OBJECTIVE: To compare the effects of starting doses of duloxetine taken with or without food on tolerability and efficacy in patients with major depressive disorder (MDD). METHOD: This double-blind, concurrent-dose-controlled, parallel-design trial contained a variable expected-duration placebo lead-in period and was conducted in adult outpatients with DSM-IV-TR-defined MDD at psychiatric outpatient sites between October 2004 and January 2006. In actuality, patients received placebo for 1 week and then were randomly assigned to duloxetine 30 mg once daily in the morning (q.a.m.) (N = 219), 30 mg twice daily (b.i.d.) (N = 213), or 60 mg q.a.m. (N = 215) for 1 week along with 1 of 2 instructions about food: take study drug with food or do not take within 1 hour of eating. For the remaining 5 weeks of acute treatment, all patients received 60 mg once daily. The primary objective was to compare incidence of treatment-emergent nausea at 30 mg q.a.m. versus 60 mg q.a.m. using item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale (AMDP-5). Secondary outcome measures included mean change on AMDP-5 item 112, discontinuations due to adverse events, mean changes in AMDP-5 items and subscales, spontaneously reported treatment-emergent adverse events, and vital signs. Efficacy was evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17). RESULTS: The primary analysis, which combined data from both food groups, showed no significant difference in the incidence of nausea between starting doses of 30 mg q.a.m. and 60 mg q.a.m. (23% vs. 29%, respectively; p = .207). However, mean changes on the AMDP-5 nausea item revealed a significant main effect of food (p = .010) and a significant interaction between food and starting dose (p = .033). The food-by-dose interaction indicated that the benefit from taking drug with food was greatest in patients started at 60 mg q.a.m., and the benefit of starting at 30 mg q.a.m. was greatest in patients taking drug without food. In patients who took study drug without food, there was a significant difference across initial-dose groups for discontinuation due to adverse events (30 mg q.a.m. = 3.6%, 30 mg b.i.d. = 14.0%, 60 mg q.a.m. = 10.2%; 30 mg q.a.m. vs. 30 mg b.i.d., p = .008; 30 mg q.a.m. vs. 60 mg q.a.m., p = .066); however, in patients who took study drug with food, discontinuations due to adverse events did not significantly differ (30 mg q.a.m. = 5.4%, 30 mg b.i.d. = 7.5%, 60 mg q.a.m. = 7.4%; all p values > .50). Patients who started at 30 mg b.i.d. or 60 mg q.a.m. without food did not differ regarding mean changes (i.e., increases) in the common adverse events score after 1 week of treatment but had significantly greater mean changes than patients who started at 30 mg q.a.m. without food (0.87, 0.82, and 0, respectively; p < .05 vs. 30 mg b.i.d. and 60 mg q.a.m.). No significant differences were found between initial-dose groups in vital signs. CONCLUSIONS: These data imply that starting dulox-etine at 30 mg q.a.m. for 1 week with or without food or starting duloxetine at the therapeutic dose of 60 mg q.a.m. with food can improve the initial tolerability of the medication. Adding this information to existing knowledge of duloxetine will enable the clinician to tailor therapy most appropriately for the individual patient. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT 00191061.
Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial.
J Clin Psychiatry. 2007 Nov;68(11):1707-16
Authors: Brecht S, Courtecuisse C, Debieuvre C, Croenlein J, Desaiah D, Raskin J, Petit C, Demyttenaere K
OBJECTIVE: Experience of pain in major depressive disorder (MDD) can complicate diagnosis and impair treatment outcomes. This study evaluated the efficacy and safety of duloxetine in the treatment of patients with moderate pain associated with depression. METHOD: In this double-blind, placebo-controlled, 8-week study, conducted from May 2005 to May 2006, outpatients 18 years of age or older, presenting with major depressive disorder (DSM-IV criteria; Montgomery-Asberg Depression Rating Scale [MADRS] score >or= 20), moderate pain (Brief Pain Inventory-Short Form [BPI-SF] average pain score >or= 3), and Clinical Global Impressions-Severity of Illness scale (CGI-S) score >or= 4 were randomly assigned to either placebo (N = 165) or duloxetine 60 mg (N = 162) once daily. Primary outcome was change in item 5 score (average pain in the last 24 hours) of the BPI-SF from baseline. Secondary measures were MADRS total score, other BPI-SF items, CGI-S, CGI-Improvement scale, Patient Global Impressions-Improvement scale, Symptom Checklist-90-Revised, response and remission rates, safety, and tolerability. RESULTS: Duloxetine, compared with placebo, significantly reduced pain and improved depression with significant mean changes at endpoint in both BPI-SF average pain scores (-2.57 vs. -1.64, p < .001) and in MADRS total scores (-16.69 vs. -11.31, p < .001). Remission of MDD and response rates in pain and MDD were significantly (p <or= .001) higher in duloxetine-treated patients. Duloxetine separated from placebo on most secondary outcome measures including the BPI-SF interference with daily life due to pain. Treatment-emergent adverse events (>or= 10%) in duloxetine-treated patients were nausea, hyperhidrosis, and dry mouth. CONCLUSION: These results support duloxetine's efficacy and tolerability in the treatment of pain and depression in patients with at least moderate pain associated with depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00191919 (http://www.clinicaltrials.gov).
Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial.
J Clin Psychiatry. 2007 Nov;68(11):1691-700
Authors: Furieri FA, Nakamura-Palacios EM
OBJECTIVE: This study examined the efficacy of a 28-day gabapentin treatment in reducing alcohol consumption and craving. METHOD: A randomized, double-blind, placebo-controlled trial was performed in a Brazilian public outpatient drug treatment center, with 60 male alcohol-dependent subjects with a mean age of 44 years and an average of 27 years of alcohol use, who consumed 17 drinks per day (165-170 g/day) over the past 90 days before baseline and had no other significant medical or psychiatric condition. Subjects were recruited between July 8, 2004, and February 24, 2005. Following screening, 60 subjects were selected and received diazepam and vitamins as treatment for acute withdrawal for at least 7 days. After the detoxification treatment, 30 subjects were randomly assigned to receive gabapentin (300 mg twice daily) for 4 weeks, and 30 subjects, with similar baseline characteristics, were randomly assigned to receive matching placebo tablets for the same period. RESULTS: After 28 days of treatment, the gabapentin group showed a significant reduction in both number of drinks per day and mean percentage of heavy drinking days (p = .02 for both), and an increase in the percentage of days of abstinence (p = .008), compared to the placebo group. Additionally, some improvement in obsessive-compulsive symptoms was noted in both groups after the treatment, but it resulted in a more pronounced decrease in automaticity of drinking and aspects of craving in the gabapentin group than in the placebo group. CONCLUSION: Gabapentin reduces alcohol consumption and craving, which may help patients to maintain abstinence. These results, together with the virtual absence of side effects and a favorable safety profile, support gabapentin as a potential drug for the treatment of alcohol withdrawal and dependence.
OBJECTIVE: To test the hypotheses that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than an active placebo, diphenhydramine. DESIGN: Randomized, controlled, double blind, triple crossover 8-week trial. SETTING: Veterans Affairs medical center. PARTICIPANTS: Community dwelling adults with spinal cord injury (N=38) were recruited by telephone, letters, and flyers. INTERVENTION: Eight-week trial each of amitriptyline, gabapentin, and diphenhydramine. MAIN OUTCOME MEASURES: Pain intensity measured with a 10-cm visual analog scale (VAS) and an 11-point (0-10) numeric rating scale (NRS) and depressive symptomatology measured with the Center for Epidemiologic Studies Depression Scale-Short Form (CESD-SF). RESULTS: Baseline VAS scores for participants with low (< 10) CESD-SF scores was 4.61 and for those with high scores (> or = 10) it was 7.41. At week 8, in participants with high baseline CESD-SF scores, amitriptyline (mean, 4.21) was more effective than diphenhydramine (mean, 6.67; P=.035), and there was a nonsignificant trend suggesting that amitriptyline may be more effective than gabapentin (mean, 6.68; P=.061). Gabapentin was no more effective than diphenhydramine (P=.97). There was no significant difference among the medications for those with lower CESD-SF scores. Results could not be attributed to dropout rates, order or dose of medications, amount of medication taken for breakthrough pain, or side effects. CONCLUSIONS: Amitriptyline is more efficacious in relieving neuropathic pain than diphenhydramine at or below the level of spinal cord injury in people who have considerable depressive symptomatology.
Pregabalin: its pharmacology and use in pain management.
Anesth Analg. 2007 Dec;105(6):1805-15
Authors: Gajraj NM
Pregabalin is a new synthetic molecule and a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid. It is an alpha2-delta (alpha2-delta) ligand that has analgesic, anticonvulsant, anxiolytic, and sleep-modulating activities. Pregabalin binds potently to the alpha2-delta subunit of calcium channels, resulting in a reduction in the release of several neurotransmitters, including glutamate, noradrenaline, serotonin, dopamine, and substance P. In this review, I will discuss the pharmacology of pregabalin and available efficacy studies in pain management. This review will focus on the advances in pregabalin pharmacology since my previous review in 2005.
Gabapentin is a second generation anticonvulsant that is effective in the treatment of chronic neuropathic pain. It was not, until recently, thought to be useful in acute perioperative conditions. However, a growing body of evidence suggests that perioperative administration is efficacious for postoperative analgesia, preoperative anxiolysis, attenuation of the haemodynamic response to laryngoscopy and intubation, and preventing chronic post-surgical pain, postoperative nausea and vomiting, and delirium. This article reviews the clinical trial data describing the efficacy and safety of gabapentin in the setting of perioperative anaesthetic management.
Pregabalin in the management of central neuropathic pain.
Expert Opin Pharmacother. 2007 Dec;8(17):3035-41
Authors: Gray P
Central neuropathic pain is a painful condition, often severe, that occurs in a person who is already affected by an injury or disease of the brain or spinal cord. This dual insult is especially threatening to the quality of life of a person and their ability to perform even the most basic of tasks. Despite this high level of suffering there are relatively few trials investigating the management of central neuropathic pain. However, two randomised placebo-controlled studies have recently emerged demonstrating efficacy of pregabalin in reducing central neuropathic pain due to spinal cord injury and central poststroke pain. Pregabalin, an anticonvulsant, has been shown to be efficacious in the management of peripheral neuropathic pain of various causes and now may have a role to play in central neuropathic pain.
BACKGROUND: Catheter-related bladder discomfort (CRBD) secondary to catheterization of urinary bladder is distressing. In the present study, we evaluated gabapentin for preventing CRBD. METHODS: One-hundred and eight consecutive adult patients, ASA physical status I and II, of either sex, undergoing elective percutaneous nephrolithotomy were randomized into two groups of 54 each. Group control: placebo and group G gabapentin: gabapentin 600 mg. Drugs were administered orally 1 h before surgery. After induction of anesthesia, patients were catheterized with a 16F Foley catheter and the balloon was inflated with 10 mL normal saline. In the postanesthesia care unit, the incidence and severity (mild, moderate, and severe) of CRBD were assessed on arrival (0) and at 1, 2, and 6 h. RESULTS: Gabapentin reduced the incidence of CRBD to 50% (27 of 54) compared with 80% (43 of 54) observed in the control group (P < 0.05). Gabapentin also reduced the severity of CRBD and postoperative pain as observed by a reduction in the number of patients requiring any fentanyl and the total fentanyl consumption postoperatively (P < 0.05). CONCLUSION: Gabapentin (600 mg) administered orally 1 h before surgery reduced the incidence and severity of CRBD, postoperative pain, number of patients requiring fentanyl and postoperative total fentanyl requirement.
A randomized, placebo-controlled trial of preoperative oral pregabalin for postoperative pain relief after minor gynecological surgery.
Anesth Analg. 2007 Nov;105(5):1449-53, table of contents
Authors: Paech MJ, Goy R, Chua S, Scott K, Christmas T, Doherty DA
BACKGROUND: Although pregabalin shows efficacy against neuropathic pain, very limited evidence supports postoperative analgesic efficacy. Our study objective was to investigate analgesic efficacy in an ambulatory day surgical population experiencing acute visceral pain. The null hypothesis was that there was no significant difference in pain relief between pregabalin and placebo. METHODS: A randomized, double-blind, parallel-group, placebo-controlled trial was performed in 90 women having minor gynecological surgery involving the uterus. Patients received either oral pregabalin 100 mg (Group PG) or placebo (Group C) approximately 1 h before surgery. The primary outcome was pain score in the recovery unit and patients were followed for 24 h. RESULTS: There was no significant difference between groups for pain experienced in the recovery room (median, interquartile range 16, 0-36 vs 10, 6.5-36 for Groups PG and C, respectively, P = 0.80) or thereafter; nor for recovery room fentanyl requirement (42% Group PG versus 27% Group C, P = 0.12) or the quality of recovery at 24 h postoperatively (median, interquartile range score 17, 17-18 Group PG versus 18, 16.5-18 Group C, P = 0.75). The incidence of posthospital discharge light-headedness, visual disturbance, and difficulty with walking was significantly higher in the pregabalin group. CONCLUSIONS: A single preoperative dose of 100 mg pregabalin does not reduce acute pain or improve recovery after minor surgery involving only the uterus.
Several lines of evidence suggest that loss of central inhibition after deprivation of input from the ear (peripheral deafferentation) may be one cause of chronic tinnitus. Aging and acoustic trauma, the two most common causes of peripheral damage to the auditory system, each decrease input to central auditory structures. Loss of input to tonic inhibitory systems would release excitatory structures from inhibitory regulation. The increased activity resulting may be interpreted by more rostral structures in the auditory pathway as tinnitus. Down-regulation of gamma-amino butyric acid (GABA), a major inhibitory neurotransmitter of the central auditory pathway, is a potential mechanism for the loss of inhibition. Both animal studies and human clinical trials implicate loss of inhibition, and specifically loss of GABA function, in the development of acoustic trauma-induced tinnitus.
Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety.
