Diclofenac epolamine topical patch for the treatment of pain.

Topical nonsteroidal anti-inflammatory drugs produce local pain relief while avoiding systemic adverse events, thanks to minimal systemic absorption. This review evaluates the effectiveness and safety of a topical diclofenac preparation, diclofenac epolamine (DHEP) patch 1.3% or diclofenac epolamine patch with heparin as excipient (DHEP+H) in treating mild-to-moderate pain. DHEP patch was associated with significant pain relief and improved function in numerous pain conditions, from minor soft tissue injuries to osteoarthritis and myofascial pain syndromes. Tolerability was good-to-excellent in all studies, with no serious adverse events. DHEP+H further improved efficacy without affecting tolerability. This patch is effective and safe for localized mild-to-moderate somatic pain.

Psoriasis and migraine.

BACKGROUND: Psoriasis and migraine share several pathogenetic mechanisms due to systemic inflammation, which increase the risk of developing cardiovascular disease. OBJECTIVE: Our aim was to investigate the prevalence of migraine with (MA) and without aura (MO) in the psoriatic population, investigating a possible new comorbidity of the psoriatic disease. METHODS: We referred 68 psoriatic patients to a nine questions survey formulated on the basis of the International Headache Society (IHS) diagnostic criteria for migraine. Then, in the case of MA, the mean monthly number of migraine crises was assessed. Data of psoriatic patients were then compared with those of a psoriasis-free control group composed of 235 migraine patients (with and without aura). RESULTS: A clinical diagnosis of migraine was performed in 32 psoriasis patients with a great prevalence in women (F: 87.50% - M: 12.5%). Moreover, we found a much higher prevalence (62.5%) of MA, with the remaining 37.5% diagnosed with MO. Comparing the prevalence of MA between psoriasis + migraine patients and the control group we observed a statistical significative difference (P < 0.0001); furthermore, the number of MA crises was significantly higher (P < 0.0001) in patients with psoriasis with respect to the MA control group. CONCLUSIONS: We showed a significant association between psoriasis and migraine, especially MA, probably due to common pathogenetic mechanisms, but further studies are needed to assess their interplay in developing cardiovascular diseases.

Lp(a) and cardiovascular risk: Investigating the hidden side of the moon.

AIMS: This article reports current evidence on the association between Lp(a) and cardiovascular (CV) disease and on pathophysiological mechanisms. The available information on therapy for reduction of lipoprotein(a) is also discussed. DATA SYNTHESIS: Although some evidence is conflicting, Lp(a) seems to increase CV risk through stimulation of platelet aggregation, inhibition of tissue factor pathway inhibitor, alteration of fibrin clot structure and promotion of endothelial dysfunction and phospholipid oxidation. Lp(a) 3.5-fold higher than normal increases the risk of coronary heart disease and general CV events, particularly in those with LDL cholesterol ≥ 130 mg/dl. High Lp(a) values represent also an independent risk factor for ischemic stroke (more relevant in young stroke patients), peripheral artery disease (PAD) and aortic and mitral stenosis. Furthermore, high Lp(a) levels seem to be associated with increased risk of cardiovascular events in patients with chronic kidney disease, particularly in those undergoing percutaneous coronary intervention. CONCLUSIONS: Lipoprotein (a) (Lp[a]) seems to significantly influence the risk of cardiovascular events. The effects of statins and fibrates on Lp(a) are limited and extremely variable. Nicotinic acid was shown effective in reducing Lp(a) but, due to its side effects and serious adverse events during clinical trials, it is no longer considered a possible option for treatment. To date, the treatment of choice for high levels of Lp(a) in high CV risk patients is represented by LDL-Apheresis. Thanks to innovative technologies, new selectively inhibiting LPA drugs are being developed and tested.

Acute pain: a multifaceted challenge - the role of nimesulide.

BACKGROUND: This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014. SCOPE: The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports. RESULTS: The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain. CONCLUSIONS: The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile.

