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PubMed2004

Cannabinoids enhance N-methyl-D-aspartate-induced excitation of locus coeruleus neurons by CB1 receptors in rat brain slices.

We studied the effect of cannabinoids on the activity of N-methyl-d-aspartate (NMDA) receptors in the locus coeruleus from rat brain slices by single-unit extracellular recordings. As expected, NMDA (100 microM) strongly excited (by nine fold) the cell firing activity of the locus coeruleus. Perfusion with the endocannabinoid anandamide (1 and 10 microM) or the anandamide transport inhibitor AM 404 (30 microM) enhanced the NMDA-induced excitation of locus coeruleus neurons. Similarly, the synthetic agonists R(+)-WIN 55212-2 (10 microM) and CP 55940 (30 microM) enhanced the effect of NMDA. In the presence of the CB(1) receptor antagonists SR 141716A (1 microM) or AM 251 (1 microM), the enhancement induced by anandamide (10 microM) was blocked. Our results suggest that cannabinoids modulate the activity of NMDA receptors in the locus coeruleus through CB(1) receptors.

Action Potentials↗
PubMed2004

Non-selective opioid receptor antagonism of the antidepressant-like effect of venlafaxine in the forced swimming test in mice.

The opioid system has been implicated in mood disorders as well as in the mechanism of action of antidepressants. Since the opioid component in venlafaxine (VLX) is still a matter of discussion, we investigated the role of opioid receptors in the antidepressant-like effect of VLX in the forced swimming test in mice. The non-selective opiate antagonist naloxone at high dose (2 mg/kg, s.c.) antagonized the effect of VLX. In contrast, beta-funaltrexamine (40 mg/kg, s.c.), which preferentially blocks mu(1)/mu(2) opioid receptors, naloxonazine (35 mg/kg, s.c.), a selective mu(1) opioid antagonist, naltrindole (10 mg/kg, s.c.), a selective delta opioid antagonist, and Nor-binaltorphimine (10 mg/kg, s.c.), which selectively blocks kappa-opioid receptors, were all ineffective. Thus, although apparently mediated by the opioid system, the behavioural effect of VLX does not involve specific opioid receptors.

Analysis of Variance↗
PubMed2004

Effects of venlafaxine on p90Rsk activity in rat C6-gliomas and brain.

The intracellular actions of the antidepressant, venlafaxine, were studied in C6-gliomas using a phosphoproteomics approach. Long-term pre-treatment of C6-gliomas with venlafaxine followed by an acute challenge with isoproterenol (a beta-adrenoceptor agonist), resulted in increased p90Rsk phosphorylation (three-fold) versus control levels (isoproterenol alone). The effect of venlafaxine pre-treatment on p90Rsk activity was dose-dependent (EC(50)=3.75nM) in C6 gliomas. In rat brain sections, intense immunoreactive phospho-p90Rsk labeling was observed for both neurons and glia, especially in cortical layers II/III and hippocampal formations. In vivo studies demonstrated an intense but similar distribution pattern of phospho-p90Rsk staining after chronic venlafaxine dosing of rats compared to naives and no region-specific drug effect was observed in vivo. In conclusion, our findings suggest that some of the centrally-mediated benefits of venlafaxine in depression may be due to its intracellular properties especially on the neuro-glial circuitry and MAPK/p90Rsk-dependent pathways at an early stage.

Animals↗
PubMed2005

Quetiapine and venlafaxine synergically regulate heme oxygenase-2 protein expression in the hippocampus of stressed rats.

