Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Venlafaxine in neuropathic pain following treatment of breast cancer. Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. Treatment response in antidepressant-naïve postherpetic neuralgia patients: double-blind, randomized trial. The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. A randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder. Efficacy of noradrenergic and serotonergic antidepressants in chronic back pain: a preliminary concentration-controlled trial. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. Oral opioid therapy for chronic peripheral and central neuropathic pain. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. [Fluoxetine versus fluvoxamine for treatment of chronic pain]. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. [Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine]. Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Venlafaxine compared with fluoxetine in outpatients with depression and concomitant anxiety. Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence. Selective serotonin reuptake inhibitors for migraine prophylaxis. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. A randomized, open-label comparison of venlafaxine and fluoxetine in depressed outpatients. Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study. Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. Randomized trial of opioids versus tricyclic antidepressants for radiation-induced mucositis pain in head and neck cancer. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Randomized, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. A pilot study investigating the effects of fast left prefrontal rTMS on chronic neuropathic pain. A randomized, placebo-controlled trial of bupropion sustained release in chronic low back pain. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. Antidepressant drugs and generic counselling for treatment of major depression in primary care: randomised trial with patient preference arms. Prefrontal repetitive transcranial magnetic stimulation as add on treatment in depression. Trazodone hydrochloride in the treatment of dysesthetic pain in traumatic myelopathy: a randomized, double-blind, placebo-controlled study. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but not major depression. Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Increased remission rates with venlafaxine compared with fluoxetine in hospitalized patients with major depression and melancholia. Duloxetine vs. placebo in patients with painful diabetic neuropathy. A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin. Comparative efficacy of SSRIs and amisulpride in burning mouth syndrome: a single-blind study. Does addition of low-dose flupentixol enhance the analgetic effects of low-dose amitriptyline in somatoform pain disorder?
Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA.
                To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine.
                The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks' duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales.
                The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine (p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine.
                Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine. To evaluate the efficacy and safety of 6 weeks of venlafaxine extended-release (ER) (75 mg and 150-225 mg) treatment in patients with painful diabetic neuropathy. This multicenter, double-blind, randomized, placebo-controlled study included 244 adult outpatients with metabolically stable type 1 or 2 diabetes with painful diabetic neuropathy. Primary efficacy measures were scores on the daily 100 mm Visual Analog Pain Intensity (VAS-PI) and Pain Relief (VAS-PR) scales. Secondary efficacy measures included the Clinical Global Impressions-Severity of Illness and the Clinical Global Impressions-Improvement, Patient Global Rating of Pain Relief, and percentage of patients achieving 50% reduction in pain intensity. Baseline pain intensity was 68.7 mm (moderately severe). At week 6, the percentage reduction from baseline in VAS-PI was 27% (placebo), 32% (75 mg), and 50% (150-225 mg; P < 0.001 vs placebo). Mean VAS-PR scores in the 150-225 mg group were significantly greater than placebo at week 6 (44 vs 60 mm; P < 0.001). The number needed to treat (NNT) for 50% pain intensity reduction with venlafaxine ER 150-225 mg was 4.5 at week 6. Nausea and somnolence were the most common treatment-emergent adverse events. Seven patients on venlafaxine had clinically important ECG changes during treatment. Venlafaxine ER appears effective and safe in relieving pain associated with diabetic neuropathy. NNT values for higher dose venlafaxine ER are comparable to those of tricyclic antidepressants and the anticonvulsant gabapentin. Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. However, adverse effects are a major problem. Venlafaxine has no anticholinergic effects and could have a better compliance. The aim of the study was to evaluate the effectiveness of venlafaxine in neuropathic pain. The study was a randomized, double-blind, crossover comparison of venlafaxine and inactive placebo. The study lasted 10 weeks. The number of tablets (18.75 mg) taken daily was increased by one at a 1 week interval. Pain intensity and pain relief were registered daily by a diary and by a questionnaire and a computer program (Painscreen) on each visit. Adverse effects were evaluated with the diaries and a 10-item list on each visit. Also, anxiety and depression were measured on each visit. Venous blood samples were collected before the treatment and at 4 weeks for the determination of the serum levels of venlafaxine and its three metabolites. Thirteen patients were analysed. The average daily pain intensity as reported in the diary (primary outcome) was not significantly reduced by venlafaxine compared with placebo. However, the average pain relief (diary) and the maximum pain intensity (retrospective assessment by the computer program) were significantly lower with venlafaxine compared with placebo. Anxiety and depression were not affected. Adverse effects did not show significant differences between treatments. The two poor responders had low venlafaxine concentrations whereas the two slow hydroxylizers had high venlafaxine concentrations and excellent pain relief. Thus, higher doses could be used in order to improve pain relief.
                Copyright 2002 European Federation of Chapters of the International Association for the Study of Pain To study in a randomized placebo-controlled design the efficacy of the antidepressant venlafaxine, a serotonin and a weak noradrenaline reuptake inhibitor, in the treatment of atypical facial pain (AFP).
                The study was a randomized, double-blind, crossover comparison of venlafaxine and a placebo. It consisted of 2 treatment periods, each of 4 weeks' duration, separated by a 2-week washout period. Thirty patients suffering from chronic pain who had been diagnosed with AFP after a thorough clinical examination were recruited. Pain intensity and pain relief were registered at 6 visits. Anxiety, depression, and adverse effects were recorded. Venous blood samples were collected at the end of each treatment period for the determination of serum levels of venlafaxine and its metabolites.
                Twenty patients completed the trial. Eight patients discontinued because of adverse effects and 2 patients were excluded because of noncompliance. Two patients completed the trial but were excluded from the analysis because they experienced no pain at the baseline visit. There was no significant difference in pain intensity reduction between the maximum tolerated dose of venlafaxine (75 mg in most cases) and the placebo. Pain relief was significantly greater with venlafaxine than with the placebo treatment. Significantly more escape medication was consumed during the placebo period compared with the venlafaxine period. No significant correlation was found between the serum concentration of the drug and the response to treatment. Anxiety and depression scores did not differ between venlafaxine and placebo treatment. Adverse effects were equally common during both treatments.
                Venlafaxine was only modestly effective in the treatment of AFP. In 47 patients with postherpetic neuralgia (PHN) who had never had an adequate trial of any antidepressant, we performed a randomized, double-blind, parallel design trial comparing desipramine, amitriptyline, and fluoxetine. Patients were titrated to a maximum of 150 mg/day for desipramine and amitriptyline and 60 mg/day for fluoxetine over a 3-week period and then treated for an additional 3 weeks before tapering off study medication. A total of 38 subjects (81%) completed the entire trial. The modified intent-to-treat analysis of percent change in daily diary pain intensity scores showed no significant differences among the 3 drugs (ANOVA P = .120). Desipramine produced the greatest reduction in pain intensity (47%), followed by amitriptyline (38%) and fluoxetine (35%). Clinically meaningful pain relief (moderate or better) was significantly more likely with desipramine (12/15 patients) than with amitriptyline (9/17) or fluoxetine (5/15); chi(2)P = 0.036). The 11 subjects using opioids at study entry had smaller reductions in pain than those not using concomitant opioids. The fluoxetine group had the highest noncompletion rate (33%), with 1 subject hospitalized for hyponatremia. Although the magnitude of pain reduction and the category pain relief rating was not significantly different among the 3 drugs, the tricyclics desipramine and amitriptyline were well tolerated and provided clinically meaningful pain relief in 53% to 80% of subjects.
                Few clinical trials focus on patients who are naïve to an entire class of medication. In this randomized blinded trial, the tricyclic antidepressants desipramine and amitriptyline were compared to the serotonin-selective antidepressant fluoxetine. All 3 drugs reduced PHN pain, with desipramine providing satisfactory relief in 80% of those treated. The aim of this randomized double blind placebo controlled study was to investigate the effectiveness and the safety of venlafaxine XR 75 and 150 mg on ongoing pain and on quantitative sensory tests in 60 patients with neuropathic pain for 8 weeks.
