Thomas Guttuso

Gabapentin, estrogen, and placebo for treating hot flushes : A randomized controlled trial

OBJECTIVE: To compare the efficacy of gabapentin, estrogen, and placebo in the treatment of hot flushes. METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 postmenopausal women to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe hot flushes. Participants were randomly assigned to receive either 0.625 mg/d of conjugated estrogens (n = 20), placebo (n = 20), or gabapentin titrated to 2,400 mg/d (n = 20) for 12 weeks. Participants recorded frequency and severity of baseline hot flushes on a hot flush diary for 2 weeks before randomization and for 12 weeks after randomization. The primary outcome measure was the weekly hot flush composite score, which takes into account both severity and frequency of hot flushes. Secondary outcome measures were differences in pre- and posttreatment scores pertaining to depression (Zung Depression Scale) and other climacteric symptoms (Greene Climacteric Scale). RESULTS: Intention-to-treat analysis showed that the reduction in the hot flush composite score for both estrogen (72%, P = .016) and gabapentin (71%, P = .004) was greater than the reduction associated with placebo (54%) at the conclusion of the 12th week. The extent of reduction in hot flush composite score, however, was not significantly different between estrogen and gabapentin (P = .63). No differences were seen between groups in the Zung Depression Scale, or in any of the Greene Climacteric subscales except for the Somatic Symptom cluster, which was significantly greater in the gabapentin arm than in the placebo arm. Despite a lack of group differences in adverse events, the Headache, Dizziness, and Disorientation cluster appeared with greater frequency in the gabapentin group. Estimation of the number needed to harm in this cluster suggests that these symptoms may occur with every fourth patient treated with gabapentin. CONCLUSION: Despite the small scale of this study, gabapentin appears to be as effective as estrogen in the treatment of postmenopausal hot flushes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT 00276081. LEVEL OF EVIDENCE: I

Newer Antidepressants and Gabapentin for Hot Flashes: An Individual Patient Pooled Analysis

PURPOSE Nonhormonal treatment options have been investigated as treatments for hot flashes, a major clinical problem in many women. Starting in 2000, a series of 10 individual double-blind placebo-controlled studies has evaluated newer antidepressants and gabapentin for treating hot flashes. This current project was developed to conduct an individual patient pooled analysis of the data from these published clinical trials. PATIENTS AND METHODS Individual patient data were collected from the various study investigators who published their study results between 2000 and 2007. Between-study heterogeneity for study characteristics and patient populations was tested via chi2 tests before a pooled analysis. The primary end point, the change in hot flash activity from baseline to week 4, for each agent was calculated via both weighted and unweighted approaches, using the size of the study as the weight. Basic summary statistics were produced for hot flash score and frequency using the following three statistics: raw change, percent reduction, and whether or not a 50% reduction was achieved. RESULTS This study included seven trials of newer antidepressants and three trials of gabapentin. The optimal doses (defined by individual study results) of the newer antidepressants paroxetine, venlafaxine, fluoxetine, and sertraline decreased hot flash scores by 41%, 33%, 13%, and 3% to 18% compared with the corresponding placebo arms, respectively. The three gabapentin trials decreased hot flashes by 35% to 38% compared with the corresponding placebo arms. CONCLUSION Some newer antidepressants and gabapentin, within 4 weeks of therapy initiation, decrease hot flashes more than placebo.

Gabapentin’s effects on hot flashes and hypothermia

Article abstract The author describes six cases in which gabapentin treatment reduced the frequency of hot flashes. In addition, gabapentin treatment enhanced the frequency of hypothermic episodes in a separate patient with known hypothalamic dysfunction. Gabapentin may act directly upon temperature regulatory centers.

