4. Discussion and conclusion
In patients with PHN, pain qualities and sensory symptoms are different if the trigeminal nerve is affected or spinal nerves in the thoracolumbar territory. First, patients with PHN in the trunk suffer from more intense burning. The burning quality of neuropathic pain is believed to be associated with sensitization of heat-sensitive C-nociceptors, thus the burning is indicative of sensitization processes in primary afferent nociceptors.2 Second, allodynia was present more frequently in the trunk than in the face. Dynamic mechanical allodynia develops if mechanosensitive A-beta fibers activate sensitized second-order neurons in the spinal cord, thus allodynia is indicative of central sensitization.20 Third, painful attacks occur more often in the trunk than in the face. Short-lasting painful attacks are perceived if bursts of discharges mainly in nociceptive neurons are conveyed to the central nervous system.1 Fourth, numbness is nearly absent in the trunk as compared to the face. Numbness is regarded as a negative sensory symptom that points to a loss of afferent functions.19 Thus, the trunk is rather characterized by preserved afferent innervation, whereas the face shows more signs of nerve degeneration.
Taken these results together, PHN in the thoracolumbar body region demonstrates more signs of sensitization in relatively intact afferent neuronal systems than PHN in the face.
According to these results, animal experiments suggest that there are fundamental pathophysiological differences between pain syndromes caused by an injury to the trigeminal nerve as compared to a lesion of other peripheral nerves. In rats, Tal and Devor18 studied pathophysiological properties of injured afferent axons in the infraorbital nerve and in the sciatic nerve. Ongoing discharge and mechanosensitivity of myelinated and unmyelinated axons were much less frequently observed in the infraorbital nerve than in the sciatic nerve. Furthermore, no injury-induced sympathetic sprouting into the trigeminal ganglion could be demonstrated after trigeminal lesion which is a common phenomenon in dorsal root ganglia after sciatic nerve injury.4 Chronic constriction injury (CCI) to the sciatic nerve in rats induced an overexpression of the proinflammatory cytokine IL-6 and subsequent microglia activation in the dorsal horn. This mechanism is believed to be involved in the development of central pain hypersensitivity. By contrast, no such upregulation could be found in the spinal nucleus of the trigeminal nerve after trigeminal CCI.13 In addition, differential treatment effects on neuropathic pain behavior were shown in the cephalic vs the extracephalic territories.16 Triptans and calcitonin gene-related peptide receptor antagonists alleviated pain behavior caused by CCI to the infraorbital nerve but not the sciatic nerve in rats.11,15,17
There are some limitations of the study. The results of this study refer to patients suffering from PHN, a peripheral neuropathic pain condition. At this point, it is not known if these results can be transferred to other neuropathic conditions, especially to central neuropathic pain. Another limitation of the study is that there was no control for the analgesic medication the participating patients were taking. Accordingly, an influence of analgesics on the somatosensory symptoms described by the patients cannot be ruled out completely. Other studies using data of large cohorts of patients suffering from neuropathic pain were facing the same problems and we know that the influence of the medication on different subgroups of patients cannot be crucial because it has not been shown that a majority of patients (>50%) was treated with the same drug or the same drug combination.3 Furthermore, it has to be kept in mind that these are overall results and that individual cases can naturally present with different sensory profiles.
The differences in sensory symptom profiles and potentially also in pathophysiological mechanisms between facial PHN and truncal PHN might have implications for the interpretation and design of clinical trials in this indication. It is very well conceivable that drugs that primarily act on sensitization processes in the nociceptive system may work better in thoracolumbar PHN than in trigeminal PHN.10 Facing future studies, it would therefore be interesting to include an analysis of the treatment results in regard to subgroups based on the localisation of pain in patients with PHN.5
S. Rehm has received speaking fees from Grünenthal GmbH, Bayer Vital GmbH and Pfizer and travel support from Astellas. M. Großkopf has received travel support from Sanofi-Genzyme GmbH. R. Freynhagen reports research support, personal consulting, or lecture fees in the past 2 years from Astellas, Develco Pharma, Galapagos, Grünenthal, Lilly, Merck, Mitsubishi Tanabe Pharma, and Pfizer. T. Tölle has given lectures and/or participated in advisory boards on behalf of Astellas, Grünenthal, Ely-Lilly, Pfizer, Mundipharma, Teva, Nevro, Angelini, and Dompe. R. Baron has received grants/research support from Pfizer, Genzyme GmbH, Grünenthal GmbH, and Mundipharma. He is a member of the EU Project No 633491: DOLORisk. A member of the IMI “Europain” collaboration (grant agreement 115007) and industry members of this are: AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal GmbH, Eli Lilly, and Boehringer Ingelheim Pharma GmbH&Co.KG.
German Federal Ministry of Education and Research (BMBF): Member of the ERA-NET NEURON/IM-PAIN Project (01EW1503). German Research Network on Neuropathic Pain (01EM0903), NoPain system biology (0316177C). German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co Ltd, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD GmbH, and Seqirus. He has been a consultant for Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Allergan, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co Ltd, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Novartis, Bristol-Myers-Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Teva Pharma, Genentech, Galapagos NV, and Kyowa Kirin GmbH. The remaining authors have no conflicts of interest to declare.
This research was supported by a grant from Pfizer Germany without restriction on publication.
The authors thank all participating patients, colleagues, and the staff of the institutions for their contributions to data collection. S. Rehm and M. Grosskopf contributed equally.
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Keywords:© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.
Neuropathic pain; Postherpetic neuralgia; Cephalic/extracephalic