Abstract
Although pains of various kinds top the list of complaints from women with endometriosis and are the most debilitating of the disease, little is known about the mechanism/mechanisms of endometriosis-associated pains. To test the hypothesis that women with endometriosis have generalized hyperalgesia which may be alleviated by a successful surgery, we recruited 100 patients with surgically and histologically confirmed endometriosis and 70 women without, and tested their responses to pain stimulations. Before the surgery, all patients rated their dysmenorrhea severity by Visual Analog scale (VAS) and went through an ischemic pain test (IPT) and an electrical pain test (EPT). The controls were also administrated with IPT/EPT. Three and 6 months after surgery, all patients were administrated with IPT/EPT and rated their severity of dysmenorrhea. We found that patients with endometriosis had significantly higher IPT VAS scores and lower EPT pain threshold than controls, but after surgery their IPT scores and EPT pain threshold were significantly and progressively improved, along with their dysmenorrhea severity. Thus, we conclude that women with endometriosis have generalized hyperalgesia, which was alleviated by surgery. Consequently, central sensitization may be a possible mechanism underlying various forms of pain associated with endometriosis, and its recognition should have important implications for the development of novel therapeutics and better clinical management of endometriosis.
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References
Olive DL, Lindheim SR, Pritts EA. New medical treatments for endometriosis. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):319–328.
Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.
Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol. 2009;16(5):540–550.
Whiteside JL, Falcone T. Endometriosis-related pelvic pain: what is the evidence?. Clin Obstet Gynecol. 2003;46(4):824–830.
Vercellini P. Endometriosis: what a pain it is. Semin Reprod Endocrinol. 1997;15(3):251–261.
Marana R, Muzii L, Caruana P, Dell’Acqua S, Mancuso S. Evaluation of the correlation between endometriosis extent, age of the patients and associated symptomatology. Acta Eur Fertil. 1991;22(4):209–212.
Fedele L, Bianchi S, Bocciolone L, et al. Pain symptoms associated with endometriosis. Obstet Gynecol. 1992;79(5 pt 1):767–769.
Fedele L, Parazzini F, Bianchi S, Arcaini L, Candiani GB. Stage and localization of pelvic endometriosis and pain. Fertil Steril. 1990;53(1):155–158.
Muzii L, Marana R, Pedullà S, Catalano GF, Mancuso S. Correlation between endometriosis-associated dysmenorrhea and the presence of typical or atypical lesions. Fertil Steril. 1997;68(1):19–22.
Guo SW, Hummelshoj L, Olive DL, Bulun SE, D’Hooghe TM, Evers JL. A call for more Transparency of registered clinical trials on endometriosis. Hum Reprod. 2009;24(6):1247–1254.
Wu EQ, Birnbaum H, Mareva M, et al. Interstitial cystitis: cost, treatment and co-morbidities in an employed population. Pharmacoeconomics. 2006;24(1):55–65.
Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F. Endometriosis is associated with prevalence of comorbid conditions in migraine. Headache. 2007;47(7):1069–1078.
Bouin M, Meunier P, Riberdy-Poitras M, Poitras P. Pain hypersensitivity in patients with functional gastrointestinal disorders: a gastrointestinal-specific defect or a general systemic condition?. Dig Dis Sci. 2001;46(11):2542–2548.
Price DD, et al. Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: evidence from human psychophysics, animal models, and neuroimaging. Neuroimage. 2009;47(3):995–1001.
Berkley KJ, Cason A, Jacobs H, Bradshaw H, Wood E. Vaginal hyperalgesia in a rat model of endometriosis. Neurosci Lett. 2001;306(3):185–188.
Giamberardino MA, Berkley KJ, Affaitati G, et al. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain. 2002;95(3):247–257.
Lu Y, Nie J, Liu X, Zheng Y, Guo SW. Tricostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010;25(4):1014–1025.
Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003;4(7):372–380.
Laursen BS, Bajaj P, Olesen AS, Delmar C, Arendt-Nielsen L. Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain. Eur J Pain. 2005;9(3):267–275.
McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain. 2009;147(1–3):255–264.
Liu X, Yuan L, Wang Y, Shen F, Guo SW. Risk factors for dysmenorrhea and its severity in women with ovarian endometriomas. Gynecol Obstet Invest. 2008;66(3):169–177.
Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975;1(3):277–299.
Liu X, Yuan L, Shen F, Zhu Z, Jiang H, Guo SW. Patterns of and risk factors for recurrence in women with ovarian endometriomas. Obstet Gynecol. 2007;109(6):1411–1420.