Effects of Gabapentin on Sleep in Menopausal Women with Hot Flashes as Measured by a Pittsburgh Sleep Quality Index Factor Scoring Model

OBJECTIVE The aim of this research was to analyze gabapentins effect on Pittsburgh Sleep Quality Index (PSQI) scores in menopausal women. METHODS Secondary analysis of data from a cohort of menopausal women participating in a randomized, double-blind, placebo-controlled trial of gabapentin 300 mg three times daily (TID) for hot flashes. The outcomes of interest were PSQI global and factor scores at weeks 4 and 12. RESULTS Subjects randomized to gabapentin demonstrated improvement in the sleep quality factor score, compared to placebo-treated subjects, at 4 and 12 weeks (p < 0.03). There was also gabapentin-associated improvement in the global PSQI score (p = 0.004) and the sleep efficiency factor score (p = 0.05) at 4 weeks. There was no significant effect of gabapentin on the daily disturbance factor score. CONCLUSIONS Gabapentin may improve sleep quality in menopausal women with hot flashes. These results warrant further prospective investigation, with an emphasis on measuring subjective sleep quality and maintenance.

Potential maternal symptomatic benefit of gabapentin and review of its safety in pregnancy

Restless legs syndrome (RLS) and nausea and vomiting of pregnancy (NVP) are both common maternal conditions affecting quality of life. Gabapentin is currently FDA-approved for treating RLS and preliminary results have shown it may be effective for treating the most severe form of NVP, hyperemesis gravidarum (HG). Because NVP and HG symptoms peak early in pregnancy, the potential teratogenicity of gabapentin needs to be considered. We reviewed published pregnancy registries and cohorts for pregnancy outcomes associated with maternal gabapentin use. Gabapentin exposures from 5 pregnancy registries, 1 HG pilot study and 2 additional cases were reviewed. Among 294 first trimester gabapentin-monotherapy exposures, there were 5 major congenital malformations (MCMs) reported (1.7%), which favorably compares to the MCM rate in the general population (1.6-2.2%). Two of the registries reported maternal gabapentin use among 261 singleton pregnancies to be associated with roughly equivalent rates of premature birth, birth weight after correction for gestational age at delivery and maternal hypertension/eclampsia as those that have been reported in the general population. These data support the safety of gabapentin use in pregnancy; however, the number of exposures to date is still small. If future pregnancy registry data confirm this positive safety profile, gabapentin therapy would likely be a safe and effective treatment for RLS during pregnancy. Controlled, clinical trials are needed to assess gabapentins effectiveness for HG.

Gabapentin use in hyperemesis gravidarum: a pilot study.

Among 7 subjects with hyperemesis gravidarum (HG), we found gabapentin therapy to be associated with mean reductions in nausea and emesis from Baseline to Days 12-14 of 80% and 94%, respectively. There have been 2 congenital defects among 7 exposed infants. Gabapentin may be effective in the treatment of HG.

Treatment of chronic insomnia disorder in menopause: evaluation of literature.

ObjectiveInsomnia both as a symptom and as part of chronic insomnia disorder is quite common in menopause. Comorbid conditions, such as restless legs syndrome and obstructive sleep apnea, occur with high prevalence among perimenopausal women with insomnia. Insomnia in this population group is associated with adverse health outcomes, and there are no clear standards on how to treat it. MethodsBased on extensive literature search, 76 articles were identified. Two authors independently graded evidence according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. ResultsEvaluation and treatment of other comorbid sleep disorders are recommended, as is cognitive-behavioral therapy for insomnia. Hormone therapy, eszopiclone, escitalopram, gabapentin, isoflavones, valerian, exercise, and hypnosis are suggested. Zolpidem, quiteiapine XL, citalopram, mirtazapine followed by long-acting melatonin, ramelteon, Pycnogenol, Phyto-Female Complex, yoga, and massage may be considered. Kampo formulas are not recommended. Acupuncture may not be suggested, and cognitive-behavioral therapy that is not tailored for insomnia probably should not be considered. ConclusionsAlthough a variety of interventions are shown to be helpful in improving sleep in menopause, there is a need for well-designed head-to-head trials with uniform outcome measures.

