Pathophysiology of Pain Unit
Since its establishement, the Pathophysiology of Pain Unit has been carrying out clinical and basic research studies in the fields of visceral pain, musculoskeletal pain and headache. Particular emphasis was devoted in the past few years to the theme of pain and nonpain comorbidities in the complex patient, also in collaboration with numerous Italian and foreign Universities
The main research lines are as follows:
(A) Pathophysiology and clinical characterization of visceral pain
Clinical studies: neurophysiological research in the genito-urinary, gastroenterologic and cardiovascular fields, particularly regarding urinary and biliary calculosis, primary dysmenorrhea, endometriosis, coronary artery disease. Evaluation of referred pain and secondary hyperalgesia from viscera: study of sensory changes (pain thresholds to different stimuli in the three body wall layers) in the areas of referred pain; correlation between site, extent, time of onset and duration of the changes and the algogenic potential of the visceral pathology (number, duration and intensity of the visceral pain episodes);
Experimental studies: behavioural, pharmacological, electrophysiological (single cell recording in the spinal cord) and anatomo-histological studies on experimental models of visceral pathology set up by the group with original methodology (model of artificial ureteral calculosis; model of viscero-visceral hyperalgesia from experimental endometriosis + artificial ureteral calculosis) or characterized in collaboration with foreign research groups (model of uterine inflammation). These models have been internationally validated and are currently being employed in various research laboratories in Europe and in the United States.
(B) Clinical characterization of musculoskeletal pain
Clinical studies on chronic muscle [Myofascial Pain Syndromes (MPS), Fibromyalgia Syndrome (FS), Chronic Fatigue Syndrome (CFS)] and joint (Osteoarthtitis) pain conditions: sensory evaluation (measurement of pain thresholds to different stimuli) in the areas of local and referred pain, and in the nonpainful control areas. The instrumental evaluation, through standardized and internationally validated algometers, of the body wall tissues (selectively: muscle and overlying subcutis and skin) allows identification of specific sensory patterns for the different conditions, facilitating differential diagnosis among clinical pictures otherwise difficult to distinguish merely based on clinical data. It also allows assessment of the effectiveness of therapeutic interventions of various nature (pharmacologic and non-pharmacologic).
(C) Pathophysiology and clinical characterization of headaches
Clinical studies, carried out through ad-hoc questionnaires and diaries (number and intensity of crises, drug intake, impairment of activity due to pain, etc) and sensory evaluation in different forms of headahce, both primary and secondary, before and after acute and preventative treatments, particularly with the most recent therapies with monoclonal antibodies for migraine (network of Headache Centers in the Abruzzo region). Study of the contribution to migraine crises by myofascial trigger points in the cervical region. Studies on possible biomarkers of headaches, also in collaboration with other headache centers in Italy. Of note, a new line of research: the impact of painful (Fibromyalgia, visceral pain, psoriatic arthritis) and nonpainful (cardiovascular pathologies, lipid dysmetabolism) comorbidities on the clinical expression of migraine (see. Comorbidities).
(D) Pathophysiology of the impact of aging and gender on the perception of visceral and musculoskeletal pain
Clinical studies: evaluation of changes in pain sensitivity (pain thresholds) in healthy subjects of both sexes and different age groups. Evaluation of sensory changes from pathologies typical of the elderly population, both visceral and musculoskeletal.
Experimental studies: evaluation of changes in pain sensitivity as a function of age and sex, at visceral and musculoskeletal level and of their pathophysiology, in experimental models of visceral pain and referred musculoskeletal pain [behavioural assessment, evaluation of the gonadal hormone asset, electrophysiological recording in the spinal cord, evaluation of c-Fos expression in the Central Nervous System (CNS), ultrastructural evaluation on muscle biopsies]. In particular, assessment of: (1) morphofunctional changes of the muscle fiber in relation to the physiological aging process; (2) behavioural changes and sensory and morphofunctional changes in the areas of referred muscle hyperalgesia in models of visceral pain (ureteral calculosis, pelvic inflammation); (3) role of gonadal hormones in the modulation of visceral pain and referred hyperalgesia; effects of the administration of supraphysiologic doses of gonadal hormones and relative blocking agents (behavioural study and biochemical evaluation on arterial blood samples).