Immunopathogenesis of sarcoidosis and risk of malignancy: a lost truth?

The hypothesis of a relationship between sarcoidosis and malignancy was firstly formulated in 1972 by Brincker. He documented an association of sarcoid reactions or sarcoidosis with 19 lymphomas and associated malignancies. Based on various epidemiological studies, for more than 20 years sarcoidosis has been considered as a condition at increased risk for cancer, particularly lymphoproliferative disorders. The existence of a sarcoidosis-lymphoma syndrome was therefore proposed, highlighting, as a potential mechanism, the uncontrolled lymphocyte proliferation and mitotic activity. A reduced ability to eliminate an antigen and chronic inflammation have been suggested as triggering events. Leading to a reduced tumor immune surveillance, a diminished myeloid dendritic cells (mDC) function, despite up-regulated co-stimulatory and maturation markers, was also raised as potential mechanism. However, some subsequent studies have questioned the presence of a close association between the two entities and have explained those previously published as the result of selection bias and misclassification. Recently, a Swedish population-based cohort study documented a significant overall excess incidence of cancer among sarcoidosis patients, especially those with multiple hospitalizations or admission in older age, emphasizing again a potential neoplastic risk. Therefore, currently, whether these patients have an increased risk of developing malignant lesions is still debated. Larger and unbiased studies are needed before drawing definite conclusions.

Controlling pain in the post-operative setting.

BACKGROUND AND AIMS: Post-operative pain (POP) is a form of acute, intense pain experienced in the period following surgery, whose adequate control is often problematic. This paper reviews determinants and characteristics of POP, together with rationale and current protocols for its management. DETERMINANTS/CONSEQUENCES OF POP: Main determinants of POP are the type of intervention and the disease motivating surgery, though other factors related to patient (age, pain threshold, socio-cultural factors, personality) and setting (pre-operative information, relationship with medical staff) may also influence its perception. POP control is essential to relieve suffering but also to prevent dangerous consequences on organ systems, e.g., reduced cough, atelectasis, increased myocardial oxygen consumption and ischemia, constipation, urinary retention, reduced musculoskeletal mobility and increased risk of deep venous thrombosis. MANAGEMENT OF POP: Constant assessment of pain intensity is recommended for optimal POP control. This is mostly achieved pharmacologically with monitoring of side-effects. Multi-modal analgesia is recommended, combining different drug classes, e.g., an opioid (morphine, pethidine, fentanyl, tramadol, codeine) with a non-opioid (NSAID; Cox-2 inhibitor), delivered through various routes, and including neuraxial use of local anesthetics (bupivacaine, ropivacaine) alone or in combination with other drugs, nerve blocks, antihyperalgesics (ketamine, dextromethorphan) and techniques such as patient-controlled analgesia (PCA) and pre-emptive analgesia. An efficient organization of pain services is also recommended. CONCLUSION: Acute post-surgical pain represents a crucial problem, but the multimodal therapeutic approach has enhanced the efficacy of pain-control while minimizing side-effects of each modality. Further improvement of POP control will necessarily involve better organization of pain services.

Fibromyalgia syndrome: preventive, social and economic aspects.

There many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteria are not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In the case of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbances as we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondary prevention is early detection of the disease when patients are largely asymptomatic and intervention improves outcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients, includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, and fatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the disease has developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeutic strategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FM are high consumers of health care services, and FM is associated with significant productivity-related costs. The degree of disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM can reduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every social assessment is closely related to the socio-economic level of the general population and to the legislation of the country in which the FM patient resides.

Fibromyalgia syndrome: definition and diagnostic aspects.

Ever since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in the field of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivity and specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists), whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particular patients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap with those of many other conditions classified in a different manner. Over the last few years, this has led to FM being considered less as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system (the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubts have been raised about even these classifications; and it now seems more appropriate to include FM among the central sensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletal symptoms of FM and other previously defined "dysfunctional" syndromes.

