How Science is Informing the Management of Pain
Martin Koltzenburg
UCL Institute of Neurology and UCL Institute of Child Health
London, UK
Despite significant advances in our understanding of the neurobiology of nociception, pain continues to be a leading health problem and a significant area of unmet clinical need for novel analgesic drugs. Results from several recent large epidemiological surveys have consistently shown that the overall prevalence of pain in the general populations is around 20% (Eriksen et al., 2003;Macfarlane et al., 2005;NFO World Group, 2003). Pain is the leading cause for absenteeism form work with nearly 500 million lost working days every year - costing the European economy at least €34 billion. Patients in chronic pain utilize the health care system twice as much as the general population and this chronification is a significant burden with an median pain duration of 7 years (NFO World Group, 2003). Approximately 10% of the population use analgesic medications on a regular basis (Eriksen et al., 2003;NFO World Group, 2003) leading to substantial direct and (because of the plethora of adverse events of these compounds) indirect costs. This is highlighted by the recent withdrawal of several coxibs and the fact that the fatality associated with non-steroidal analgesic drug use exceeds 5 per 100,000 – higher than that for asthma, cervical cancer or malignant melanoma (Singh, 1998). Thus, a better understanding of the neurobiology of pain is likely to have a significant impact on the general heath system and the development and appropriate use of analgesic drugs for the symptomatic treatment of pain.
Currently, much research is directed towards understanding the cellular and molecular properties of peripheral nociceptors and spinal cord processes, the primary gateway of the pain pathway (McMahon and Koltzenburg, 2005). Contemporary research has identified that nociceptive primary afferent neurons are essential for the perception of pain and this is perhaps best illustrated by individuals who suffer form insensitivity to pain as a consequence of a congenital lack of the nociceptors (following cell death of these neurons during embryogenesis) or lack of function. Nociceptors express a unique set of receptors and ion channels: Transient receptor potentials (TRP) channels including the prototypical capsaicin receptor TRPV1 are major transducers for thermal stimuli. Different set of ion channels including the sodium channels Nav1.7, Nav1.8 and Nav1.9 appear to be essential for the transmission of noxious information. The exceedingly rare individuals with a loss of function mutations of Nav1.7 show that pain perception in humans requires nociceptors and Nav1.7. The importance of these ion channels is also shown by the fact that gain of function mutations of Nav1.7 cause several hereditary painful conditions in humans such as erythermalgia or paroxysmal extreme pain disorder. Studies have shown that some anticonvulsant drugs can reduce the abnormally increased excitability of nociceptors expressing mutant ion channels.
At the pivotal first synapse in the dorsal horn of the spinal cord transmission involving excitatory aminoacids and neuropeptides such as Substance P is controlled by a number of mechanisms and it is one site of action for the analgesic effect of opiates. In the spinal cord a dedicated set of neurons is employed to signal nociception to the brain. In primates painful somatic information travels through the spinothalamic tract whereas in rodents where direct spinothalamic projections are rather small in number, spino-parabrachial projection neurons expressing the Substance P receptor appear to be more important. Ablation of these neurons –sometimes referred to as chemical cordotomy – provides powerful analgesia in animal models of acute and chronic pain (Mantyh et al., 1997).
The experience of pain is more than the detection of actual or potentially tissue damaging stimuli. Excitation of nociceptive system engages supraspinal centres that greatly influence the perception of pain. How these primary afferent through spinal neurons interact with the supraspinal centres is currently poorly understood and using novel tracing techniques we are only beginning to understand how information from subpopulations of sensory neurons is represented supraspinally (Braz et al., 2005). This has already revealed unsuspected areas receiving nociceptive input such as the globus pallidus. How painful stimuli are processed supraspinally and how this affects emotions or learning and how in turn the sensation of pain is shaped by prior experience and expectancies is important for the clinical effects of placebo analgesia and cognitive modulation of pain.
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Macfarlane GJ, Jones GT, McBeth J (2005) Epidemiology of pain. In: Wall and Melzack's Textbook of Pain (McMahon SB, Koltzenburg M, eds), pp 1199-1214. Philadelphia: Elsevier.
Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, Simone DA (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278:275-279.
McMahon SB, Koltzenburg M (2005) Wall and Melzack's Textbook of Pain. Philadelphia: Elsevier.
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Time of Presentation
830 - 1000, 26 May 2007