                Evaluation parameters consisted of ongoing pain intensity (VAS), patient satisfaction, side effects, global efficacy and tolerance. Quantitative sensory measurements taken from the affected area before and after the drug treatment included pin-prick hyperalgesia, allodynia, detection and pain thresholds to electrical and heat stimuli, temporal summation of repetitive electrical and heat stimuli.
                A total of 55 patients completed the study. VAS scores decreased significantly compared to the baseline measurements in all groups. There was no significant difference between the groups regarding pain intensity and escape medication. The areas of allodynia and pin-prick hyperalgesia decreased significantly in venlafaxine groups compared to the placebo. There was no significant difference between the groups regarding the detection thresholds (electrical and heat). The pain threshold and the summation threshold to electrical stimuli and the summation threshold to heat stimuli increased significantly following treatment in both venlafaxine groups. In addition, the degree of the temporal summation to electrical and heat stimuli decreased significantly following treatment in both venlafaxine groups compared to the placebo.
                The study showed significant effect of venlafaxine in the manifestations of hyperalgesia and temporal summation, but not on the ongoing pain intensity. Furthermore, the quantitative sensory tests provided complementing information to the clinical measures. Tricyclic antidepressants (TCA) provide less than satisfactory pain relief for postherpetic neuralgia (PHN), and the role of opioids is controversial.
                To compare the analgesic and cognitive effects of opioids with those of TCA and placebo in the treatment of PHN.
                Seventy-six patients with PHN were randomized in a double-blind, placebo-controlled, crossover trial. Each subject was scheduled to undergo three treatment periods (opioid, TCA, and placebo), approximately 8 weeks' duration each. Doses were titrated to maximal relief or intolerable side effects. The primary outcome measures were pain intensity (0 to 10 scale), pain relief (0 to 100%), and cognitive function. Analyses included patients who provided any pain ratings after having received at least a single dose of a study medication.
                Fifty patients completed two periods, and 44 patients completed all three. Mean daily maintenance doses were morphine 91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCA reduced pain (1.9 and 1.4) more than placebo (0.2; p < 0.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%; p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%; p = 0.02).
                Opioids effectively treat PHN without impairing cognition. Opioids and TCA act via independent mechanisms and with varied individual effect. Antidepressant drugs are increasingly used in the management of chronic pain. They are mainly prescribed for cancer-related pain and central pain, e.g. phantom or stump pain, post-herpetic neuropathy. However, no controlled clinical trials have validated their in either pathology. Thus, physicians still do not know whether antidepressants are really effective and which might be best. It is still debated whether the effect of antidepressants in the management of chronic pain is limited to the amelioration of frequently concomitant depression or extends to pain itself. To verify both the analgesic effect of tricyclic antidepressants, and the possible relationship between their antidepressant effect and the relief of central pain, we carried out a randomized, within-patient (cross-over) placebo-controlled study in patients suffering from central pain. The results clearly indicate the better analgesic effect of tricyclic antidepressants over placebo (p less than 0.0001). Within the antidepressants tested, chlorimipramine, a blocker of serotonin reuptake, is significantly more effective (p less than 0.0001) than notriptyline, a blocker of noradrenaline reuptake. Finally, the antinociceptive effect is independent of the effects of the two drugs on the symptoms of depression. We sought to develop an enrichment crossover study design that would allow us to efficiently evaluate and compare promising candidate neuropathic pain drugs. We evaluated the efficacy of gabapentin or tramadol vs. active placebo (diphenhydramine) in subjects with biopsy-proven painful idiopathic small fiber neuropathy (SFN) who were self-reported gabapentin responders. Eligible subjects entered two single blind run-in phases. In the first phase (Period A), subjects were treated with single blinded gabapentin at their prestudy dose followed by a second run-in phase (Period B) in which they were treated with diphenhydramine active placebo. Subjects with >or=3 pain and a >or=30% increase in pain intensity in Period B compared to Period A were then randomized to a double-blind three period cross over trial of gabapentin at pre study dosage, tramadol 50mg QID and diphenhydramine 50mgqhs. Of the 59 subjects enrolled, 41 subjects were excluded: Twenty-three had an insufficient rise in pain intensity in Period B; eight had skin biopsies that did not confirm SFN. Eighteen subjects were randomized into the double-blind, crossover phase. There was a significant treatment effect of gabapentin vs. diphenhydramine (p=0.001) and tramadol vs. diphenhydramine (p=0.018) by the before-bed daily pain score averaged over the final 7 days of each treatment period. We conclude that gabapentin and tramadol were effective in the treatment of painful SFN and that this experimental enrichment paradigm is attractive to screen potential neuropathic pain compounds for efficacy in proof-of-concept studies. Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation. Sertraline may produce dual neurotransmitter effects similar to the serotonin-norepinephrine reuptake inhibitors (SNRIs); however, it has been tested against an SNRI in only 1 previous study, and never at an optimal dose. The objective of the current multisite study was to compare relatively higher doses of sertraline (i.e., 150 mg/day) and venlafaxine extended release (XR) (225 mg/day) in outpatients with major depressive disorder.
                Subjects with DSM-IV major depressive disorder were randomly assigned to 8 weeks of double-blind treatment with sertraline (N = 82) or venlafaxine XR (N = 78). The study ran from January 2002 through January 2003. The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Questionnaire; secondary outcome variables included the 17-item Hamilton Rating Scale for Depression.
                Both treatments led to significant improvement in depressive symptoms and quality-of-life measures. No significant differences were noted between treatment groups for final scores on the primary or secondary measures. The treatment groups did not differ significantly in the percentage of responders (sertraline = 55%, venlafaxine XR = 65%; intent-to-treat [ITT] sample) or remitters (sertra-line = 38%, venlafaxine XR = 49%; ITT sample), although the proportions are similar to those found in earlier selective serotonin reuptake inhibitor (SSRI) vs. venlafaxine meta-analyses. In patients who achieved the maximum dose of drug and maintained it for 3 weeks, response rates were similar to those found at lower doses (sertraline = 59%, venlafaxine XR = 70%); however, remission rates for this sample were comparable for both drug groups (sertraline = 48%, venlafaxine XR = 50%).
                The efficacies of sertraline and venlafaxine XR were comparable. Although response and remission rates did not differ statistically, the rates were analogous to those reported in previous meta-analyses. However, at clinically relevant higher doses, the remission rates were very similar.
                ClinicalTrials.gov identifier NCT00179283. Although antidepressants are widely prescribed as analgesics in chronic back pain, their clinical pharmacology is not well established. Norepinephrine transporter blockade seems to be essential for analgesia, but optimal concentrations are unknown. Fixed-dose studies of serotonin reuptake inhibitors are generally negative, but such studies cannot be interpreted clearly because efficacy might be detected if concentration-response relationships were known. We evaluated (1) the feasibility of conducting a controlled-concentration study of a norepinephrine (desipramine) and a serotonin reuptake (fluoxetine) inhibitor and (2) the relationship between achieved concentrations and analgesic response.
                This single-center, 12-week, double-blind, prospective, controlled-concentration study randomized 121 chronic back pain patients without major depression to active placebo (benztropine mesylate) or to predetermined low, medium, or high concentrations of desipramine (targets were 50, 110, and 150 ng/mL, respectively) or fluoxetine (targets were 100, 200, and 400 ng/mL, respectively). Of these, 83 completed the trial: 38 withdrew primarily due to side effects.
