Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm

Abstract

Aim: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs.

Methods: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on (1) disease mechanisms leading to chronic/neuropathic pain and (2) druggable targets which are currently under evaluation in drug development. Attention was also given to the role of biomarkers and pharmacokinetic-pharmacodynamic modelling.

Results: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti-inflammatory drugs (NSAIDs).

Conclusion: A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials.

Keywords: Analgesics; Chronic pain; Drug development; Hyperalgesia; Inflammatory pain; Neuropathic pain; PKPD modelling.

Fig. 1

A flow diagram showing the different dimensions and progression from aetiology to the ultimate clinical overt manifestations of neuropathic and chronic pain. The current paradigm for the screening of novel candidate molecules is based on the evaluation of drug effects on overt behavioural symptoms of pain. This represents an important limitation for the identification of efficacious compounds in humans and is partly explained by the lack of (1) diagnostic markers that allow the detection of pathophysiological or structural changes before the onset of overt symptoms and (2) clinical and non-clinical experimental models that reflect the timing and progression of the disease in patients with chronic and neuropathic pain

Fig. 2

Central and peripheral mediators and neurochemicals associated with the pathophysiology of inflammatory, neuropathic and chronic pain. a Upper panel: Following nerve injury, neurochemical modulation of synaptic transmission occurs in the dorsal horn, post-synaptic receptors and ion channels are activated by excitatory amino acids released presynaptically and further sensitised by cytokines from activated glial cells. b Lower panel: Peripheral mediators of pain transduction after tissue injury. Following tissue injury, mast cells, macrophages, and other injured cells directly or indirectly release numerous chemicals that alter the sensitivity of receptors and ion channels on peripheral nerve endings. These receptors release secondary messengers such as protein kinase A and C, which can activate other membrane bound receptors and gene transcription. A ₂ adenosine 2 receptor, ASIC acid sensing channels, B1/2 bradykinin receptors, CNS central nervous system, EAA excitatory amino acids, EP prostaglandin E receptor, GABA γ-amino-butyric acid, GIRK G-protein coupled inwardly rectifying K+, H ₁ histamine receptor, 5HT 5-hydroxy-tryptamine, IL 1/2 interleukins 1/2, M ₂ muscarinic-2 receptor, NO nitric oxide, P ₂ X ₃ purinergic receptor X₃, PAF platelet-activating factor, PGs prostaglandins, ROS reactive oxygen species, TNF tumour necrosis factor, TTXr tetrodoxin receptor, TrkA tyrosine receptor kinase A. Reprinted with permission from [4]

Fig. 4

Overview of arachidonic acid cascade associated with inflammatory pain response. Arachidonic acid is released from cellular membranes by cytosolic phospholipase A ₂ (PLA ₂ ). The free arachidonic acid can further be converted to eicosanoids by three different pathways involving lipoxygenases (LO), cyclooxygenases (COX), and the cytochrome P450 monooxygenase pathway (not shown), respectively. COX enzymes catalyse the conversion of arachidonic acid to prostaglandin G2, which is reduced to prostaglandin H ₂ (PGH ₂ ). By specific prostaglandin (PG) and thromboxane (TXA ₂ ) synthases, PGH₂ is subsequently converted to different prostaglandins and thromboxane A ₂. Different LO enzymes convert the arachidonic acid to biologically active metabolites such as leukotrienes and hydroperoxyeicosatetraenoic acids (HPETEs). In the leukotriene pathway, arachidonic acid is converted to 5-HPETE, which is further metabolised to the unstable leukotriene A ₄ (LTA ₄ ). LTA ₄ is converted to LTB ₂ or the cysteinyl-containing LTC ₄, LTD ₄, and LTE ₄. Adapted from [39]

Fig. 5

Current paradigm for the discovery and development of analgesic drugs. Typically, R&D efforts start with target selection and end with regulatory approval for the indication in the target patient population. Failures in phases 2 or 3 are a major cause of attrition, and represent the core expenditure in this therapeutic area. Clinical programmes are likely to fail without informative, predictive experimental protocols at the screening phase. The lack of construct validity of preclinical models currently used during drug screening, the irreversibility of changes induced by signalling dysfunction and the absence of early diagnostic tools in humans lead to significant differences in treatment response in animals and humans. Reprinted with permission from [1]

Fig. 6

Fallacies of pain comparisons using the visual analogue scale (VAS). If one subject’s worst pain is childbirth and another’s is a stubbed toe, rating the same point on a scale would result in a discrepancy between the actual magnitude of pain experienced and that reported on a conventional VAS. Thus, as depicted in a, subject A has experienced greater magnitude of pain than B; it appears that the pain intensity is the same for both subjects. In c, the discrepancy is compounded. Subject A experiences pain that is only slightly greater than that of subject B. When maximum pain is treated as it were the same for both subjects, the pain depicted by the arrows in d erroneously suggests greater pain for B than for A. This is referred to as reversal artefact. Thus, a conventional VAS anchored by “no pain” and “worst pain imaginable” can conceal real differences in pain intensity across subjects. Reprinted with permission from [72]

Fig. 7

Main steps for the implementation of model-based approaches in drug development. NME new molecular entity. Adapted with permission from [99]