Drugs Today (Barc). 2007 Sep;43(9):601-10
Authors: Owen RT
Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA), one of the key inhibitory neurotransmitters in the brain. Its mode of action is believed to be mediated by the alpha-2-delta-1 subunit protein of voltage-gated calcium channels to bring about its anxiolytic, anticonvulsant and antinociceptive effects. Pregabalin has linear pharmacokinetics, undergoes minimal metabolism and is excreted largely unchanged. It has a mean elimination half-life of 6.3 hours. Pregabalin's anxiolytic activity in generalized anxiety disorder has been demonstrated in seven acute randomized, double-blind, placebo-controlled trials of four to eight weeks duration, and in one six-month relapse-prevention study at doses of 150-600 mg/day using twice-daily or three-times-daily regimes. The magnitude of pregabalin's anxiolytic effects was similar to that of alprazolam, lorazepam or venlafaxine. However, pregabalin had a more consistent effect on psychic and somatic anxiety factors than the active comparators. Its speed of onset was apparent within one week - similar to the benzodiazepines, but faster than that of venlafaxine. Moreover, pregabalin's anxiolytic effect was apparent in patients with moderate or severe baseline anxiety and high or low baseline severity of sub-syndromic depression. A long-term, 26-week, open-label study showed that pregabalin's anxiolytic effects were maintained, although the fixed-dose design may have contributed to a high attrition rate. Pregabalin showed less cognitive and psychomotor impairment than alprazolam, and it showed different effects on sleep architecture to the latter in terms of REM sleep latency and slow wave stage 3/4 sleep. The most frequently reported adverse events were dizziness and somnolence, although tolerance to these developed within a few weeks. Withdrawal symptoms during a one-week taper phase were mild and were similar after both acute and chronic administration.
BACKGROUND: To assess the efficacy (in particular, in pain, functional impairment, and quality of life) and safety and tolerability (incidence of adverse events, discontinuation rates, changes in laboratory findings, and vital signs) of duloxetine in female patients with fibromyalgia. METHODS: Data were pooled from two placebo-controlled clinical trials of similar design (randomized, 12-week, and double-blind), comparing duloxetine 60 mg a day (q.d.) or 60 mg twice daily (b.i.d.) (n = 326) with placebo (n = 212), in women who met the American College of Rheumatology criteria for primary fibromyalgia. RESULTS: Compared with the patients receiving placebo, duloxetine-treated female patients demonstrated a significantly greater improvement in the Brief Pain Inventory (BPI) average pain severity score and in the Fibromyalgia Impact Questionnaire (FIQ) total score, beginning at week 1 and continuing through week 12 (p < 0.001). Duloxetine was superior to placebo on all efficacy measures, including mean tender point threshold, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and average interference from pain scores. The duloxetine-treated group was superior to placebo on all quality of life and functional measures, including each domain of the Medical Outcomes Study Short Form-36 (SF-36). A direct treatment effect of duloxetine on pain reduction was demonstrated and shown to be independent of secondary improvement in mood (based on BPI average pain score). Significantly more duloxetine-treated patients reported treatment-emergent adverse events (296 [90.8%] duloxetine-treated and 165 [77.8%] placebo-treated, p < 0.001). Rates of serious adverse events were similar between duloxetine-treated and placebo-treated patients. CONCLUSIONS: The pooled results of these studies demonstrate that duloxetine is a safe and efficacious treatment for both the pain and functional impairment associated with fibromyalgia in female patients, while significantly improving quality of life.
Duloxetine and other antidepressants in the treatment of patients with fibromyalgia.
Pain Med. 2007 Sep;8 Suppl 2:S63-74
Authors: Arnold LM
OBJECTIVE: To review the use of duloxetine, a new selective serotonin and norepinephrine reuptake inhibitor (SNRI), and other antidepressants in the treatment of patients with fibromyalgia. DESIGN: Two randomized, placebo-controlled, double-blind, parallel-group, 12-week trials of duloxetine in the treatment of fibromyalgia were reviewed. Other published, randomized, placebo-controlled, double-blind trials, and meta-analyses of antidepressant treatment of fibromyalgia were identified by a PubMed search that was augmented by reference cross-check. RESULTS: Duloxetine has been shown to be an effective and safe treatment for many of the symptoms associated with fibromyalgia, particularly for women. Other selective SNRIs also show promise in the treatment of fibromyalgia. Until recently, tricyclic agents that have serotonin and norepinephrine reuptake inhibitory activity had been the most commonly studied group of antidepressants, and they are effective in treating pain and other symptoms associated with fibromyalgia, although their use may be limited by safety and tolerability concerns. There are few randomized, controlled studies of selective serotonin reuptake inhibitors in fibromyalgia, and the results have been mixed. CONCLUSIONS: Antidepressants play an important role in the treatment of patients with fibromyalgia. Agents with dual effects on serotonin and norepinephrine appear to have more consistent benefits than selective serotonin antidepressants for the treatment of persistent pain associated with fibromyalgia.
A retrospective evaluation of the use of gabapentin and pregabalin in patients with postherpetic neuralgia in usual-care settings.
Clin Ther. 2007 Aug;29(8):1655-70
Authors: Gore M, Sadosky A, Tai KS, Stacey B
BACKGROUND: Both gabapentin and pregabalin are approved for the management of postherpetic neuralgia (PHN), although dosing and pharmacokinetic differences between these medications may affect their use in actual practice. OBJECTIVES: This study was conducted to characterize the use of gabapentin and pregabalin in the management of PHN in clinical practice, with a specific focus on the doses actually prescribed and changes in the use of other neuropathic pain-related medications after the initiation of gabapentin or pregabalin. METHODS: The PharMetrics Patient-Centric Database was used to identify patients with PHN who were newly prescribed gabapentin or pregabalin between September 1, 2005, and March 31, 2006. The out-comes of interest were the prevalence of comorbidities, exposure to neuropathic pain-related medications (ie, the proportions of patients receiving >or=1 prescription for these medications in the 6-month periods before and after the date of the first gabapentin or pregabalin prescription), and attainment of therapeutic dose levels (gabapentin, >or=1800 mg/d; pregabalin, >or=150 mg/d). RESULTS: The database search identified 151 patients with PHN who were newly prescribed gabapentin (57.0% female; mean [SD] age, 55.8 [11.3] years) and 100 patients who were newly prescribed pregabalin (62.0% female; mean age, 52.8 [9.4] years). The prevalence of comorbidities did not differ significantly between recipients of prescriptions for gabapentin or pregabalin, with the exception of hyperlipidemia, which was more prevalent in those prescribed gabapentin (33.8% vs 22.0%, respectively; P = 0.044), and depression, which was more prevalent in those prescribed pregabalin (12.0% vs 4.6%, respectively; P = 0.031). In the pretreatment period, those who were prescribed pregabalin had significantly greater use of long-acting opioids (P = 0.005), anticonvulsants (P < 0.001), selective norepinephrine reuptake inhibitors (P < 0.001), and the lidocaine 5% patch (P = 0.005) compared with those prescribed gabapentin. Use of any opioid increased from pretreatment to follow-up in those prescribed gabapentin, significantly so in those who received >or=2 opioid prescriptions (P = 0.016). Use of any opioid decreased significantly from pre-treatment to follow-up in those prescribed pregabalin (P = 0.005), particularly in those who received >or=2 opioid prescriptions (P = 0.004). Tramadol use decreased significantly in those prescribed gabapentin (P = 0.045), and anticonvulsant use decreased significantly in those prescribed pregabalin (P = 0.004). Among patients prescribed gabapentin or pregabalin who received 1 prescription, 2 consecutive prescriptions, and >or=3 consecutive prescriptions, a greater proportion of those prescribed pregabalin attained therapeutic dose levels by their first, second, and third consecutive prescriptions compared with those prescribed gabapentin (69.0% vs 3.5%, respectively [P < 0.001]; 71.4% vs 21.7% [P < 0.001]; and 89.3% vs 46.2% [P < 0.001], respectively). CONCLUSIONS: In these patients with PHN in the usual-care setting, opioid use increased after the initiation of gabapentin and decreased after the initiation of pregabalin. Few of those prescribed gabapentin received a prescription for a therapeutic dose, whereas a greater proportion of patients who were prescribed pregabalin received a prescription for a therapeutic dose.
Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.
Optimization of an HPLC method for determination of gabapentin in dosage forms through derivatization with 1-fluoro-2,4-dinitrobenzene.
Chem Pharm Bull (Tokyo). 2007 Oct;55(10):1427-30
Authors: Souri E, Jalalizadeh H, Shafiee A
A rapid, sensitive and accurate high performance liquid chromatography with UV detection method was developed and validated for the quantification of gabapentin in dosage forms. Gabapentin was quantified after pre-column derivatization with 1-fluoro-2,4-dinitrobenzene. Amlodipine was used as an internal standard. The chromatographic separation was carried out on a Nova-Pak C(18) column using a mixture of acetonitrile-sodium dihydrogenphosphate (pH 2.5; 0.05 M) (70:30, v/v) as mobile phase with UV detection at 360 nm. The method was linear over the range of 10-500 microg/ml of gabapentin (r(2)>0.999). The within-day and between-day precision values were in the range of 0.86-1.11%. The method was successfully used for quantitative determination and dissolution rate study of Neurontin capsules.
Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study.
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Oct 15;858(1-2):269-75
Authors: Senthamil Selvan P, Gowda KV, Mandal U, Sam Solomon WD, Pal TK
A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometry (LC-MS-MS) method is described for the determination of duloxetine in human plasma. Duloxetine was extracted from plasma using methanol and separated on a C18 column. The mobile phase consisting of a mixture of acetonitrile and 5mM ammonium acetate (45:55, v/v, pH 3.5) was delivered at a flow rate of 0.3 ml/min. Atmospheric pressure ionization (API) source was operated in positive ion mode. Multiple reaction monitoring (MRM) mode using the transitions of m/z 298.1-->m/z 44.0 and m/z 376.2-->m/z 123.2 were used to quantify duloxetine and internal standard (I.S.), respectively. The linearity was obtained over the concentration range of 0.1-50.0 ng/ml and the lower limit of quantitation (LLOQ) was 0.1 ng/ml. This method was successfully applied to pharmacokinetic study of a duloxetine formulation product after oral administration to healthy human subjects.
The preoperative use of gabapentin, dexamethasone, and their combination in varicocele surgery: a randomized controlled trial.
Anesth Analg. 2007 Oct;105(4):1137-42, table of contents
Authors: Koç S, Memis D, Sut N
BACKGROUND: We investigated the effects of gabapentin and dexamethasone given together or separately 1 h before the start of surgery on laryngoscopy, tracheal intubation, intraoperative hemodynamics, opioid consumption, and postoperative pain in patients undergoing varicocele operations. METHODS: Patients were randomly divided into four double-blind groups: group C (control, n = 20) received placebo, group G (gabapentin, n = 20) received 800 mg gabapentin, group D (dexamethasone, n = 20) received 8 mg dexamethasone, group GD (gabapentin plus dexamethasone) received both 800 mg gabapentin and 8 mg dexamethasone IV 1 h before the start of surgery. Standard induction and maintenance of anesthesia were accomplished and continued by propofol and remifentanil infusion. Heart rate and arterial blood pressure were recorded before induction and after intubation. Intraoperative total remifentanil consumption was recorded. Hemodynamic variables and visual analog scale were recorded for 24 h. Side effects were noted. RESULTS: Hemodynamics at 1, 3, 5, and 10 min after tracheal intubation, total remifentanil consumption during surgery, postoperative visual analog scale scores at 30 min, 1, 2, 4, 6, and 12 h, and postoperative nausea and vomiting were found to be significantly lower in group GD than in group G and group D (P < 0.05 for both), and substantially lower when compared with group C (P < 0.001). All values in group C were also higher than in groups G and D (P < 0.05). CONCLUSION: Gabapentin and dexamethasone administered together an hour before varicocele surgery results in less laryngeal and tracheal intubation response, improves postoperative analgesia, and prevents postoperative nausea and vomiting better than individual administration of each drug.
There are reports indicating that gabapentin may have place in the treatment of postoperative pain. No study has evaluated the effects of gabapentin on acute, postoperative pain in patients undergoing surgery for brachial plexus injuries. In this preliminary study, we evaluated gabapentin as preemptive analgesic for intraoperative period and during the acute postoperative period at rest and during movement. Twenty consecutive adult patients undergoing surgery for brachial plexus injury were enrolled for the study. Patients randomly received either oral gabapentin 800 mg or placebo capsules 2 hours before surgery. General anesthesia was induced and maintained with propofol, at bispectral index value between 40 and 60. Intraoperative fentanyl and propofol requirements were noted. Postoperatively, all patients were alert and pain was assessed using visual analog scale (VAS) for 24 hours, both during rest and movement. Whenever VAS score was more than 50 or on patients' demand, ketorolac 30 mg was given as rescue analgesic. The demographics, duration of surgery, and propofol consumption in both groups were comparable. Intraoperative and postoperative heart rate and mean blood pressure were also comparable. Significant difference was noted in intraoperative fentanyl consumption (P=0.03), total dose of rescue analgesic (P=0.004), and VAS score at rest and movement, between the 2 groups; less in gabapentin group as compared with placebo group (P=0.01 and 0.04, at rest and movement, respectively). A single oral dose of gabapentin 800 mg, as preemptive analgesic in patients undergoing surgery for brachial plexus injury is found to be an effective adjunct to intraoperative and postoperative pain. Pain is reduced not only at rest but also during movement.
Inhibitory mechanisms of gabapentin, an antiseizure drug, on platelet aggregation.
J Pharm Pharmacol. 2007 Sep;59(9):1255-61
Authors: Pan CF, Shen MY, Wu CJ, Hsiao G, Chou DS, Sheu JR
Gabapentin (Neurontin) is an analogue of gamma-aminobutyric acid (GABA) that is effective against partial seizures. Gabapentin has been reported to modulate serotonin release from platelets, but the effects of gabapentin on platelet activation have not been explored. In this study, gabapentin concentration-dependently (60-240 microM) inhibited platelet aggregation in washed platelets stimulated by collagen (1 microg mL(-1)), ADP (20 microM) and arachidonic acid (60 microM). Gabapentin (120 and 240 microM) also concentration-dependently inhibited collagen (1 microg mL(-1))-induced phosphoinositide breakdown, intracellular Ca(2+) mobilization, thromboxane A(2) formation, and p38 MAPK phosphorylation in human platelets. In conclusion, the most important findings of this study suggest that gabapentin inhibits platelet aggregation, at least in part, through the phospholipase C-inositol 1,4,5-trisphosphate-thromboxane A(2)-Ca(2+) pathway. Thus, it is possible that gabapentin treatment, alone or in combination with other antiplatelet drugs, may induce or potentiate inhibition of platelet aggregation, which may affect haemostasis in-vivo.