                Manipulation check revealed significant overlap of assigned and achieved concentrations related to drug intolerability. Completers' analysis of achieved concentrations revealed reduction in pain intensity was significantly greater for low-concentration desipramine (<60 ng/mL, mean Descriptor Differential Scale [DDS], 4.5) compared with placebo (DDS 6.2), higher concentrations of desipramine (>60 ng/mL, DDS 7.9), and all concentrations of fluoxetine (P < 0.05, DDS 7.1). Significant improvement in everyday function mirrored findings for pain intensity.
                Preliminary evidence for a low-concentration "therapeutic window" for noradrenergic analgesia may warrant additional study. Previous studies have reported the efficacy of selective serotonin reuptake inhibitors as monotherapy in the treatment of delusional depression. The clinical efficacy of venlafaxine, a serotonin-norepinephrine reuptake blocker, has been demonstrated in the treatment of patients with moderate-to-severe depression, but, to date, no evidence is available about its use in depressed patients with psychotic features.
                Under double-blind conditions, 28 hospitalized patients who met DSM-IV criteria for major depression, severe with psychotic features, were randomly assigned to receive fluvoxamine or venlafaxine, 300 mg/day, for 6 weeks. Severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D) and the Dimensions of Delusional Experience Rating Scale (DDERS) administered at baseline and every week thereafter. Side effects were also recorded. Clinical response was defined as a reduction of the scores in the 21-item HAM-D to 8 or below and in the DDERS to 0.
                At study completion, the response rates were 78.6% (N = 11) and 58.3% (N = 7) for fluvoxamine and venlafaxine, respectively. No significant difference was found between drugs (Fisher exact test, p = .40). Analysis of covariance on HAM-D scores did not reveal a significantly different decrease of depressive symptomatology between the 2 treatment groups (p = .14). Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded. The overall safety profile of both fluvoxamine and venlafaxine was favorable.
                The results of this pilot double-blind trial show that fluvoxamine is useful in the treatment of delusional depression and suggest that venlafaxine may also be an effective compound in the treatment of this disorder. The latter finding, although promising, warrants further replication in a larger sample of patients. Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied.
                Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels.
                Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit.
                The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.
                Copyright 2003 Massachusetts Medical Society The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P=0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain. This study aimed: 1) to compare the analgesic efficacy and profile of two antidepressants with the same mechanism of action (SSRI: selective serotonine reuptake inhibitors): fluoxetine vs fluvoxamine; 2) to investigate the relationship between analgesic efficacy and antidepressant effects in both drugs; 3) to evaluate the relationship between the analgesic profile and the quality (global or neuropathic) of pain.
                Fifty-three depressed patients were randomly treated with 20 mg/die of fluoxetine and 100 mg/die of fluvoxamine for chronic pain. Forty subjects (20 with fluoxetine and 20 with fluvoxamine) completed the 2-month study and were followed up on day 14, 28 and 56 of treatment. The intensity and quality of pain was assessed using Quid and depression-anxiety symptoms with the Hamilton Rating Scale (HAMD).
                The intensity and overall quality of pain deteriorated at day 14 in the fluvoxamine group and improved in those treated with fluoxetine. However, a comparable level of analgesia was achieved with both drugs at 2 months. After 2 weeks the neuropathic component of pain improved in patients treated with fluvoxamine. The improvement in pain observed in patients treated with fluoxetine depended on an improvement in depressive symptoms, whereas this relationship was not observed in the fluvoxamine group.
                Although a comparable level of analgesia was observed after two months of treatment, the two drugs show different analgesic profiles. Their analgesic action appears to depend on different mechanisms. To test the hypotheses that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than an active placebo, diphenhydramine.
                Randomized, controlled, double blind, triple crossover 8-week trial.
                Veterans Affairs medical center.
                Community dwelling adults with spinal cord injury (N=38) were recruited by telephone, letters, and flyers.
                Eight-week trial each of amitriptyline, gabapentin, and diphenhydramine.
                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).
                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.
                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. Escitalopram is the most selective serotonin reuptake inhibitor (SRI) antidepressant available. Venlafaxine is a non-selective SRI that also inhibits noradrenergic re-uptake. This study compared escitalopram and venlafaxine extended release (XR) in depressed outpatients at the highest doses recommended in the United States.
                In this randomized trial, patients (diagnosis of DSM-IV-defined major depressive disorder; baseline Hamilton Rating Scale for Depression score of >/= 20) received 1 week of single-blind placebo treatment, followed by 8 weeks of double-blind, fixed-dose treatment with either escitalopram or venlafaxine XR (rapidly titrated to 20 mg/day and 225 mg/day, respectively, in accordance with prescribing information). The primary efficacy variable was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Data were collected from May to December 2002.
                Mean baseline MADRS scores for the escitalopram (N = 97) and venlafaxine XR (N = 98) groups were 30.7 and 30.0, respectively. There were no significant differences in measures of efficacy between the 2 antidepressants. Mean changes from baseline to endpoint in MADRS total score for escitalopram and venlafaxine XR were -15.9 and -13.6, respectively. Remission (MADRS score of </= 10) rates at endpoint were 41.2% for escitalopram and 36.7% for venlafaxine XR. Response (>/= 50% reduction from baseline MADRS score) rates for the escitalopram and venlafaxine XR groups were 58.8% and 48.0%, respectively. Tolerability measures favored escitalopram over venlafaxine XR treatment. The venlafaxine XR group had a higher incidence than the escitalopram group of treatment-emergent adverse events (85.0% vs. 68.4%) and discontinuation due to adverse events (16.0% vs. 4.1%; p <.01).
                Results of this study indicate that, when titrated rapidly to their maximum recommended doses, escitalopram is at least as effective as venlafaxine XR and significantly better tolerated. These results do not support the hypothesis that nonselective SRIs have greater efficacy than selective SRIs. To date, no universally applicable recommendations are available for the treatment of patients with postherpetic neuralgia. A mixture of clinical anecdotes, experimental findings and observations from clinical trials form the basis of the medical arsenal for this condition. Tricyclic antidepressants are commonly used, and clinical experience and several investigations have documented their effectiveness. Today, single entity antidepressants, which can be combined with neuroleptics to increase analgesia, are generally recommended for the treatment of postherpetic neuralgia. Some authors also recommend the additional administration of an opioid if analgesia is inadequate. Just over a decade ago, opioids were considered ineffective for the treatment of neuropathic pain; however, more recent investigations relating to the use of opioids, primarily in the treatment of nontumour-related chronic pain, have led to a revision of their use in neuropathic pain. Nevertheless, the use of opioid therapy for neurogenic pain remains controversial. Tramadol is a synthetic, centrally acting analgesic with both opioid and nonopioid analgesic activity. The nonopioid component is related to the inhibition of noradrenaline (norepinephrine) reuptake and stimulation of serotonin (5-hydroxytryptamine; 5-HT) release at the spinal level. In this regard, there are parallels with antidepressants, which are believed to potentiate the effect of biogenic amines in endogenous pain-relieving systems. There is evidence that, in tramadol, both mechanisms act synergistically with respect to analgesia. The aim of this pilot study was to investigate, for the first time, the analgesic efficacy and tolerability of tramadol, compared with the antidepressant clomipramine, in the treatment of postherpetic neuralgia. If necessary, clomipramine was used in combination with the neuroleptic levomepromazine. The study allowed individualised dosages at predetermined intervals up to a maximum daily dose of tramadol 600mg and clomipramine 100mg, or clomipramine 100mg with or without levomepromazine 100mg. 21 (60%) of 35 randomised patients (> or = 65 years) received the study medication over the 6-week period [tramadol n = 10; clomipramine with or without levomepromazine) n = 11]. After 3 weeks' treatment the dosage in both groups remained almost constant for the rest of the 6-week treatment phase (mean daily dose: tramadol 250 to 290mg; clomipramine 59.1 to 63.6mg). Only 3 patients required the combination of clomipramine and levomepromazine. At the outset, both groups recorded an average pain level of 'moderate' to 'very severe'. In correlation with increasing the study medication, this had decreased to 'slight' by the end of the treatment, when 9 of 10 patients in the tramadol group and of 6 of 11 patients in the clomipramine group retrospectively rated their analgesia as excellent, good or satisfactory. The psychological/physical condition of the patients did not change significantly during tramadol treatment. Sensitivity and depression parameters decreased in the clomipramine group. The incidence of adverse events for all patients was similar in both groups (tramadol 76.5%; clomipramine with or without levomepromazine 83.3%). In conclusion, tramadol would appear to be an interesting therapeutic alternative for pain relief in postherpetic neuralgia, particularly in patients who are not depressed. In clinical practice, tramadol and clomipramine can best be used differentially. For example, tramadol could be the drug of first choice in patients with obvious cardiovascular disease (not an uncommon problem in the > or = 65 year age group) in whom antidepressants are contraindicated, and similarly in patients in whom an antidepressant effect is not required. (ABSTRACT TRUNCATED) The comparative efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) was recently debated. Meta-analyses, based mainly on fluoxetine comparator data, suggest that the SNRI venlafaxine has superior efficacy to SSRIs in treatment of major depression.
