ABSTRACT: Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a β2-agonist action. The aim of this study was to test if the β2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo-controlled and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5-15 mg), imipramine (30-150 mg), or placebo in a random order. Drug doses depended on age and metabolizer status. The change in total pain recorded from ratings in diaries (numeric rating scale [NRS] 0-10) was the primary outcome, and the change in rating of specific pain symptoms (NRS 0-10), patient global impression of change, and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. The median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared with placebo of 0.13 (95% confidence interval -0.12 to 0.38, P = 0.32). The median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared with placebo of -1.17 (95% confidence interval -1.42 to -0.92, P < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The β2-agonist terbutaline has no effect in painful polyneuropathy. β2-agonism seems not to be an important mechanism of action of tricyclic antidepressants in neuropathic pain.
Chronic neck pain (CNP) is a major concern for pain therapists. Many drugs including antidepressants such as amitriptyline have been used in the management of CNP. This study compared the efficacy and safety of 2 different doses of amitriptyline (5 mg and 10 mg at bedtime) in patients with CNP. A total of 80 patients of both sexes with idiopathic CNP, ranging in age from 18 to 75 years, were divided into 2 groups that received 5 or 10 mg oral amitriptyline at bedtime for 120 days. The primary outcome measure was neck pain disability index (NPDI). Neck pain intensity, Athens Insomnia Scale score, Hospital Anxiety and Depression Scale (HADS), side effects of the drug, and patient satisfaction were secondary outcome measures. NPDI decreased by 71.9% ± 13.4% in the 10 mg group compared to 47.3% ± 17.3% in the 5 mg group, representing a statistically significant difference (95% confidence interval: 27.3-12.6). Additionally, the 10 mg group showed greater mean reductions in pain score and HADS scores (both the anxiety and depression subscales), as well as improvement in sleep disturbance compared to the 5 mg group. A higher dose (10 mg) of amitriptyline at bedtime significantly reduced neck pain intensity, sleep disturbance, and anxiety and depression compared to a lower dose (5 mg) in patients with idiopathic and nontraumatic CNP after 120 days of treatment, with no significant difference between groups in the rate of side effects.
BACKGROUND: There is a need for newer therapies for chronic painful diabetic neuropathy as the existing drugs have their own limitations. Clinical trials on low-dose naltrexone (1-5 mg/d) showed efficacy and safety in certain chronic painful conditions, but not in painful diabetic neuropathy. Hence the present study was planned.
METHODS: Sixty-seven participants with painful diabetic neuropathy were randomized to receive either 2 mg naltrexone or 10 mg amitriptyline daily following a 2-week run-in period. The participants were followed up every 2 weeks for a total of 6 weeks. Up-titration was done (to 4 mg naltrexone or 25/50 mg amitriptyline) if the pain reduction was less than 20% on the visual analog scale (VAS) during the next follow-up visit. Efficacy was assessed using the change in VAS score at the end of 6 weeks from baseline. Safety was evaluated at each follow-up visit. After 2 weeks of washout period, the participants were crossed over to receive the comparator drug for another 6 weeks with similar evaluations.
RESULTS: The difference (confidence interval) in the change in VAS score between groups from baseline was 1.64 (-0.92 to 4.20) in per-protocol analysis and 1.5 (-1.11 to 4.13) in intention-to-treat analysis. Eight and fifty-two adverse events were reported in the naltrexone and amitriptyline groups, respectively (P < .001). The most common adverse events were mild diarrhea with naltrexone and somnolence with amitriptyline.
CONCLUSIONS: Low-dose naltrexone exhibited similar efficacy and a superior safety profile compared with amitriptyline in painful diabetic neuropathy.
BACKGROUND: Osteoarthritis (OA) of the knee is a common cause of chronic pain. Analgesics that are currently available have limited efficacy and may be poorly tolerated. Tricyclic antidepressants are used as analgesics for other chronic conditions, but they have not been evaluated as analgesics in OA.
AIM: To investigate the analgesic efficacy of nortriptyline in people with knee OA.
