain. Nature Reviews. Drug Discovery. 2008;7:629.
Middleton L.S., Nuzzo P.A., Lofwall M.R., et al. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction. 2011;106:1460–1473.
Negus S.S., Vanderah T.W., Brandt M.R., et al. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. Journal of Pharmacology and Experimental Therapeutics. 2006;319:507–514.
Nelson D.L., Phebus L.A., Johnson K.W., et al. Preclinical pharmacology profile of the selective 5HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30:1159–1169.
Nitu A.N., Wallihan R., Skljarevski V., et al. Emerging trends in the pharmacotherapy of chronic pain. Expert Opinion on Investigational Drugs. 2003;12:545–559.
Notcutt W., Price M., Miller R., et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “n of 1” studies. Anesthesia. 2004;59:440–452.
Petersen K.A., Lassen L.H., Birk S., et al. BIBN4096BS antagonizes human CGRP induced headache and extracerebral artery dilatation. Clinical Pharmacology and Therapeutics. 2005;77:202–213.
Rawlins M.D. Cutting the cost of drug development? Nature Reviews. Drug Discovery. 2004;3:360–364.
Rice A.S.C., Maton S., Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
Salvatore C.A., Hershey J.C., Corcoran H.A., et al. Pharmacological characterization of MK-0974, a potent and orally active CGRP receptor antagonist for the treatment of migraine. Journal of Pharmacology and Experimental Therapeutics. 2007;324:416–421.
Sang C.M. Clinically available glutamate receptor antagonists in neuropathic pain states. In: Sirinathsinghji D.J.S., Hill R.G., eds. NMDA antagonists as potential analgesic drugs. Basel: Birkhauser; 2002:165–180.
Sawynok J. Topical and peripherally acting analgesics. Pharmacological Reviews. 2003;55:1–20.
Scadding J.W. Neuropathic pain. Advances in Clinical Neuroscience and Rehabilitation. 2003;3:8–14.
Seghal N., Smith H., Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14:249–258.
Sindrup S.H., Bach F.W., Madsen C., et al. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60:1284–1289.
Sirinathsinghji D.J.S., Hill R.G., eds. NMDA antagonists as potential analgesic drugs. Basel: Birhauser, 2002.
Stein C., Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacological Reviews. 2011;63:860–881.
Vanderah T. Delta and kappa opioid receptors as suitable drug targets for pain. Clinical Journal of Pain. 2009;26:S10–S15.
Vay L., Gu C., McNaughton P.A. The thermo-TRP ion channel family: properties and therapeutic implications. British Journal of Pharmacology. 2012;165:787–801.
Wesselmann U., Baranowski A.P., Börjesson M., et al. Emerging therapies and novel approaches to visceral pain. Drug Discovery Today. Therapeutic Strategies. 2009;6(3):89–95.
Woodcock J., Witter J., Dionne R.A. Stimulating the development of mechanism-based individualized pain therapies. Nature Reviews. Drug Discovery. 2007;6:703–710.