                To compare quality of life (QOL), efficacy, safety, and tolerability associated with sertraline and venlafaxine extended release (XR) for treatment of DSM-IV major depression.
                This was an 8-week, double-blind, randomized study of sertraline (50-150 mg/day) versus venlafaxine XR (75-225 mg/day), followed by a 2-week taper period. Subjects were recruited from 7 sites in Turkey and 6 sites in Australia between October 2002 and July 2003. The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Questionnaire. Secondary outcome measures included measures of depression (including response and remission), anxiety, pain, safety (e.g., blood pressure), and tolerability (e.g., discontinuation symptoms).
                A total of 163 subjects received study treatment (women, 69%; mean age, 37.0 [SD = 12.9] years). No significant differences in QOL or efficacy were noted between treatments on the primary or secondary endpoints for the total study population or the anxious depression and severe depression subgroups. A priori analyses of symptoms associated with treatment discontinuation demonstrated no difference between treatment groups. However, in post hoc analyses, sertraline was associated with less burden of moderate to severe discontinuation symptoms. Venlafaxine XR was associated with a relative increase in mean blood pressure (supine diastolic blood pressure, -4.4 mm Hg difference at week 8/last observation carried forward).
                Sertraline and venlafaxine XR demonstrated comparable effects on QOL and efficacy in treatment of major depression, although sertraline may be associated with a lower symptom burden during treatment discontinuation and a reduced risk of blood pressure increase. We compared the efficacy and tolerability of venlafaxine XR with that of fluoxetine in a multicenter, randomized, double-blind, placebo-controlled study in depressed outpatients.
                Outpatients, 18 years and older, who met DSM-IV criteria for major depressive disorder were included (n = 301 randomized; 232 completed). Patients were randomly assigned to eight weeks of treatment with either venlafaxine XR 75-225 mg/day (n = 100), fluoxetine 20-60 mg/day (n = 103), or placebo (n = 98). The primary efficacy outcome measures were the final ratings on the Hamilton Rating Scale for Depression (HAM-D21) total score, HAM-D21 depressed mood item, Montgomery-Asberg Depression Rating Scale total score, and Clinical Global Impressions Scale.
                Withdrawal from the study due to adverse events occurred in 6% of the patients in the venlafaxine XR group and 9% of the patients in the fluoxetine group. Patients treated with venlafaxine XR, but only rarely those treated with fluoxetine, had statistically significant improvements in their depression ratings compared with placebo at the end of the study. The percentages of patients who achieved full remission of their depression (HAM-D21 total score < or = 7) at the end of treatment were 37%, 22% and 18% for the venlafaxine XR, fluoxetine and placebo groups, respectively. The differences in remission rates between venlafaxine XR and the other groups were statistically significant (p < 0.05).
                The superior remission outcome observed with venlafaxine XR treatment needs to be replicated in additional studies.
                Venlafaxine XR is a well-tolerated and efficacious treatment for depression. The results of this study suggest that venlafaxine XR is as well-tolerated as fluoxetine but may have some efficacy advantages over fluoxetine. Postmastectomy pain syndrome (PMPS) is a neuropathic pain syndrome that may develop following breast surgery. Venlafaxine has been shown to be efficacious in the management of PMPS. The preemptive administration of venlafaxine has been shown to be efficacious in reducing the incidence of neuropathic pain in the rat model. We examined the efficacy of administering either venlafaxine or placebo for two weeks starting the night before surgery to 100 patients scheduled for either partial or radical mastectomy with axillary dissection. Patients were administered PCA morphine for the first 24 hours following surgery and then acetaminophen/oxycodone tablets. Pain scores were recorded at rest and movement on day 1, at 1 month, and at 6 months after surgery. At 6 months postoperatively, the presence of pain in the chest, arm, and axilla; edema; decreased sensation in the operative area; and phantom breast pain were recorded. There was no difference in postoperative opioid use. Pain scores with movement were lower in the venlafaxine group at 6 months. Pain scores at all other time intervals were similar. There was a significant decrease in the incidence of chest wall pain (55% vs. 19%, P = 0.0002), arm pain (45% vs. 17%, P = 0.003), and axilla pain (51% vs. 19%, P = 0.0009) between the control group and the venlafaxine group, respectively. No significant differences were noted between the two groups with regard to edema, phantom pain, or sensory changes. We conclude that the perioperative administration of venlafaxine beginning the night prior to surgery significantly reduces the incidence of PMPS following breast cancer surgery. The relative efficacy of psychotherapy and combined therapy in the treatment of depression is still a matter of debate.
                To investigate whether combined therapy has advantages over psychotherapy alone.
                A 6-month randomised clinical trial compared Short Psychodynamic Supportive Psychotherapy (n=106) with combined therapy (n=85) in ambulatory patients with mild or moderate major depressive disorder diagnosed using DSM-IV criteria. Antidepressants were prescribed according to a protocol providing four successive steps in case of intolerance or inefficacy: venlafaxine, selective serotonin reuptake inhibitor, nortriptyline and nortriptyline plus lithium. Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression, the Clinical Global Impression of Severity and of Improvement, and the depression sub-scale of the Symptom Checklist.
                The advantages of combining antidepressants with psychotherapy were equivocal. Neither the treating clinicians nor the independent observers were able to ascertain them, but the patients experienced them clearly.
                The advantages of combining antidepressants with psychotherapy are equivocal. To evaluate the effectiveness and safety of bupropion sustained-release (SR) for the treatment of neuropathic pain.
                This single-center, outpatient, randomized, double-blind, placebo-controlled, crossover study consisted of two phases. Forty-one nondepressed patients with neuropathic pain spent 6 weeks in each phase in random order and received identical tablets of 150 mg bupropion SR or placebo. Patients were instructed to take one tablet once daily for 1 week followed by one tablet twice daily for 5 weeks.
                While the patients took bupropion SR, neuropathic pain relief was improved or much improved in 30 (73%) patients, and one of these patients became pain-free. The mean average pain score at baseline was 5.7, which remained unchanged at the end of week 6 with placebo, but decreased by 1.7 points to 4.0 (p < 0.001) during therapy with bupropion SR. Pain relief with bupropion SR was significant at week 2 (p < 0.05) and continued throughout weeks 3 through 6 (p < 0.001). A significant decrease in interference of pain on quality of life was observed while patients were receiving bupropion SR compared with placebo. Side effects experienced with bupropion SR were not dose-limiting and consisted primarily of dry mouth, insomnia, headache, gastrointestinal upset, tremor, constipation, and dizziness.