HO-2 is a constitutive isoform of heme oxygenase (HO), a microsomal enzyme that catalyzes the cleavage of the heme ring to form ferrous iron, carbon monoxide, and biliverdin. In contrast to HO-1, which is inducible, HO-2 is not responsive to stimuli tested to date except for prolonged exposure to the adrenal glucocorticoids (GCs). Previous studies have shown that high GC concentrations or stress damage or kill hippocampal neurons. In the present study, it was found that chronic restraint stress decreased HO-2 protein levels in hippocampal neurons, as demonstrated by immunohistochemistry and Western blot analysis. Moreover, our results showed that the combination of 2.5mg/kg of venlafaxine and 5mg/kg of quetiapine effectively prevented the HO-2 protein decrease in hippocampal neurons of stressed rats, whereas either of the drugs alone did not show any effect. At higher dose levels, both quetiapine (10mg/kg) and venlafaxine (5mg/kg) produced significant effects comparable to that of their combination. Quetiapine is an atypical antipsychotic and venlafaxine an antidepressant. In previous studies, these two drugs have been shown to prevent or protect against the stress-induced decrease in hippocampal neurogenesis and BDNF expression. These data suggest that both quetiapine and venlafaxine share the hippocampus as their common target by enhancing hippocampal resilience, which may be impaired in patients with schizophrenia or depression.

Animals↗
PubMed2006

Characterization of cannabinoid-binding sites in zebrafish brain.

We present here the pharmacological characterization of cannabinoid-binding sites in zebrafish brain homogenates using radiolabeled binding techniques. The nonselective agonist [3H]-CP55940 binds with high affinity (KD = 0.50+/-0.06 nM and a Bmax = 1047+/-36.01 fmol/mg protein), displaying one binding site. The slightly CB2 selective agonist [3H]-WIN55212-2 also binds with high affinity to zebrafish brain membranes displaying two different binding sites with affinities KD1 = 0.35+/-0.09 nM and KD2 = 105.81+/-66.36 nM. Competition binding assays using [3H]-WIN55212-2 and several unlabeled ligands were performed. WIN55212-2 significantly displaced the tritiated ligand binding showing the two binding sites observed with its tritiated homologous, while the slightly selective CB1 cannabinoid ligand HU-210, the nonselective cannabinoid ligand CP55940 and the endogenous cannabinoid ligand anandamide presented one binding site. Also, the functionality of these cannabinoid sites was analyzed using the known [35S]GTPgammaS assay. All the agonist used presented an agonist profile and the rank order for potency was HU-210 > WIN55212-2 > CP55940 >anandamide. Our results provide evidence that, although some of the typical cannabinoid ligands for mammalian receptors do not fully recognize the cannabinoid-binding sites in zebrafish brain, the activity of the endogenous zebrafish cannabinoid system might not significantly differ from that displayed by the cannabinoid system described in other species. Hence the study of zebrafish cannabinoid activity may contribute to an understanding of the endogenous cannabinoid system in higher vertebrates.

Animals↗
PubMed2006

Effect of CP55,940 on mechanosensory spinal neurons following chronic inflammation.

Cannabinoid receptor agonists have previously been shown to produce antinociceptive effects in rodent models of inflammatory pain. In the present study, we characterized responses of spinal dorsal horn neurons receiving sensory input from the hind paw in rats that had received intraplantar injection of complete Freund's adjuvant (CFA), and examined effects of the nonselective CB1/2 receptor agonist CP55,940 on spinal neuron responses. Systemic (i.v.) administration of CP55,940 failed to attenuate responses of dorsal horn neurons to noxious mechanical stimulation in naïve rats, but significantly reduced responses in CFA-inflamed rats to 25.78+/-13.7% of vehicle control at a cumulative dose of 0.8 mg/kg (ID50=0.28+/-0.02 mg/kg). Additionally, local administration of CP55,940 (10 microM) to the spinal cord reduced responses of mechanosensory dorsal horn neurons in CFA-inflamed rats to 67.15+/-7.1% of vehicle control. The inhibitory action of CP55,940 on spinal dorsal horn neurons in CFA-inflamed rats was mediated by CB1 receptors since local pretreatment with the CB1 receptor antagonist AM251 (10 microM) blocked this effect, while the CB2 receptor antagonist AM630 (10 microM) was ineffective. Our results suggest that following inflammation, the inhibition of spinal nociceptive transmission by CP55,940 is mediated in part by spinal CB1 receptors, and not spinal CB2 receptors.

Afferent Pathways↗
PubMed2004

Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA ("Ecstasy") in rats.

