Unusual Pain Disorders - What Can Be Learned from Them?

Abstract

Pain is common in many different disorders and leads to a significant reduction in quality of life in the affected patients. Current treatment options are limited and often result in insufficient pain relief, partly due to the incomplete understanding of the underlying pathophysiological mechanisms. The identification of these pathomechanisms is therefore a central object of current research. There are also a number of rare pain diseases, that are generally little known and often undiagnosed, but whose correct diagnosis and examination can help to improve the management of pain disorders in general. In some of these unusual pain disorders like sodium-channelopathies or sensory modulation disorder the underlying pathophysiological mechanisms have only recently been unravelled. These mechanisms might serve as pharmacological targets that may also play a role in subgroups of other, more common pain diseases. In other unusual pain disorders, the identification of pathomechanisms has already led to the development of new drugs. A completely new therapeutic approach, the gene silencing, can even stop progression in hereditary transthyretin amyloidosis and porphyria, ie in pain diseases that would otherwise be rapidly fatal if left untreated. Thus, pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.

Keywords: central sensitization; gene silencing; hereditary pain diseases; pain mechanisms; sensory modulation disorder; sodium channelopathies.

Figure 1

Model of amyloid fibril formation in hereditary transthyretin (ATTRv) amyloidosis. Mutations in the TTR protein lead to a loss of its stable conformation. TTR dissociates into monomers that are misfolded, aggregate and deposit as amyloid in the extracellular spaces of various organs. *The rate-limiting step is the dissociation of the tetrameric TTR protein to dimers.

Figure 2

Potential red‐flag symptom clusters that may warn of a diagnosis of hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy (Reused from Conceição et al with permission of John Wiley and Sons, Copyright © 2016 Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society).

Figure 3

The heme biosynthetic pathway showing intermediates, enzymes and types of porphyria associated with each enzyme (Adapted from Ramanujam and Anderson, Porphyria diagnostics-part 1: a brief overview of the porphyrias. Current Protocols in Human Genetics with permission of John Wiley and Sons, Copyright © 2015 John Wiley & Sons, Inc.).