Etiopathogenetic mechanisms of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.

Non pharmacological treatments in fibromyalgia.

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.

Symptoms and signs in fibromyalgia syndrome.

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.

Fibromyalgia syndrome: the pharmacological treatment options.

Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capable of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definite conclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trials present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. In this review, we will evaluate those pharmacological therapies that have produced the most significant clinical results in treating FM patients. The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologic therapies seems to be the most appropriate treatment strategy to date.

The evaluation of the fibromyalgia patients.

Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11 of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treating physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluation for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened a meeting to develop consensus recommendations for chronic pain clinical trials.

Update on burning mouth syndrome: overview and patient management.

Burning Mouth Syndrome (BMS) is a chronic pain syndrome that mainly affects middle-aged/old women with hormonal changes or psychological disorders. This condition is probably of multifactorial origin, often idiopathic, and its etiopathogenesis remains largely enigmatic. The present paper discusses several aspects of BMS, updates current knowledge, and provides guidelines for patient management. There is no consensus on the diagnosis and classification of BMS. The etiopathogenesis seems to be complex and in a large number of patients probably involves interactions among local, systemic, and/or psychogenic factors. In the remaining cases, new interesting associations have recently emerged between BMS and either peripheral nerve damage or dopaminergic system disorders, emphasizing the neuropathic background in BMS. Based on these recent data, we have introduced the concepts of "primary" (idiopathic) and "secondary" (resulting from identified precipitating factors) BMS, since this allows for a more systematic approach to patient management. The latter starts with a differential diagnosis based on the exclusion of both other orofacial chronic pain conditions and painful oral diseases exhibiting muco-sal lesions. However, the occurrence of overlapping/overwhelming oral mucosal pathologies, such as infections, may cause difficulties in the diagnosis ("complicated BMS"). BMS treatment is still unsatisfactory, and there is no definitive cure. As a result, a multidisciplinary approach is required to bring the condition under better control. Importantly, BMS patients should be offered regular follow-up during the symptomatic periods and psychological support for alleviating the psychogenic component of the pain. More research is necessary to confirm the association between BMS and systemic disorders, as well as to investigate possible pathogenic mechanisms involving potential nerve damage. If this goal is to be achieved, a uniform definition of BMS and strict criteria for its classification are mandatory.

Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma.

The thiobarbituric acid (TBA) reactivity of human plasma was studied to evaluate its adequacy in quantifying lipid peroxidation as an index of systemic oxidative stress. Two spectrophotometric TBA tests based on the use of either phosphoric acid (pH 2.0, method A) or trichloroacetic plus hydrochloric acid (pH 0.9, method B) were employed with and without sodium sulfate (SS) to inhibit sialic acid (SA) reactivity with TBA. To correct for background absorption, the absorbance values at 572 nm were subtracted from those at 532 nm, which represent the absorption maximum of the TBA:MDA adduct. Method B gave values of TBA-reactive substances (TBARS) 2-fold higher than those detected with method A. SS lowered TBARS by about 50% with both methods, indicating a significant involvement of SA in plasma TBA reactivity. Standard SA, at a physiologically relevant concentration of 1.5 mM, reacted with TBA, creating interference problems, which were substantially eliminated by SS plus correction for background absorbance. When method B was carried out in the lipid and protein fraction of plasma, SS inhibited by 65% TBARS formation only in the latter. Protein TBARS may be largely ascribed to SA-containing glycoproteins and, to a minor extent, protein-bound MDA. Indeed, EDTA did not affect protein TBARS assessed in the presence of SS. TBA reactivity of whole plasma and of its lipid fraction was instead inhibited by EDTA, suggesting that lipoperoxides (and possibly monofunctional lipoperoxidation aldehydes) are involved as MDA precursors in the TBA test. Pretreatment of plasma with KI, a specific reductant of hydroperoxides, decreased TBARS by about 27%. Moreover, aspirin administration to humans to inhibit prostaglandin endoperoxide generation reduced plasma TBARS by 40%. In conclusion, reaction conditions affect the relationship between TBA reactivity and lipid peroxidation in human plasma. After correction for the interfering effects of SA in the TBA test, 40% of plasma TBARS appears related to in vivo generated prostaglandin endoperoxides and only about 60% to lipoperoxidation products. Thus, the TBA test is not totally specific to oxidant-driven lipid peroxidation in human plasma.