Cannabinoid-MDMA interactions were examined in male Wistar rats. MDMA (4 x 5 mg/kg or 2 x 10 mg/kg over 4 h on each of 2 days) was administered with or without Delta 9-tetrahydrocannabinol (THC) (4 x 2.5 mg/kg), the synthetic cannabinoid receptor agonist CP 55,940 (2 x 0.1 or 0.2 mg/kg) or the cannabinoid receptor antagonist SR 141716 (2 x 5 mg/kg). Co-administered Delta 9-THC and CP 55,940 but not SR 141716 prevented MDMA-induced hyperthermia, causing a powerful hypothermia. Co-administered Delta 9-THC, CP 55,940 and SR 141716 all tended to decrease MDMA-induced hyperactivity. Co-administered Delta 9-THC provided protection against the long-term increases in anxiety seen in the emergence test, but not the social interaction test, 6 weeks after MDMA treatment. Co-administered Delta 9-THC and CP 55,940, but not SR 141716, partly prevented the long-term 5-HT and 5-HIAA depletion caused by MDMA in various brain regions. SR 141716 administered with CP 55,940 and MDMA prevented the hypothermic response to the CP 55,940/MDMA combination but did not alter the CP 55,940 attenuation of MDMA-induced 5-HT depletion. These results suggest a partial protective effect of co-administered cannabinoid receptor agonists on MDMA-induced 5-HT depletion and long-term anxiety. This action appears to operate independently of cannabinoid CB1 receptors.

Animals↗
PubMed2005

Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.

To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.

Amines↗
PubMed2005

Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores.

Exogenously administered cannabinoids are neuroprotective in several different cellular and animal models. In the current study, two cannabinoid CB1 receptor ligands (WIN 55,212-2, CP 55,940) markedly reduced hippocampal cell death, in a time-dependent manner, in cultured neurons subjected to high levels of NMDA (15 microM). WIN 55,212-2 was also shown to inhibit the NMDA-induced increase in intracellular calcium concentration ([Ca2+](i)) indicated by FURA-2 fluorescence imaging in the same cultured neurons. Changes in [Ca2+](i) occurred with similar concentrations (25-100 nM) and in the same time-dependent manner (pre-exposure 1-15 min) as CB1 receptor mediated neuroprotective actions. Both effects were blocked by the CB1 receptor antagonist SR141716A. An underlying mechanism was indicated by the fact that (1) the NMDA-induced increase in [Ca2+](i) was inhibited by ryanodine, implicating a ryanodine receptor (RyR) coupled intracellular calcium channel, and (2) the cannabinoid influence involved a reduction in cAMP cAMP-dependent protein kinase (PKA) dependent phosphorylation of the same RyR levels that regulate channel. Moreover the time course of CB1 receptor mediated inhibition of PKA phosphorylation was directly related to effective pre-exposure intervals for cannabinoid neuroprotection. Control studies ruled out the involvement of inositol-trisphosphate (IP3) pathways, enhanced calcium reuptake and voltage sensitive calcium channels in the neuroprotective process. The results suggest that cannabinoids prevent cell death by initiating a time and dose dependent inhibition of adenylyl cyclase, that outlasts direct action at the CB1 receptor and is capable of reducing [Ca2+](i) via a cAMP/PKA-dependent process during the neurotoxic event.

Animals↗
PubMed2005

Cannabinoid CB(1) antagonist SR 141716A attenuates reinstatement of heroin self-administration in heroin-abstinent rats.