                This placebo-controlled crossover trial showed that bupropion SR (150-300 mg daily) was effective and well tolerated for the treatment of neuropathic pain. The aim of this double-blind study was to compare the efficacy and safety of venlafaxine vs. fluoxetine in the treatment of patients with depression and anxiety. A total of 146 moderately depressed patients with associated anxiety were randomized to receive 75 mg/d venlafaxine or 20 mg/d fluoxetine for 12 wk. Dose increases were permitted after 2 wk of treatment, to 150 mg/d venlafaxine and 40 mg/d fluoxetine, to optimize response. At the final visit, a statistically significantly greater efficacy of venlafaxine over fluoxetine was observed on depressive symptoms and concomitant anxiety, and 75.0 and 50.7% of patients administered venlafaxine and fluoxetine, respectively, showed an overall response. A sustained response (for at least 2 wk), present at the end of the study was achieved in 57.8 and 43.3% of patients in the venlafaxine and fluoxetine groups, respectively, and at the final visit, 59.4 and 40.3% of patients, respectively, were in remission (virtually asymptomatic). Dose increases were required by a greater percentage of patients in the fluoxetine group (52.9%), than in the venlafaxine group (37.1%), and in those patients whose dose was increased, a higher efficacy was again observed with venlafaxine. Venlafaxine and fluoxetine were well tolerated, with the most frequently experienced adverse events being nausea and headache. Fewer patients in the venlafaxine group than in the fluoxetine group reported at least one adverse event (55.7 and 67.1% patients, respectively). Venlafaxine therefore proved to be significantly more effective than fluoxetine in improving depressive symptoms and concomitant anxiety. The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence.
                A multi-arm, modified blinded, placebo-controlled design was used.
                The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU).
                Participants met criteria for cocaine dependence during a 2-week screening period.
                Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study.
                Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period.
                None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated.
                This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups. The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis. Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis, but this is the first report with sertraline. Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period. Subjects were then randomized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period. Subjects completed a daily diary reporting the occurrence, severity, and degree of impairment associated with migraine. The headache index, a composite measure of migraine frequency and severity, scores did not significantly improve between assessments at baseline (20.8 +/- 14.88), 8 weeks (17.6 +/- 12.27), and 12 weeks (16.7 +/- 6.38) in the treatment group (n=6) (P=0.956). This finding is compared to other studies with the serotonin selective reuptake inhibitors, fluoxetine, fluvoxamine, and paroxetine. The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers, tricyclic antidepressants, or divalproex sodium, but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective. Based on preliminary evidence of its usefulness in treatment-resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12-week double-blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open-label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double-blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery-Asberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =-7.2, baseline =29.6), in comparison to olanzapine (-4.8, P=.03), fluoxetine (-4.7, P=.03), or venlafaxine (-3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (-14.1 vs. -7.7, P<.001). Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (-14.6) versus olanzapine (-9.4, P<.001) versus fluoxetine (-10.7, P=.006) versus venlafaxine (-14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low-dose OFC all appeared to be similarly effective. In this randomized, open-label, 8-week comparative study, the efficacy and safety of venlafaxine and fluoxetine were assessed in outpatients with major depression. One hundred forty-five patients were assigned to receive venlafaxine 37.5 mg twice daily or fluoxetine 20 mg once daily. On day 15, if clinically indicated to improve patient response, the dosage could be increased at the investigator's discretion to venlafaxine 75 mg twice daily or fluoxetine 40 mg once daily. One hundred forty-five patients were evaluated for safety and 110, for efficacy. The mean age was 37 years, and 70% of the patients were female. In both treatment groups, mean scores on the Hamilton Depression Rating Scale decreased significantly between baseline (27.8, venlafaxine; 29.2, fluoxetine) and the end of the study (8.7, venlafaxine; 8.2, fluoxetine). Similarly, mean scores on the Montgomery-Asberg Depression Rating Scale decreased significantly between baseline (31.4, venlafaxine; 31.6, fluoxetine) and the end of the study (8.3, venlafaxine; 7.6, fluoxetine). In venlafaxine patients, the most common adverse events were nausea (44.3%), headache (40.0%), insomnia (31.4%), dizziness (30.0%), and dry mouth (22.9%); in fluoxetine patients, they were headache (32.0%), nausea (28.0%), insomnia (24.0%), anxiety (21.3%), sleepiness (20.0%), and generalized tremor (20.0%). The results of this study indicate that venlafaxine is effective and well tolerated for the treatment of major depression at doses of 37.5 or 75 mg twice daily and not significantly different from fluoxetine 20 or 40 mg once daily. This double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with selective serotonin reuptake inhibitors (SSRIs)/venlafaxine in 58 patients with major depressive disorder, comorbid anxiety symptoms (HAM-A-14 score > or =14), and residual depressive symptoms (HAM-D-17 score > or =18, CGI-S score > or =4). Patients had received an SSRI/venlafaxine (at a predefined therapeutic dose) for > or =6 weeks. Overall, 62% (18/29) of quetiapine- and 55% (16/29) of placebo-treated patients completed the study. The mean change in HAM-D and HAM-A total scores from baseline to Week 8 (primary endpoint) was significantly greater with quetiapine (mean dose 182 mg/day) than placebo: -11.2 vs. -5.5 (P=.008) and -12.5 vs. -5.9 (P=.002), respectively. The onset of quetiapine efficacy (HAM-D/HAM-A/CGI-I) was rapid (by Week 1) and continued through to Week 8. Significant differences (P<.05) from baseline to Week 8 were observed between groups in 7/17 HAM-D (including feelings of guilt, suicide) and 6/14 HAM-A items (including tension, cardiovascular symptoms). Response (> or =50% decrease in total score) was higher for quetiapine than placebo: HAM-D, 48% vs. 28% (not significant, NS); HAM-A, 62% vs. 28% (P=.02). Remission (total score < or =7) was higher for quetiapine than placebo: HAM-D, 31% vs. 17% (NS); HAM-A, 41% vs. 17% (NS). CGI-S, CGI-I, and the Global Assessment Scale showed that quetiapine was significantly more effective than placebo. For quetiapine, adverse events (AEs) were similar to those previously observed; sedation/somnolence/lethargy was the most commonly reported. Here quetiapine was shown to be effective as augmentation of SSRI/venlafaxine therapy in patients with major depression, comorbid anxiety, and residual depressive symptoms, with no unexpected tolerability issues. Further studies are warranted.
