November 14, 2016
Research on monogenic disorders has made vital contributions to all aspects of medical care, including our understanding of pain pathophysiology.
Nearly every advance in modern medicine, from diagnosis to treatment, has benefited from animal studies. Basic research has made vital contributions to all aspects of medical care, including our understanding of pain pathophysiology.
However, the applicability of these findings to humans remains limited. “Translation from animal to human is hindered by many obstacles, in particular with the subject of pain, where the human organism and mind interact in quite a unique way,” Claudia Sommer, MD, a professor of neurology at the University of Würzburg in Germany, told Clinical Pain Advisor.
Even so, valuable insights have been gained by the direct study of humans with chronic pain. In a special issue on pain, Science published a review article by Dr Sommer that highlights some of the most notable developments, including the 3 below.1
Quantitative sensory testing (QST)
QST is a “psychophysical method that uses a battery of sensory stimuli with predetermined physical properties following specific protocols,” and it is “able to capture and quantify stimulus-evoked negative and positive sensory phenomena,” Dr Sommer wrote.
These sensory phenomena should indicate the type of nerve fiber involved because of the unique characteristics of the fibers. The use of QST has led to the unexpected discovery that small nerve fibers are involved in Parkinson’s disease, fibromyalgia, and other disorders in which large nerve fibers were believed to be the only type involved.2,3 These findings suggest that pain in such disorders may be in part due to primary or secondary peripheral nociceptors.
In other disorders, QST has led to the identification of “sensory profiles” that may reflect the pain pathophysiology of individual patients and facilitate targeted treatment planning.
For example, one study found that patients in whom QST revealed preserved nociceptor function were more responsive to the antiepileptic drug oxcarbazepine than patients with impaired nociceptor function.4
In other research, the 8% capsaicin patch appeared to be more effective in patients whose QST results indicated hyperalgesia vs small-nerve fiber loss.5
Further research will be required to determine the utility of QST sensory phenotyping in individualized treatment. Such data may be most informative when combined with neurophysiological and molecular phenotyping.
Genetic Testing (PAIN IS IN THE GENES)
Though human genomic studies have not yet yielded substantial gains in this area, research focusing on monogenic disorders have led to highly valuable discoveries.
“One successful example is the monogenic pain diseases based on mutations in voltage-gated sodium channels (Nav),” said Dr Sommer. “Here, the sodium channel blocking anti-epileptics, which are usually second- to third-line in the treatment of neuropathic pain, have been proven to be useful analgesics.”
Investigations in this area have established a role for voltage-gated sodium channel activity in pain etiology and elucidated the nature of its malfunction in various genetic mutations.
For example, erythromelalgia and paroxysmal extreme pain disorder can result from gain-of-function mutations of Nav1.7 ion channels, while congenital analgesia is caused by a loss-of-function mutation in Nav1.7. In addition, mutations of the genes for Nav1.7, Nav1.8, and Nav1.9 have been found in as many as 30% of patients with idiopathic small-fiber neuropathy (SFN).6
Other studies have linked a single-nucleotide polymorphism in the SCN9A gene [rs6746030, substitution of arginine-1150 with tryptophan (R1150W)] with pain in disorders such as Parkinson’s disease and interstitial cystitis, and it may render affected individuals more sensitive to pain.
“With the exception of rare monogenetic diseases like the ones mentioned above, changes in one gene or its product often do not have a major effect on pain perception,” Dr Sommer noted in the review.
Scientists are currently attempting to identify “master switches” that have a much broader, multifaceted reach than single genes, and microRNAs have shown promise in this regard.
While standard evoked potential testing is a cornerstone of neurophysiology, they do not measure the activity of small nerve fibers and typically do not indicate the location of the lesion along the trajectory from the peripheral nervous system (PNS) to the central nervous system (CNS).
Laser-evoked potential (LEP) testing is the most well-established technique that selectively activates Aδ and C fibers. Findings from LEP research have shown, for instance, that spinothalamic pathway damage may predict pain in patients with multiple sclerosis.7
More recent studies have focused on contact heat-evoked potentials (CHEPs), which can be used to measure Aδ and C fiber activity and “may reflect the reported magnitude of evoked pain,” according to the review article.
Further efforts have combined neurophysiology and psychophysics to explore pain mechanisms using techniques such as temporal summation testing, in which a standard pain response by the patient was expected as stimuli were administered, and conditioned pain modulation, which recorded pain ratings in one arm as the other was immersed in hot water.
Increased temporal summation ratings accompanied by decreased conditioned pain modulation are proposed to indicate deficient, “pro-nociceptive” endogenous pain modulation. Patients who demonstrated this pattern showed the greatest response to the serotonin noradrenalin reuptake inhibitor duloxetine, which is thought to improve descending pain inhibition.8
Additional new and emerging methods covered in the review include those that allow imaging of peripheral pain–including intraepidermal nerve fiber (IENF) quantification and corneal confocal microcopy–and techniques to assess a patient’s inflammatory profile via body fluid or tissue samples.
A technique that Dr Sommer finds especially intriguing, though it has not yet begun to influence pain treatment, is the use of somatic cell reprogramming to generate neurons from skin cells of patients with pain diseases.
“With all caveats that the cells may change their properties during the different culture phases, this could lead to new experimental systems that may give us information on how pain is generated and possibly influenced in an individual patient,” she said.
“It is a long way from understanding pain pathophysiology to changing the practice of pain management, even if the insights are derived from human studies,” noted Dr Sommer.
Future studies should expand on patient-centered research and employ multiple methods to gain a more comprehensive understanding of the pain pathophysiology involved in certain diseases and specific individuals.
- Sommer C. Exploring pain pathophysiology in patients. Science; 2016: 354(6312):588-592.
- De Sousa EA, Hays AP, Chin RL, Sander HW, Brannagan TH 3rd. Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy. J Neurol Neurosurg Psychiatry. 2006; 77(8):983-985.
- Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013; 136(Pt 6):1857-1867.
- Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014; 155(11):2263-2273.
- Mainka T, Malewicz NM, Baron R, Enax-Krumova EK, Treede RD, Maier C. Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain. Eur J Pain. 2016; 20(1):116-129.
- Dib-Hajj SD, Waxman SG. Translational pain research: Lessons from genetics and genomics. Sci Transl Med. 2014; 6(249):249sr4.
- Truini A, Galeotti F, La Cesa Silvia, et al. Mechanisms of pain in multiple sclerosis: A combined clinical and neurophysiological study. Pain. 2012; 153(10): 2048-2054.
- Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012; 153(6):1193-1198.