Rats with a previous history of heroin self-administration were studied to assess interactions occurring between cannabinoids and opioids in an animal model of reinstatement of heroin-seeking behaviour. Rats were trained to self-administer heroin and after a long-term extinction were primed with one of the following non-contingent non-reinforced drug administrations: saline (or vehicle), heroin, synthetic cannabinoid CB(1) receptor agonists (WIN 55,212-2 or CP 55,940), opioid antagonist (naloxone) or CB(1) antagonist (SR 141716A), alone or in combination. After primings, lever-pressing activity was recorded and compared to those observed during previous phases of training and extinction. Results of this study showed that (i) priming injections of heroin (0.1 mg/kg) as well as CB(1) agonists WIN 55,212-2 (0.15 or 0.30 mg/kg) and CP 55,940 (0.05 or 0.1 mg/kg) completely restore heroin-seeking behaviour; (ii) primings of naloxone (1 mg/kg) and SR 141716A (0.3 mg/kg) had no effect when administered alone; (iii) heroin-induced reinstatement was fully prevented by pre-treatment with either naloxone or SR 141716A; (iv) pre-treatment with SR 141716A significantly reduced WIN 55,212-2 and CP 55,940 priming effects. These results suggest that cannabinoid CB(1) receptors play an important role in the mechanisms underlying relapse to heroin-seeking and depict CB(1) antagonists as possible therapeutic agents for use in the prevention of relapse to heroin abuse.

Animals↗
PubMed2005

Cannabinoids augment the release of neuropeptide Y in the rat hypothalamus.

Little is known about the mechanism of action behind the orexigenic activity of cannabinoids. Neuropeptide Y (NPY) is one of the most potent orexigenic factors and is a key mediator in the hypothalamic control of food intake. We examined the effect of cannabinoids on NPY release using a rat hypothalamic explant model. The cannabinoid agonists anandamide (AEA) and CP55,940 both significantly augmented resting and KCl-evoked NPY release. AM251, a cannabinoid receptor antagonist, blocked the augmentation of NPY release elicited by AEA and CP55,940. Additionally, AM251 administered alone, in the absence of exogenous cannabinoid agonists, inhibited NPY release demonstrating the role of endogenous cannabinoids in NPY release. Combined, these findings demonstrate that cannabinoids augment NPY release in the hypothalamus and that this may be a potential mechanism behind the orexigenic activity of cannabinoids.

Analgesics↗
PubMed2006

Depolarization and Ca(2+) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons.

Presynaptic terminals of cerebellar granule neurons are primary targets of cannabinoids, which act through type 1 G alpha(i/o)-coupled cannabinoid receptors (CB1) to modulate glutamate release. To study CB1 signaling investigators use primary cultures of granule neurons, typically grown in medium supplemented with elevated KCl to improve long-term survival. Herein, we demonstrate that CB1 expression and signaling are perturbed under these conditions. Specifically, immunochemical and RT-PCR assays indicate that depolarizing growth conditions decrease CB1 protein, mRNA and CB1-mediated inhibition of adenylyl cyclase compared to cultures grown in physiologic medium containing 5mM KCl. Depolarization-dependent downregulation of CB1 mRNA, like survival, is attenuated by L-type VDCC antagonists but not the Na(+)-channel antagonist, tetrodotoxin. Comparison of oligonucleotide microarrays from cultures grown in 5mM versus 25 mM KCl confirms that depolarization reduces CB1 mRNA, but not mRNAs encoding several G-protein subunits or adenylyl cyclases. However, significant alterations in synaptic signaling proteins that likely lie downstream of CB1 are observed, including K(+) channels, alpha-neurexins, cAMP-GEFII, Munc13-3, secretogranin and synaptotagmin. These findings make a compelling argument to adopt cultures grown in 5mM KCl for future study of CB1 signaling in granule neurons. Further, they suggest that a depolarization and Ca(2+)-dependent signaling pathway represses CB1 gene transcription.

Age Factors↗
PubMed2006

Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21.