                2006 Wiley-Liss, Inc Transdermal therapeutic system-fentanyl (TTS-F) has been extensively studied in cancer pain management. However, few studies have addressed the long-term management of noncancer pain, especially when it relates to neuropathic pain. A total of 529 patients were recruited into this prospective open-label study to determine the safety and effectiveness of TTS-F in relation to quality-of-life (QOL) stratified according to pain type and etiology. TTS-F significantly improves QOL within 28 days, and pain management within 48 hours. The frequency of side effects rapidly decreases over time, and patients not experiencing adequate pain management are identified within 28 days. The median duration of therapy for effective pain management was 10 months, and 90% of patients sustained such efficacy. TTS-F offers statistically significant increases in QOL-Short Form 12 (including the Physical Component Scale and Mental Component Scale measures) and pain control (Greek Brief Pain Inventory) from one time point to the next (P <.0001). These improvements are not influenced by pain type or etiology. TTS-F is a safe and effective pain management system independent of patient characteristics and demographic factors. What is of most importance is that in those patients with neuropathic pain, for whom opioids have long been thought to be ineffective, similar effectiveness is demonstrated when compared to patients with nociceptive pain. Patients who receive radiotherapy for head and neck cancer are likely to develop painful mucositis. The pain is characterized by a burning or stinging sensation similar to neuropathic pain sensations. The purpose of the present study was to compare the analgesic effect of a tricyclic antidepressant (TC), commonly used in the treatment of neuropathic pain, with the effect of opioids on radiation-induced mucositis pain. Forty-three patients receiving 66-68 Gy external radiation according to the DAHANCA guidelines (the Danish Head and Neck Cancer Study Group) were randomized to either morphine or TC when mucositis pain was insufficiently managed with weak analgesics. Patients with insufficient pain control in either treatment arm received supplementary medication from the opposite treatment arm. Pain was evaluated weekly using a VAS scale and the McGill Pain Questionnaire. The degree of mucositis and the degree of depression were measured at the same time intervals. Twenty-two patients entered the opioid arm and 21 the TC arm. Two patients in each arm were non-evaluable. VAS pain scores were significantly reduced in the opioid treatment arm one week after randomization (p = 0.01). Eight patients in the TC arm were managed with TC alone, but for 11 patients it was necessary to add morphine. The 20 evaluable patients in the morphine arm required no additional treatment. There were no significant differences in side effects between the two groups. Higher pain scores in the TC arm, but not in the opioid arm, were significantly correlated with higher BDI scores. Some head and neck cancer patients with radiation-induced nucositis pain may have sufficient pain control on TC alone. This might be useful in patients with relative counter-indications to opioid treatment. Forty-three patients with peripheral neuropathic pain, exclusively pain reduced by spinal cord stimulation (SCS), were switched into a painful state after SCS inactivation. This mode was used to assess the pain-relieving effect of carbamazepine (CMZ) and opioids in a double-blinded, placebo-controlled trial. In Phase 1, the patients were randomly allocated to receive either CMZ (600 mg/d) or placebo during an SCS-free period of 8 days. In Phase 2, after a CMZ elimination interval of 7 days, 38 patients received either sustained-release morphine (90 mg/d) or placebo for 8 days. In cases of intolerable pain, the patients were authorized to reactivate their SCS. The pain intensity was rated on a numeric analog scale. In 38 patients who completed Phase 1, significant delay in pain increase was observed in the CMZ group as compared with placebo (P = 0.038). In Phase 2, the trend observed with morphine was insignificant (P = 0.41). Two CMZ patients and one morphine patient showed complete pain relief and preferred to continue the medication. Thirty-five patients returned to SCS. We conclude that CMZ is effective in peripheral neuropathic pain. Morphine obviously requires larger individually titrated dosages than those used in this study for results to be adequately interpreted. Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients.
                To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain.
                Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997.
                Sixteen US outpatient clinical centers.
                A total of 229 subjects were randomized.
                A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study.
                The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events.
                One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group).
                Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy. Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord.
                To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP).
                In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed.
                Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient's Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered.
                This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain. This was an 8-week, multicenter, randomized, double-blind, parallel-group study of the efficacy and tolerability of venlafaxine and fluoxetine.
                Outpatients with DSM-III-R major depression, a minimum score of 20 on the 21-item Hamilton Rating Scale for Depression (HAM-D), and depressive symptoms for at least 1 month were eligible. Patients were randomly assigned to treatment with venlafaxine, 37.5 mg twice daily, or fluoxetine, 20 mg once daily. The dose could be increased to venlafaxine, 75 mg twice daily, or fluoxetine, 20 mg twice daily, after 3 weeks for a poor response. The primary efficacy variables were the final on-therapy scores on the HAM-D, Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions Severity of Illness (CGI-S) and Improvement (CGI-I) scales.
                Three hundred eighty-two patients were randomly assigned to therapy and included in the intent-to-treat analysis. Both venlafaxine and fluoxetine produced significant reductions from baseline to day 56 in mean HAM-D, MADRS, and CGI-S scores, but no significant differences were noted between groups. Among patients who increased their dose at 3 weeks, significantly (p < .05) more patients taking venlafaxine than taking fluoxetine had a CGI-I score of 1 (very much improved) at the final evaluation. The most frequent adverse events were nausea, headache, and dizziness with venlafaxine and nausea, headache, and insomnia with fluoxetine.
                These results support the efficacy and tolerability of venlafaxine in comparison with fluoxetine for treating outpatients with major depression. Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective.
                We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period.
                After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients.
                Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain. Stimulating the human cortex using transcranial magnetic stimulation (TMS) temporarily reduces clinical and experimental pain; however, it is unclear which cortical targets are the most effective. The motor cortex has been a popular target for managing neuropathic pain, while the prefrontal cortex has been investigated for an array of nociceptive pain conditions. It is unclear whether the motor cortex is the only effective cortical target for managing neuropathic pain, and no published studies to date have investigated the effects of prefrontal stimulation on neuropathic pain.
                This preliminary pilot trial employed a sham-controlled, within-subject, crossover design to evaluate clinical pain as well as laboratory pain thresholds among four patients with chronic neuropathic pain. Each participant underwent three real and three sham 20-minute sessions of 10 Hz left prefrontal repetitive TMS. Daily pain diaries were collected for 3 weeks before and after each treatment phase along with a battery of self-report pain and mood questionnaires.
                Time-series analysis at the individual patient level indicated that real TMS was associated with significant improvements in average daily pain in 3 of the 4 participants. These effects were independent of changes in mood in two of the participants. At the group level, a decrease of 19% in daily pain on average, pain at its worst, and pain at its least was observed while controlling for changes in mood, activity level and sleep. The effects of real TMS were significantly greater than sham. Real TMS was associated with increases in thermal and mechanical pain thresholds, whereas sham was not. No statistically significant effects were observed across the questionnaire data.
                The prefrontal cortex may be an important TMS cortical target for managing certain types of pain, including certain neuropathic pain syndromes. Clinical trials of the efficacy of antidepressant drugs in patients with chronic low back pain have had mixed results, possibly because of the different mechanisms of action of the drugs that have been studied. Because bupropion has a mechanism of action that differs from other antidepressants and has shown efficacy in neuropathic pain, a randomized, placebo-controlled, 2-period crossover trial was conducted to evaluate its efficacy in subjects with chronic low back pain. The primary efficacy variable was mean daily diary pain intensity ratings, and secondary pain intensity and relief outcomes included weekly pain intensity ratings, the McGill Pain Questionnaire (MPQ) Present Pain Intensity scale, pain relief ratings, and satisfaction with pain relief ratings. Adverse events were also assessed throughout the trial. Analyses were performed of an intention-to-treat sample of 44 patients, only 3 of whom met criteria for neuropathic low back pain. Daily and weekly pain intensity ratings, the MPQ Present Pain Intensity scale, and pain relief ratings were not significantly different following treatment with bupropion sustained release (SR) vs. placebo. These results suggest that bupropion SR was not significantly better than placebo in the treatment of patients with non-neuropathic chronic low back pain.
                Antidepressant medications that have both noradrenergic and serotonergic effects appear to have greater efficacy in patients with chronic low back pain than those with only serotonergic activity. We studied bupropion because it inhibits the reuptake of both norepinephrine and dopamine, but found no evidence of efficacy in patients with non-neuropathic chronic low back pain. To evaluate the safety and efficacy of gabapentin and venlafaxine in the treatment of painful diabetic neuropathy in patients whose pain did not improve with gabapentin monotherapy.
                (1) A randomized, double-blind, placebo-controlled, 8-week clinical trial comparing gabapentin versus placebo to define a patient population whose pain did not improve with monotherapy; (2) a second 8-week trial comparing gabapentin plus venlafaxine with gabapentin plus placebo; (3) a third uncontrolled 8-week trial of patients who did not improve on gabapentin monotherapy and then received venlafaxine in addition to gabapentin.