(E) Pathophysiology and clinical characterization of the interactions among pain comorbidities
Clinical studies on the interactions between: 1) multiple visceral pathologies (viscero-visceral hyperalgesia; cardiac ischemic conditions and gallbladder calculosis; dysmenorrhea/endometriosis and irritable bowel syndrome; renal-ureteral calculosis and dysmenorrhea/endometriosis) and impact of the specific treatment of the single visceral conditions on the other concurrent conditions; 2) visceral pain (also in the post-operative period) and Fibromyalgia; 3) Headache and Fibromyalgia; 4)Myofascial Pain Syndromes and Headache; 5) Myofascial Pain Syndromes and Fibromyalgia; 6) Myofascial Pain Sydromes and Visceral Pain. Evaluation of specific parameters typical of each condition and of the sesnory changes in the body wall tissues (pain thresholds) in comorbid patients vs patients with a single pathology, before and after specific treatments of each condition.
Experimental studies of viscero-visceral hyperalgesia in the model of endometriosis + ureteral calculosis, with behavioural, electrophysiological, histological, anatomical and pharmacological evaluations.
(F) Physical activity and pain
Studies in healthy subjects on muscle pain from physical exercise (concentric, isometric and eccentric effort) and on musculoskeletal pain induced by major and minor traumas from different sports activities (strains, sprains, latent trigger points). Sensory evaluations before and after specific training and before and after targeted therapies in the pathologic conditions.
MAG and GA have a longstanding experience in clinical and experimental studies on pain and in the techniques of sensory evaluation, behavioural characterization and electrophysiological recording in experimental pain models; they are currently involved in both the clinical and experimental ongoing projects. Since 2012 MAG has been a member of the Task Force of the International Association for the Study of Pain for Pain Classification in the framework of the International Classification of Diseases ICD-11; in this context she has been contributing her experience to pain classification, particualrly in the visceral pain field.
FC, YD, IM, CS, VZ are involved in the clinical sensory evaluations in both healthy subects and patients, with particular regard to the effects of physical activity on the skeletal muscle.
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- Affaitati G, Costantini R, Fabrizio A, Lapenna D, Tafuri E, Giamberardino MA. Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain. 2011 Jan;15(1):61-9. doi: 10.1016/j.ejpain.2010.09.002.
-Affaitati G, Costantini R, Tana C, Cipollone F, Giamberardino MA. Co-occurrence of pain syndromes. J Neural Transm (Vienna). 2020 Apr;127(4):625-646. doi: 10.1007/s00702-019-02107-8. Epub 2019 Nov 29.
-Affaitati G, Costantini R, Tana C, Lapenna D, Schiavone C, Cipollone F, Giamberardino MA. Effects of topical vs injection treatment of cervical myofascial trigger points on headache symptoms in migraine patients: a retrospective analysis. J Headache Pain. 2018 Nov 8;19(1):104. doi: 10.1186/s10194-018-0934-3.
-Aloisi AM, Affaitati G, Ceccarelli I, Fiorenzani P, Lerza R, Rossi C, Pace MC, Chiefari M, Aurilio C, Giamberardino MA. Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats. Eur J Pain. 2010 Jul;14(6):602-7. doi: 10.1016/j.ejpain.2009.10.016. Epub 2009 Nov 30.
-Aloisi A, Ceccarelli I, Affaitati G, Lerza R, Vecchiet L, Lapenna D, Giamberardino MA. C-Fos expression in the spinal cord of female rats with artificial ureteric calculosis. Neurosci Lett. 2004 May 6;361(1-3):212-5. doi: 10.1016/j.neulet.2003.12.026.
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-Capo A, Affaitati G, Giamberardino MA, Amerio P. Psoriasis and migraine. J Eur Acad Dermatol Venereol. 32(1)(2018):57-61.
