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Complete pain relief: potential problems and diagnostic solutions

Nature Clinical Practice Neurology volume 3, pages 648–649 (2007)Cite this article

The idea that complete elimination of pain would be beneficial is commonplace, but is the development of perfect pain control really a desirable goal? Nonmalignant pain syndromes such as fibromyalgia, migraine, back pain, and arthritis are a small sample of the chronic pain problems that afflict a vast patient population worldwide. A WHO study conducted in 14 countries in Asia, Africa, Europe and the Americas reported that 22% of patients in primary care experience pain that persists for longer than 6 months.1 Debilitating pain conditions have a tremendous influence on quality of life, and the expense of chronic medications, interventions and lost work time is a tremendous financial burden. In the US, direct costs for back pain alone were estimated to be US$33.6 billion in 1994,2 and European countries experience similarly high costs (approximately €350 per capita3). While the burden of pain problems is increasing, after much research into therapeutic agents and methods of drug delivery, a new generation of potent analgesic treatments is beginning to materialize.

Several drugs targeting pain-specific pathways are in clinical and preclinical development. In a recent publication by Brown et al., administration of a plant extract—resiniferatoxin, a potent vanilloid receptor agonist—was reported to confer lifelong relief from canine bone cancer pain with minimal side effects.4 Resiniferatoxin opens TRPV1, a ligand-gated ion channel that binds vanilloid ligands such as capsaicin, and senses noxious heat. Excessive activation of TRPV1 results in an intracellular calcium overload, causing lysis of a specific population of nociceptive primary afferent neurons. A second approach to pain control utilizes protein (usually a plant or bacterial toxin that blocks protein synthesis) combined with a ligand that confers specific cellular targeting. Again, the therapeutic effect is elicited by selective cell deletion, in this case using conjugates that target the neurokinin 1 receptor (the substance P [SP] receptor) in neurons of the spinal cord dorsal horn (SP–diphtheria toxin5 or SP–saporin6) or molecules in dorsal root ganglia (isolectin B4-conjugated saporin7). Furthermore, on the basis of fundamental advances in the understanding of nociceptive circuitry, gene expression patterns and ion channel biophysics, and following persistent medicinal chemistry efforts, other—more traditional—small-molecule drugs are being developed that block specific molecular targets within the peripheral tissue, the primary afferents or the CNS. A high therapeutic index of these agents allows profound symptom relief without hindrance from the dose-limiting toxicities associated with current analgesic compounds such as morphine.

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Authors and Affiliations

  1. AJ Mannes is a Staff Clinician in the Department of Anesthesia and Surgical Services and in the National Institute of Dental and Craniofacial Research, and MJ Iadarola is Chief of the Neurobiology and Pain Therapeutics Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.,

    Andrew J Mannes & Michael J Iadarola

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  1. Andrew J Mannes
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  2. Michael J Iadarola
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Correspondence to Michael J Iadarola.

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Mannes, A., Iadarola, M. Complete pain relief: potential problems and diagnostic solutions. Nat Rev Neurol 3, 648–649 (2007). https://doi.org/10.1038/ncpneuro0660

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