Effects of topical diclofenac (DHEP plaster) on skin, subcutis and muscle pain thresholds in subjects without spontaneous pain.

The aim of this study was to determine whether topical application of diclofenac hydroxyethylpyrrolidine (DHEP) modifies somatic pain sensitivity in subjects without spontaneous pain. Twenty male subjects (aged 19-40 years), who had not reported any pain for at least 1 month, underwent measurement of pain thresholds to bilateral electrical stimulation in the quadriceps muscle and overlying subcutis and skin. Following the double-blind study design, one diclofenac adhesive plaster (13 x 10 cm; 180 mg DHEP) was then applied over one quadriceps while a matched placebo plaster was placed contralaterally. Each subject was given two other plasters (diclofenac and placebo) and instructed to substitute those over the quadriceps after 12 h and to wear them for a further 12 h. Thirty minutes after removal of the second plasters, thresholds. were remeasured in all subjects as on the previous day. Thresholds at the first evaluation were within normal range in nine subjects (group 1) and below normal in muscle (hyperalgesia) in the remaining 11 (group 2). No significant changes were observed in skin or subcutis thresholds after diclofenac or placebo treatment in either group. In contrast, muscle thresholds significantly increased after diclofenac compared with placebo treatment (group 1: p < 0.05; group 2: p < 0.007); the increase was significantly higher in group 2 than in group 1 (p < 0.002). Topical application of diclofenac had a selective hypoalgesic effect on muscles, which was more pronounced in the case of hyperalgesia. These results suggest that the preparation is particularly effective in the treatment of algogenic conditions of deep somatic tissues.

Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women.

This study investigated the impact of algogenic conditions of the reproductive organs upon urinary pain perception in women. A 5-year survey was conducted among 69 fertile women with calculosis of one upper urinary tract via an ad-hoc questionnaire. At both retrospective (3 years) and prospective (2 years) investigation, dysmenorrheic women (D) reported more colics than non-dysmenorrheic women (ND) (P<0.001) and women with previous dysmenorrhea treated with estroprogestins (DH)(P<0.05). Pain thresholds (electrical stimulation) of the oblique musculature ipsilateral to the stone (L1, site of referred hyperalgesia from upper urinary tract) were lower in D than in ND (P<0.01) and DH (P<0.05). Calculosis women with asymptomatic endometriosis / ovarian cysts also reported more colics (6-month prospective study) and greater threshold lowering (P<0.05) than women with calculosis alone. The results show enhancement of urinary pain / hyperalgesia by both manifest and latent algogenic conditions of the female reproductive organs. This enhancement could derive from neuronal sensitization in spinal segments of common projection of the two visceral districts (T10-L1).

Pre-emptive analgesia in rats with artificial ureteric calculosis. Effects on visceral pain behavior in the post-operative period.