The present study evaluates the pharmacological profile of the new neutral cannabinoid CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole -LH-21- on feeding behavior and alcohol self-administration in rats, two behaviors inhibited by cannabinoid CB1 receptor antagonists. Administration of LH-21 (0.03, 0.3 and 3 mg/kg) to food-deprived rats resulted in a dose-dependent inhibition of feeding. Subchronic administration of LH-21 reduced food intake and body weight gain in obese Zucker rats. Acute effects on feeding were not associated with anxiety-like behaviors, or induction of complex motor behaviors such as grooming or scratching sequences, usually observed after central administration of cannabinoid receptor blockers with inverse agonist properties. LH-21 did not markedly reduce alcohol self-administration (30% reduction observed only at a high dose of 10 mg/kg). This pharmacological pattern partially overlaps that of the reference cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, SR141716A, (0.3, 1 and 3 mg/kg) that reduced feeding and alcohol self-administration with similar efficacy. In vitro analysis of blood-brain barrier permeability using a parallel artificial membrane permeation assay demonstrated that LH-21 has lower permeation through membranes than SR141716A. That was confirmed in vivo by studies showing lower potency of peripherally injected LH-21 when compared to SR141716A to antagonize motor depression induced by intracerebroventricular administration of the CB1 agonist CP55,940. The neutral antagonist profile and the lower penetration into the brain of LH-21 favour this class of antagonists with respect to reference inverse agonists for the treatment of obesity because they potentially will display reduced side effects.

Animals↗
PubMed2006

Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition.

The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1-30mg/kg, i.p.), a balanced serotonergic-noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3-100mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03-10mg/kg, i.p.) and desipramine (1-30mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3-10mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or SSRI-NRI combinations, produces synergistic analgesic efficacy.

Adrenergic Uptake Inhibitors↗
PubMed2006

Comparison of subjective perception with objective measurement of olfaction.

OBJECTIVE: To see if nasal peak inspiratory flow rate and subjective sense of smell had any correlation with olfactory thresholds. STUDY DESIGN AND SETTING: A cohort study of 186 normal volunteers was recruited from among staff and visitors at a university hospital. Olfactory thresholds were detected for each subject (103 with eucalyptol and 83 with phenethyl alcohol), along with nasal peak inspiratory flow (PIFR). Subjective sense of smell, along with nasal symptoms, mood, and alertness, were recorded on visual analogue scores. RESULTS: Subjective perception of smell had no correlation with olfactory thresholds detected (P = 0.4057) and the other subjective measures also had no correlation. There was a significant relationship of PIFR to thresholds in the group tested with phenethyl alcohol (P = 0.002). CONCLUSION: As with the sensation of nasal patency, the self-assessment of a subject's sense of smell has poor correlation with their actual olfactory ability. SIGNIFICANCE: A patient's history cannot be relied upon when determining their olfactory ability and formal testing should be performed. EBM RATING: A-1b.

Adolescent↗
PubMed2004

Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat.

The roles of the two cannabinoid receptor subtypes, CB-1 and CB-2, have not been clarified in cannabinoid-mediated analgesia. We investigated the efficacy of the non-selective cannabinoid receptor agonist CP55,940 in the modulation of responses in the rat to both acute pain (tail flick) and neuropathic pain (tactile allodynia following chronic L5/6 spinal nerve ligation). Responses were also assessed in the presence of the CB-1 antagonist SR141716A (SR1) and the CB-2 antagonist SR144528 (SR2). CP55,940 attenuated tactile allodynia (ED(50) 0.04 mg/kg i.t. (95% CI 0.032-0.044 mg/kg), 0.12 mg/kg i.p. (95% CI 0.10-0.15 mg/kg)) and induced thermal antinociception (ED(50) tail flick 0.07 mg/kg i.t. (95% CI 0.05-0.10 mg/kg), 0.17 mg/kg i.p. (95% CI 0.11-0.26 mg/kg)). SR1 0.5 mg/kg i.t. attenuated the antinociceptive effect of CP55,940 in both modalities. However, SR1 1.0 mg/kg i.p. decreased tail flick latency but had no effect on tactile allodynia antinociception. In contrast, SR2 1.0 mg/kg i.p. significantly decreased the effect of i.p. CP55,940 on both tail flick antinociception and tactile allodynia (P<0.005). The combination of SR1 and SR2 (i.p.) had an additive effect in decreasing the antinociception induced by CP55,940 on tail flick responses (P<0.005). These results suggest a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms.

Analgesics↗
PubMed2004

Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study.

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.

Aged↗