Efficacy of duloxetine as a migraine preventive medication: possible predictors of response in a retrospective chart review.
Headache. 2007 Sep;47(8):1200-3
Authors: Taylor AP, Adelman JU, Freeman MC
OBJECTIVE: This case series is a retrospective chart analysis conducted to evaluate the efficacy of duloxetine as a migraine preventive medication and to suggest possible predictors of response. BACKGROUND: Duloxetine, a relatively new selective serotonin and norepinephrine reuptake inhibitor, is FDA-approved for treatment of depression and diabetic peripheral neuropathic pain. The efficacy of duloxetine as a headache preventive medication is currently unknown. METHOD: A retrospective chart review was performed using the electronic medical records of Headache Wellness Center, a headache specialty practice in Greensboro, North Carolina. From January 2004 to December 2006, 65 patients were identified who were prescribed duloxetine for migraine prevention for at least 2 months. Doses ranged from 30 mg qd to 90 mg qd. Frequency, severity, and impact of migraine disability were measured at baseline and compared to values obtained after 2 months of treatment. RESULTS: The total patient sample demonstrated a reduction in mean monthly headache frequency from 19.40 (SD=7.1) to 15.70 (SD=8.2) (P= .01). The 50% responder rate was 22%. In subset analysis, individuals with abnormal baseline Zung anxiety scores demonstrated a greater reduction in mean monthly headache frequency (4.28, P= .03) and a greater responder rate (25%) than those in the total patient sample. Non-statistically significant trends were observed in those patients with abnormal baseline Zung Depression scores exhibiting a less robust mean monthly migraine reduction (2.75, P= .18) than those with normal baseline depression scores (3.42, P= .07). CONCLUSIONS: Duloxetine demonstrates minimal effectiveness as a headache preventive medication. An interesting trend suggests that the presence of anxiety may be a positive predictor in treatment with duloxetine.
Cost-effectiveness analysis of pregabalin versus gabapentin in the management of neuropathic pain due to diabetic polyneuropathy or post-herpetic neuralgia.
Curr Med Res Opin. 2007 Oct;23(10):2585-96
Authors: Rodríguez MJ, Díaz S, Vera-Llonch M, Dukes E, Rejas J
OBJECTIVE: To estimate the cost-effectiveness of branded pregabalin (PGB) versus generic gabapentin (GBP) in patients with neuropathic pain (NeP) due to painful diabetic polyneuropathy (DPN) or post-herpetic neuralgia (PHN) in Spain. METHODS: Using stochastic simulation, we estimated the cost-effectiveness of PGB 150-600 mg/d vs. GBP 900-3600 mg/d in a hypothetical cohort of 1000 patients. The model used data from three randomized controlled clinical trials. Pain was evaluated using a 0-10 scale. Mean baseline pain was 6.9 in both treatment groups. The model assigned untreated pain scores over 84 days. Treated scores were calculated using weekly changes in pain scores from trials. Outcomes included the numbers of days with no or mild pain (score < 4), days with >or= 30% and >or= 50% reductions in pain intensity, quality-adjusted life-years (QALYs), and estimated health costs. RESULTS: Compared with GBP, PGB yielded an estimated mean of 8 (standard error, 0.4) additional days with no or mild pain, 6 (0.4) days with >or= 30% reduction in pain intensity, 9 (0.5) days with >or= 50% reduction in pain intensity, and a gain of 0.1186 (0.0002) QALYs for 12 weeks. The estimated total health costs of therapies were euro 1049 (euro 35) for PGB and euro 951 (euro 38) for GBP, respectively. Incremental cost-effectiveness ratio (ICER) for PGB versus GBP were a mean of euro 12 (95% confidence interval, euro 1-24) per additional day with no or mild pain, euro 431 (dominant-euro 876) per additional patient with no or mild pain, and euro 20 535 (euro 1607-40 345) per QALY gained. CONCLUSIONS: According with data used in this modeling in patients with NeP due to DPN and/or PHN, PGB was shown to be more cost-effective than generic gabapentin in Spain.
Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3).
Cancer. 2007 Nov 1;110(9):2110-8
Authors: Rao RD, Michalak JC, Sloan JA, Loprinzi CL, Soori GS, Nikcevich DA, Warner DO, Novotny P, Kutteh LA, Wong GY,
BACKGROUND: The antiepileptic agent, gabapentin, has been demonstrated to relieve symptoms of peripheral neuropathy due to various etiologies. On the basis of these data, a multicenter, double-blind, placebo-controlled, crossover, randomized trial was conducted to evaluate the effect of gabapentin on symptoms of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN who complained of 'average' daily pain scores of either 1) >/=4 on a 0-10 numerical rating scale (NRS); or 2) >/=1 on the 0-3 Eastern Cooperative Oncology Group neuropathy scale (ENS) were eligible (higher numbers indicate greater severity of symptoms in both scales). Patients were randomized to receive gabapentin (target dose, 2700 mg) or placebo for 6 weeks. Crossover occurred after a 2-week washout period. CIPN-related symptoms were evaluated weekly by questionnaires. Statistical methods followed established methods for crossover designs, including Student t tests to compare average intrapatient differences between treatments and linear models to adjust for potential concomitant covariates. RESULTS: There were 115 patients who were randomly assigned to the treatment or control arm. Both groups were well matched by symptoms at study entry. Changes in symptom severity were statistically similar between the 2 groups during the study. Adverse events were mild and similar in both groups. CONCLUSIONS: This trial failed to demonstrate any benefit to using gabapentin to treat symptoms caused by CIPN.
Cost-effectiveness of a lidocaine 5% medicated plaster relative to gabapentin for postherpetic neuralgia in the United Kingdom.
Clin Ther. 2007 Jul;29(7):1491-507
Authors: Dakin H, Nuijten M, Liedgens H, Nautrup BP
BACKGROUND: Approximately 50% of elderly patients develop postherpetic neuralgia (PHN) after herpes zoster infection (shingles). A lidocaine 5% medicated plaster marketed in the United Kingdom in January 2007 has been shown to be an effective topical treatment for PHN with minimal risk of systemic adverse effects. OBJECTIVE: This paper assessed the cost-effectiveness of using a lidocaine plaster in place of gabapentin in English primary care practice to treat those PHN patients who had insufficient pain relief with standard analgesics and could not tolerate or had contraindications to tricyclic antidepressants (TCAs). The analysis took the perspective of the National Health Service (NHS). METHODS: The costs and benefits of gabapentin and the lidocaine plaster were calculated over a 6-month time horizon using a Markov model. The model structure allowed for differences in costs, utilities, and transition probabilities between the initial 30-day run-in period and maintenance therapy and also accounted for add-in medications and drugs received by patients who discontinued therapy. Most transition probabilities were based on non-head-to-head clinical trials identified through a systematic review. Data on resource utilization, discontinuation rates, and add-in or switch medications were obtained from a Delphi panel; cost data were from official price tariffs. Published utilities were adjusted for age and were supplemented and validated by the Delphi panel. RESULTS: Six months of therapy with the lidocaine plaster cost pound 549 per patient, compared with pound 718 for gabapentin, and generated 0.05 more quality-adjusted life-years (QALYs). The lidocaine plaster therefore dominated gabapentin (95% CI, dominant- pound 2163/QALY gained). Probabilistic sensitivity analysis showed that there was a 90.15% chance that the lidocaine plaster was both less costly and more effective than gabapentin and a 99.99% chance that it cost < pound 20,000/QALY relative to gabapentin. Extensive deterministic sensitivity analyses confirmed the robustness of the conclusions. CONCLUSION: This study found that the lidocaine 5% medicated plaster was a cost-effective alternative to gabapentin for PHN patients who were intolerant to TCAs and in whom analgesics were ineffective, from the perspective of the NHS.
Single-blind, placebo-controlled pilot study of pregabalin for ataxia in cortical cerebellar atrophy.
Acta Neurol Scand. 2007 Oct;116(4):235-8
Authors: Gazulla J, Benavente I
OBJECTIVE : To preliminarily compare the efficacy of pregabalin with that of placebo on the cerebellar signs caused by cortical cerebellar atrophy (CCA). A deficiency of gamma-aminobutyric acid (GABA) has been described in the cerebellum in CCA, and pregabalin has been shown to enhance GABA release in rat hippocampus. PATIENTS AND METHODS: Two consecutive patients with clinical diagnoses of CCA took part in the study. A placebo and pregabalin, 225 mg per day, were administered in a single-blind scheme during 15 day periods to every patient; cerebellar function was evaluated with the Scale for the Assessment and Rating of Ataxia (SARA) at the end of each period. A video recording of the SARA items performed by the first patient accompanies this article. RESULTS: Total SARA scores of 19 and 15 were obtained for the patients after placebo administration. The SARA scores decreased to 11 and 8, respectively, with the administration of pregabalin; an important amelioration of the ataxia was also evident. Both patients preferred continuing treatment with pregabalin when the trial was over. CONCLUSION: Pregabalin was superior to placebo in the improvement of the cerebellar signs caused by CCA. Further studies are needed to confirm the present results.
Exploratory polysomnographic evaluation of pregabalin on sleep disturbance in patients with epilepsy.
J Clin Sleep Med. 2007 Aug 15;3(5):473-8
Authors: de Haas S, Otte A, de Weerd A, van Erp G, Cohen A, van Gerven J
OBJECTIVES: To evaluate the effects of adjunctive pregabalin 300 mg/day versus placebo on polysomnographic (PSG) variables in patients with well controlled partial seizures and subjectively reported sleep disturbance. METHODS: An exploratory, 4-week, double-blind, randomized study in patients with well controlled partial seizures on AED monotherapy and subjective sleep disturbance over the previous 6 months. Mean changes from baseline to endpoint in PSG and subjective sleep variables (MOS Sleep Scale, Groningen Sleep Questionnaire) in patients on adjunctive pregabalin 300 mg/day (n=8) were compared with patients on placebo (n=7). RESULTS: Baseline PSGs showed sleep fragmentation. Mean sleep efficiency improved significantly in both treatment groups in the mean baseline to endpoint change; there was no significant between-group difference. Pregabalin treatment was associated with a significant reduction in number of awakenings (p = 0.02), and improvement in wake time after sleep onset approached significance (p = 0.055), suggesting improvement in sleep continuity that was not observed in the placebo group. Pregabalin was also associated with significant improvements in the MOS sleep disturbance and sleep quantity subscales compared with placebo (p < or =0.03). There were no changes in self-reported seizure control. CONCLUSIONS: This exploratory pilot study suggests that pregabalin may improve sleep continuity in patients with clinically relevant sleep disturbance. The effect on disturbed sleep appears independent of seizure control. The effects of pregabalin on disturbed sleep and seizures and their interrelationships warrant further study.
Gabapentin Extended-Release - Depomed: Gabapentin ER, Gabapentin Gastric Retention, Gabapentin GR.
Drugs R D. 2007;8(5):317-20
Depomed is developing an extended-release (ER) oral formulation of gabapentin, a GABA receptor agonist commonly used for the treatment of epilepsy and seizures, neuropathic pain and hot flushes. Gabapentin ER is based on the company's proprietary AcuForm drug delivery technology, which is part of the Gastric Retention (GR) family of technologies; this offers improved drug absorption and bioavailability compared with the existing immediate-release formulation of gabapentin (Neurontin), making gabapentin ER suitable for twice-daily dosing. The product is in clinical development for the treatment of postherpetic neuralgia and diabetic neuropathies in the US. Additionally, Depomed has commenced a phase II trial of gabapentin ER in postmenopausal patients with hot flushes.Depomed's AcuForm platform is based on polymer technology that provides targeted drug delivery for a variety of compounds. Following ingestion, AcuForm tablets swell and are retained for 6-8 hours in the stomach, enabling controlled and prolonged release of gabapentin to the upper intestinal tract; this extends the time of drug delivery to the small intestine for complete and safe elimination via the lower intestinal track.Gabapentin ER is available for licensing.Depomed acquired exclusive development and commercialisation rights to gabapentin ER in September 2003 via its subsidiary, Depomed Development Ltd (DDL). Depomed is not required to pay upfront license fees, but will make royalty and milestone payments to DDL upon successful commercialisation of gabapentin ER.Gabapentin ER was originally developed by DDL, a joint venture between Depomed and Elan established in January 2000 to design products using the GR family of technologies. However, in efforts to restructure joint venture relationships, Elan withdrew from operational involvement of DDL in September 2003, and Depomed has gained full ownership of DDL. Depomed sublicensed exclusive rights to a US patent (held by the University of Rochester) covering the use of gabapentin in the treatment of hot flushes from PharmaNova in October 2006. Under the agreement, Depomed paid PharmaNova an upfront fee of US dollars 500 000. PharmaNova is also entitled to milestone payments and royalties on sales of gabapentin ER in this indication only.Depomed has reported significant safety and efficacy benefits from gabapentin ER in its phase II trial. This study was initiated in February 2005 following positive results from a phase I trial in which gabapentin ER demonstrated a pharmacokinetic profile suitable for twice-daily dosing. In two pharmacokinetic studies, gabapentin ER achieved improved bioavailability at higher doses. This result supports Depomed's development of a once- or twice-daily product with potentially fewer adverse events.The basic US patents relating to gabapentin expired in 2000. Depomed holds exclusive rights to a US patent (No. 6 310 098) held by the University of Rochester covering the use of gabapentin to treat hot flushes.Additionally, Depomed was issued a US patent (No. 6 723 340) in May 2004 that covers proprietary polymer combinations (as used in AcuForm tablets) to create improved formulations of existing drugs.
The effect of duloxetine on primary pain symptoms in Parkinson disease.