DESIGN AND SETTING: A two-arm, parallel-group, 1:1, double-blind, randomised, placebo-controlled trial in Christchurch, New Zealand.
METHOD: Participants were recruited from orthopaedic outpatient clinics, primary care, and through public advertising. Adults with knee OA and a pain score of ≥20 points on the 50-point Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale were randomised to receive either nortriptyline or identical placebo for 14 weeks. The primary outcome was knee pain at 14 weeks measured using the WOMAC pain subscale. Secondary outcomes included: function; stiffness; non-steroidal anti-inflammatory drug, opioid, and/or paracetamol use; each participant's global assessment; and adverse effects at 14 weeks.
RESULTS: Of the 205 randomised participants, 201 (98.0%) completed follow-up at 14 weeks. The baseline-adjusted mean WOMAC pain subscale score at week 14 was 6.2 points lower (95% confidence interval = -0.26 to 12.6, P = 0.06) in the nortriptyline arm versus the placebo arm. Differences in secondary outcomes generally favoured the nortriptyline arm, but were small and unlikely to be clinically relevant. However, the following were all more commonly reported by participants taking nortriptyline than those taking a placebo: dry mouth (86.9% versus 51.0%, respectively, P<0.001), constipation (58.6% versus 30.4%, respectively, P<0.001), and sweating (31.3% versus 20.6%, respectively, P = 0.033).
CONCLUSION: This study suggests nortriptyline does not significantly reduce pain in people with knee OA. The adverse effect profile was as expected.
Background & Objective: Both duloxetine (DLX) and transcutaneous electrical nerve stimulation (TENS) are recommended as safe and effective treatments for diabetic peripheral neuropathic pain. However, these methods have not been compared. This study aimed to compare the efficacy of treatment by DLX and TENS in diabetic neuropathy pain relief. Materials & Methods: This survey was performed on 60 eligible diabetic patients randomly divided into two groups of DLX (20, 40, and 60 mg/day for weeks 1, 2, and 3-12, respectively), and TENS (20 min,80 HZ, 50 Amp, 0.2 ms Square pulses 2-3 times sensory threshold). The participants were evaluated according to the numerical rating scale (NRS) after four and twelve weeks of treatment. Moreover, adverse drug reactions were documented during the study period. Results: Baseline demographic data had no significant difference between the two groups (P≥0.05). The average NRS scores were significantly lower in the DLX group in both measurement times. At the end of weeks four (P=0.01) and 12 (P=0.001), the trend of changes was significant from baseline to the third month (P=0.0001). No patient in the TENS group reported any side effects, while 18% did in the DLX group. Conclusion: We found that both DLX and TENS were effective and safe for the management of painful diabetic neuropathy. The DLX seemed to be better, compared to TENS. However, in some conditions, such as drug intolerance or contraindication for medications, TENS could be a proper intervention.
This clinical trial evaluated the independent and combined effects of a tricyclic antidepressant (desipramine) and cognitive behavioral therapy (CBT) for chronic back pain relative to an active placebo treatment. Participants (n = 142) were patients experiencing daily chronic back pain at an intensity of ≥4/10 who were randomized to a single-center, double-blind, 12-week, 4-arm, parallel groups controlled clinical trial of (1) low concentration desipramine titrated to reach a serum concentration level of 15 to 65 ng/mL; (2) CBT and active placebo medication (benztropine mesylate, 0.125 mg); (3) low concentration desipramine and CBT; and (4) active benztropine placebo medication. Participants completed the Differential Description Scale and Roland Morris Disability Questionnaires before and after treatment as validated measures of outcomes in back pain intensity and disability, respectively. Participants within each condition showed significant reductions from pre-treatment to post-treatment in pain intensity (mean changes ranged from = -2.58 to 3.87, Cohen's d's = 0.46-0.84) and improvements in pain disability (mean changes = -3.04 to 4.29, Cohen's d's = 0.54-0.88). However, intent-to-treat analyses at post-treatment showed no significant differences between any condition, with small effect sizes ranging from 0.06 to 0.27. The results from this clinical trial did not support the hypothesis that desipramine, CBT, or their combination would be statistically superior to an active medicine placebo for reducing chronic back pain intensity or disability. Key limitations included recruiting 71% of the planned sample size and use of multiple inclusion/exclusion criteria that may limit generalizability to broader populations of patients with chronic back pain.
