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  • Review Article
  • Published:

Breaking barriers to novel analgesic drug development

Nature Reviews Drug Discovery volume 16, pages 545–564 (2017)Cite this article

Subjects

A Corrigendum to this article was published on 06 October 2017

This article has been updated

Key Points

  • Pain is the primary reason why people seek medical care; more than 40% of the US population is affected by chronic pain.

  • Opioids, which are the most commonly used and often the most effective class of analgesics, produce tolerance, dependence and constipation, and are associated with major abuse liabilities. The respiratory depression associated with high doses has led to a catastrophic increase in the number of drug overdose deaths in the United States.

  • Several new or previously overlooked targets are gaining significant attention. In the field of G-protein-coupled receptors (GPCRs), these include new ligands targeting opioid receptor heteromers, different opioid receptor subtypes and biased agonists. Non-opioid GPCRs currently being pursued include cannabinoid receptor 2 (CB2), angiotensin type 2 receptor (AT2R) and chemokine receptors.

  • Various academic and industry groups are pursuing ion channel strategies by targeting sodium, potassium and calcium channels — specifically, certain Nav1.7, Nav1.8 and voltage-dependent calcium channel (Cavs) ligands are showing particular promise in early preclinical and clinical trials.

  • Several enzyme targets that modulate pain pathways are also being pursued.

  • Despite considerable efforts, there have been several high-profile failures of novel analgesics in the clinic.

  • Barriers that need to be overcome to develop efficacious analgesics include issues related to the lack of predictability of preclinical models in certain contexts, the translation of pathways from animal models to humans, exaggerated placebo effects and issues with clinical trial design.

Abstract

Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.

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Figure 1: Mechanisms relevant for nociception and analgesia.
Figure 2: Peripheral analgesic drug discovery targets.

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Change history

  • 23 June 2017

    In the original published article, the ligands RB-64 and PZM21 have been shown as attributed to Trevena in table 1 in the 'biased GPCR ligands' row. This error has been corrected in the HTML and PDF versions of the article.

  • 06 October 2017

    The compounds APD371,LY2828360, S-777469 and KHK6188 were incorrectly referred to as inhibitors of the cannabinoid receptors CB1 and CB2 in Table 1, when they are cannabinoid receptor agonists. In addition, KHK6188 is not currently in a Phase 2 clinical trial for neuropathic pain as stated in Table 1 and development of this agent has been discontinued. The error has been corrected in the html and pdf versions online.

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Acknowledgements

The authors acknowledge generous funding support from the following US National Institutes of Health grants: NS039518 and NS038253 (US National Institute of Neurological Disorders and Stroke (NINDS) to C.J.W); NS072040 and NS036855 (NINDS to B.P.B.); and DA041912 (US National Institute on Drug Abuse to A.S.Y.).

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Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Ajay S. Yekkirala, David P. Roberson, Bruce P. Bean & Clifford J. Woolf

  2. FM Kirby Neurobiology Center Boston Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Ajay S. Yekkirala, David P. Roberson & Clifford J. Woolf

  3. Blue Therapeutics, Harvard Innovation Launch Lab, 114 Western Avenue, Allston, 02134, Massachusetts, USA

    Ajay S. Yekkirala & David P. Roberson

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Correspondence to Ajay S. Yekkirala or Clifford J. Woolf.

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Competing interests

A.S.Y and D.P.R. are co-founders of Blue Therapeutics in Allston, Massachusetts, USA, which is focused on developing non-addictive painkillers targeting G-protein-coupled receptor heteromers. A.S.Y. holds a patent on an analgesic agent. B.P.B. is a co-founder of Flex Pharma in Boston, Massachusetts, USA, and co-holds patents on using charged sodium channel blockers for pain relief and other indications. C.J.W is co-founder and scientific advisor to Quartet Medicine in Cambridge, Massachusetts, USA, which is focused on developing treatments for chronic pain and inflammation targeting the tetrahydrobiopterin pathway; he is also a consultant and stock holder for Abide Therapeutics in San Diego, California, USA, and holds several patents related to methods and approaches for studying and treating pain.

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Glossary

Analgesics

Pharmacological agents or ligands that produce analgesia.

Tolerance

A state in which the drug no longer produces the same effect and a higher dose is therefore needed.

Dependence

An adaptive state that develops when a pharmacological agent is used repeatedly and leads to withdrawal on cessation of the drug regimen.

Hyperalgesia

Enhanced nociceptive response to a noxious stimulus, leading to greater discomfort than before.

Allodynia

Nociceptive response elicited even to previously non-noxious stimuli.

Phenocopy

When an organism shows phenotypic characteristics that reflect a different genotype from its own.

Neuropathic pain

A condition leading to pain due to damage or disease of nervous system tissues.

Central sensitization

A condition of the nervous system in which neurons in the central nervous system are in a state of prolonged increase in excitability and synaptic efficacy, coupled with the loss of inhibitory activity.

Analgesia

A lack of, or insensibility to, pain.

Nociception

Sensory neuronal responses to noxious or damaging stimuli that attribute the sensation of pain.

Depersonalization

A state in which an individual's thoughts, feelings and emotions seem to not belong to them.

Antinociception

Inhibition of sensory neuronal response to noxious stimuli that leads to reduction of pain sensation.

Ligand bias

Occurs when a ligand shows selectivity or preference to a particular signal transduction mechanism for a target receptor. Also called 'functional selectivity'.

Psychotomimetic effects

A state of psychosis of the mind leading to delusions, hallucinations, and so on that are precipitated by a pharmacological agent or ligand.

Post-herpetic neuralgia

Pain caused by nerve damage due to infection with varicella zoster virus.

Withdrawal

Symptoms such as anxiety and shaking that develop on cessation of a drug that has been used repeatedly.

Trigeminal neuralgia

A painful condition caused by disease affecting, dysfunction of or damage to the trigeminal nerve.

Anosmia

Loss of the sense of smell.

Allosteric modulators

Ligands that alter the activity of an agonist, antagonist or inverse agonist of a target by binding to a site distinct from the active site.

Phenotypic screens

Unbiased screening strategies in which the functional output is a pre-determined alteration of phenotype.

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Yekkirala, A., Roberson, D., Bean, B. et al. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 16, 545–564 (2017). https://doi.org/10.1038/nrd.2017.87

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