Electrophysiological evidence from cutaneous nociceptors suggested a synergism between excitatory actions of inflammatory mediators (IM) and low pH. In human skin it is possible to induce constant ongoing pain with continuous infusion of acid buffer. This method was used to study the interaction with mediators of inflammation psychophysiologically. A skin area on the palmar forearm of 6 subjects (either gender, age 22-35 years) was continuously infiltrated with a phosphate buffered electrolyte solution (pH 5.2) using a motorized syringe pump that was adjusted so as to produce constant pain of about 20% on a visual analog scale (VAS; extending from 'no' to 'unbearable pain'). Pain was assessed on the VAS at 10-sec intervals; the rating was called up by means of an acoustic signal. An additional cannula was placed in the skin before the infusion of acidic buffer started. Injections of an acidic combination of IM (BK, 5-HT, HIS, PGE2) 0.2 ml were then given through the cannula at intervals of 10 min in a randomized double blind order of concentrations. The other arm was used for negative control, i.e. IM in neutral solution were injected into normal skin continuously infiltrated with a buffer solution at pH 7.4. The IM induced dose-dependent, transient burning pain on both arms-markedly more intense and prolonged, however, in the acidotic skin (P < 0.004, U-test). The difference corresponded to a 10-fold increase in algogenic potency with 10(-7) M IM, being smaller with 10(-6) and 10(-5) M concentration. The interaction between low pH and IM was mutual: additional injections of plain phosphate buffer (pH 5.2) into the acidotic skin were significantly more painful (20-fold) after application of IM than under control conditions. Thus, we tend to conclude that it is the inflammatory mediators that potentiate the algogenic effect of low pH rather than vice versa. Tissue acidosis appears as a dominant factor in inflammatory pain.
Langerhans cell histiocytosis (LCH) can be a difficult therapeutic problem. We present a 40-year-old woman with a 4-year history of LCH who was successfully treated with low-dose methotrexate (20 mg weekly).
Cutaneous applications are gaining popularity in the treatment of cutaneous pain and of painful disorders in joints and muscle. The low pH-pain model in human skin has previously been able to demonstrate the effects of NSAIDs in dose-dependent manner and to establish time-effect relationships. We examined the analgesic action of ibuprofen after cutaneous application and compared the effects with oral administration. The two studies (with n = 12 subjects each) were performed in a double-blind, randomized fashion with a 1-week cross-over interval. In study 1 volunteers received intradermal infusions with phosphate buffered saline solution of pH 5.2 and received either 800 mg ibuprofen per os and topical placebo, or 4 g of a 5% commercial ibuprofen gel topically applied and oral placebo capsules, respectively. In study 2 the same protocol was applied with painful intramuscular infusion of stronger, isotonic phosphate buffer (pH 5.2). The flow rate of the pH-infusion was individually adjusted to induce pain with a magnitude of 20% on a visual analogue scale (ranging from 'no' (0%) to 'unbearable pain' (100%)). Ibuprofen (S-, R-) plasma levels after oral administrations were measured with HPLC, and after topical applications, by gas chromatography combined with mass spectroscopy to determine plasma levels in the range of ng/ml. In the cutaneous model pain ratings decreased to zero after topical verum gel within 45 min of the observation period of 55 min. Pain reduction after peroral ibuprofen was of the same magnitude, but was achieved within only 30 min. In the muscle model, the commercial ibuprofen gel did not reduce the pain in the acidic muscle. The peroral ibuprofen was less effective in the muscle compared to the skin pain model, although there was a significant progressive pain reduction within 55 min. Reasons for the differential susceptibility of cutaneous vs muscular acidosis pain to ibuprofen remain to be established.
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