BACKGROUND: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy.
OBJECTIVE: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy.
METHODS: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety.
RESULTS: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders.
CONCLUSIONS: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ.
CLINICAL TRIAL REGISTRATION: NCT03202979, date of registration: 29/06/2017.
BACKGROUND: Duloxetine proved effective for treating pain in people with Parkinson's disease in a single-arm, open-label study.
OBJECTIVE: To evaluate the efficacy of duloxetine in a double-blind, randomized, placebo-controlled trial.
METHODS: We randomly assigned 46 patients with Parkinson's disease with pain to either the duloxetine 40 mg/day arm or the placebo arm. After 10 weeks, we tested the change from baseline in 24-hour average pain severity measured by a visual analogue scale.
RESULTS: We could not confirm the effect of duloxetine on pain. Exploratory analyses indicated that treatment with duloxetine was associated with improved scores on the Unified Parkinson's Disease Rating Scale Part III and 3 domains of the Parkinson's Disease Questionnaire - 39.
CONCLUSIONS: The study failed to provide evidence for the use of duloxetine for treating pain in people with Parkinson's disease.
Purpose: Diabetic peripheral neuropathic pain (DPNP) is one of the most sufferings, disabling, and dominant complications of diabetes. Duloxetine (DLX) and Pregabalin (PGB) are among first-line therapy and the most prescribed drugs for DPNP relief. The effectiveness-risk profile of drugs may differ from region to region due to variations in genetic and health situation of populations. This study aims to evaluate the efficacy and safety of DLX and PGB in a sample of Iranian population with DPNP. Methods: A double-blind, randomized clinical trial was conducted on 180 type-2 diabetic patients with DPNP≥40 mm according to Visual Analogue Scale (VAS), with other eligibility criteria throughout twelve weeks. We divided the patients randomly into two equal groups: DLX and PGB. Each patient received ten days placebo as a washout period, then blind capsules of DLX (group 1) or PGB (group 2). We assessed the efficacy and safety of drugs by VAS and recorded the Adverse Drug Reactions (ADRs) during the study. Results: In the DLX group, sixty-six and the PGB group, seventy-eight patients completed the study. The intensity of patients’ pain was improved by both drugs significantly (p0.001), but there was no significant difference between the two groups. Average daily doses of DLX and PGB were 42.5 and 235.5 mg, respectively. In the DLX group, 74% of patients and the PGB group, 37% reported ADRs. The discontinuation rates due to ADRs were 19% and 7% correspondingly. Conclusion: We found that in Iranian patients, the mean effective doses of these drugs are different in comparison with several other studies. Surprisingly intolerance and discontinuation of DLX in our patients were attributed to mild and severe Serotonin Syndrome, which had not much occurred in other studies. Accordingly, despite the same efficacy, PGB was better tolerated than DLX in our patients. Thus we would recommend PGB for DPNP treatment in Iranian patients.
Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a β2-agonist action. The aim of this study was to test if the β2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo-controlled and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5-15 mg), imipramine (30-150 mg), or placebo in a random order. Drug doses depended on age and metabolizer status. The change in total pain recorded from ratings in diaries (numeric rating scale [NRS] 0-10) was the primary outcome, and the change in rating of specific pain symptoms (NRS 0-10), patient global impression of change, and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. The median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared with placebo of 0.13 (95% confidence interval -0.12 to 0.38, P = 0.32). The median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared with placebo of -1.17 (95% confidence interval -1.42 to -0.92, P < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The β2-agonist terbutaline has no effect in painful polyneuropathy. β2-agonism seems not to be an important mechanism of action of tricyclic antidepressants in neuropathic pain.