-Costantini R, Affaitati G, Massimini F, Tana C, Innocenti P, Giamberardino MA. Laparoscopic Cholecystectomy for Gallbladder Calculosis in Fibromyalgia Patients: Impact on Musculoskeletal Pain, Somatic Hyperalgesia and Central Sensitization. PLoS One. 2016 Apr 15;11(4):e0153408. doi: 10.1371/journal.pone.0153408. eCollection 2016.PMID:27081848.
-Costantini R, Affaitati G, Wesselmann U, Czakanski P, Giamberardino MA. Visceral pain as a triggering factor for fibromyalgia symptoms in comorbid patients.
Pain. 2017 Oct;158(10):1925-1937. doi: 10.1097/j.pain.0000000000000992.
-De Matteis E, Affaitati G, Frattale I, Caponnetto V, Pistoia F, Giamberardino MA, Sacco S, Ornello R. Early outcomes of migraine after erenumab discontinuation: data from a real-life setting. Neurol Sci. 2021 2021 Aug;42(8):3297-3303 doi: 10.1007/s10072-020-05022-z.
-Frattale I, Caponnetto V, Casalena A, Assetta M., Maddestra M, Marzoli F, Affaitati G, Giamberardino MA, Viola S, Gabriele A, Pistoia F, Cerone D, Marini C, Sacco S, Ornello R. Association between response to triptans and response to erenumab: real-life data. J Headache Pain. 2021 Jan 6;22(1):1. doi: 10.1186/s10194-020-01213-3.
-Giamberardino MA, Affaitati G, Costantini R, Cipollone F, Martelletti P.
Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab. J Pain Res. 2017 Dec 8;10:2751-2760. doi: 10.2147/JPR.S128143. eCollection 2017.PMID:29263689.
-Giamberardino MA, Affaitati G, Costantini R, Guglielmetti M, Martelletti P. Acute headache management in emergency department. A narrative review. Intern Emerg Med. 2020 Jan;15(1):109-117. doi: 10.1007/s11739-019-02266-2.
-Giamberardino MA, Affaitati G, Lerza R, Fanò G, Fulle S, Belia S, Lapenna D, Vecchiet L. Evaluation of indices of skeletal muscle contraction in areas of referred hyperalgesia from an artificial ureteric stone in rats. Neurosci Lett. 2003 Mar 6;338(3):213-6. doi: 10.1016/s0304-3940(02)01409-x.
-Giamberardino MA, Affaitati G, Martelletti P, Tana C, Negro A, Lapenna D, Curto M, Schiavone C, Stellin L, Cipollone F, Costantini R. Impact of migraine on fibromyalgia symptoms. J Headache Pain. 2015;17:28. doi: 10.1186/s10194-016-0619-8.
-Giamberardino MA, Berkley KJ, Affaitati G, Lerza R, Centurione L, Lapenna D, Vecchiet L. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain. 2002 Feb;95(3):247-257. doi: 10.1016/S0304-3959(01)00405-5.
-Giamberardino MA, Costantini R. Challenging chronic migraine: targeting the CGRP receptor. Lancet Neurol. 2017 Jun;16(6):410-411. doi: 10.1016/S1474-4422(17)30126-6.
-Giamberardino MA, Costantini R, Affaitati G, Fabrizio A, Lapenna D, Tafuri E, Mezzetti A. Viscero-visceral hyperalgesia: characterization in different clinical models. Pain. 2010 Nov;151(2):307-322. doi: 10.1016/j.pain.2010.06.023.
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-Giamberardino MA, Dragani L, Valente R, Di Lisa F, Saggini R, Vecchiet L. Effects of prolonged L-carnitine administration on delayed muscle pain and CK release after eccentric effort. Int J Sports Med. 1996 Jul;17(5):320-4. doi: 10.1055/s-2007-972854.
-Giamberardino MA, Valente R, de Bigontina P, Vecchiet L. Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia. Pain. 1995 Jun;61(3):459-469. doi: 10.1016/0304-3959(94)00208-V.
