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Fibromyalgia is a pain disorder associated with frequent comorbid mood, anxiety, and sleep disorders. Despite the frequent use of a complex, poly-drug pharmacotherapy, treatment for fibromyalgia is of limited efficacy. Oxytocin has been reported to reduce the severity of pain, anxiety, and depression, and improve the quality of sleep, suggesting that it may be useful to treat fibromyalgia. To evaluate this hypothesis, 14 women affected by fibromyalgia and comorbid disorders, assuming a complex pharmacotherapy, were enrolled in a double-blind, crossover, randomized trial to receive oxytocin and placebo nasal spray daily for 3 weeks for each treatment. Order of treatment (placebo-oxytocin or oxytocin-placebo) was randomly assigned. Patients were visited once a week. At each visit, the following instruments were administered: an adverse drug reaction record card, Visual Analog Scale of Pain Intensity, Spielberger State Anxiety Inventory, Zung Self-rating Depression Scale, and SF-12. Women self-registered painkiller assumption, pain severity, and quality of sleep in a diary. Unlikely, oxytocin nasal spray (80 IU a day) did not induce positive therapeutic effects but resulted to be safe, devoid of toxicity, and easy to handle.

The present paper describes the results of recent preclinical and clinical studies conducted in this laboratory in order to characterize the anti-alcohol properties of the GABA(B) receptor agonist, baclofen. At a preclinical level, the repeated administration of non-sedative doses of baclofen dose-dependently suppressed the acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats tested under the homecage, 2-bottle "alcohol vs water" choice regimen. Acute injection of baclofen completely blocked the temporary increase in voluntary alcohol intake occurring after a period of alcohol abstinence (the so-called alcohol deprivation effect, which models alcohol relapses in human alcoholics). Acute treatment with baclofen also dose-dependently suppressed extinction responding for alcohol (an index of motivation to consume alcohol) in sP rats trained to lever-press for oral alcohol self-administration. Taken together, these results suggest the involvement of the GABA(B) receptor in the neural substrate mediating alcohol intake and alcohol motivational properties in an animal model of excessive alcohol consumption. Further, acutely administered baclofen dose-dependently reduced the severity of alcohol withdrawal signs in Wistar rats made physically dependent upon alcohol. Preliminary clinical surveys suggest that the anti-alcohol properties of baclofen observed in rats may generalize to human alcoholics. Indeed, a double-blind survey demonstrated that repeated daily treatment with baclofen was associated, when compared to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of days of total abstinence. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of alcohol craving. Finally, a single non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology, including delirium tremens, in alcohol-dependent patients. In both clinical studies, baclofen was well tolerated with minimal side effects. These results suggest that baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients.

studies [8–10]. The first study found that 32 IU of oxytocin nasal spray induced better results in patients with chronic migraine if they had not taken NSAIDs [8]. However, this study failed to report the number of patients and statistical evaluation. The second study found that 40 IU of oxytocin (twice a day, for 13 weeks) reduced abdominal discomfort but not constipation in 59 women with refractory constipation [9]. However, this study did not report whether NSAIDs were used or not [1, 9]. The third study found that oxytocin dose dependently reduced the severity of headache in 112 patients not taking analgesic medications [10]. However, the doses of oxytocin were not specified. It is reported that patients received six puffs of a solution containing different concentrations of oxytocin (100, 200 or 400 ng) without specifying whether these concentrations were referred to 1 ml, to 1 puff, or to 6 puffs. Considering that usually 1 puff consists of 0.1 ml of solution, and 1 IU corresponds to 2 μg of oxytocin [11], we calculated the maximum dose of oxytocin expressed in IU. If the highest dose (400 ng) was referred to 1 ml, each patient received 0.12 IU (400 ng/ml; each patient received 0.6 ml; 0.6 ml contains 240 ng, corresponding to 0.12 IU); if the dose was referred to 1 puff, each patient received 1.2 IU (400 ng/ puff; 400 ng × 6 = 2,400 ng corresponding to 1.2 IU); if it referred to the total of 6 puffs, each patient received 0.2 IU (400 ng/6 puffs corresponding to 0.2 IU). Accordingly, the maximum dose administered (1.2 IU) would be much lower than those usually administered. For instance, 27 and 33 times lower than that used in the first (32 IU) and in the second study (40 IU), respectively [8, 9]. The limits of these studies did not allow any conclusions to be drawn on the possible influence of NSAIDs on the effects induced by oxytocin. It has been observed that NSAID administration reduces the secretion of endogenous oxytocin [12], although this effect should not influence response We read with interest the Commentary of Drs. Kwong and Chan on the lack of analgesic effects induced by the administration of oxytocin nasal spray to fibromyalgic patients [1–3]. We agree with them that these negative results are very disappointing, particularly as the inverse relationship between plasma oxytocin levels and the severity of pain found by other studies persuaded us to conduct our study [4]. We also agree with them on the possibility that the severity of pain may change throughout the menstrual cycle of fertile women. Indeed, in fibromyalgic patients, the severity of pain is higher in the luteal than in the follicular phase [5], and, in healthy fertile women, plasma oxytocin levels are lower during the luteal than the follicular phase [6]. The expression of brain oxytocin receptors is modulated by estrogen and progesterone [7]. However, in our study, patients included seven postmenopausal and seven premenopausal women, most of the latter with irregular cycles (n = 5). This sample was not adequate to investigate possible swing of fibromyalgic symptoms throughout the menstrual cycle. Finally, we read with great interest the hypothesis that the lack of efficacy of oxytocin may be due to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. This hypothesis was based on the results of three clinical

