Attacking Pain At Its Source: New Perspectives on Opioids

Christoph Stein, Michael Schäfer, Halina Machelska

Disclosures

Nat Med. 2003;9(8) 

In This Article

Abstract and Introduction

Abstract

The treatment of severe pain with opioids has thus far been limited by their unwanted central side effects. Recent research promises new approaches, including opioid analgesics acting outside the central nervous system, targeting of opioid peptide-containing immune cells to peripheral damaged tissue, and gene transfer to enhance opioid production at sites of injury.

Introduction

The first step in pain treatment is usually pharmacologic, along with cognitive and behavioral approaches in more chronic stages. Opioids are the most powerful drugs for severe acute and chronic pain, but their widespread use is hampered by side effects such as depression of breathing, nausea, clouding of consciousness, constipation, addiction and tolerance[1]. A new generation of opioid drugs is now emerging. This class selectively activates opioid receptors outside the central nervous system, thus avoiding all centrally-mediated, unwanted effects[2]. Endogenous ligands of these peripheral opioid receptors are produced within skin and immunocytes[3]. This has led to new directions of research, such as the selective targeting of opioid peptide-containing cells to sites of painful injury, and the augmentation of opioid synthesis by gene transfer.

Acute and chronic pain are frequently associated with inflammation as a result of tissue destruction, abnormal immune reactivity or nerve injury. Within damaged peripheral tissue, primary sensory neurons transduce mechanical, chemical or heat stimuli into action potentials. These sensory neurons have myelinated (A ) or small-diameter unmyelinated axons (C-fibers, or 'nociceptors'). The latter are particularly sensitive to the vanniloid receptor-1 ligand and the neurotoxin capsaicin, and are considered the dominant fibers in clinical pain. Fibers normally transferring innocuous touch (Aß) can also contribute to pain after nerve damage. After synaptic transmission and modulation within the spinal cord, nociceptive signals reach supraspinal and cortical sites, where they can be perceived as painful.

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