Alstergren P, Forstrom J. Acute oral pain intensity and pain threshold assessed by intensity matching to pain induced by electrical stimuli. J Orofac Pain. 2003;17(2):151–159.
Sherman JJ, LeResche L. Does experimental pain response vary across the menstrual cycle?. A methodological review. Am J Physiol Regul Integr Comp Physiol. 2006;291(2):R245–R256.
Lundeberg T, Lund I, Dahlin L, et al. Reliability and responsiveness of three different pain assessments. J Rehabil Med. 2001;33(6):279–283.
Stener-Victorin E, Kowalski J, Lundeberg T. A new highly reliable instrument for the assessment of pre- and postoperative gynecological pain. Anesth Analg. 2002;95(1):151–157.
Inhaka R, Gentleman RR. R: a language for data analysis and graphics. J comput Graph Statist. 1996;5:1923–1927.
Gerlinger C, Schmitz H, Schumacher U, Seitz C. Minimally clinically important difference for endometriosis associated pelvic pain measured on a visual analogue scale. Int J Gynecol Obstet. 2009;107(suppl 2):S190.
Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms?. Trends Neurosci. 2003;26(12):696–705.
Sheth RN, Dorsi MJ, Li Y, et al. Mechanical hyperalgesia after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat. Pain. 2002;96(1–2):63–72.
Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Giani C, Zbinden AM, Radanov BP. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain. 2001;17(4):306–315.
O’Neill S, Manniche C, Graven-Nielsen T, Arendt-Nielsen L. Generalized deep-tissue hyperalgesia in patients with chronic low-back pain. Eur J Pain. 2007;11(4):415–420.
Price DD, Zhou Q, Moshiree B, Robinson ME, Verne GN. Peripheral and central contributions to hyperalgesia in irritable bowel syndrome. J Pain. 2006;7(8):529–535.
Staud R, Spaeth M. Psychophysical and neurochemical abnormalities of pain processing in fibromyalgia. CNS Spectr. 2008;13(3 suppl 5):12–17.
Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two distinct perceptual alterations in irritable bowel syndrome. Gut. 1997;41(4):505–512.
Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11):3001–3007.
Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noël JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril. 2006;86(5):1336–1343.
Tokushige N, Markham R, Russell P, Fraser IS. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril. 2007;88(4):795–803.
Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod. 2006;21(3):782–787.
Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009;24(4):827–834.
Wang G, Tokushige N, Russell P, Dubinovsky S, Markham R, Fraser IS. Hyperinnervation in intestinal deep infiltrating endometriosis. J Minim Invasive Gynecol. 2009;16(6):713–719.
Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids. Fertil Steril. 2009;92(5):1799–1801.
Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci U S A. 2004;101(30):11094–11098.
Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296.
Kosek E, Ordeberg G. Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment. Eur J Pain. 2000;4(3):229–238.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.
Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688.
Richmond CE, Bromley LM, Woolf CJ. Preoperative morphine pre-empts postoperative pain. Lancet. 1993;342(8863):73–75.
Sekar C, Rajasekaran S, Kannan R, Reddy S, Shetty TA, Pithwa YK. Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine J. 2004;4(3):261–264.
Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol. 2006;19(5):551–555.
Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril. 2008;89(1):246–250.
Basselin M, Chang L, Chen M, Bell JM, Rapoport SI. Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats. Neurochem Res. 2008;33(11):2229–2240.
Ren K, Dubner R. Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol Neurobiol. 2007;35(3):224–235.
Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2005;34(1):215–220.
Al-Obaidi SM, Nelson RM, Al-Awadhi S, Al-Shuwaie N. The role of anticipation and fear of pain in the persistence of avoidance behavior in patients with chronic low back pain. Spine (Phila Pa 1976). 2000;25(9):1126–1131.
Porro CA, Baraldi P, Pagnoni G, et al. Does anticipation of pain affect cortical nociceptive systems?. J Neurosci. 2002;22(8):3206–3214.
Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698–2704.
Holt VL, Weiss NS. Recommendations for the design of epidemiologic studies of endometriosis. Epidemiology. 2000;11(6):654–659.
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He, W., Liu, X., Zhang, Y. et al. Generalized Hyperalgesia in Women With Endometriosis and Its Resolution Following a Successful Surgery. Reprod. Sci. 17, 1099–1111 (2010). https://doi.org/10.1177/1933719110381927
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DOI: https://doi.org/10.1177/1933719110381927