Minimum Trial Duration to Reasonably Assess Long-Term Efficacy of Nonhormonal Hot Flash Therapies

BACKGROUND Because hot flashes usually persist for years after menopause, a clinically meaningful hot flash therapy needs to have long-term efficacy; however, it is unclear for how long a therapy needs to be compared with a placebo before long-term efficacy can be reasonably deduced. The Food and Drug Administration (FDA) requires a 12-week treatment period for industry-initiated hot flash trials, whereas most academic-initiated trials have ranged from 4 to 12 weeks. We have focused on reviewing nonhormonal hot flash trials to identify inadequate trial durations as a guide toward deducing adequate trial duration to reasonably assess for long-term efficacy. METHODS An electronic database search of MEDLINE, Web of Science, and PsycINFO was performed from 1966 to May 2009 to identify target studies showing a nonhormonal hot flash therapy to be effective at early time points only to become ineffective at later time points (i.e., showing short-term but not long-term efficacy) in a randomized controlled trial (RCT). The longest early time point of efficacy from the target studies plus 1 additional week would be considered the minimum treatment duration necessary to assess for long-term efficacy. RESULTS Of 2518 citations, 54 RCTs met our inclusion criteria, from which 3 target studies were identified. These 3 target studies evaluated Bellergal Retard (Sandoz, East Hanover, NJ), soy, and venlafaxine and showed times of 2, 6, and 7 weeks, respectively, when the nonhormonal compound last demonstrated efficacy before subsequently losing efficacy in a single RCT. CONCLUSIONS This analysis supports a hot flash RCT duration of at least 8 weeks to reasonably assess a nonhormonal compounds long-term efficacy.

Phase white matter signal abnormalities in patients with clinically isolated syndrome and other neurologic disorders

BACKGROUND AND PURPOSE: Identifying MRI biomarkers that can differentiate multiple sclerosis patients from other neurological disorders is a subject of intense research. Our aim was to investigate phase WM signal abnormalities for their presence, prevalence, location, and diagnostic value among patients with clinically isolated syndrome and other neurologic disorders and age-, sex-, and group-matched healthy controls. MATERIALS AND METHODS: Forty-eight patients with clinically isolated syndrome and 30 patients with other neurologic diseases and a healthy control group (n = 47) were included in the study. Subjects were scanned at 3T by using SWI-filtered phase and T2WI, with WM signal abnormalities ≥3 mm being classified. RESULTS: Patients with clinically isolated syndrome had significantly more phase and T2 WM signal abnormalities than healthy controls (P < .001). Phase WM signal abnormalities were more prevalent among patients with clinically isolated syndrome compared with patients with other neurologic disorders (4:1 ratio), whereas T2 WM signal abnormalities were more ubiquitous with a 2:1 ratio. The presence of phase WM signal abnormalities was sensitive for clinically isolated syndrome (70.8%) and achieved a moderate-to-high specificity for differentiating patients with clinically isolated syndrome and healthy controls, patients with other neurologic disorders, and patients with other neurologic disorders of other autoimmune origin (specificity, 70%–76.7%). Combining the presence of ≥2 phase lesions with the McDonald 2005 and 2010 criteria for dissemination in space improved the specificity (90%), but not the accuracy, in differentiating patients with clinically isolated syndrome from those with other neurologic disorders. In subanalyses among patients with clinically isolated syndrome who converted to clinically definite multiple sclerosis versus those who did not within a 3-year follow-up period, converters had significantly more phase (P = .008) but not T2 or T1 WM signal abnormalities. CONCLUSIONS: Phase WM signal abnormalities are prevalent among patients with clinically isolated syndrome. The presence of (multiple) phase WM signal abnormalities tended to be more predictive of conversion to clinically definite multiple sclerosis and was specific in differentiating patients with clinically isolated syndrome and other neurologic disorders, compared with T2 WM signal abnormalities; however, the accuracy remains similar to that of the current McDonald criteria.

Nighttime Awakenings Responding to Gabapentin Therapy in Late Premenopausal Women: A Case Series

Insomnia related to nighttime awakenings is known to be more prevalent in women than men. Three cases are presented here of late premenopausal women experiencing frequent nighttime awakenings that responded well to bedtime treatment with gabapentin. In one case, what started as isolated nighttime awakenings slowly progressed to awakenings accompanied by typical menopausal night sweats. This led to the theory that the initial isolated nighttime awakenings in this patient may have been secondary to a menopausal etiology related to low serum estradiol levels. In the subsequent 2 cases, early follicular phase serum estradiol was confirmed to be low. It is theorized that isolated nighttime awakenings in some premenopausal women may be caused by low serum estradiol, triggering events physiologically related to menopausal night sweats. Further research is needed to determine if low early follicular phase serum estradiol is associated with nighttime awakenings in premenopausal women not experiencing night sweats.