Current status of atypical antipsychotics for the treatment of fibromyalgia.

The treatment of fibromyalgia requires pharmacological and nonpharmacological therapies. The pharmacological treatment of fibromyalgia is limited to a few drugs that have been demonstrated to be moderately effective in some but not all dimensions of the disease. Therefore, the search for new drugs to treat this condition is warranted. Atypical antipsychotics offered an attractive alternative because they had been shown to be active against several key symptoms of fibromyalgia. The results of open-label studies, however, appear to indicate that atypical antipsychotics are poorly tolerated in patients with fibromyalgia, and only quetiapine XR has been studied in randomized controlled trials. Quetiapine XR has demonstrated effectiveness in treating comorbid major depression, anxiety and sleep disturbance. However, in two randomized controlled trials, quetiapine XR was not differentiated from placebo and failed to demonstrate noninferiority to amitriptyline in terms of improving overall symptomatology. The effect of quetiapine XR on pain and its usefulness as part of a combination pharmacological regimen should be further evaluated. Overall, the use of quetiapine (initiated at a low dose and slowly titrated) in fibromyalgia should be limited to patients with comorbid major depression or patients who are currently receiving other treatments and have unresolved and disabling depressive and/or anxiety symptoms.

Agomelatine for the treatment of patients with fibromyalgia and depressive symptomatology: an uncontrolled, 12-week, pilot study.

INTRODUCTION: Agomelatine, a melatonin agonist and selective 5-HT2C antagonist, is a novel antidepressant with sleep-enhancing properties. The purpose of this study was to assess the efficacy and tolerability of agomelatine among patients with fibromyalgia and depression. METHODS: 23 patients with fibromyalgia and depressive symptomatology received 25-50 mg of agomelatine daily for 12 weeks. The primary outcome measure was the change of the Beck depression inventory score. Secondary outcome measures included the hospital anxiety and depression scale, Pittsburgh sleep quality index, Fibromyalgia Impact Questionnaire, short-form health survey, brief pain inventory and patient's global impression scale. RESULTS: Agomelatine significantly improved depression, global fibromyalgia severity and pain intensity but effect sizes were small. No improvement was seen in sleep quality. Patients categorized as responders to treatment had milder disease severity than non-responders. Agomelatine therapy was well tolerated and patients only reported mild and transient side effects. DISCUSSION: Agomelatine slightly improved depressive and fibromyalgia symptomatology but did not improve sleep quality. Our data do not support agomelatine as a first-line treatment option for the treatment of fibromyalgia and depression.

An open-label study of levopromazine (methotrimeprazine) as an add-on therapy in fibromyalgia management.

OBJECTIVES: To assess the potential efficacy and tolerability of levopromazine(methotrimeprazine) in the treatment of fibromyalgia. METHODS: Unicentre, open-label study conducted in thirty-five outpatients, aged 18 years or older, who met the ACR criteria for fibromyalgia and had not satisfactorily responded to previous fibromyalgia treatment. Levopromazine, flexibly dosed (12.5-100 mg/d), was added to the outpatients' original treatment regimens for 12 weeks. The primary outcome measure was the mean change from baseline to endpoint in the Fibromyalgia Impact Questionnaire (FIQ) total score in the intent-to-treat sample. Secondary outcomes included the Clinical Global Impression (CGI) of Severity scale, Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory, State-Trait Anxiety Inventory, 12-Item Short Form Health Survey, and individual items of the FIQ. RESULTS: The mean FIQ total score did not decrease significantly at the study endpoint (63.37 SD 11.32 vs. 61.19 SD 9.32, p=0.73). Pain intensity, as evaluated by the Visual Analogue Scale, remained unchanged at study endpoint (8.5 SD 1.6 vs. 8.2 SD 1.2, p=0.49). A statistically significant reduction was observed in the PSQI score (15.65 SD 3.33 vs. 12.23 SD 3.79, p<0.001, effect size: 1.03) and the CGI-severity score (4.71 SD 0.64 vs. 4.03 SD 1.01, p<0.002, effect size: 1.06). No significant or relevant changes were seen in the remaining fibromyalgia symptoms, psychopathological scales or quality-of-life. The drug was well tolerated. CONCLUSIONS: Despite its efficacy in improving sleep quality, levopromazine does not appear to be a useful alternative treatment for fibromyalgia.

Effects of pool-based exercise in fibromyalgia symptomatology and sleep quality: a prospective randomised comparison between stretching and Ai Chi.