-Iuvone T, Affaitati G, De Filippis D, Lopopolo M, Grassia G, Lapenna D, Negro L, Costantini R, Vaia M, Cipollone F, Ialenti A, Giamberardino MA. Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis: role of mast cells. Pain. 2016 Jan;157(1):80-91. doi: 10.1097/j.pain.0000000000000220.
-Korwisi B, Hay G, Attal N, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ, Treede RD, Rief W, Barke A. Classification algorithm for the International Classification of Diseases-11 chronic pain classification: development and results from a preliminary pilot evaluation. Pain. 2021 Jul 1;162(7):2087-2096. doi: 10.1097/j.pain.0000000000002208.
-Lopopolo M, Affaitati G, Fabrizio A, Massimini F, Lapenna D, Giamberardino MA, Costantini R. Effects of tramadol on viscero-visceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis. Fundam Clin Pharmacol. 2014 Jun;28(3):331-41. doi: 10.1111/fcp.12038.
-Nicholas M, Vlaeyen JWS, Rief W, Barke A, Aziz Q, Benoliel R, Cohen M, Evers S, Giamberardino MA, Goebel A, Korwisi B, Perrot S, Svensson P, Wang SJ, Treede RD; IASP Taskforce for the Classification of Chronic Pain. The IASP classification of chronic pain for ICD-11: chronic primary pain. Pain. 2019 Jan;160(1):28-37. doi: 10.1097/j.pain.0000000000001390.
-Ornello R, Baraldi C, Guerzoni S, Lambru G, Fuccaro M, Raffaelli B, Gendolla A, Barbanti P, Aurilia C, Cevoli S, Favoni V, Vernieri F, Altamura C, Russo A, Silvestro M, Dalla Valle E, Mancioli A, Ranieri A, Alfieri G, Latysheva N, Filatova E, Talbot J, Cheng S, Holle D, Scheffler A, Nežádal T, Čtrnáctá D, Šípková J, Matoušová Z, Sette L, Casalena A, Maddestra M, Viola S, Affaitati G, Giamberardino MA, Pistoia F, Reuter U, Sacco S. Gender Differences in 3-Month Outcomes of Erenumab Treatment-Study on Efficacy and Safety of Treatment With Erenumab in Men. Front Neurol. 2021 Dec 16;12:774341. doi: 10.3389/fneur.2021.774341. eCollection 2021.
-Ornello R, Casalena A, Frattale I, Caponnetto V, Gabriele A, Affaitati G, Giamberardino MA, Assetta M, Maddestra M, Marzoli F, Viola S, Cerone D, Marini C, Pistoia F, Sacco S. Conversion from chronic to episodic migraine in patients treated with erenumab: real-life data from an Italian region. J Headache Pain. 2020 Aug 15;21(1):102. doi: 10.1186/s10194-020-01171-w.
-Ornello R, Casalena A, Frattale I, Gabriele A, Affaitati G, Giamberardino MA, Assetta M, Maddestra M, Marzoli F, Viola S, Cerone D, Marini C, Pistoia F, Sacco S, Real-life data on the efficacy and safety of erenumab in the Abruzzo region, central Italy. J Headache Pain. 2020 Apr 7;21(1):32. doi: 10.1186/s10194-020-01102-9.
-Sandner P, Tinel H, Affaitati G, Costantini R, Giamberardino MA. Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis PLoS One 10(10)(2015): e0141477. doi:10.1371/journal.pone.0141477
-Tafuri E, Santovito D, de Nardis V, Marcantonio P, Paganelli C, Affaitati G, Bucci M, Mezzetti A, Giamberardino MA, Cipollone F. MicroRNA profiling in migraine without aura: pilot study. Ann Med. 2015;47(6):468-73. doi: 10.3109/07853890.2015.1071871.
-Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015 Jun;156(6):1003-1007. doi: 10.1097/j.pain.0000000000000160.
-Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Korwisi B, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ. Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain. 2019 Jan;160(1):19-27. doi: 10.1097/j.pain.0000000000001384.
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