Efficacy and safety of duloxetine in Chinese patients with chronic pain due to osteoarthritis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: We assessed the efficacy and safety of duloxetine (60 mg, once daily), compared with placebo, during a 13-week treatment period in Chinese patients with chronic pain due to osteoarthritis (OA). DESIGN: Patients were at least 40 years old (male or female) who met American College of Rheumatology clinical and radiographic criteria for the diagnosis of OA of the knee or hip. The primary efficacy measure in this phase 3, randomized, double-blind, placebo-controlled clinical trial was assessment of pain severity by the Brief Pain Inventory (BPI) 24-h Average Pain rating. The clinical trial was conducted at 17 study centers. Statistical approaches included mixed-effects model repeated measures and analysis of covariance. A Fisher exact test was applied to categorical variables. RESULTS: Of 407 patients randomized (duloxetine: N = 205; placebo: N = 202), 166 (81.0%) patients from the duloxetine group and 176 (87.1%) patients from the placebo group completed the 13-week treatment phase. The majority (76.4%) of patients was female; mean age was 60.5 years. Duloxetine-treated patients reported significant pain reduction, compared with placebo treatment, on the BPI 24-h Average Pain rating (least-squares mean (LS Mean) change from baseline to endpoint [95% confidence interval (CI)], duloxetine: -2.23; placebo: -1.73; difference = -0.50 [-0.80, -0.20]; P = 0.001). The incidence of discontinuations due to adverse events was 9.0% in duloxetine-treated patients and 4.5% in placebo-treated patients (P = 0.109). CONCLUSIONS: This study demonstrated the efficacy of duloxetine in Chinese patients with chronic pain due to OA. The safety profile of duloxetine observed in this study was consistent with that in previous duloxetine trials. This trial is registered with ClinicalTrials.gov (NCT01931475).

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

Treatment of patients with diabetic peripheral neuropathic pain in China: a double-blind randomised trial of duloxetine vs. placebo.

BACKGROUND: Duloxetine has been approved in the United States, European Union and some Asian countries for the treatment of diabetic peripheral neuropathic pain (DPNP). We assessed the efficacy and safety of duloxetine (60 mg once daily) compared with placebo in Chinese patients suffering from DPNP. METHODS: This was a phase 3, multicenter, randomised, double-blind, parallel, placebo-controlled, 12-week trial of the treatment of DPNP with duloxetine. Subjects were male and female outpatients ≥ 18 years of age with DPNP, as assessed by the Michigan Neuropathy Screening Instrument, and had a rating of ≥ 4 on the Brief Pain Inventory-Modified Short Form-Severity weekly average pain item. The primary efficacy measure was the reduction in pain severity from baseline to 12 weeks, as measured by the weekly mean of 24-h average pain ratings recorded in the patient's diary. Mean changes from baseline in efficacy measures were analysed by a restricted maximum likelihood-based, mixed-effects model repeated measures approach and by analysis of covariance. RESULTS: Of the 405 patients randomised, 203 patients were assigned to duloxetine 60 mg once daily and 202 patients were assigned to placebo. Duloxetine-treated patients showed significantly greater pain relief on 24-h average pain ratings compared with placebo-treated patients each week of the 12-week study period [week 12: least squares (LS) mean change duloxetine: -2.40, placebo: -1.97; LS mean change difference (95% confidence interval) = -0.43 (-0.82, -0.04), p = 0.030]. Compared with placebo, patients treated with duloxetine experienced higher rates of nausea (p = 0.010), somnolence (p < 0.001) and asthenia (p = 0.002). CONCLUSIONS: Duloxetine-treated patients showed significantly greater pain relief compared with placebo-treated patients over the 12-week study period. Duloxetine was shown in Chinese patients to have a safety profile similar to that found in previous duloxetine trials.

Duloxetine use in chronic painful conditions--individual patient data responder analysis.

BACKGROUND: Duloxetine has been studied in four distinct chronic pain conditions - osteoarthritis (OA), fibromyalgia, chronic low back pain (CLBP) and diabetic peripheral neuropathic pain (DPNP). These trials have involved large numbers of patients with at least moderate pain, and have used similar methods for recording pain intensity, over about 12 weeks. METHODS: Data from the trials were pooled according to painful condition, and reanalysed at the level of the individual patient and using increasing levels of pain intensity reduction (<15%, 15-29%, 30-49%, ≥ 50%), with different imputation methods on withdrawal. RESULTS: The proportion of patients recording at least 50% pain intensity reduction plateaued after 2-6 weeks in fibromyalgia, and 8-12 weeks in other conditions. The duloxetine-specific benefit [number needed to treat (NNT) for at least 50% pain intensity reduction] was fairly constant after about 2 weeks for DPNP and fibromyalgia and after about 4 or 5 weeks for OA and CLBP. In all conditions, responses were bimodal, with patients generally experiencing either very good or very poor pain relief. Last-observation-carried-forward imputation produced numerically and occasionally statistically better (lower) NNTs than use of baseline-observation-carried-forward (true response). CONCLUSIONS: Baseline-observation-carried-forward (true response), which combines the success of high levels of pain relief with the failure to experience pain relief on withdrawal of the drug is conservative and probably reflective of clinical practice experience. The distribution of effect was not normal; few patients had the average response and averages are not an appropriate descriptor for these data.