A possible acute, analgesic effect of oxytocin was investigated at the beginning of the study. After baseline evaluation, patients self-administered oxytocin (20-IU) or placebo and waited for 1 h, when central oxytocin levels achieve the highest values [4–6]. Then, the severity of actual pain was investigated, but no difference was found (placebo 43.3 ± 10.6; oxytocin 47.2 ± 16.2, p = 0.15, t test). The acute effects of 40-IU was not examined as patients started with this dose after 1 week of a 20-IU treatment, and this evaluation would not be a reliable measure of 40-IU acute effects. Under our experimental conditions, chronic treatments with 20-IU or 40-IU did not reduce the severity of pain. We concluded that higher doses or long periods of treatment might unravel an analgesic effect of oxytocin. Recent studies found that 24-IU of oxytocin (1) induced stronger effects than 48-IU in cortisol response to intense exercise [7] and (2) was effective in reducing obesity if administered 4 times daily for 8 weeks [8]. Accordingly, the ideal schedule seems to be constituted by more frequent daily administrations of lower doses, and for longer periods of time than those used in our studies (e.g., 24-IU, 4 times daily for at least 8 weeks rather than 40-IU twice daily for 3 weeks). Despite the large body of preclinical evidence suggesting an analgesic effect of oxytocin, the number of clinical studies is scarce. A recent review [9] reported that only five studies investigated this effect: among these, three studies found positive effects [10–12], one promising results [13], and one inconclusive results [14]. Recently, two additional clinical studies found opposite results [2, 15]. The difference between results may be due, at least in part, to the different patient samples (fibromyalgic patients vs. healthy adults) and methodological procedures (chronic vs. acute treatment; chronic unresponsive vs. acute cold pressor pain). We read with interest the letter of Drs. Rash and Campbell [1] and are grateful to them for the opportunity to provide additional information to our short communication [2]. Regarding the procedure of the administration, the recommendations suggested by Guastella and colleagues were adopted [3]. During the first week, the dose was equal to 5 puffs (20-IU) twice a day, then, to 10 puffs (40-IU) twice a day. The composition of the oxytocin and placebo nasal sprays was identical, except for the hormone. It is difficult to determine what influence the expectation of effects had on our results, as no data were collected on expectations. However, the lack of differences between the groups suggests that oxytocin did not enhance placebo analgesia in our experimental conditions. Our study was aimed at investigating the possible effectiveness of chronic treatment in reducing the severity of pain. Accordingly, medications were self-administered by participants, twice daily, with a 12-h interval, for 3 weeks. patients registered the severity of pain at the end of the day, regardless of the time of the administration. At each weekly visit, the experimenter registered the severity of pain, regardless of the time of administration.