'Pre-emptive' analgesia is a controversial issue in both the clinical and experimental literature on pain. This paper investigates the effect of chronic (4 days) administration of morphine or ketoprofen initiated pre- or post-operatively on behavioral indicators of visceral pain and referred hyperalgesia in an animal model of artificial ureteric calculosis. In the morphine experiment, female Sprague-Dawley rats were treated i.p. with saline or morphine sulphate (2.5 or 5 mg/kg/day) starting either 45 min before or 45 min after surgery (pentobarbital anesthesia) for stone implantation in the left ureter, until the 4th day after intervention. Behavioral crises of ureteric pain were recorded (video-tape) in all rats over 4 days post-operatively. Number, duration and complexity of crises of stone-rats were significantly and dose-dependently reduced by administration of morphine with respect to saline in an identical manner for the pre- and post-operative treatment. In the ketoprofen experiment, rats were given saline or ketoprofen (15 mg/kg/day, in 3 i.p. injections per day) starting either pre- or post-operatively with the same paradigm as for the morphine study. Vocalization thresholds to electrical stimulation of the left oblique musculature were measured daily for 3 days pre- and 4 days post-operatively. Muscle hyperalgesia (post-operative decrease in threshold with respect to pre-stone implantation) was significantly reduced in extent and duration in ketoprofen with respect to saline-injected animals but no difference was found between the pre- and post-operative treatment. It is concluded that pre-emptive administration of morphine or ketoprofen has no advantage in reducing behavioral indicators of visceral pain and referred hyperalgesia in this animal model.

Uterine inflammation as a noxious visceral stimulus: behavioral characterization in the rat.

We have developed a model of uterine inflammation in the rat. The purpose of this study was to characterize the behavioral manifestations of uterine pain. Mustard oil was injected into one uterine horn to produce chemical inflammation. Control rats were sham-operated. Non-stop videotape recording was performed for 7 days to monitor rat behavior. Rats with uterine inflammation showed abnormal behavior during the first 4 days (hunching, hump-backed position, licking of the lower abdomen, repeated waves of contraction of the ipsilateral oblique musculature with inward turning of the ipsilateral hindlimb, stretching, squashing of the lower abdomen against the floor) suggestive of visceral pain and evidence of flank muscle hyperalgesia over 7 days indicative of referred visceral pain. This model resembles closely a state of inflammatory uterine pain and will allow to gain further insight into the neural processes which contribute to visceral nociception.

Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorrheic women, dysmenorrheic women and men.

Pain symptoms of many disorders are reported to vary with menstrual stage. This study investigated how pain thresholds to electrical stimulation of the skin, subcutis and muscle tissue varied with menstrual stage in normal women and compared these variations with those in women with dysmenorrhea and in healthy men at matched intervals. Thresholds of the three tissues were measured four times during the course of one menstrual cycle at four sites. Two of the sites were on the abdomen within the uterine viscerotome (abdomen-rectus abdominis, left and right) and two were outside it on the limbs (leg-quadriceps, arm-deltoid). Calculated from the beginning of menstruation (day 0), the menstrual phases studied were menstrual (days 2-6), periovulatory (days 12-16), luteal (days 17-22) and premenstrual (days 25-28). Spontaneous pain associated with menstruation was measured from diary estimates on a VAS scale. Whereas the highest thresholds always occurred in the luteal phase regardless of segmental site or stimulus depth, the lowest thresholds occurred in the periovulatory stage for skin, whereas those for muscle/subcutis occurred perimenstrually. Dysmenorrhea accentuated the impact of menstrual phase. For non-dysmenorrheic women menstrual trends were significant only in abdominal muscle and subcutis, but for dysmenorrheic women the trends were also significant in abdominal skin and in limb muscle and subcutis. Dysmenorrhea also lowered thresholds mainly in muscle and sometimes in subcutis, but never in skin, with the greatest hyperalgesic effects in left abdominis muscle. Abdominal sites were more vulnerable to menstrual influences than limb sites. Muscle thresholds, but not skin or subcutis thresholds, were significantly lower in abdomen than in limbs, particularly in dysmenorrheic women. The amount of abdominal muscle hyperalgesia correlated significantly with the amount of spontaneous menstrual pain. Only minor sex differences were observed for pain thresholds of the arm and leg, but there was a unanimous refusal by men, but not by women, to be tested at abdominal sites. These results indicate that menstrual phase, dysmenorrhea status, segmental site, tissue depth and sex all have unique interacting effects on pain thresholds, thus adding more items to the lengthy and still-growing list of biological factors that enter into an individual's judgment of whether or not a stimulus is painful.