Clin Neuropharmacol. 2007 Jul-Aug;30(4):201-5
Authors: Djaldetti R, Yust-Katz S, Kolianov V, Melamed E, Dabby R
OBJECTIVES: To study the effect of duloxetine (Cymbalta), a selective serotonin and norepinephrine reuptake inhibitor, on pain symptoms in Parkinson Disease (PD). METHODS/PATIENTS: Twenty-three patients with PD with painful phenomena were treated with duloxetine for 6 weeks in an open-label design. Assessments were performed before and at treatment completion and consisted of a Visual Analogue Scale, the Brief Pain Inventory, Short-Form McGill Pain Questionnaire, Parkinson Disease Quality of Life Questionnaire-39-item version, and motor part of the Unified Parkinson Disease Rating Scale. Pain threshold was assessed by quantitative sensory tests. RESULTS: Thirteen of the 20 patients who completed the study reported varying degrees of pain relief. The mean Visual Analogue Scale, Brief Pain Inventory, and Short-Form McGill Pain Questionnaire scores decreased significantly. There was no change in pain threshold after treatment. CONCLUSIONS: Duloxetine seems to be effective for the treatment of central pain in PD.
Duloxetine in the treatment of major depressive disorder: an open-label study.
BMC Psychiatry. 2007;7:43
Authors: Hudson JI, Perahia DG, Gilaberte I, Wang F, Watkin JG, Detke MJ
BACKGROUND: Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined. METHODS: Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score >or=18 and a Clinical Global Impression of Severity (CGI-S) score >or=4 at baseline. Efficacy measures included the HAMD17 total score, HAMD17 subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale. RESULTS: The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by >or=10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD17, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment. CONCLUSION: In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.
Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy.
Eur J Neurol. 2007 Sep;14(9):1060-2
Authors: Poujois A, Vidailhet M, Trocello JM, Bourdain F, Gaymard B, Rivaud-Péchoux S
The efficacy of gabapentin on motor, oculomotor and frontal lobe symptoms was evaluated in patients with progressive supranuclear palsy (PSP) in a pilot study. Fourteen patients were included and seven of them received gabapentin. Clinical evaluation and horizontal eye movement recordings were performed at inclusion and 5-weeks later. Motor score and saccade latency in the visually guided saccade (VGS) task were identical in the two groups. However, the error rate in the antisaccade task was significantly decreased in the gabapentin group. This preliminary study shows that gabapentin improves reflexive saccade inhibition in patients with PSP but does not improve the latency of VGSs.
Pregabalin-induced remission in a 62-year-old woman with a 20-year history of vulvodynia.
Pain Res Manag. 2007;12(3):212-4
Authors: Jerome L
A case of a 62-year-old woman presenting with a 20-year history of vulvodynia previously unresponsive to medical treatment is described. The epidemiology, phenomenology and medical management of vulvodynia is reviewed. The case presentation illustrates the role of pregabalin in successful medical management of this chronic pain disorder, as well as the management of common psychiatric morbidities associated with this condition.
An open-label 52-week clinical extension comparing duloxetine with routine care in patients with diabetic peripheral neuropathic pain.
Pain Med. 2007 Sep;8(6):503-13
Authors: Wernicke JF, Wang F, Pritchett YL, Smith TR, Raskin J, D'Souza DN, Iyengar S, Chappell AS
OBJECTIVE: To assess the safety of duloxetine at a fixed-dose of 60 mg twice daily (BID) for up to 52 weeks, and compare duloxetine with routine care in the management of patients with diabetic peripheral neuropathic pain (DPNP). DESIGN AND INTERVENTIONS: Patients who completed a 13-week, randomized, double-blind, placebo-controlled acute therapy period were randomly reassigned in a 2:1 ratio to therapy with duloxetine 60 mg BID (N = 197) or routine care (N = 96) for an additional 52 weeks. PATIENTS: The trial included outpatients > or =18 years of age diagnosed with moderate to severe DPNP caused by type 1 or type 2 diabetes. RESULTS: Fourteen patients discontinued due to adverse events or death (11 [5.6%] duloxetine- and 3 [3.1%] routine care-treated patients). There were no significant therapy-group differences observed for patients with >/=1 serious adverse event. In total, 110 (55.8%) duloxetine- and 47 (49%) routine care-treated patients had > or =1 treatment-emergent adverse event (TEAE). The TEAE with a significant therapy-group difference, with patients in the duloxetine therapy group experiencing a higher percentage of events, was asthenia (11 [5.6%] duloxetine- vs no routine care-treated patients). Duloxetine did not appear to adversely affect lipid profiles, or nerve or eye function. There were no significant therapy-group differences observed in mean change in systolic blood pressure, weight, or electrocardiogram parameters. Significant therapy-group differences were observed in favor of duloxetine in the SF-36 physical component summary score, and subscale scores of physical functioning, bodily pain, mental health, and vitality. CONCLUSIONS: The results of this study provide support for the use of duloxetine in the long-term management of DPNP.
Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects.
Clin Pharmacokinet. 2007;46(9):767-75
Authors: Tianmei S, Knadler MP, Lim MT, Yeo KP, Teng L, Liang S, Pan AX, Lobo ED
OBJECTIVES: The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing. METHODS: This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations. RESULTS: Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported. CONCLUSION: Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.
Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials.
Pharmacopsychiatry. 2007 Jul;40(4):163-8
Authors: Bech P
BACKGROUND: Pregabalin has been evaluated in randomised clinical trials in patients with generalised anxiety disorder (GAD) in a fixed-dose design and with the Hamilton Anxiety Scale (HAM-A) as outcome measure. Four of the available six placebo-controlled trials were found acceptable for a pooled analysis of dose-response relationship. METHOD: Both the full HAM-A (14) and the six-item subscale covering the core items of GAD (HAM-A (6)) were analysed. The unbiased effect size statistic was used to evaluate the advantage of pregabalin over placebo. An effect size of 0.40 or higher was used to indicate a clinically significant effect. RESULTS: Four placebo-controlled trials running over four weeks and covering the dose range from 150 mg to 600 mg pregabalin were sufficiently homogeneous to be pooled for the analysis. Both HAM-A (6) and HAM-A (14) showed that for the dose of 150 mg pregabalin daily the effect size was clearly below 0.40. For the dose range of 200-450 mg daily, the effect sizes exceeded 0.40, with a plateau-like curve. The maximum dose of 600 mg daily did not increase effect size. On the HAM-A (14) as well as the item of sleep, effect size was generally higher, but followed the same pattern as the HAM-A (6). DISCUSSION: The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily.
Low-dose gabapentin in treatment of high-altitude headache.
Cephalalgia. 2007 Nov;27(11):1274-7
Authors: Jafarian S, Gorouhi F, Salimi S, Lotfi J
Headache is the most prevalent symptom of acute mountain sickness. We conducted a pilot clinical trial at an altitude of 3500 m to evaluate the efficacy of gabapentin in treatment of high-altitude headache (HAH). Twenty-four adult HAH patients (10 female, 14 male; age 18-50 years) were randomly assigned to receive either 300 mg of gabapentin capsule or identical placebo. After 1 h the presence of HAH and need to receive supplementary analgesic were assessed. The duration of the HAH-free phase after taking additional analgesic was also registered. Four patients in the gabapentin group asked for additional analgesics, whereas nine placebo recipients did not find primary medication satisfactory after the first hour of treatment (P = 0.04). The mean HAH-free period was 17.10 h in the gabapentin group, which was significantly higher than in the placebo group with a mean of 10.08 h (P = 0.02). This preliminary observation indicates that gabapentin is effective in treatment and alleviation of HAH.
Despite advances made in treatment, uremic pruritus remains a common and distressing symptom in patients on hemodialysis (HD). Gabapentin is an effective drug in the management of neuropathic pain. Considering that neuropathic pain and pruritus share similar pathogenic mechanisms, we conducted this study to evaluate the efficacy of gabapentin in controlling uremic itch. In a double blind, placebo-controlled trial, 34 adult patients on maintenance HD were enrolled. The patients were assigned to receive four weeks of treatment with either gabapentin (400 mg) or placebo administered twice weekly after HD sessions. Pruritus scores were measured using a visual analogue scale and compared between the two groups.After four weeks of treatment, the mean decrease in pruritus score in gabapentin and placebo groups was 6.7 +/- 2.6 and 1.5 +/- 1.8, respectively (p< 0.001). None of the patients was forced to drop out of the study due to side effects of the treatment. Our study suggests that gabapentin is a safe and effective treatment for uremic itch.
A cost-effectiveness comparison of desipramine, gabapentin, and pregabalin for treating postherpetic neuralgia.
J Am Geriatr Soc. 2007 Aug;55(8):1176-84
Authors: O'Connor AB, Noyes K, Holloway RG
OBJECTIVES: To compare the net health effects and costs resulting from treatment with different first-line postherpetic neuralgia (PHN) medications. DESIGN: Cost-utility analysis using published literature. PARTICIPANTS: Hypothetical cohort of patients aged 60 to 80 with PHN. INTERVENTIONS: Desipramine 100 mg/d, gabapentin 1,800 mg/d, and pregabalin 450 mg/d. MEASUREMENTS: A decision model was designed to describe possible treatment outcomes, including different combinations of analgesia and side effects, during the first 3 months of therapy for moderate to severe PHN. The main outcome was cost per quality-adjusted life-year (QALY) gained. Costs were estimated using the perspective of a third-party payer. Multivariate, univariate, and probabilistic sensitivity analyses were performed, and the time frame of the model was varied to 1-month and 6-month horizons. RESULTS: Desipramine was more effective and less expensive than gabapentin or pregabalin (dominant) under all conditions tested. Gabapentin was more effective than pregabalin but at an incremental cost of $216,000/QALY. Below $140/month, gabapentin became more cost-effective than pregabalin at a threshold of $50,000/QALY, and below $115/month gabapentin dominated pregabalin. CONCLUSION: Desipramine appears to be more effective and less expensive than gabapentin or pregabalin for the treatment of older patients with PHN in whom it is not contraindicated. After its price falls, generic gabapentin will likely be more cost-effective than pregabalin.
Duloxetine for the management of diabetic peripheral neuropathic pain: evaluation of functional outcomes.
Pain Med. 2007 Jul-Aug;8(5):410-8
Authors: Armstrong DG, Chappell AS, Le TK, Kajdasz DK, Backonja M, D'Souza DN, Russell JM
OBJECTIVE: To assess the effectiveness of duloxetine, compared with placebo, on patient-reported health outcomes over a 12-week period, in the management of diabetic peripheral neuropathic pain (DPNP). METHODS: The results were pooled from three 12-week multicenter, double-blind studies. In study 1 (N = 457), patients with DPNP were randomly assigned to treatment with duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), or placebo. In studies 2 (N = 334) and 3 (N = 348), patients with DPNP were randomly assigned to treatment with duloxetine 60 mg QD, 60 mg BID, or placebo. Patient-reported functional outcomes were measured by the Short Form 36 (SF-36), the interference portion of the Brief Pain Inventory (BPI), and EuroQol 5D Health Questionnaire (EQ-5D). Results for all functional outcomes from the intent-to-treat and completer populations are discussed. RESULTS: In the SF-36 health survey and the BPI interference, duloxetine 60 mg QD and 60 mg BID were significantly superior to placebo in all the domains (P <or= 0.03). In the analysis of the EQ-5D, duloxetine 60 mg QD (P = 0.004) and 60 mg BID (P < 0.001) were significantly better than placebo on all items. CONCLUSIONS: Acute treatment with duloxetine was associated with significant improvement in functional outcomes in persons with DPNP.
OBJECTIVE: The current analysis examines the response profile in patients receiving duloxetine for the management of diabetic peripheral neuropathic pain (DPNP). PATIENTS/DESIGN: Data were pooled from three double-blind, randomized, placebo-controlled 12-week acute therapy trials of patients with DPNP of at least 6 months' duration. Study 1 (N = 457) had treatment groups of duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N = 334) and 3 (N = 348) compared duloxetine 60 mg QD and 60 mg BID with placebo. The primary efficacy measure in each study was the weekly mean score of the 24-hour average pain severity. Treatment response was defined as a 30% reduction in pain severity, although some analyses were repeated using alternative response criteria (50% reduction, or 2-point reduction, in pain severity). RESULTS: Consistently across the three studies, response rates at endpoint were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than among those receiving placebo, regardless of the chosen response criterion (30% reduction, 50% reduction, or 2-point reduction in weekly mean of 24-hour average pain severity). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at Week 1 and at all subsequent study visits to the end of acute phase therapy. Using diary data (24-hour average pain severity) from the first 7 days of treatment, the first significant separation from placebo in pain severity reduction for duloxetine 60 mg QD occurred at Day 1 (Study 1), Day 2 (Study 2), and Day 4 (Study 3), while significant separation in response rates first occurred at Day 3 when using pooled data. CONCLUSIONS: Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher rates of treatment response, when compared with patients receiving placebo, regardless of the chosen response criterion. Response to duloxetine treatment tended to occur early in therapy.
Pre-emptive gabapentin significantly reduces postoperative pain and morphine demand following lower extremity orthopaedic surgery.
Singapore Med J. 2007 Aug;48(8):748-51
Authors: Montazeri K, Kashefi P, Honarmand A
INTRODUCTION: Gabapentin has demonstrated analgesic effects in clinical trials as a preemptive analgesic and in acute postoperative pain management. This study was conducted to evaluate whether the pre-emptive use of gabapentin could reduce postoperative pain and morphine consumption in patients after lower extremity orthopaedic surgery. METHODS: 70 ASA I and II patients were randomly assigned to receive 300 mg gabapentin or placebo in a double-blind manner two hours before surgery under general anaesthesia. Postoperatively, the pain was assessed on a visual analogue scale (VAS) at 2, 4, 12, and 24 hours at rest. Morphine 0.05 mg/kg intravenously was used to treat postoperative pain on patients' demand. Total morphine consumption in the first 24 hours after surgery was also recorded. RESULTS: Patients in the gabapentin group had significantly lower VAS scores at all time intervals of 2, 4, 12, and 24 hours, than those in the placebo group (respectively, 55.50 [mean] +/- 15.80 [standard deviation], 57.30 +/- 19.30, 45.74 +/- 16.00, 44.60 +/- 17.64, versus 72.30 +/- 14.00, 70.50 +/- 18.13, 62.00 +/- 23.32, 66.50 +/- 25.70; p-value is less than 0.05). The total morphine consumed after surgery in the first 24 hours in the gabapentin group (15.43 +/- 2.54) was significantly less than in the placebo group (17.94 +/- 3.00; p-value is less than 0.05). CONCLUSION: Pre-emptive use of gabapentin 300 mg orally significantly decreases postoperative pain and rescue analgesic requirements in patients who undergo lower extremity orthopaedic surgery.
