Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. A randomized, placebo-controlled trial of bupropion sustained release in chronic low back pain. Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. [Fluoxetine versus fluvoxamine for treatment of chronic pain]. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Desipramine relieves postherpetic neuralgia. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. [Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine]. Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen.
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. Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect. 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. 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. 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 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. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressant agents, but its pain-relieving potential has received little study. Other antidepressant agents--notably amitriptyline--are known to ameliorate postherpetic neuralgia, but those agents are often toxic. In a randomized double-blind crossover design, we gave 26 postherpetic neuralgia patients 6 weeks of treatment with desipramine (mean dose, 167 mg/day) and placebo. Nineteen patients completed both treatments; 12 reported at least moderate relief with desipramine and two reported relief with placebo. Pain relief with desipramine was statistically significant from weeks 3 to 6. Psychiatric interview at entry into the study produced a diagnosis of depression for 4 patients; pain relief was similar in depressed and nondepressed patients and was statistically significant in the nondepressed group alone. We conclude that desipramine administration relieves postherpetic neuralgia and that pain relief is not mediated by mood elevation. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressant agents that have relieved neuropathic pain, may be involved in relief of postherpetic neuralgia. Inositol has been reported to be an effective treatment in depression, and we hypothesized that inositol addition might enhance or speed up response to serotonin selective reuptake inhibitors (SSRI).
                Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol. Hamilton Depression Rating Scale was used as an assessment tool at baseline, and 1, 2, 3, and 4 weeks.
                No significant difference was found between the two treatment groups.
                Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [e.g., monoamine oxidase inhibitors (MAOI) plus tricyclic antidepressants (TCA), TCA plus lithium]. By contrast, augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol. 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) Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs).
                To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants.
                In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163).
                Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype.
                It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression. 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 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.