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Stimulating the development of mechanism-based, individualized pain therapies

Nature Reviews Drug Discovery volume 6, pages 703–710 (2007)Cite this article

Key Points

  • Virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin-like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. As a consequence, pain-related conditions frequently lack effective therapy.

  • In this Perspective, we discuss factors contributing to the lack of innovation in therapies for pain and advocate public–private partnerships to translate new knowledge into more efficacious and safer treatments.

  • Factors confounding this lack of innovation include: assessing compounds with new mechanisms of action, using animal models that have been validated with older prototypic drugs, conducting proof-of-concept studies in clinical models that may not readily extrapolate to chronic pain syndromes and evaluating new drugs with group measures of central tendency and variation that may limit our understanding on how to manage the individual patient's pain.

  • Recognition of the multiplicity of cells, receptors and genetic changes involved in pain processing suggests that analgesic drug development may be reinvigorated by targeting multiple events and determining which series or combinations of targets yield effective analgesia for specific diseases and diverse patients.

  • Development of responder approaches might identify drugs with therapeutic value for chronic pain that is resistant to normal therapies and identify molecular–genetic markers for predicting analgesic drug actions in individual patients.

  • Clinical outcomes, such as pain, that require consideration of more than one endpoint may be assessed better with a composite approach that is able to encompass and accommodate these variables. This approach has the advantage of grouping clinically important outcomes into a metric that defines the response of the individual, not the individual's contribution to the group outcome.

  • The US Food and Drug Administration's Critical Path Initiative for medical product development spans the continuum from prototype design or discovery, through preclinical and clinical development to approval and product launch. Progress in critical path pain-related research is dependent on the development of consortia to organize public–private partnerships and identify resources to start the process of improving pain therapy through the development of better and safer drugs.

Abstract

Biomedical science has greatly improved our understanding of pain in recent decades, but few novel molecular entities that address fundamentally new pain mechanisms have entered the clinic, despite dramatically increased pharmaceutical investment. Indeed, virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin-like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. Here, we discuss factors contributing to this lack of innovation in therapies for pain and advocate public–private partnerships (PPPs) to translate new knowledge into more efficacious and safer treatments.

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Figure 1: Schematic illustration of the 'moving pain target'.
Figure 2: Wide variability in inflammation-induced gene expression across subjects alters the responseto analgesics.

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Author information

Authors and Affiliations

  1. Department of Health and Human Services, Janet Woodcock and James Witter are at the Food and Drug Administration, Rockville, Maryland, USA.,

    Janet Woodcock & James Witter

  2. Department of Health and Human Services Bethesda, Raymond A. Dionne is at the National Institutes of Health, Maryland, USA.,

    Raymond A. Dionne

Authors
  1. Janet Woodcock
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  2. James Witter
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  3. Raymond A. Dionne
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Corresponding author

Correspondence to Raymond A. Dionne.

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The authors declare no competing financial interests.

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FURTHER INFORMATION

FDA Critical Path Initiative

Foundation for the NIH

Osteoarthritis Initiative

Patient-reported outcomes measurement information system

Predictive Safety Testing Consortium

Glossary

Cyclooxygenase-2

(COX-2). An enzyme that is expressed in cell membranes in response to tissue injury and catalyses the formation of pro-inflammatory cytokines from arachidonic acid.

Item response theory

Psychometric models that link patient responses to the probability of an underlying trait.

Haplotype

A combination of alleles or seqquence variations on the same chromosome.

Non-steroidal anti-inflammatory drugs

(NSAIDs). A structurally diverse class of drugs that block the enzymatic activity of cyclooxygenase to produce analgesia.

Off label

The use of an approved drug for a condition that is not mentioned in the original labelling.

Open-label segment

Identification of responders to a known drug by administration prior to randomization into the double-blind phase of a clinical trial.

Pharmacogenetics

The study of genetic variation that results in differing responses to drugs. Pharmacogenetics considers one or a few genes of interest, whereas pharmacogenomics considers the entire genome.

Plasticity

Changes in the nervous system that alter the processing of sensory information to augment or suppress the sensory responses elicited by a fixed input to a potentially painful stimulus.

Single nucleotide polymorphisms

(SNPs). Inter-individual differences in the DNA sequence at a single position in the genome, currently estimated to be greater than 10 million in the human genome. Differences in a single base could change the protein sequence, leading to differences in susceptibility to diseases or therapies.

Visual analogue scales

(VAS). A pain measurement scale consisting of a vertical or horizontal line, which defines a continuous response dimension between two words that anchor each end of the scale, usually 'no pain' at one end and 'worst possible pain' at the other.

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Woodcock, J., Witter, J. & Dionne, R. Stimulating the development of mechanism-based, individualized pain therapies. Nat Rev Drug Discov 6, 703–710 (2007). https://doi.org/10.1038/nrd2335

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