Chronic orchialgia: consider gabapentin or nortriptyline before considering surgery.
Int J Urol. 2007 Jul;14(7):622-5
Authors: Sinclair AM, Miller B, Lee LK
OBJECTIVE: To establish if there is a role for gabapentin or nortriptyline in the treatment of chronic orchialgia. METHODS: Twenty-six consecutive patients with chronic orchialgia were seen in the chronic pain clinic by a multidisciplinary team. A pain questionnaire was completed prior to commencing either gabapentin or nortriptyline. They were reviewed at 3 months and a repeat questionnaire completed. A 50% improvement in pain was considered successful. RESULTS: Complete data was available for 19 patients. Overall, 61.5% of patients commenced on gabapentin and 66.6% of patients commenced on nortriptyline had a greater than 50% improvement in pain. Patients with post-vasectomy testicular pain were considered as a subgroup. None of these patients had a greater than 50% improvement in pain. However, 80% of patients in the subgroup with idiopathic chronic orchialgia had a greater than 50% improvement in pain. CONCLUSION: Although this is a small study, it appears that gabapentin and nortriptyline are effective in the treatment of idiopathic chronic orchialgia but not post-vasectomy pain.
Life-threatening status epilepticus following gabapentin administration in a patient with benign adult familial myoclonic epilepsy.
Epilepsia. 2007 Oct;48(10):1995-8
Authors: Striano P, Coppola A, Madia F, Pezzella M, Ciampa C, Zara F, Striano S
We report the case of a 57-year-old man who experienced life-threatening myoclonic status after the administration of gabapentin. Based on familial data, the patient was determined to be a member of a previously described family with benign adult familial myoclonic epilepsy (BAFME). The myoclonic status did not respond to benzodiazepines, but resolved after discontinuing the gabapentin. As for other idiopathic generalized epilepsies, gabapentin may precipitate myoclonic status in a benign syndrome, such as BAFME, as is reported herein for the first time. A correct diagnosis and prompt discontinuation of the drug may reverse a potentially severe, life-threatening condition.
Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder.
J Sex Med. 2007 Jul;4(4 Pt 1):917-29
Authors: Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M
INTRODUCTION: Depression and antidepressant therapy have been associated with sexual dysfunction in short-term and point-prevalence trials. AIM: This report describes effects of duloxetine and escitalopram on sexual functioning during acute and long-term treatment of major depressive disorder (MDD). METHODS: In this 8-month, double-blind, placebo-controlled study, adult outpatients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)-defined MDD were randomized to duloxetine 60 mg/day (N = 273; 173 female), escitalopram 10 mg/day (N = 274; 186 female), or placebo (N = 137; 87 female). After the first 8 weeks of treatment, dose increases were permitted to optimize treatment. MAIN OUTCOME MEASURE: The 14-item Changes in Sexual Functioning Questionnaire (CSFQ) was used to assess sexual functioning. RESULTS: Of the 114 patients who did not meet total CSFQ score criteria for global sexual dysfunction at baseline (duloxetine, N = 51; escitalopram, N = 39; placebo, N = 24), the incidence of treatment-emergent sexual dysfunction was significantly higher for escitalopram compared with placebo at 4 and 8 weeks, and significantly higher compared with duloxetine at 4 weeks. At 8 weeks, the incidence of treatment-emergent sexual dysfunction was 17/51 (33.3%) for duloxetine-treated patients; 19/39 (48.7%) for escitalopram-treated patients; and 4/24 (16.7%) for placebo-treated patients (P = 0.01 escitalopram vs. placebo; P = 0.13 duloxetine vs. placebo). After 12 weeks, no significant differences were observed between active drugs. At 8 months, the incidence of treatment-emergent sexual dysfunction was 33.3% for duloxetine, 43.6% for escitalopram, and 25.0% for placebo. Regardless of treatment, patients who achieved remission of MDD showed improvement in global sexual functioning, whereas worsening was observed for patients who did not achieve remission (P < 0.001). Discontinuation rates for sexual side effects did not differ between duloxetine (N = 2) and escitalopram (N = 7) (P = 0.07). CONCLUSIONS: Short-term treatment demonstrated a higher incidence of treatment-emergent sexual dysfunction with escitalopram compared with duloxetine and placebo. After 12 weeks, there were no statistically significant differences between drugs; however, MDD outcome (regardless of treatment) had a significant impact on improvement in global sexual functioning.
Patterns of depressive symptom response in duloxetine-treated outpatients with mild, moderate or more severe depression.
Int J Clin Pract. 2007 Aug;61(8):1337-48
Authors: Shelton RC, Prakash A, Mallinckrodt CH, Wohlreich MM, Raskin J, Robinson MJ, Detke MJ
AIMS: This was a post hoc analysis to determine whether baseline severity of depression influenced the efficacy of duloxetine in treating major depressive disorder (MDD) and to better characterise the symptom response profile for duloxetine in patients with mild, moderate or more severe depression. METHODS: Data were pooled from four double-blind, placebo-controlled studies in which outpatients with MDD were randomised to duloxetine (60 mg/day) or placebo for 8-9 weeks. Patients were retrospectively stratified according to baseline 17-item Hamilton Depression Rating scale (HAMD17) total scores: mild=total score<or=19 (duloxetine, n=246; placebo, n=184); moderate=20-24 (duloxetine, n=333; placebo, n=217); severe=25+ (duloxetine, n=127; placebo, n=87). RESULTS: Duloxetine produced significantly greater baseline-to-end-point improvement vs. placebo (p<0.05) on the HAMD17 total score, Maier and retardation subscales, HAMD17 items 1 (depressed mood), 7 (work and activities) and 10 (psychic anxiety) in all three patient cohorts. The largest effect sizes were observed in assessments of core emotional depressive symptoms. A significant improvement for duloxetine vs. placebo was not observed for sleep-related symptoms at end-point or genital symptoms at any time point during acute treatment. With respect to the time course of depressive symptom improvement, the data show that regardless of baseline severity, the most rapid and consistent improvement for duloxetine compared with placebo was observed in the core symptoms of MDD (measured by the Maier subscale). CONCLUSION: Regardless of baseline MDD severity, duloxetine at one dose (60 mg/day) produced a significant improvement compared with placebo on the core emotional symptoms of MDD.
Pregabalin: an antiepileptic agent useful for neuropathic pain.
Am J Health Syst Pharm. 2007 Jul 15;64(14):1475-82
Authors: Blommel ML, Blommel AL
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pregabalin are reviewed. SUMMARY: Pregabalin is the first drug to receive approved labeling from the Food and Drug Administration (FDA) for the treatment of painful diabetic neuropathy and postherpetic neuralgia and is the first antiepileptic agent to receive FDA-approved labeling since 1999. Pregabalin is the pharmacologically active S-enantiomer of racemic 3-isobutyl gamma-aminobutyric acid. Pregabalin has demonstrated efficacy in the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjunctive therapy for adult patients with partial onset seizures. Its exact mechanism of action is unknown. Pregabalin is rapidly absorbed and exhibits linear pharmacokinetics after oral administration. The lack of hepatic metabolism and lack of interaction with cytochrome P-450 isoenzymes explain the absence of drug interactions with pregabalin. Several clinical studies have demonstrated pregabalin's efficacy for each of the FDA-approved indications, with dizziness and somnolence reported as the most common adverse events. Pregabalin has been designated as a Schedule V controlled substance because of its potential for abuse and dependence. The starting dosage for patients with neuropathic pain associated with diabetic peripheral neuropathy is 50 mg three times daily and may be increased to 300 mg daily within one week based on efficacy and tolerability. The starting dosage for patients with partial-onset seizures is 75 mg twice daily or 50 mg three times daily and may be increased to 600 mg daily based on individual response and tolerability. CONCLUSION: Pregabalin may be beneficial for the treatment of neuropathic pain or partial-onset seizures in patients who do not respond to conventional treatments or cannot tolerate their adverse effects.
Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders.
Ann Clin Psychiatry. 2007 Apr-Jun;19(2):125-32
Authors: Gupta S, Nihalani N, Masand P
BACKGROUND: The discovery of antidepressant medications has revolutionized the treatment of depression and other psychiatric illnesses. The coming of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) marked a new era in the treatment of depression. These therapies frequently fall short of getting the patient to remission. Agents with a dual action have subsequently been developed which inhibit the reuptake of both 5-HT and NE, getting more patients to remission. Physical symptoms are associated with depression, preventing the patient from obtaining complete recovery. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of duloxetine, a dual reuptake inhibitor, which has recently become available. METHODS: The English literature has been reviewed including both controlled and uncontrolled studies. RESULTS: Duloxetine is a dual reuptake inhibitor with actions on serotonin as well as norepinephrine. It has been shown to have efficacy in treating depressive symptoms including those with painful physical symptoms. Common side effects include nausea, insomnia, and dizziness. CONCLUSIONS: The article has been written with clinicians as the target audience, the data suggesting it can be used as a first line agent.
Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention.
Expert Rev Neurother. 2007 Jul;7(7):769-81
Authors: Bandelow B, Wedekind D, Leon T
Pregabalin is the first anxiolytic pharmacologic alternative for the treatment of generalized anxiety disorder (GAD) to be introduced in more than 10 years. GAD is a significant psychiatric condition with lifetime prevalence rates ranging between 5.7 and 6.4%. It causes significant impairment in quality of life and functional abilities equivalent to those associated with major depression. Randomized, controlled trials confirm that pregabalin is superior to placebo and comparable with lorazepam, alprazolam and venlafaxine for the treatment of patients with moderate-to-severe GAD. The onset of anxiolytic activity for pregabalin is apparent within 1 week following initiation of treatment, which is more rapid than that obtained with paroxetine and venlafaxine. Additionally, pregabalin has demonstrated potential for the prevention of relapse of GAD. Recently, the efficacy, safety and tolerability of pregabalin were also shown in a placebo-controlled study with elderly patients. Safety and tolerability profiles are favorable, with transient dizziness and somnolence of mild-to-moderate severity being the most commonly reported adverse events. Pregabalin has minimal potential for drug-drug interactions and does not provoke a clinically significant withdrawal response. Furthermore, pregabalin has low potential for abuse and dependence, unlike other classes of medications used for the treatment of GAD. Clinicians may consider the use of pregabalin in lieu of benzodiazepines as an alternative therapy for their patients with GAD.
Serotonin and noradrenaline involvement in urinary incontinence, depression and pain: scientific basis for overlapping clinical efficacy from a single drug, duloxetine.
Int J Clin Pract. 2007 Aug;61(8):1349-55
Authors: Thor KB, Kirby M, Viktrup L
AIMS: Serotonin (5-HT) and noradrenaline (NA) are important monoamine neurotransmitters that are ubiquitously distributed throughout the peripheral and central nervous system and modulate functions that are vital to survive. Both neurotransmitters may be involved in the pathophysiological process or the treatment of--at first glance--divergent disease areas, namely stress urinary incontinence, major depressive disorder and neuropathic pain. The present review aims at describing the neurophysiological similarities between these disease areas, focussing on the role of the neurotransmitters 5-HT and NA at synapses of the spinal and supraspinal neural circuitry. RESULTS/DISCUSSION: Recent clinical studies show convergence of symptoms (i.e. comorbidity) for incontinence, depression and pain, suggesting common biochemical imbalances. Duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, has a central mechanism of action at different locations in the central nervous system and has proven to be a sound treatment of all these different diseases. Data obtained from animal model studies, randomised placebo-controlled clinical trials, as well as open label trials have provided evidence of the efficacy and safety of duloxetine as a suitable compound for the treatment of stress urinary incontinence in women as well as major depressive disorder and diabetic neuropathic pain in both men and women.
Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial.
J Pain Symptom Manage. 2007 Aug;34(2):183-9
Authors: Keskinbora K, Pekel AF, Aydinli I
Neuropathic cancer pain represents a major challenge. Treatment often requires adjuvant analgesics, including gabapentin, to complement the effects of opioids. This study aimed to compare the effectiveness and safety of gabapentin combined with an opioid versus opioid monotherapy for the management of neuropathic cancer pain. Seventy-five cancer patients who were receiving opioid therapy and reported sufficient pain relief of nociceptive, but not neuropathic, pain were enrolled. Sixty-three patients completed the study. Patients were randomized to one of the following treatment protocols: 1) gabapentin adjuvant to ongoing opioid treatment titrated according to pain response while opioid dose was kept constant (group GO), and 2) continuation of opioid monotherapy according to the World Health Organization treatment ladder approach (group OO). Changes in pain intensity, allodynia, and analgesic drug consumption were evaluated at Day 4 and Day 13. Side effects were also recorded. Both treatments resulted in a significant reduction of pain intensity at Day 4 and Day 13 compared to baseline. However, mean pain intensity for burning and shooting pain was significantly higher in the OO group compared to the GO group at both the fourth (P=0.0001) and 13th (P=0.0001) days of the study. An earlier significant decrease (at Day 4, P=0.002) was observed for allodynia in the GO group compared to the OO group. The rate of side effects in the GO group was significantly lower than that in the OO group (P=0.015). These data suggest that gabapentin added to an opioid provides better relief of neuropathic pain in cancer patients than opioid monotherapy; this combination of gabapentin and an opioid may represent a potential first-line regimen for the management of pain in these patients.
