Analgesic Drugs in Development

Introduction

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 ( , , , ) 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, 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 and Chapter 61, Chapter 62, Chapter 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 ( ), 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 ( , , ), 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.

The Drug Discovery and Development Process

A large number of potential targets for the discovery of novel analgesic drugs have emerged in the past 5 years or so ( , , , ), 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:

• 1.

  Incremental improvement on an existing drug mechanism

• 2.

  Novel selective mechanism arising from better understanding of the mechanism of an existing analgesic drug

• 3.

  Completely novel mechanism arising from basic biological studies or from human pathophysiological or genomic studies

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 ( , ).

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 , , ). 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. 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% ( ). Clinical testing is both expensive and time-consuming; it costs up to $450 million ( ) and takes an average of 5 years ( ) to establish the needed clinical efficacy, safety, and a suitable dose range for routine use ( ). 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 ( ). The introduction of increased regulatory and safety requirements and increased levels of competition in the pharmaceutical industry add to the difficulties of the process ( , ).

Variations on the Theme of Non-Steroidal Anti-Inflammatory Drugs and Cyclooxygenase-2 Blockers

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 Chapter 32, Chapter 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 ( ; see also ). 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 ).

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 ( ), although recently the Food and Drug Administration (FDA) refused to approve the registration of naproxcinod ( ). 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 ( ). 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 ( , ) 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 , ) has shifted emphasis to alternative strategies such as specific 5-Lip inhibitors ( ), prostaglandin E synthase blockers ( ), or prostaglandin receptor (EP receptor) blockers ( ).

Opioid Analgesics

New formulations of traditional opioids such as morphine continue to be introduced as advances in formulation technology are made (see ). The morphine metabolite morphine-6-glucuronide is also being developed as an injectable analgesic ( , ). 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 ( ). 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 ( , ). 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 ( ).

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 ). 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. 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 ( ). 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 ( ). A small open trial has indicated that this regimen may be useful in treating neuropathic trigeminal pain ( ). It has been claimed that opioids that have mixed agonism at both μ- and δ-opioid receptors, such as DPI-3290 ( ), 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 ( , ). The utility of selective δ-opioid agonists has not yet been confirmed in published human clinical trials.

Cannabinoids and Adenosine Receptor Ligands

Self-medication with cannabis is commonly used to relieve pain and other symptoms in patients with multiple sclerosis ( ), 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 ( ). Some positive data have been reported ( ), but there are also negative studies on experimental pain in volunteers ( ) and on postoperative pain ( ). 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 ( ).

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 ( ). 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 ( ). 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 ( ). 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 ( ), 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 ( , ). Clinical analgesia has been observed in volunteer studies on cutaneous hyperalgesia following inflammatory pain when adenosine was given intravenously ( ) and in patients with neuropathic pain when adenosine was given intrathecally ( ). A recent clinical study on postoperative pain patients failed to show analgesia after administration of the selective A ₁ receptor agonist GR79236X, although the active control diclofenac was effective ( ). Recent animal experiments suggest that both A _2A and A _2B antagonists have potential in the treatment of inflammatory pain ( ).

Adrenoceptor Agonists

The α ₂ 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 ( ; ), 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 ( ). 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 ( ), has been suggested to be useful in treating a range of painful conditions, including myofascial and neuropathic pain ( ). 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 α ₂ 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 α ₂ receptors within the dorsal horn of the spinal cord suggest that activation of the α _2A receptor is responsible for the analgesic properties ( ). This conclusion is supported by the observation that in mice with the gene for the α _2A 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 ( ). 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 α ₂ 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.