Raffaele Costantini

Viscero-visceral hyperalgesia: characterization in different clinical models.

&NA; Co‐existing algogenic conditions in two internal organs in the same patient may mutually enhance pain symptoms (viscero‐visceral hyperalgesia). The present study assessed this phenomenon in different models of visceral interaction. In a prospective evaluation, patients with: (a) coronary artery disease (CAD) + gallstone (Gs) (common sensory projection: T5); (b) irritable bowel syndrome (IBS) + dysmenorrhea (Dys) (T10‐L1); (c) dysmenorrhea/endometriosis + urinary calculosis (Cal)(T10‐L1); and (d) gallstone + left urinary calculosis (Gs + LCal) (unknown common projection) were compared with patients with CAD, Gs, IBS, Dys or Cal only, for spontaneous symptoms (number/intensity of pain episodes) over comparable time periods and for referred symptoms (muscle hyperalgesia; pressure/electrical pain thresholds) from each visceral location. In patients’ subgroups, symptoms were also re‐assessed after treatment of each condition or after no treatment. (a) CAD + Gs presented more numerous/intense angina/biliary episodes and more referred muscle chest/abdominal hyperalgesia than CAD or Gs; cardiac revascularization or cholecystectomy also reduced biliary or cardiac symptoms, respectively (0.001 < p < 0.05). (b) IBS + Dys had more intestinal/menstrual pain and abdomino/pelvic muscle hyperalgesia than IBS or Dys; hormonal dysmenorrhea treatment also reduced IBS symptoms; IBS dietary treatment also improved dysmenorrhea (0.001 < p < 0.05) while no treatment of either conditions resulted in no improvement in time of symptoms from both. (c) Cal + Dys had more urinary/menstrual pain and referred lumbar/abdominal hyperalgesia than Cal or Dys; hormonal dysmenorrhea treatment/laser treatment for endometriosis also improved urinary symptoms; lithotripsy for urinary stone also reduced menstrual symptoms (0.001 < p < 0.05). (d) In Gs + LCal, cholecystectomy or urinary lithotripsy did not improve urinary or biliary symptoms, respectively. Mechanisms of viscero‐visceral hyperalgesia between organs with documented partially common sensory projection probably involve sensitization of viscero‐viscero‐somatic convergent neurons.

Effects of treatment of peripheral pain generators in fibromyalgia patients

Fibromyalgia syndrome (FS) frequently co‐occurs with regional pain disorders. This study evaluated how these disorders contribute to FS, by assessing effects of local active vs placebo treatment of muscle/joint pain sources on FS symptoms.

Myofascial pain syndromes and their evaluation

This article reviews the available published knowledge about the diagnosis, pathophysiology and treatment of myofascial pain syndromes from trigger points. Furthermore, epidemiologic data and clinical characteristics of these syndromes are described, including a detailed account of sensory changes that occur at both painful and nonpainful sites and their utility for diagnosis and differential diagnosis; the identification/diagnostic criteria available so far are critically reviewed. The key role played by myofascial trigger points as activating factors of pain symptoms in other algogenic conditions--headache, fibromyalgia and visceral disease--is also addressed. Current hypotheses on the pathophysiology of myofascial pain syndromes are presented, including mechanisms of formation and persistence of primary and secondary trigger points as well as mechanisms beyond referred pain and hyperalgesia from trigger points. Conventional and most recent therapeutic options for these syndromes are described, and their validity is discussed on the basis of results from clinical controlled studies.