BACKGROUND: Postmenopausal women with depression frequently have co-occurring symptoms of hot flashes (vasomotor symptoms), sleep disturbance, anxiety, and pain. Treatment strategies that target all of these symptoms together have not been investigated to date. METHOD: Study participants were postmenopausal women, 40 to 60 years old, with major depressive disorder (DSM-IV criteria) and vasomotor symptoms. The study design included a 2-week, single-blind placebo run-in phase followed by an 8-week open-label flexible-dosing (60-120 mg per day) study of duloxetine for women who did not respond to placebo. The primary outcome measure was change in Montgomery-Asberg Depression Rating Scale (MADRS) score during 8 weeks of duloxetine therapy. Secondary outcome measures included changes in vasomotor symptoms, sleep quality, anxiety, and pain. Analyses were conducted using non-parametric methods. Patients were enrolled in the study from May 31, 2005, through May 22, 2006. RESULTS: Of 30 women eligible to participate in this study, 20 initiated treatment with open-label duloxetine. Fourteen (70.0%) of these women completed the study. There was a statistically significant decrease in MADRS scores after 8 weeks of treatment (p < .001), with scores declining from 19.0 (interquartile range [IQR] = 15.0-21.0) to 5.5 (IQR = 3.0-9.0). There was also a statistically significant improvement in vasomotor symptoms (p = .003), anxiety (p = .002), sleep quality (p < .001), and pain (p < .05). CONCLUSIONS: Postmenopausal women with depression and vasomotor symptoms had significant improvement in depression, vasomotor symptoms, sleep, anxiety, and pain after 8 weeks of open-label duloxetine therapy. Given the common co-occurrence of these symptoms in postmenopausal women, duloxetine may offer important therapeutic benefits for postmenopausal women who have depression and menopause-related symptoms.
AIM AND METHODS: The impact of medical comorbidity on the efficacy and tolerability of duloxetine in elderly patients with major depressive disorder (MDD) was investigated in this study. Data were obtained from a multicentre, randomised, double-blind, placebo-controlled study in 311 patients with MDD aged 65-89. The primary outcome measure was a prespecified composite cognitive score based on four cognitive tests: (i) Verbal Learning and Recall Test; (ii) Symbol Digit Substitution Test; (iii) 2-Digit Cancellation Test and (iv) Letter-Number Sequencing Test. Secondary measures included the Geriatric Depression Scale (GDS), 17-Item Hamilton Depression Scale (HAMD17), Clinical Global Impression-Severity (CGI-S) Scale, Visual Analogue Scale (VAS) for pain and 36-Item Short Form Health Survey (SF-36). Tolerability measures included adverse events reported as the reason for discontinuation and treatment-emergent adverse events (TEAEs). The consistency of the effect of duloxetine vs. placebo comparing patients with and without medical comorbidity (vascular disease, diabetes, arthritis or any of these) was investigated. RESULTS: Overall, duloxetine 60 mg/day demonstrated significantly greater improvement compared with placebo for the composite cognitive score, GDS and HAMD17 total scores, CGI-Severity, HAMD17 response and remission rates, and some of the SF-36 and VAS measures. There were few significant treatment-by-comorbidity subgroup interactions for these efficacy variables, or for adverse events reported as the reason for discontinuation and common TEAEs. CONCLUSIONS: The present analyses suggested that the efficacy of duloxetine on cognition and depression in elderly patients, and its tolerability, were not largely affected by the comorbidity status. These results further support the use of duloxetine in elderly patients with MDD.
Pregabalin: new indication. Generalised anxiety: better to use benzodiazepine.
Prescrire Int. 2007 Jun;16(89):104
Seven placebo-controlled trials have shown that pregabalin has a modest effect on generalised anxiety in the short term. Pregabalin has not been shown to be as effective as a benzodiazepine or better tolerated.
A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor.
Mov Disord. 2007 Aug 15;22(11):1660-3
Authors: Zesiewicz TA, Ward CL, Hauser RA, Salemi JL, Siraj S, Wilson MC, Sullivan KL
We performed a pilot, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and tolerability of pregabalin (PGB, Lyrica), an antiepileptic agent, in treating essential tremor (ET). Twenty two patients with ET were randomly assigned to receive PGB or placebo. PGB was initiated at 50 mg/day and was escalated by 75 mg/day every 4 days to a maximum dose of 600 mg/day. Patients were evaluated by accelerometry and the Fahn-Tolosa-Marin (FTM) rating scale. There was a significant reduction in tremor amplitude in the PGB group compared with the placebo group, as measured by accelerometry, at a mean dose of 286.76+/-100.05 mg/day. Action tremor limb scores on the FTM also improved in the PGB group compared with the placebo group (P-value for multilevel modeling=0.04). PGB was fairly well tolerated, with about one-third of patients dropping out of the study because of adverse events. PGB provided significant improvements in accelerometry and in action tremor limb scores on the FTM. However, larger studies are needed to further evaluate the potential effect of PGB on ET.
Duloxetine: a review of its use in the treatment of major depressive disorder.
CNS Drugs. 2007;21(7):581-609
Authors: Frampton JE, Plosker GL
Duloxetine (Cymbalta) is an orally administered, selective serotonin and noradrenaline reuptake inhibitor (SNRI) that has been approved for the treatment of major depressive disorder (MDD).Based on a considerable body of evidence, duloxetine at dosages ranging from 40 to 120 mg/day was effective in the short- and long-term treatment of MDD. Significant improvements versus placebo in core emotional symptoms as well as painful physical symptoms associated with depression, were seen in most, but not all, appropriately designed studies; results of meta-analyses suggested that improvements in these efficacy measures were apparent after 1-2 weeks' treatment with the highest recommended dosage of 60 mg once daily. Short-term (< or =15 weeks) administration of duloxetine at fixed or flexible dosages between 60 and 120 mg/day was noninferior to paroxetine 20 mg once daily, noninferior or inferior to escitalopram 10-20mg once daily, and had a similar global benefit-risk (GBR) profile to that of venlafaxine extended-release (XR) 150-225 mg/day in the treatment of MDD. Longer-term (6-8 months) treatment with duloxetine was similar in efficacy to paroxetine and escitalopram. Duloxetine is generally well tolerated, although it may be appropriate to avoid initiating treatment with the 60 mg/day dosage, as this has been associated with a higher discontinuation rate due to adverse events in some (but not all) comparative studies with escitalopram and venlafaxine XR.Definitive comparisons are awaited, although duloxetine seemingly provides a useful alternative to SSRIs and other SNRIs for the treatment of MDD. It also appears to be an attractive option for MDD patients presenting with painful physical symptoms.
The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of approximately 12 mm Hg and approximately 7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.
HPLC analysis of the novel antidepressant duloxetine in human plasma after an original solid-phase extraction procedure.
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Sep 1;856(1-2):81-7
Authors: Mercolini L, Mandrioli R, Cazzolla R, Amore M, Raggi MA
Duloxetine is the most recent serotonin and norepinephrine reuptake inhibitor (SNRI) drug introduced for the therapy of depression. Thus, it is evident that there is a need for having on hand new reliable analytical methods for the determination of duloxetine plasma levels in depressed patients. The present paper deals with the development of a rapid and sensitive high-performance liquid chromatographic method for duloxetine analysis in human plasma. The assays were carried out using a C8 reversed-phase column and a mobile phase composed of 60% aqueous phosphate buffer containing triethylamine at pH 3.0 and 40% acetonitrile. The UV detector was set at 230 nm and loxapine was used as the internal standard. An original pre-treatment of plasma samples was developed, based on solid-phase extraction (SPE) with mixed-mode reversed phase-strong cation exchange cartridges (30 mg, 1 mL). The extraction yields values were higher than 90%. Linearity was found in the 2-200 ng mL(-1) duloxetine concentration range; the limit of quantitation was 2.0 ng mL(-1) and the limit of detection was 0.7 ng mL(-1). The method was applied to plasma samples from depressed patients undergoing therapy with duloxetine. Precision data and accuracy results were satisfactory and no interference from other drugs was found. Thus, the method seems to be suitable for the therapeutic drug monitoring of duloxetine in depressed patients' plasma.
Gabapentin improves sleep in the presence of alcohol.
J Clin Sleep Med. 2005 Jul 15;1(3):284-7
Authors: Bazil CW, Battista J, Basner RC
STUDY OBJECTIVES: To evaluate the ability of a single dose of gabapentin to improve sleep disruption caused by alcohol consumption. METHODS: Double-blind, randomized, single-dose, crossover study of normal subjects (age 21-45 years) who were free of known sleep disorders or medical conditions that could interfere with sleep. Subjects first received baseline polysomnography and, upon awakening, subjective scales of drowsiness and functioning. One to 2 weeks later, they returned to the sleep lab. They consumed 4 ounces of 40% alcohol and gabapentin (300 or 600 mg) or placebo 1 hour prior to bedtime. Polysomnography and subjective scales were repeated. One to 2 weeks later, subjects returned and were given the same dose of alcohol and the other treatment, followed by repeat testing. Differences between baseline and placebo (alcohol) results were compared to the difference between baseline and gabapentin (alcohol) by paired t tests. RESULTS: Thirteen subjects were enrolled; 12 completed the study. Mean age was 30.8 years (range 25-37 years). No difference in total sleep time was seen for any of the groups. Gabapentin (300 or 600 mg) showed a significant decrease in stage 1 (9.3% vs 5.5%) and number of awakenings (11 vs 6) with increased sleep efficiency (93% vs 96.2%). Subjects receiving 600 mg also showed increased slow wave sleep, decreased rapid eye movement sleep, and decreased arousals. No differences were seen in any of the subjective tests of drowsiness and performance. CONCLUSIONS: Single-dose gabapentin at bedtime can improve sleep through decreased stage 1 sleep, increased slow-wave sleep, increased sleep efficiency, and decreased arousals. Gabapentin may be useful in the treatment of conditions in which frequent awakenings and decreased sleep efficiency are seen.
Authors: Tuccori M, Lombardo G, Lapi F, Vannacci A, Blandizzi C, Del Tacca M
OBJECTIVE: To report and discuss a case of rhabdomyolysis in an elderly patient with neuropathic pain who was treated with gabapentin. CASE SUMMARY: An 85-year-old diabetic woman was hospitalized for severe pain in her lower limbs and difficulty in walking, compromising her daily activities. On admission, the woman's laboratory parameters, including creatine kinase (CK) and myoglobin, were in the normal range. Neurologic evaluation suggested a diagnosis of diabetic neuropathic pain, and therapy with gabapentin 150 mg 3 times daily was started. On the same day, the patient developed psychomotor agitation and gastric pain, which were treated with haloperidol 10 mg and lansoprazole 30 mg, respectively. In the following hours, the severity of muscular pain increased and the patient developed myopathy with acute renal failure (CK 459 U/L, myoglobin 11 437 ng/mL, creatinine 4.59 mg/dL), which worsened progressively during the next 2 days (CK 3095 U/L, myoglobin 17,000 mg/dL, creatinine 4.77 mg/dL) despite discontinuation of haloperidol and lansoprazole. No signs of trauma or edema, suggesting possible compartmental or crush syndrome, were detected. Gabapentin was then withdrawn and the patient's condition rapidly improved. Complete recovery followed in about 10 days. DISCUSSION: Severe myopathy is an unexpected adverse reaction to gabapentin therapy. In this patient, a possible contribution of haloperidol or lansoprazole to the adverse event cannot be excluded. However, worsening of the clinical picture despite discontinuation of these drugs, together with rapid improvement observed after withdrawal of gabapentin, strongly suggest a causative role of gabapentin. According to the Naranjo probability scale, gabapentin was the probable cause of myopathy in this patient. The mechanism by which gabapentin may induce myopathy is unknown. The early onset of the syndrome after initiation of treatment with gabapentin in therapeutic doses is compatible with the picture of an idiosyncratic adverse response. CONCLUSIONS: Pathogenetic and clinical investigations are required to explore what mechanisms account for gabapentin-related muscular alterations at the time of onset, including electromyographic recordings as well as muscle and nerve histopathologic examinations. Until more information is available, clinicians should consider the possibility of discontinuing gabapentin treatment in patients showing muscular pain and signs of myopathy.
Double-blind comparison of escitalopram and duloxetine in the acute treatment of major depressive disorder.
Clin Drug Investig. 2007;27(7):481-92
Authors: Khan A, Bose A, Alexopoulos GS, Gommoll C, Li D, Gandhi C
BACKGROUND AND OBJECTIVE: Escitalopram is the most selective serotonin reuptake inhibitor antidepressant; in contrast, duloxetine inhibits both serotonin and norepinephrine reuptake. Double-blind comparison studies may help guide treatment decisions by revealing the relative benefits of different therapeutic approaches. This study evaluated the efficacy and safety of escitalopram versus duloxetine in the acute treatment of patients with moderate to severe major depressive disorder. METHODS: A 1-week, single-blind, placebo lead-in period followed by an 8-week, randomised, double-blind, multicentre, parallel-group comparison was conducted from 20 April 2005 to 10 March 2006 in independent psychiatric research facilities with principal investigators who were board certified in psychiatry. A total of 278 outpatients of 382 patients screened with Diagnostic and Statistical Manual of Mental Disorders (4th edition)-diagnosed major depressive disorder (Montgomery-Asberg Depression Rating Scale [MADRS] total score > or =26) were randomised to the two treatment groups. Eight patients received no medication and were excluded from the safety group. Patients were treated with either escitalopram 10-20 mg/day (fixed at 10 mg/day for the first 4 weeks) or duloxetine 60 mg/day. The primary efficacy variable was change from baseline at week 8 in MADRS total score using the last observation carried forward (LOCF) approach. Efficacy, safety and tolerability measures were prospectively defined in the statistical analysis plan prior to study initiation unless otherwise specifically noted as conducted post hoc. RESULTS: A significantly greater proportion of escitalopram-treated patients completed the 8-week study compared with duloxetine-treated patients (87% vs 69%, respectively; p < 0.01). Mean baseline MADRS total scores were 31.0 for the escitalopram group and 31.6 for the duloxetine group. At week 8, escitalopram treatment resulted in significantly greater improvement compared with duloxetine on the prospectively defined primary efficacy endpoint of mean change from baseline in MADRS total score using the LOCF approach (least-squares mean difference [LSMD] -2.42; 95% CI -4.73, -0.11; p < 0.05). There was no difference between treatment groups in the observed cases (OC) analysis (LSMD -0.32; 95% CI -2.71, 2.07; p = 0.79). Significantly fewer escitalopram-treated patients discontinued because of adverse events compared with duloxetine (2% vs 13%, respectively; p < 0.01). CONCLUSION: These findings suggest that escitalopram is better tolerated and at least as effective as the serotonin-norepinephrine reuptake inhibitor duloxetine in the treatment of major depressive disorder.
A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder.
