Date Published: July 7, 2017
Publisher: Public Library of Science
Author(s): Jorien Werumeus Buning, Karl-Heinz Konopka, Pauline Brummelman, Janneke Koerts, Robin P. F. Dullaart, Gerrit van den Berg, Melanie M. van der Klauw, Oliver Tucha, Bruce H. R. Wolffenbuttel, André P. van Beek, Kathrin Eller.
Low cortisol levels are associated with several functional pain syndromes. In patients with secondary adrenal insufficiency (SAI), the lack in endogenous cortisol production is substituted by the administration of oral hydrocortisone (HC). Our previous study showed that a lower dose of HC led to an increase in reported subjective pain symptoms. Whether different doses of HC substitution alter somatosensory functioning in SAI patients has not been established yet.
In this randomized double blind cross-over trial, forty-six patients with SAI participated. Patients randomly received either first a lower dose (0.2–0.3 mg HC/kg body weight/day) for 10 weeks followed by a higher dose (0.4–0.6 mg HC/kg body weight/day) for another 10 weeks, or vice versa. After each treatment period, blood samples were drawn and somatosensory functioning was assessed by determining the mechanical detection threshold (MDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and the pain pressure threshold (PPT), according to the Quantitative Sensory Testing (QST) battery by the German Network on Neuropathic Pain.
The administration of the higher dose of HC resulted in significantly higher levels of cortisol (mean [SD] 748  nmol/L) than the lower dose (537  nmol/L, P<0.001). No differences were found in MDT, MPT, MPS and PPT z-scores between the two doses of HC. Furthermore, the number of patients showing sensory abnormalities did not differ between the two different doses. The results suggest that the dose of HC has no impact on somatosensory functioning in response to mechanical stimuli in patients with SAI, despite previously found altered subjective pain reports.
Stress hormones are known to play an important role in stress-related bodily disorders, such as functional pain syndromes. Stress, i.e. internal or external threats to the maintenance of homeostasis, activates the hypothalamic-pituitary-adrenal (HPA) axis in order to reestablish homeostasis. Activation of the HPA axis results among others in the secretion of cortisol. There is some evidence that cortisol increases the tolerance of pain [1,2]. Several functional pain syndromes are linked to hypocortisolism [1,3]. For instance, patients with fibromyalgia showed reduced 24 h-urinary cortisol excretion compared to healthy controls [4–6]. Fibromyalgia is characterized by central sensitization, a process of hypersensitivity of neural nociceptive pathways . Cortisol has immunosuppressive effects, and reduced cortisol levels might disinhibit the secretion of inflammatory mediators and thereby promote the sensitization of peripheral or central nociceptive neurons . On the other hand, it was found that higher cortisol levels are associated with decreased pain thresholds  and increased pain sensitivity in response to thermal stimuli . Other studies were unable to find an effect of cortisol levels and pain sensitivity . Thus, the relationship between cortisol levels and pain sensitivity remains unclear.
In this randomized double blind cross-over study, the effect of dose of HC on mechanical pain perception were studied. The administration of two different doses of HC for a period of 10 weeks did not result in a difference in mechanical QST parameters. This suggests that dose of HC does not alter mechanical pain perception in patients with SAI.