A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain.

BACKGROUND: Duloxetine has demonstrated analgesic effect in chronic pain states. This study assesses the efficacy of duloxetine in chronic low back pain (CLBP). METHODS: Adult patients with non-radicular CLBP entered this 13-week, double-blind, randomized study comparing duloxetine 20, 60 or 120 mg once daily with placebo. The primary measure was comparison of duloxetine 60 mg with placebo on weekly mean 24-h average pain. Secondary measures included Roland-Morris Disability Questionnaire (RMDQ-24), Patient's Global Impressions of Improvement (PGI-I), Brief Pain Inventory (BPI), safety and tolerability. RESULTS: Four hundred four patients were enrolled, 267 completed. No significant differences existed between any dose of duloxetine and placebo on reduction in weekly mean 24-h average pain at end-point. Duloxetine 60 mg was superior to placebo from weeks 3-11 in relieving pain, but not at weeks 12-13. Duloxetine 60 mg demonstrated significant improvement on PGI-I, RMDQ-24, BPI-average pain and BPI-average interference. Significantly more patients taking duloxetine 120 mg (24.1%) discontinued because of adverse events, versus placebo (8.5%). CONCLUSIONS: Duloxetine was superior to placebo on the primary objective from weeks 3-11, but superiority was not maintained at end-point. Duloxetine was superior to placebo on many secondary measures, and was well-tolerated.

5-HT1F receptor agonists in acute migraine treatment: a hypothesis.

Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.

Emerging trends in the pharmacotherapy of chronic pain.

The pharmacotherapy for pain is dominated by conventional analgesics such as the opioids and the non-steroidal anti-inflammatory drugs. Recent advances in the understanding of the mechanisms of pain in general and chronic pain in particular, opened the field of analgesic therapy to newer pharmacological targets, which are aimed at improved efficacy and enhanced tolerability over conventional antipain treatments. Many novel targets are still in preclinical development, but some have made it into human trials and have shown promise. Newer anticonvulsants, new generation cyclooxygenase inhibitors, better tolerated glutamate modulators and balanced serotonin/noradrenaline re-uptake inhibitors are some targets that have shown promise in the clinic. These and other compounds that are in advanced phases of development for chronic pain are reviewed in this paper. It is hoped that the decade of pain control and research will lead us to an arsenal of effective and safe analgesics that will conquer the problem of chronic pain.

The nociceptive flexion reflex in humans -- review article.

The nociceptive flexion reflex (NFR) is a physiological, polysynaptic reflex allowing for painful stimuli to activate an appropriate withdrawal response. NFR is easily measurable in clinical setting, and is a reliable and objective tool for measurement of an individual's pain experience. An exhaustive review of the literature, covering multiple search engines, indicates that the NFR method is valuable in studying the impact of diverse pharmacological and non-pharmacological interventions on the flexion reflex, in conditions of acute pain and in healthy volunteers. More recently, the NFR method has gained particular attention as a research tool in studies of central sensitization and persistent or chronic pain.

Cervical artery dissection is associated with widened aortic root diameter.

OBJECTIVE: Dissection of the internal carotid and vertebral arteries is a well recognized cause of stroke, especially in the middle-aged. The exact etiology of this condition is controversial. According to one theory there is an underlying vasculopathy originating from disturbed development of the neural crest. The neural crest gives rise to several tissues, including the tunica media of large cervical arteries and the outflow tract of the heart. We attempted to test the theory that developmental abnormality at the level of the neural crest may play a role in dissection of the large cervical arteries. METHODS: We designed a retrospective case control study. By means of transthoracic echocardiography we measured the aortic root diameter in a group of patients with radiographically determined dissection of at least one large artery in the neck. The results were compared to a control group. RESULTS: In comparison to age matched controls, male patients were found to have a significantly larger aortic root. Although a similar trend was apparent in females, the difference between the patient and control group of females was not statistically significant. CONCLUSIONS: Patients with cervical artery dissections may have other abnormalities in other organs arising from the neural crest. A larger prospective clinical study and further research are needed to establish a firm link between dissection of the cervical arteries and abnormalities in other organs.

[Surgical treatment of the upper thoracic outlet syndrome]. / Hirurski tretman sindroma gornje torakalne aperture.

In a five year period we have treated surgically eight patients with TOS in the Neurosurgical Clinic Sarajevo. We have concluded that there is not specific diagnostic procedure for the verification of TOS and as surgical method of choice we suggest supraclavicular scalenectomy with neurolysis of plexus brachialis and resection of cervical rib, if exists.