The effects of tramadol versus placebo administration on behavioral indicators of ureteral pain, pelvic pain and referred lumbar muscle hyperalgesia were investigated in a rat model of viscero-visceral hyperalgesia from endometriosis plus ureteral calculosis (endo + stone). Fifty female Sprague-Dawley rats underwent surgical induction of endometriosis and, 2 weeks later, were randomly assigned to five groups (10 each), to be treated i.p., twice a day, with tramadol (0.625, 1.25, 2.5, or 5 mg/kg) or saline for 5 days (14-18th day postendometriosis; prestone treatment). On the 21st day, they underwent laparotomy for stone formation in the upper left ureter (dental cement injection). All were video-taped 24 h nonstop for 7 days before and 4 days after stone formation (14-25th day postendometriosis) to record ureteral and pelvic pain behaviors. Lumbar sensitivity (L1) was tested bilaterally, daily over the same period, by verifying presence/absence of vocalization upon muscle pinching at a predefined pressure (calibrated forceps). Additional fifty endo + stone rats underwent the same protocol, except that treatment was performed on 21st-25th day (poststone treatment). Tramadol vs. saline significantly reduced number and duration of ureteral crises, duration of pelvic behavior, and incidence of muscle hyperalgesia (P < 0.0001), with a dose-dependent effect. Prestone treatment was significantly more effective than poststone treatment for the 1.25 dose for all parameters and 2.5 dose for pelvic and muscle parameters (0.003 > P < 0.02). Tramadol, even at low doses, is thus highly protective against pain from 'viscero-visceral hyperalgesia' in endometriosis plus ureteral calculosis; it can represent a valid therapeutic approach in women with these comorbidities.

The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01), chymase (P < 0.05), NGF (P < 0.05), VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in cysts and NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics.

Nonsteroidal anti-inflammatory drug use in headache was higher than could be hypothesized based on guidelines, with NSAID preferences not entirely coinciding with international recommendations. This outcome suggests the need for greater awareness of all treatment options in headache by both patients and physicians.

Topical diclofenac+heparin is significantly more effective than diclofenac alone in reducing muscle hyperalgesia in subjects without spontaneous pain, independently of the anti-edematous action of heparin. The results provide a rationale for the use of diclofenac+heparin also in algogenic conditions without evident signs of injury/edema/hematoma.

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