OBJECTIVE: To evaluate the effectiveness and tolerability of two pool-based physical therapies, stretching and Ai Chi, in fibromyalgia symptomatology and sleep quality. METHODS: Eighty-one patients, randomly assigned to stretching (n=39) or Ai Chi (n=42), received 18 physiotherapy sessions and were evaluated at baseline, at treatment termination, and after 4 and 12 weeks of follow-up. Main outcome measures were the Fibromyalgia Impact Questionnaire (FIQ) and the Pittsburgh Sleep Quality Index (PSQI). Secondary outcome measures included the Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI), and the SF-12 Health Survey (SF-12). Data analysis was done with repeated measures ANOVA and effect size estimation. RESULTS: No differences were found between groups but significant reduction in the FIQ and the PSQI scores were observed in Ai Chi but not in stretching group, with larger effect sizes and longer effect duration on sleep measures. BDI scores decreased in stretching but not in Ai Chi group with small effect sizes. Trait-anxiety scores decreased in both groups also with small effect sizes. The mental component summary of the SF-12 increased only in stretching group with effect sizes moderate to large. CONCLUSIONS: Although no global differences were found between groups, Ai Chi significantly improved fibromyalgia symptomatology and sleep quality, whereas stretching only improved subjects' psychological well-being.

Pregabalin augmentation of quetiapine therapy in the treatment of fibromyalgia: an open-label, prospective trial.

INTRODUCTION: Quetiapine has been shown to improve fibromyalgia symptoms, especially sleep disturbance, fatigue, morning stiffness, and mental well-being, but lacks an effect on pain. The purpose of this study was to evaluate if pregabalin, which has shown antialgic activity in fibromyalgia, added to quetiapine treatment additionally improved fibromyalgia symptomatology. METHODS: This was an open-label, 12-week study. Pregabalin was administered to 19 female fibromyalgia patients at a starting dose of 75 mg/day subsequently adjusted in according to the drug's efficacy and tolerability. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index, the Beck Depression Inventory, the State and Trait Anxiety Inventory, and the SF-12 Health Survey. RESULTS: Data analysis was done on the Intention-To-Treat sample which included 18 patients. Pregabalin significantly improved the pain and tiredness after awakening subscales of the FIQ as well as the physical component of the SF-12. Six patients withdrew from the study, 3 because of side effects. CONCLUSIONS: Our results suggest that the use of pregabalin can be a useful augmentation strategy in fibromyalgia patients partially responding to quetiapine.

Trigger point evaluation in migraine patients: an indication of peripheral sensitization linked to migraine predisposition?

Although migraine is a neurovascular disorder, both scalp tenderness and referred pain have been observed in migraine patients. The present study was carried out to investigate the presence of trigger points eliciting referred pain in 98 migraine patients and in 32 healthy subjects. Trigger points were found in 92 (93.9%) migraineurs and in nine (29%) controls (P < 0.0001). The number of individual migraine trigger points varied from zero to 14 (modal number: 4), and was found to be related to both the frequency of migraine attacks (P < 0.0001), and the duration of the disease (P = 0.017). About 74% of the total detected trigger points were found in temporal and/or suboccipital areas; other locations were mainly found in patients showing more than four trigger points. Trigger point palpation provoked a migraine attack in 30 (30.6%) patients. Pericraneal allodynia was found in 15 (15.3%) patients. These data indicate that nociceptive peripheral sensitization is a usual finding in migraine, and that central sensitization can develop in patients with frequent attacks and long-lasting disease. Trigger points' detection in migraine patients could be useful when applying therapies like acupuncture, needling or botulinum toxin injections directed to reduce peripheral sensitization.

Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: their relationship with the clinical manifestations of the illness.

The purpose of the present study was to evaluate neuropsychological performance and regional cerebral blood flow in migraine patients, and to investigate whether possible abnormalities in any of these fields could be related to the chronicity of the disease. The sample included 60 patients and 30 healthy control subjects; all of them were subjected to a complete neuropsychological assessment, including emotional variables. In addition an interictal 99Tc-HMPAO SPECT was performed in 56 patients and 15 controls. Disturbances in memory, attention and visuomotor speed processing were observed among migraineurs experiencing higher frequency of attacks and in those with a long history of migraine. Anxiety levels were higher in patients than in controls and were positively correlated with attack frequency, but not with cognitive test scores. Brain perfusion abnormalities, mostly hypoperfusion areas, were found in the 43% of patients; poorer performance in two tests, measuring verbal and visual memory, respectively, was found in these patients.

The effect of chronic phenytoin treatment on serum lipid profile in adult epileptic patients.

Total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein cholesterol, apolipoproteins A, A1, and B and gamma-glutamyltransferase (ggt) serum concentrations were measured in 100 adult epileptic patients receiving chronic phenytoin (PHT) treatment and in 100 control subjects. In relation to controls, patients showed higher HDL cholesterol, apolipoproteins A and A1, and ggt levels and lower LDL cholesterol and apolipoprotein B values; the significance of the results was greater in women than in men. Among patients, ggt levels were positively correlated with PHT plasma concentrations; likewise, a negative correlation was found between the apolipoprotein A/A1 ratio and the PHT and ggt plasma levels, and a positive correlation between the apolipoprotein A/A1 ratio and the LDL/HDL cholesterol ratio. These data indicate that PHT exerts a beneficial effect on the serum lipids profile.

Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital.

Serum lipids, lipoproteins and apolipoproteins A and B were measured in 101 epileptic patients receiving chronic treatment with valproic acid, carbamazepine or phenobarbital and in 75 age- and sex-matched control subjects. In relation to controls, subjects treated with valproic acid showed significantly lower values of total and LDL-cholesterol levels; subjects treated with carbamazepine showed significantly higher values of HDL-cholesterol and apolipoprotein A concentrations and subjects treated with phenobarbital showed significantly higher values of total cholesterol, HDL-cholesterol, apolipoprotein A and apolipoprotein B levels. The total cholesterol/HDL-cholesterol ratio was significantly lower in patients receiving valproic acid or carbamazepine but not in the phenobarbital-treated group. Changes in serum lipids profile did not correlate with drug plasma concentrations nor the duration of the treatment.

Efficacy of oral streptokinase-streptodornase in the treatment of ankle sprains.

To evaluate the analgesic and antiinflammatory properties of oral streptokinase-streptodornase (SS) in cases of minor trauma, 190 patients with ankle sprains were studied. Subjects were randomly given an active drug or a placebo in doses of two tablets three times a day for eight days. A scoring system was used to rate the following symptoms: spontaneous pain, mobilization pain, wearing pain, articular disability, flaccidity, muscular spasm, edema, and hematoma. Each symptom was categorized as none (0), mild (1), moderate (3), or severe (4). Patients were evaluated at the beginning of the study and on the fourth and eighth days of treatment. At the end of the trial, the decrease in each symptom score was significantly greater in patients receiving SS than in patients receiving a placebo. Analgesic intake during the study was also noticeably lower in the SS group. The incidence of drug-induced side effects (mainly abdominal discomfort) was minimal. Oral SS ameliorates the inflammatory symptoms associated with ankle sprains and therefore may be used as an alternative to nonsteroidal antiinflammatory drugs.

Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children.

The Wechsler Intelligence Scales for Children was applied to 64 epileptic children and 60 healthy subjects; patients followed chronic treatment with valproic acid (n = 32) or phenobarbital (n = 32). None of the children suffered mental retardation or neurological abnormalities. The test was repeated after a 9-12 month interval: 26 of the valproate treated children and 23 of the phenobarbital-treated children performed the second evaluation. At baseline, total, verbal and performance IQ scores of children receiving phenobarbital were lower than those of controls. When the results of the first and the second tests were compared, a significant increase in IQ scores was detected among controls and patients treated with valproic acid, but not among phenobarbital-treated patients. It is concluded that long-term phenobarbital therapy induces a significant impairment in learning ability whereas long-term valproate therapy does not exert a noticeable noxious effect at this respect.

Theophylline binding to plasma proteins in patients with chronic obstructive pulmonary disease.

The binding of theophylline to plasma proteins was studied in samples from healthy adults at different pH values and drug concentrations and in samples from patients with chronic obstructive pulmonary disease (COPD). Binding determinations were performed by ultrafiltration and drug concentrations were measured by high performance liquid chromatography. Total plasma levels of theophylline did not influence the degree of the binding. The percentage of bound theophylline was positively correlated with pH both in vitro (r = 0.998, p less than 0.005) and in vivo (r = 0.579, p less than 0.005). Mean theophylline binding values in vivo (mean 56.3 +/- 12.5) and in vitro (mean 48.3 +/- 9.4) were significantly different. The increase in theophylline free levels detected in COPD patients was partially dependent on low pH values but the influence of other factors must also be considered. The therapeutic implications of altered theophylline binding are discussed.

Monitoring aminophylline therapy using Jusko's dosage guidelines.

Treatment with aminophylline, according to the nomogram published by Jusko and coworkers, was monitored in 13 patients suffering from acute exacerbations of COPD. After 24 h of therapy, the clinical state, the pO2 and the pCO2 values were markedly improved. Theophylline plasma concentrations were maintained within the therapeutic range. A slight but noticeable increase of drug serum levels during therapy could be related to changes in the arterial pH; the implications of this finding are discussed.

Methapyrilene kinetics and dynamics.

A study was undertaken to characterize the H1 receptor blockade, central nervous system depressant properties, and kinetic parameters of methapyrilene in man. Eight healthy subjects received, in random order at weekly intervals, placebo and methapyrilene 20 mg intravenously and 50 mg and 25 mg orally. Methapyrilene exhibited a moderate antihistaminic effect as measured by the reduction of histamine-provoked skin wheals. Sedation and drowsiness were detected only at the first sampling time (0.75 hr) after intravenous doses. The terminal plasma half-life ranged from 1.1 to 2.1 hr, apparent volume of distribution from 2.14 to 6.61 1/kg, and plasma clearance from 0.013 to 0.048 1/min/kg. Systemic bioavailability was low and showed large interindividual differences, ranging from 4% to 46%. Recovery of unchanged drug from the 24-hr urine was under 2% of the doses.