                (1) Gabapentin-treated patients showed statistically significant improvement in pain reduction as well as improvement in quality of life and mood disturbance when compared with placebo-treated patients; (2) patients who received gabapentin plus venlafaxine showed significant improvement in pain reduction, mood disturbance, and quality of life when compared with patients treated with gabapentin plus placebo; (3) patients who received gabapentin plus venlafaxine showed significant improvement in pain reduction, mood disturbance, and quality of life.
                (1) Gabapentin is efficacious in the treatment of painful diabetic neuropathy; (2) and (3) in patients who do not respond to gabapentin monotherapy, the addition of venlafaxine is also efficacious. To compare the efficacy of antidepressant drugs and generic counselling for treating mild to moderate depression in general practice. To determine whether the outcomes were similar for patients with randomly allocated treatment and those expressing a treatment preference.
                Randomised controlled trial, with patient preference arms. Follow up at 8 weeks and 12 months and abstraction of GP case notes.
                31 general practices in Trent region.
                Patients aged 18-70 who met research diagnostic criteria for major depression; 103 patients were randomised and 220 patients were recruited to the preference arms.
                Difference in mean Beck depression inventory score; time to remission; global outcome assessed by a psychiatrist using all data sources; and research diagnostic criteria.
                At 12 months there was no difference between the mean Beck scores in the randomised arms. Combining the randomised and patient preference groups, the difference in Beck scores was 0.4 (95% confidence interval -2.7 to 3.5). Patients choosing counselling did better than those randomised to it (mean difference in Beck score 4.6, 0.0 to 9.2). There was no difference in the psychiatrist's overall assessment of outcome between any of the groups. 221/265 (83%) of participants with a known outcome had a remission. Median time to remission was shorter in the group randomised to antidepressants than the other three groups (2 months v 3 months). 33/221 (15%) patients had a relapse.
                Generic counselling seems to be as effective as antidepressant treatment for mild to moderate depressive illness, although patients receiving antidepressants may recover more quickly. General practitioners should allow patients to have their preferred treatment. A growing number of studies report antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The hypothesis that high frequency (20 Hz) rTMS (HF-rTMS) may speed up and strengthen the therapeutic response to sertraline in MD was tested. Twenty eight patients who had not yet received medication for the present depressive episode (n=12) or had failed a single trial of an antidepressant medication (n=16) were started on sertraline and randomised to receive either real of sham HF-rTMS. HF-rTMS was applied to the left dorsolateral prefrontal area in daily sessions (30 trains of 2 s, 20-40 s intertrain interval, at 90% motor threshold) on 10 consecutive working days. The results suggest that in this patient population, HF-rTMS does not add efficacy over the use of standard antidepressant medication. Dysesthetic pain following traumatic myelopathy is characterized by diffuse burning and tingling sensations distal to the level of spinal injury. The dysesthetic pain syndrome (DPS) can compromise performance of functional abilities and inhibit participation in rehabilitation programs. Recent laboratory evidence suggests that antidepressant medications with selective inhibition of serotonin reuptake in the brain may be associated with superior analgesic effect compared to such non-selective agents as amitriptyline. Trazodone hydrochloride is a potent presynaptic serotonin reuptake blocker with few anticholinergic and cardiovascular side effects. This study was a randomized, double-blind, placebo-controlled trial of trazodone hydrochloride for the treatment of DPS. Following a 2-week placebo lead-in period, patients were randomized to a 6-week course of 150 mg trazodone hydrochloride/day or placebo. Evaluations of pain quality and intensity were performed at 2-week intervals, utilizing the McGill Pain Questionnaire, Sternbach Pain Intensity Scale, and Zung Pain and Distress Index. Neurologic examination and assessment of side effects were performed at each evaluation session. No significant changes were noted in reported pain measures between patients allocated to the active drug group and those given placebo during the course of the protocol. However, significantly more patients randomized to trazodone complained of side effects and prematurely terminated their participation in the study. The results of this investigation are consistent with those of other earlier trials which indicate that such antidepressant medications as trazodone hydrochloride which selectively inhibit presynaptic reuptake of serotonin, may not be effective in the control of certain pain syndromes. These results do not preclude the possible utility of these agents in the treatment of other pain syndromes or at higher doses than previously studied. To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain.
                One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opioid analgesics.
                Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P =.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P =.0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%).
                Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids. To understand the relative efficacy of noradrenergic and serotonergic antidepressants as analgesics in chronic back pain without depression, we conducted a randomized, double-blind, placebo-control head-to-head comparison of maprotiline (a norepinephrine reuptake blocker) and paroxetine (a serotonin reuptake blocker) in 103 patients with chronic low back pain. Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects. The intervention consisted of an 8-week course of maprotiline (up to 150 mg daily) or paroxetine (up to 30 mg daily) or an active placebo, diphenhydramine hydrochloride (up to 37.5 mg daily). Patients were excluded for current major depression. Reduction in pain intensity (Descriptor Differential Scale scores) was significantly greater for study completers randomized to maprotiline compared to placebo (P=0.023), and to paroxetine (P=0.013), with a reduction of pain by 45% compared to 27% on placebo and 26% on paroxetine. These results suggest that at standard dosages noradrenergic agents may provide more effective analgesia in back pain than do selective serotonergic reuptake inhibitors. We conducted a randomized, double-blind, placebo-controlled study of the efficacy and safety of once-daily venlafaxine extended release (XR) and fluoxetine in outpatients with major depression and concomitant anxiety.
                Patients who met DSM-IV criteria for major depressive disorder and satisfied eligibility criteria were randomly assigned to once-daily venlafaxine XR, fluoxetine, or placebo for 12 weeks. Efficacy was assessed with the Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions scale.
                Among 359 outpatients, venlafaxine XR and fluoxetine were significantly superior (p < .05) to placebo on the HAM-D total score beginning at week 2 and continuing to the end of the study. Venlafaxine XR but not fluoxetine was significantly better than placebo at week 2 on the HAM-D depressed mood item. At week 12, the HAM-D response rate was 43% on placebo, 67% on venlafaxine XR, and 62% on fluoxetine (p < .05). The HAM-D remission rate was significantly higher (p < .05) at weeks 3, 4, 6, 8, 12, and final evaluation with venlafaxine XR and at weeks 8, 12, and final evaluation with fluoxetine than with placebo. The HAM-A response rate was significantly higher (p < .05) with venlafaxine XR than with fluoxetine at week 12. The incidence of discontinuation for adverse events was 5% with placebo, 10% with venlafaxine XR, and 7% with fluoxetine.
                Once-daily venlafaxine XR is effective and well tolerated for the treatment of major depression and concomitant anxiety and provides evidence for superiority over fluoxetine. To evaluate pregabalin in central neuropathic pain associated with spinal cord injury.
                A 12-week, multicenter study of patients randomized to either flexible-dose pregabalin 150 to 600 mg/day (n = 70) or placebo (n = 67), administered BID. Patients were allowed to remain on existing, stable pain therapy. The primary efficacy variable was the endpoint mean pain score, derived from patients' last 7 days daily pain diary entries. Key secondary endpoints included pain responder rates, the SF-MPQ, sleep interference, mood, and the patient global measure of change.
                The mean baseline pain score was 6.54 in the pregabalin group and 6.73 in the placebo group. The mean endpoint pain score was lower in the pregabalin group (4.62) than the placebo group (6.27; p < 0.001), with efficacy observed as early as week 1 and maintained for the duration of the study. The average pregabalin dose after the 3-week stabilization phase was 460 mg/day. Pregabalin was significantly superior to placebo in endpoint assessments on the SF-MPQ. The > or =30% and > or =50% pain responder rates were higher with pregabalin than placebo (p < 0.05). Pregabalin was associated with improvements in disturbed sleep (p < 0.001) and anxiety (p < 0.05), and more patients reported global improvement at endpoint in the pregabalin group (p < 0.001). Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events.