A Randomized, Controlled Study Comparing a Lidocaine Patch, a Placebo Patch, and Anesthetic Injection for Treatment of Trigger Points in Patients With Myofascial Pain Syndrome: Evaluation of Pain and Somatic Pain Thresholds

BACKGROUND Myofascial pain syndrome (MPS), a regional pain condition caused by trigger points in muscle or muscle fascia, produces muscle pain, tenderness, and disability. The gold standard of treatment for MPS-infiltration of trigger points with anesthetic-may provoke discomfort to the patients and require medical intervention. OBJECTIVES This study was designed to compare the effects of a topical lidocaine patch, a placebo patch, and injection of anesthetic (infiltration) for the symptoms of MPS in terms of pain, disability, and local tissue hypersensitivity, and to determine the acceptability of the lidocaine patch to the patients. METHODS Patients were randomly allocated to receive 1 of 3 treatments: a lidocaine patch applied to the trigger point for 4 days (replacement every 12 hours; total daily dose, 350 mg), a placebo patch applied to the trigger point for 4 days (replacement every 12 hours), or infiltration of the trigger point with two 1-mL injections of 0.5% bupivacaine hydrochloride given 2 days apart. Treatment with the patches was double-blinded, whereas treatment with infiltration was single-blinded. The number of pain attacks, pain intensity at rest and on movement, and pain-related interference with daily activity, work activity, mood, and quality of life were recorded before, during, and after treatment using a visual analog scale (VAS). Pressure and electrical pain thresholds of the skin, subcutis, and muscle in the trigger point, target area, and a pain-free area were evaluated before starting therapy (day 1) and on days 5 and 9. A VAS was used to measure discomfort from therapy, and a diary was given to each patient to record requests for additional treatment (if needed) and adverse effects. RESULTS Sixty white patients (46 women and 14 men) 19 to 76 years of age were studied. Mean (SD) age was 46.88 (15.37) years, and mean (SD) weight was 69.58 (13.94) kg. Twenty patients were assigned to each treatment group. Subjective symptoms did not change with placebo, but decreased significantly with the lidocaine patch and infiltration (both, P < 0.001) relative to baseline. Pain thresholds did not vary with the placebo patch, but increased significantly with the lidocaine patch and infiltration (all, P < 0.001); effects at muscle trigger points and target areas were greater with infiltration. Discomfort from therapy was greater with infiltration than with the lidocaine patch. Only patients in the placebo group requested additional treatment (P < 0.001). No adverse events occurred in any group. CONCLUSION Lidocaine patches were effective in, and highly acceptable to, these patients with MPS and high tissue hypersensitivity.

Relationship between pain symptoms and referred sensory and trophic changes in patients with gallbladder pathology

&NA; The relationship was investigated between algogenic potential of gallbladder pathology and occurrence/extent of sensory and trophic changes in the referred area. Five groups of subjects were studied, with: symptomatic gallbladder calculosis (3–20 colics); asymptomatic calculosis; symptomatic gallbladder shape abnormality (8–18 colics); asymptomatic shape abnormality; normal gallbladder/no symptoms. At the cystic point (CP) and contralaterally, all underwent measurement of: pain thresholds to electrical stimulation of skin, subcutis and muscle; thickness of subcutis and muscle via ultrasounds. Contralaterally to CP, all thresholds were not significantly different in the five groups. At CP, subcutis and muscle thresholds were significantly lower in symptomatic vs asymptomatic patients and/or normals (0.0001<P< 0.05). In symptomatic cases, at CP compared to contralaterally, subcutis and muscle thresholds were significantly lower (0.0001<P<0.02), subcutis thickness was significantly higher and muscle thickness significantly lower (0.006<P<0.02). Subcutis and muscle thresholds at CP in symptomatic patients were significantly and inversely correlated linearly to the number of colics (P<0.0004; P<0.0001). Patients with symptomatic calculosis were re‐evaluated after 6 months; those not presenting further colics showed a significant increase in subcutis and muscle thresholds at CP, while those who continued presenting colics showed a further significant threshold decrease (0.01<P<0.05); tissue thickness did not vary. Referred hyperalgesia and altered trophism from the gallbladder only occur in painful pathology, their extent being modulated by the amount of perceived pain. The results suggest different mechanisms by which visceral nociceptive inputs trigger sensory vs trophic changes in the referred area.

Pain thresholds in women with chronic pelvic pain.