Curr Med Res Opin. 2007 Jul;23(7):1605-14
Authors: Wade A, Gembert K, Florea I
OBJECTIVE: This study evaluated the efficacy and tolerability of escitalopram and duloxetine in the treatment of major depressive disorder (MDD). RESEARCH DESIGN AND METHODS: Patients were randomised to 24 weeks of double-blind treatment with fixed doses of escitalopram (20 mg) (n = 143) or duloxetine (60 mg) (n = 151). The primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 24) in MADRS total score (last observation carried forward). MAIN OUTCOME MEASURES; RESULTS: At week 8, the mean change from baseline in total MADRS score was -19.5 for patients treated with escitalopram (n = 141) and -17.4 for patients treated with duloxetine (n = 146), a difference of 2.1 points (p < 0.05). At week 8, the proportion of responders (> or = 50% decrease in MADRS) was 69% (escitalopram) and 58% (duloxetine) (p < 0.05) and remission (MADRS < or = 12) rates were 56% (escitalopram) and 48% (duloxetine) (NS). For the primary endpoint, the mean change from baseline in total MADRS score at week 24 was -23.4 for patients treated with escitalopram and -21.7 for patients treated with duloxetine, a difference of 1.7 points (p = 0.055, one-sided). The difference in mean change from baseline in MADRS total score favoured escitalopram at weeks 1, 2, 4, 8, 12 and 16 (p < 0.05). The overall withdrawal rates were 22% (escitalopram) and 25% (duloxetine) (NS). The withdrawal rate due to adverse events was lower for escitalopram (9%) compared to duloxetine (17%) (p < 0.05) and significantly more patients treated with duloxetine reported insomnia (12.6% vs. 4.9%) and constipation (8.6% vs. 2.8%). CONCLUSION: Escitalopram was superior to duloxetine in acute treatment and at least as efficacious and better tolerated in long-term treatment of MDD.
STUDY OBJECTIVES: Insomnia is a central symptom of alcohol withdrawal and increases relapse potential. The primary objective of this study was to compare the efficacy of gabapentin to lorazepam in alleviating sleep disturbances and daytime sleepiness during an episode of alcohol withdrawal. The secondary objective of this study was to determine if drug treatment efficacy differed by the patient history of previous treatments for alcohol withdrawal. METHODS: Outpatients in treatment for alcohol withdrawal received a 4-day fixed-dose taper of gabapentin or lorazepam in a double-blind, randomized, controlled trial with an 8-day follow-up. Daily across a 5 day outpatient treatment and Days 7 and 12 post-treatment, patients self-reported daytime sleepiness using the Epworth Sleepiness Scale. Self-reports of depression (Beck Depression Inventory) were completed at Days 1, 5, 7 and 12. Staff assessed daily alcohol withdrawal using the Clinical Institute Withdrawal Assessment for Alcohol. From these instruments, self-reported sleep and sleepiness were extracted and assessed in the context of limited (0-1) or multiple (2 or more) previously treated alcohol withdrawal episodes. RESULTS: Patients with limited previous withdrawals reported similar treatment effects on self-reports of sleep and sleepiness for gabapentin and lorazepam. In contrast, patients with multiple previous alcohol withdrawals receiving gabapentin reported reduced sleep disturbances and sleepiness in comparison to those receiving lorazepam. CONCLUSIONS: During treatment for alcohol withdrawal, gabapentin as compared to standard therapy with lorazepam, was superior on multiple sleep measures, in patients who had previous withdrawals. Lorazepam subjects experienced rebound symptoms. Early drinking was related to persisting insomnia with both drugs.
OBJECTIVE: To report a patient with intractable hiccup which improved with gabapentin. CASE REPORT: A 69-year-old woman diagnosed with refractory hiccup that started 50 years before improved dramatically after a trial of gabapentin for essential tremor. Gabapentin withdrawal led to reappearance of hiccup, which improved again after its reintroduction. CONCLUSIONS: Gabapentin should be considered as a possible therapy for refractory hiccup.
OBJECTIVE: This study compared the effects of duloxetine, 60 mg/day, versus placebo on cognition, depression, and pain in elderly patients with recurrent major depressive disorder. METHOD: Patients were randomly assigned (2:1) to duloxetine, 60 mg/day (N=207), or placebo (N=104) for 8 weeks in a double-blind study. The primary outcome measure was a prespecified composite cognitive score composed of four individual tests. Secondary measures included the Geriatric Depression Scale, the Hamilton Depression Rating Scale, the Visual Analogue Scale assessing pain, and standard safety and tolerability assessments. RESULTS: Patients had a median age of 72 years (range=65-90). Duloxetine demonstrated significantly greater improvement in the composite cognitive score versus placebo (least-squares mean change from baseline to endpoint: 1.95 versus 0.76), driven by improved verbal learning and memory. Duloxetine treatment showed significantly greater baseline-to-endpoint reductions in both Hamilton depression scale (-6.49 versus -3.72) and Geriatric Depression Scale (-4.07 versus -1.34) total scores compared with placebo. Hamilton depression scale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were significantly higher for duloxetine than for placebo. Duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake versus placebo. Significantly fewer patients receiving duloxetine withdrew from the study because of lack of efficacy (2.9% versus 9.6%); the incidences of discontinuation due to adverse events were similar for duloxetine and placebo (9.7% versus 8.7%). CONCLUSIONS: Duloxetine improved cognition, depression, and some pain measures and was safe and well tolerated in elderly patients with recurrent major depressive disorder.
The use of gabapentin in chronic cluster headache patients refractory to first-line therapy.
Eur J Neurol. 2007 Jun;14(6):694-6
Authors: Schuh-Hofer S, Israel H, Neeb L, Reuter U, Arnold G
Chronic cluster headache (CCH) is a rare but challenging condition. About 20% of CCH patients get refractory to treatment. Gabapentin has recently been reported to be efficacious in the treatment of CCH. To test the potential of gabapentin as second-line drug, we prospectively studied the efficacy of gabapentin as add-on drug in eight patients suffering from CCH refractory to first-line treatment. Six of eight CCH patients responded to treatment. After the end of the study phase, the patients' clinical course was further followed up until January 2006. The longest period of being continuously pain-free under gabapentin treatment was 18 months. In some individuals, increasing doses were needed with time. We conclude that gabapentin may be offered as treatment trial in patients refractory to first-line treatment. However, patients may fail to respond to treatment and drug tolerance may occur with time.
Patients with hereditary spastic paraplegia (HSP) are often treated with antispastic drugs to relieve symptoms but documentation is lacking. In this study, gabapentin was tested in a double-blind crossover trial on a group of patients with HSP and linkage to the SPG4 locus. There was no difference between periods with gabapentin and placebo treatment in clinical assessment, self-reported parameters or paired transcranial magnetic stimulation evaluation of motor cortical excitability.
Validated HPLC method for the determination of gabapentin in human plasma using pre-column derivatization with 1-fluoro-2,4-dinitrobenzene and its application to a pharmacokinetic study.
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jul 1;854(1-2):43-7
Authors: Jalalizadeh H, Souri E, Tehrani MB, Jahangiri A
A rapid, sensitive and accurate high-performance liquid chromatographic method with UV detection was developed and validated for the quantification of gabapentin in human plasma. Gabapentin was quantified using pre-column derivatization with 1-fluoro-2,4-dinitrobenzene following protein precipitation of plasma with acetonitrile. Amlodipine was used as internal standard. The chromatographic separation was carried out on a Nova-Pak C(18) column using a mixture of 50 mM NaH(2)PO(4) (pH=2.5)-acetonitrile (30:70, v/v) as mobile phase with UV detection at 360 nm. The flow rate was set at 1.5 ml/min. The method was linear over the range of 0.05-5 microg/ml of gabapentin in plasma (r(2)>0.999). The within-day and between-day precision values were in the range of 2-5%. The limit of quantification of the method was 0.05 microg/ml. The method was successfully used to study the pharmacokinetics of gabapentin in healthy volunteers.
Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety.
Anesth Analg. 2007 Jun;104(6):1545-56, table of contents
Authors: Tiippana EM, Hamunen K, Kontinen VK, Kalso E
BACKGROUND: Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain. These properties may also be beneficial in acute postoperative pain. In this study we evaluated randomized, controlled trials examining the analgesic efficacy, adverse effects, and clinical value of gabapentinoids in postoperative pain. METHODS: A systematic search of Medline, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) databases yielded 22 randomized, controlled trials on perioperative administration of gabapentinoids for postoperative pain relief. RESULTS: Pain relief was better in the gabapentin groups compared with the control groups. The opioid-sparing effect during the first 24 h after a single dose of gabapentin 300-1200 mg, administered 1-2 h preoperatively, ranged from 20% to 62%. The combined effect of a single dose of gabapentin was a reduction of opioid consumption equivalent to 30 +/- 4 mg of morphine (mean +/- 95% CI) during the first 24 h after surgery. Metaregression analysis suggested that the gabapentin-induced reduction in the 24-h opioid consumption was not significantly dependent on the gabapentin dose. Gabapentin reduced opioid-related adverse effects, such as nausea, vomiting, and urinary retention (number-needed-to-treat 25, 6, and 7, respectively). The most common adverse effects of the gabapentinoids were sedation and dizziness (number-needed-to-harm 35 and 12, respectively). CONCLUSIONS: Gabapentinoids effectively reduce postoperative pain, opioid consumption, and opioid-related adverse effects after surgery. Conclusions about the optimal dose and duration of the treatment cannot be made because of the heterogeneity of the trials. Studies are needed to determine the long-term benefits, if any, of perioperative gabapentinoids.
Prolonged myotonia and dystonia after general anaesthesia in a patient taking gabapentin.
Br J Anaesth. 2007 Aug;99(2):218-20
Authors: Allford MA
This is the report of a 55-yr-old female who developed severe myotonia and dystonia after general anaesthesia. Before starting on gabapentin therapy for a neuropathic pain condition, she had undergone numerous uneventful general anaesthetics. Since receiving treatment with gabapentin, she has experienced severe movement disorders on emergence from each subsequent general anaesthetic. The events were unrelated to the choice of anaesthetic or anti-emetic. The most recent event that required a protracted stay in hospital after a day-case surgery is presented in detail, and the possible mechanisms to explain the interaction are discussed.
Duloxetine compared with placebo for treating women with symptoms of overactive bladder.
BJU Int. 2007 Aug;100(2):337-45
Authors: Steers WD, Herschorn S, Kreder KJ, Moore K, Strohbehn K, Yalcin I, Bump RC,
OBJECTIVE: To evaluate duloxetine (a serotonin-noradrenaline reuptake inhibitor) in women with symptoms of overactive bladder (OAB), as it has been shown to increase the bladder capacity in an animal model. PATIENTS AND METHODS: In all, 306 women (aged 21-84 years) were recruited and randomly assigned to placebo (153) or duloxetine (80-mg/day for 4 weeks increased to 120-mg/day for 8 weeks; 153). Symptoms of OAB were defined as bothersome urinary urgency and/or urge urinary incontinence (UI) for > or =3 months. Participants were also required to have a mean daytime voiding interval (VI) of < or=2 h and urodynamic observations of either detrusor overactivity (DOA) or urgency which limited bladder capacity to <400 mL, both with no stress UI (SUI). The primary efficacy analysis compared the treatment effects on mean change from baseline to endpoint in the mean number of voiding episodes (VE)/24 h. The secondary efficacy analyses compared the treatment effects on the number of UI episodes (IE)/24 h, in the Incontinence Quality of Life questionnaire (I-QOL) score, and on the mean daytime VI. Safety was assessed with vital signs, adverse event reporting, routine laboratory testing, electrocardiogram, and the measurement of postvoid residual urine volumes (PVR). RESULTS: Patients randomized to duloxetine had significant improvements over those randomized to placebo for decreases in VE and IE, for increases in the daytime VI, and for improvements in I-QOL scores at both doses of duloxetine. Urodynamic studies showed no significant increases in maximum cystometric capacity or in the volume threshold for DOA. The most common treatment-emergent adverse events with duloxetine (nausea, 31%; dry mouth, 16%; dizziness, 14%; constipation, 14%; insomnia, 13%; and fatigue, 11%) were the same as those reported by women with SUI and were significantly more common with duloxetine than placebo. Laboratory assessments, vital signs and electrocardiograms were stable relative to baseline, with no relevant differences detected between groups. There was a significant difference in the change in PVR with duloxetine (<5 mL mean increase) but no patient reported hesitancy or retention. CONCLUSION: In this trial, duloxetine was better than placebo for treating women with 'wet' and 'dry' symptoms of OAB associated with DOA or a bladder capacity of <400 mL.
Use of gabapentin for perioperative pain control -- a meta-analysis.
Pain Res Manag. 2007;12(2):85-92
Authors: Peng PW, Wijeysundera DN, Li CC
BACKGROUND: Gabapentin, an anticonvulsant, has recently been suggested as an effective postoperative 'analgesic' agent. The objective of the present study was to examine the analgesic effectiveness, opioid-sparing effects and side effects associated with the use of gabapentin in a perioperative setting. METHODS: Following the Quality of Reporting of Meta-analyses recommendations, nine electronic databases until February 2006 were searched, without language restriction, for randomized controlled trials comparing gabapentin with control for postoperative pain control. Outcome measures, namely, 24 h cumulative opioid consumption, visual analogue scale pain scores and adverse effects, were expressed as odds ratios, ratio of means or weighted mean differences (as appropriate), which were aggregated under the fixed or random effects models. RESULTS: Gabapentin caused a 35% reduction in total opioid consumption over the first 24 h following surgery (ratio of means 0.65, 95% CI 0.59 to 0.72), a significant reduction in postoperative pain at rest (in the first 24 h) and with movement (at 2 h, 4 h and 12 h), regardless of whether treatment effects were expressed as ratios of means or weighted mean differences, and a reduction of vomiting (relative risk [RR] 0.73, 95% CI 0.56 to 0.95) and pruritus (RR 0.30, 95% CI 0.13 to 0.70). It was associated with a significant increase in dizziness (RR 1.40, 95% CI 1.06 to 1.84) and an increase in sedation of borderline significance (RR 1.65, 95% CI 1.00 to 2.74). CONCLUSION: Gabapentin improves the analgesic efficacy of opioids both at rest and with movement, reduces analgesic consumption and opioid-related adverse effects, but is associated with an increased incidence of sedation and dizziness.