                Pregabalin 150 to 600 mg/day was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury. Suicidal behavior has been associated with reduced central serotonergic function. Because selective serotonin reuptake inhibitors (SSRIs) enhance serotonergic function, the authors studied the efficacy of an SSRI, paroxetine, in the prevention of recurrent suicidal behavior.
                They conducted a 1-year double-blind study comparing paroxetine (40 mg/day) and placebo in 91 patients who had recently attempted suicide for at least a second time. None of the patients had experienced a major depressive episode or had any other major DSM-III-R axis I diagnoses. At least one cluster B personality disorder was present in 74 patients.
                With adjustment for the number of previous suicide attempts, paroxetine showed significant efficacy in the prevention of recurrent suicidal behavior. Among the patients who had attempted suicide fewer than five times, 12 (36%) in the placebo group (N = 33) and five (17%) in the paroxetine group (N = 30) made a subsequent suicide attempt. Paroxetine was also significantly more effective in patients who met fewer than 15 criteria for cluster B personality disorders than in those who met more than 15 criteria. Overall, paroxetine was not significantly different from placebo in its effect on depressive mood, hopelessness, and anger. However, the data suggest that paroxetine may have some temporary effect in reducing anger.
                This study indicates that enhancing serotonergic function with an SSRI may reduce suicidal behavior in a subgroup of patients who have attempted suicide more than once but who do not suffer from major depression. This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated. Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.
                In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636.
                45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial.
                Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain.
                Canadian Institutes of Health Research. This study was designed to assess the efficacy and safety of pregabalin-a novel alpha(2)-delta ligand with analgesic, anxiolytic, and anticonvulsant activity-for treating neuropathic pain in patients with post-herpetic neuralgia (PHN). Two hundred and thirty-eight patients were randomised into this multicentre, doubleblind, placebo-controlled trial to receive 150 (n=81), 300 mg/day (n=76) pregabalin, or placebo (n=81) for 8 weeks. Among the exclusion criteria was failure to respond to previous treatment for PHN with gabapentin at doses > or =1200 mg/day. Endpoint mean pain scores were significantly reduced in patients receiving 150 or 300 mg/day pregabalin compared with placebo. Efficacy was observed as early as week 1 and was maintained throughout the study. Significantly more patients in both pregabalin groups (150 mg, 26%; 300 mg, 28%) were responders (> or =50% decrease in mean pain score from baseline to endpoint) than in the placebo group (10%). Additionally, by week 1 and for the study's duration, 150 and 300 mg/day pregabalin significantly reduced weekly mean sleep interference scores. More pregabalin-treated patients than placebo-treated patients reported that they were 'much improved' or 'very much improved'. Health-related quality-of-life (HRQoL) measurements using the SF-36 Health Survey demonstrated improvement in the mental health domain for both pregabalin dosages, and bodily pain and vitality domains were improved in the 300 mg/day group. The most frequent adverse events were dizziness, somnolence, peripheral oedema, headache, and dry mouth. Pregabalin efficaciously treated the neuropathic pain of PHN. Additionally, pregabalin was associated with decreased sleep interference and significant improvements in HRQoL measures. This was a 6-week, double-blind, randomized trial of the efficacy and tolerability of venlafaxine and fluoxetine in 109 patients with major depression and melancholia. Hospitalized and day care patients with DSM-IV major depression and melancholia and a baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of > or = 25 were eligible. The doses were venlafaxine 75 mg/day or fluoxetine 20 mg/day from days 1-4, venlafaxine 150 mg/day or fluoxetine 40 mg/day from days 5-10, and venlafaxine 225 mg/day or fluoxetine 60 mg/day from days 11-42. The intention-to-treat analyses included 55 patients on venlafaxine and 54 on fluoxetine. At the final evaluation, 70% of patients with venlafaxine and 66% with fluoxetine had > or = 50% reduction in the MADRS score, and 70% with venlafaxine and 62% with fluoxetine had a Clinical Global Impression (CGI) score of 1 or 2. A CGI improvement score of 1 was observed in 51% of patients with venlafaxine and 32% with fluoxetine (P = 0.018). A final Hamilton Depression Rating Scale (HAM-D) score < 7 was attained in 41% of venlafaxine-treated and 36% of fluoxetine-treated patients. Overall, 22% of patients in each group discontinued therapy, but only 5% on venlafaxine and 9% on fluoxetine discontinued for adverse events. Nausea was reported in 5.5% of venlafaxine-treated patients and 14.8% of fluoxetine-treated patients. Venlafaxine was effective and well tolerated for treating inpatients with major depression and melancholia. Based on remission criteria (HAM-D < 7 or CGI of 1), venlafaxine was superior to fluoxetine. The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain. The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain.
                Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in approximately 40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.
                Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved. Although a significant amount of evidence indicates the efficacy of some antidepressants in treating psychogenic pain and somatoform disorder, very few studies have investigated their possible therapeutic action in burning mouth syndrome (BMS). The purpose of this 8-week, single-blind study was to provide preliminary data on the efficacy and tolerability of amisulpride and the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline for patients with BMS.
                Seventy-six patients with BMS (diagnosed according to the criteria in the literature and integrating the Diagnostic Interview Schedule-Revised for a complete psychiatric assessment), with no possible local or systemic causes and without concurrent major depression, were randomly assigned to receive amisulpride (50 mg/day), paroxetine (20 mg/day), or sertraline (50 mg/day). Efficacy assessments included a visual analogue scale (VAS) for pain intensity, the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), and the Clinical Global Impressions scale (CGI).
                All 3 treatment regimens resulted in a significant improvement from baseline in burning mouth symptoms at week 8 as demonstrated by the quantitative (mean reduction in VAS, HAM-D, and HAM-A scores) and qualitative (percentage of responders) analyses. Amisulpride showed a shorter response latency than the SSRIs. No serious adverse events were reported, and the incidence of side effects did not differ among the 3 groups. None of the patients who received amisulpride withdrew from the trial, whereas withdrawal from the trial occurred within the first week of treatment in 11.5% of patients (N = 3) treated with paroxetine and in 21.7% of patients (N = 5) treated with sertraline.
                The data suggest that amisulpride and SSRIs may be effective treatments for BMS; they are equally effective and equally well tolerated in the short-term treatment of BMS. Amisulpride is associated with better compliance within the first week of treatment and with a shorter response latency in comparison with SSRIs. This finding may indicate that amisulpride is especially useful at the beginning of drug therapy of BMS. Double-blind, placebo-controlled trials are needed to further document the efficacy of amisulpride and SSRIs in the treatment of BMS. In a double-blind, crossover study, the effects of 75 mg amitriptyline alone during 5 weeks on pain intensity were compared with the effects of a combination of 75 mg amitriptyline and 3 mg flupentixol during 5 weeks in 34 patients with somatoform pain disorder. Both treatments resulted in a statistically significant reduction in pain. However, pain reduction in the combined treatment did not differ from that in the treatment with amitriptyline as a single drug. Neither tardive dyskinesias nor other serious side effects were observed. The results do not support the clinical practice of adding low-dose neuroleptics to low-dose antidepressants in the treatment of somatoform pain disorder.
This update has provided additional confirmation on the effectiveness of antidepressants for neuropathic pain and has provided new information on another antidepressant - venlafaxine. There is still limited evidence for the role of SSRIs. Whether antidepressants prevent the development of neuropathic pain (pre-emptive use) is still unclear. Both TCAs and venlafaxine have NNTs of approximately three. This means that for approximately every three patients with neuropathic pain who are treated with either of these antidepressants, one will get at least moderate pain relief. There is evidence to suggest that other antidepressants may be effective but numbers of participants are insufficient to calculate robust NNTs. SSRIs are generally better tolerated by patients and more high quality studies are required.