Purpose of review To update on the latest developments in sensory changes of female patients with chronic pelvic pain (CPP). CPP is very common, but its pathophysiology is still controversial. Evaluation of pain sensitivity in painful and nonpainful areas is key to understanding the underlying peripheral vs. central contributions to the symptom. This in turn is fundamental to improving the treatment strategies. Recent findings We reviewed the experimental studies published over the last year on pain thresholds to different stimuli measured at both the somatic and visceral level in women with different forms of recurrent or CPP. The majority of the studies indicate a pain threshold decrease to most stimuli in skin, subcutis and muscle in painful pelvic areas, the site of referred pain from pelvic viscera, as well as a decreased pain threshold in most viscera (colon and urinary bladder). A significant threshold decrease is also found in deep somatic tissues (subcutis and muscle) outside the painful zone in the most severe cases, indicating a state of central sensitization. Summary These findings have important implications for clinical practice: pain threshold measurement in both painful and nonpainful sites could have important predictive value of the clinical evolution and response to therapy of CPP.

New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters?

The role of migraine as an independent risk factor for cardiovascular events has been debated for several years, while it is more established for ischemic stroke. Recently, new studies have examined the likelihood of migraine to determine cardiovascular events, supporting the hypothesis of a predominant role in patients with migraine with aura, the risk including both sexes. In the literature, multiple pathophysiological mechanisms are described to explain this association, and are here discussed. Furthermore, the emerging evidence that a higher headache frequency and long-term migraine may worsen the cardio-metabolic profile in migraineurs (e.g. with a higher Framingham risk score and risk of developing atherosclerosis, insulin resistance and metabolic syndrome) makes it increasingly necessary to reduce the number and severity of attacks, not only to alleviate the painful symptoms, but also to improve the prognosis in these patients.

Effects of Treatment of Myofascial Trigger Points on the Pain of Fibromyalgia

Myofascial pain syndromes (MPSs) from trigger points (TrPs) and fibromyalgia syndrome (FMS) are common musculoskeletal pain conditions that frequently coexist in the same patients. In recent decades, it has become evident that these entities greatly influence each other’s clinical expression. FMS is mainly rooted in the central nervous system, while TrPs have a peripheral origin. However, the nociceptive impulses from TrPs may have significant impact on symptoms of FMS, probably by enhancing the level of central sensitization typical of this condition. Several attempts have been made to assess the effects of treatment of co-occurring TrPs in FMS. We report the outcomes of these studies showing that local extinction of TrPs in patients with fibromyalgia produces significant relief of FMS pain. Though further studies are needed, these findings suggest that assessment and treatment of concurrent TrPs in FMS should be systematically performed before any specific fibromyalgia therapy is undertaken.

Anti-CGRP monoclonal antibodies in migraine: current perspectives

Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration. Monoclonal antibodies against CGRP (LY2951742, ALD-403, and LBR-101/TEV-48125) or its receptor (AMG334) were subsequently developed. As reviewed in this study, numerous phase 1 and 2 trials and preliminary results of phase 3 trials have shown a good safety/tolerability profile and efficacy in migraine prevention, especially in high frequent episodic and chronic forms. Being macromolecules, these mAbs are not suitable for oral administration; however, their intravenous or subcutaneous delivery can be performed at relatively low frequency—every month or even quarterly—which enhances patients’ compliance. Although not all migraineurs respond to this treatment, and longer administration periods will be needed to assess long-term effects, the results so far obtained are extraordinarily promising. The future introduction of mAbs on the market will probably represent a turning point for prevention similar to that represented by triptans for abortive treatment in migraine.

Epithelioid Angiosarcoma of the Gallbladder: Case Report

A patient with epithelioid angiosarcoma of the gallbladder is described. This is only the second case of an extremely rare but highly aggressive tumor reported in the international literature. Pathophysiological, clinical, and therapeutic aspects are discussed in relation to the available data on angiosarcomas of the gallbladder.