Duloxetine treatment of dysthymia and double depression: an open-label trial.
J Clin Psychiatry. 2007 May;68(5):761-5
Authors: Koran LM, Aboujaoude EN, Gamel NN
BACKGROUND: Although not as common as major depressive disorder, dysthymia is not rare and is associated with substantial impairment. Antidepressants and some psychotherapies are often effective. We explored the efficacy of the antidepressant duloxetine, a serotonin and norepinephrine reuptake inhibitor. METHOD: Between February 2005 and April 2006, we recruited 24 adults with DSM-IV dysthymia or dysthymia and concurrent major depression ("double depression") who had an entry score of > or = 17 on the clinician-rated Inventory for Depressive Symptomatology (IDS-C). We excluded subjects with significant medical illnesses and those requiring other psychotropic agents or undergoing psychotherapy. Subjects received duloxetine 60 mg/day for 6 weeks, increased as tolerated to 120 mg/day for the remainder of the 12-week trial for those with an inadequate treatment response. RESULTS: The subjects' mean +/- SD IDS-C scores decreased significantly from baseline (27.3 +/- 6.3) to endpoint (7.8 +/- 7.4, Student t = 12.38, df = 23, p < or = .001). The IDS-C response rate (intent-to-treat [ITT]) was 83% (20/24); the remission rate (ITT) was 79% (19/24). Among study completers, these rates were 89% (17/19) and 84% (16/19). Five subjects (21%) discontinued for side effects. CONCLUSION: Duloxetine appears to be an effective and well-tolerated treatment for dysthymia and double depression. A double-blind, placebo-controlled study is under way. If duloxetine is found to be effective, studies powered to detect potential, clinically important differences between duloxetine and other antidepressants will be needed. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00185575.
Pregabalin in restless legs syndrome with and without neuropathic pain.
Acta Neurol Scand. 2007 May;115(5):347-50
Authors: Sommer M, Bachmann CG, Liebetanz KM, Schindehütte J, Tings T, Paulus W
BACKGROUND: Restless legs syndrome (RLS) is a common neurological disorder complicated in many patients by augmentation to dopaminergic therapy or comorbidities such as neuropathic pain. AIMS: To explore the effectiveness of pregabalin in RLS in a pragmatic clinical setting. METHODS: After observing improvement of restless legs symptoms in seven patients treated with pregabalin for neuropathic pain, we extended the clinical observation to a total of 16 patients with secondary RLS, in most of them due to neuropathy, and to three patients with idiopathic RLS. RESULTS: Three patients discontinued pregabalin because of side effects (rash, fatigue, loss of efficacy). The other 16 patients self-rated a satisfactory or good alleviation of RLS symptoms and maintained pregabalin, five with add-on medication, on a mean daily dose of 305 mg (standard deviation, 185 mg), and with a mean duration of 217 (standard deviation, 183) days. CONCLUSION: These data propose pregabalin as a new option in the treatment of secondary RLS for patients with neuropathic pain, which should be further investigated with randomized, placebo-controlled trials.
Duloxetine treatment for role functioning improvement in generalized anxiety disorder: three independent studies.
J Clin Psychiatry. 2007 Apr;68(4):518-24
Authors: Endicott J, Russell JM, Raskin J, Detke MJ, Erickson J, Ball SG, Marciniak M, Swindle RW
OBJECTIVE: Generalized anxiety disorder (GAD) is associated with impaired role functioning and diminished well-being. The present work examined the efficacy of duloxetine treatment for improving functional outcomes for patients with GAD in 3 independent clinical studies. METHOD: Studies were randomized, double-blind, placebo-controlled multicenter trials conducted in adult outpatients with DSM-IV-defined GAD. One study compared 9-week fixed-dose treatment with duloxetine 60 or 120 mg (N = 168 and N = 170, respectively) with placebo (N = 175). The other 2 studies compared 10-week flexible-dose treatment with duloxetine 60-120 mg (study 2, N = 168; study 3, N = 162) with placebo (study 2, N = 159; study 3, N = 161). The main functional outcome measure for each study was the Sheehan Disability Scale (SDS). Additional measures were the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form and the European Quality of Life 5 Dimensions. The 3 studies were conducted in the time period from June 2004 to November 2005. RESULTS: Duloxetine-treated patients improved significantly more than placebo-treated patients on SDS global functioning (study 1, p <or= .001; studies 2 and 3, p <or= .01) and SDS work, social life, and family/home responsibility scores (p values range from <or= .05 to <or= .001). At treatment endpoint, a greater percentage of duloxetine-treated patients had obtained SDS global functioning scores in the normative range than placebo-treated patients (p values range from <or= .05 to <or= .001). Duloxetine-treated patients also reported greater increases in quality of life, well-being, and health compared with the placebo group on the other functional measures (p values range from <or= .05 to <or= .001). CONCLUSIONS: Duloxetine consistently reduced role functioning disabilities associated with GAD and enhanced patients' quality of life and well-being in 3 independent clinical studies. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifiers NCT00122824 (study 1) and NCT00122850 (study 3). Study 2 was completed prior to the requirement to post trials at initiation and does not have a registration number.
Once-daily duloxetine 60 mg in the treatment of major depressive disorder: multicenter, double-blind, randomized, paroxetine-controlled, non-inferiority trial in China, Korea, Taiwan and Brazil.
Psychiatry Clin Neurosci. 2007 Jun;61(3):295-307
Authors: Lee P, Shu L, Xu X, Wang CY, Lee MS, Liu CY, Hong JP, Ruschel S, Raskin J, Colman SA, Harrison GA
The aim of the present paper was to compare the efficacy and safety of duloxetine with paroxetine in the acute treatment of major depressive disorder (MDD). In a randomized, double-blind trial of 8 weeks active treatment, patients with non-psychotic MDD were randomized to duloxetine 60 mg (n = 238) or paroxetine 20 mg (n = 240) once daily. Efficacy was primarily measured on change in the 17-item Hamilton Rating Scale for Depression (HAMD(17)) using a non-inferiority test with a margin of 2.2. Secondary efficacy measures included the HAMD(17) subscales, Hamilton Rating Scale for Anxiety, Clinical Global Impressions-Severity, Patient Global Impressions-Improvement, Somatic Symptoms Inventory and Visual Analog Scales (VAS) for pain. Safety measures included treatment-emergent adverse events (TEAE), vital signs, weight, laboratory analyses and electrocardiograms. Non-inferiority of duloxetine to paroxetine was demonstrated because the upper bound of the confidence interval for mean difference in HAMD(17) change (0.71) was less than the non-inferiority margin. Secondary efficacy end-points did not differ significantly between treatments with the exception of VAS back pain, where the pooled mean was lower in the duloxetine group (17.1) compared with the paroxetine group (20.3, P = 0.048). No significant differences were observed in the number of early discontinuations and overall TEAE. However, significantly greater proportions of patients in the duloxetine group experienced nausea and palpitations. No clinically relevant changes in laboratory values, vital signs, weight or electrocardiograms were observed with either treatment. The present study verifies the utility of duloxetine as an efficacious and safe treatment for both emotional and physical symptoms of MDD in this predominantly Asian patient sample.
An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.
Drug Saf. 2007;30(5):437-55
Authors: Wernicke J, Lledó A, Raskin J, Kajdasz DK, Wang F
BACKGROUND AND OBJECTIVE: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). METHODS: The cardiovascular safety of duloxetine was assessed using all placebo-controlled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebo-controlled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. RESULTS: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia's formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. CONCLUSION: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.
Characteristics and impact of drug detailing for gabapentin.
PLoS Med. 2007 Apr;4(4):e134
Authors: Steinman MA, Harper GM, Chren MM, Landefeld CS, Bero LA
BACKGROUND: Sales visits by pharmaceutical representatives ("drug detailing") are common, but little is known about the content of these visits or about the impact of visit characteristics on prescribing behavior. In this study, we evaluated the content and impact of detail visits for gabapentin by analyzing market research forms completed by physicians after receiving a detail visit for this drug. METHODS AND FINDINGS: Market research forms that describe detail visits for gabapentin became available through litigation that alleged that gabapentin was promoted for "off-label" uses. Forms were available for 97 physicians reporting on 116 detail visits between 1995 and 1999. Three-quarters of recorded visits (91/116) occurred in 1996. Two-thirds of visits (72/107) were 5 minutes or less in duration, 65% (73/113) were rated of high informational value, and 39% (42/107) were accompanied by the delivery or promise of samples. During the period of this study, gabapentin was approved by the US Food and Drug Administration only for the adjunctive treatment of partial seizures, but in 38% of visits (44/115) the "main message" of the visit involved at least one off-label use. After receiving the detail visit, 46% (50/108) of physicians reported the intention to increase their prescribing or recommending of gabapentin in the future. In multivariable analysis, intent to increase future use or recommendation of gabapentin was associated with receiving the detail in a small group (versus one-on-one) setting and with low or absent baseline use of the drug, but not with other factors such as visit duration, discussion of "on-label" versus "off-label" content, and the perceived informational value of the presentation. CONCLUSIONS: Detail visits for gabapentin were of high perceived informational value and often involved messages about unapproved uses. Despite their short duration, detail visits were frequently followed by physician intentions to increase their future recommending or prescribing of the drug.
Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports.
Ann Clin Psychiatry. 2007 Jan-Mar;19(1):31-6
Authors: Khan A, Schwartz K
BACKGROUND: We assessed suicide and suicide attempt risk as well as symptom reduction among 3,282 depressed patients participating in duloxetine and escitalopram clinical trials assigned to either an antidepressant or placebo. METHODS: We reviewed the FDA Summary Basis of Approval reports for data regarding safety and efficacy for duloxetine and escitalopram. Furthermore, we compared suicide risk among antidepressant clinical trials in this study with our two previous analyses on seven antidepressant clinical trials. RESULTS: Suicide and suicide attempt risk varied considerably among the three analyses, showing up to ten fold differences. Interestingly, the variability exists across the three reports, rather than between treatments (antidepressants versus placebo). CONCLUSIONS: These findings suggest caution in generalizing suicide risk even from a relatively large number of participants and thus, firm conclusions can only be drawn if the number of participants is overwhelmingly large (approximately two million patients). We also noted similar magnitude of response to placebo and antidepressants among the three studies.
Duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, is licensed in the UK under two brand names for a total of three different indications. It is available as Cymbalta (jointly promoted by Boehringer Ingelheim and Lilly) for the treatment of patients with major depression, or with diabetic peripheral neuropathic pain; and as Yentreve (Lilly) for the treatment of women with "moderate to severe" stress urinary incontinence. Here we consider whether duloxetine has a role in the treatment of patients with any of these conditions.
The efficiency of gabapentin therapy in patients with lumbar spinal stenosis.
Spine. 2007 Apr 20;32(9):939-42
Authors: Yaksi A, Ozgönenel L, Ozgönenel B
STUDY DESIGN: Randomized controlled study. OBJECTIVES: To investigate the efficacy of treatment with gabapentin on the clinical symptoms and findings in patients with lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: LSS is a syndrome resulting from the narrowing of the lumbar nerve root canal, spinal canal, and intervertebral foramen, causing compression of the spinal cord. The most significant clinical symptom in patients with LSS is neurologic intermittent claudication (NIC). Gabapentin, which has been used in the treatment of neuropathic pain, may be effective in the treatment of symptoms associated with LSS. METHODS: Fifty-five patients with LSS, who had NIC as the primary complaint, were randomized into 2 groups. All patients were treated with therapeutic exercises, lumbosacral corset with steel bracing, and nonsteroidal anti-inflammatory drugs. The treatment group received gabapentin orally in addition to the standard treatment. RESULTS: Gabapentin treatment resulted in an increase in the walking distance better than what was obtained with standard treatment (P = 0.001). Gabapentin-treated patients also showed improvements in pain scores (P = 0.006) and recovery of sensory deficit (P = 0.04), better than could be attained with the standard treatment. CONCLUSION: Based on the results of our pilot study, extensive clinical studies are warranted to investigate the role of gabapentin in the management of symptomatic LSS.
We report a case of intentional overdose in a 29-year-old male with two of the newer anti-epileptic agents, lamotrigine and pregabalin. To our knowledge, this case report details the highest plasma levels of lamotrigine ever recorded in the literature. The patient presented with seizures and a reduced level of consciousness. Management of these and subsequent complications centres on supportive care in the high dependency and intensive therapy units.
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.
Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome.
Gut. 2007 Sep;56(9):1218-25
Authors: Houghton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, Gale JD
BACKGROUND: Visceral hypersensitivity is an important pathophysiological factor in irritable bowel syndrome (IBS). Pre-clinical studies suggest that the alpha(2)delta ligand pregabalin reduces both visceral allodynia and hyperalgesia, but is inactive on basal sensitivity. AIM: To assess the effect of pregabalin on the perception of rectal distension in hypersensitive IBS patients. METHODS: Twenty-six patients with Rome-II-defined IBS (aged 18-46 years, 7 male) were included in a randomized, double-blind, placebo-controlled, parallel-group study in which they received either 3 weeks oral pregabalin (titrated: 50 mg tid days 1-3, 100 mg tid days 4-7, 150 mg tid days 8-11; fixed 200 mg tid days 12-21 +/-4) or placebo control. Rectal sensitivity was assessed using a barostat technique, in which sensory thresholds were determined using the ascending method of limits, followed by tracking both before and after treatment. Only patients with a pain threshold of <or=28 mmHg were included in the study. RESULTS: Pregabalin significantly increased the sensory thresholds from baseline for first sensation (p = 0.045), desire to defecate (p = 0.008) and pain (p = 0.048) compared with placebo control. In addition, pregabalin significantly increased rectal compliance (p<0.0001), although this appeared to be unrelated to the changes in sensitivity. Despite the occurrence of mild dizziness and somnolence, pregabalin was generally well tolerated. CONCLUSIONS: Pregabalin increased distension sensory thresholds to normal levels in IBS patients with rectal hypersensitivity. A concomitant increase in rectal compliance appeared to be unrelated to the reduction in sensitivity. These data suggest that alpha(2)delta ligands are worthy of further investigation in the treatment of visceral pain disorders, including IBS.