Treatment Of Diabetic Peripheral Neuropathic Pain Research Articles

224-OR: The Efficacy and Safety of HSK 16149 in Chinese with Diabetic Peripheral Neuropathic Pain—A Randomized, Double-Blinded, Placebo and Pregabalin-Controlled Phase II/III Study

Background: Chronic diabetic peripheral neuropathic pain (DPNP) is common and difficult to treat. The recommended medications are either inadequate effective or limited by the side effects. This study aims to evaluate the efficacy and safety of HSK16149, a potent, selective ligand of the a2δ subunit of voltage-gated calcium channels (VGCC), as analgesia treatment for DPNP. Materials and Methods: This was a randomized, double-blind, placebo and active-controlled phase II/III study of patients aged ≥18 years with diabetic peripheral neuropathy in China. Firstly, the patients with moderate to severe pain were randomized to receive placebo, HSK 16149 40,80 mg/d without titration, and HSK16149 120, 160mg/d, pregabalin 300mg/d with 1 week titration on average. Then more patients were recruited and randomized to placebo and two HSK16149 dose groups, continued the treatment for up to 13 weeks. The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 13. The secondary endpoint was the responder rates as ≥30% and ≥50% improvement in ADPS. Results: Compared with placebo, the pain was reduced since week 1 in HSK16149 groups. At week 13, the mean ADPS change from baseline was -1.23, -2.24 and -2.16 for placebo (n=177), HSK 16149 40mg/d (n=178) and 80mg/d (n=179), showing statistical significance for both HSK groups versus placebo (P<0.0001). The 30% and 50% responder rate were both significantly greater for two HSK groups versus placebo (≥30%: 57.3%, 51.4% versus 31.6%; ≥50%: 32.0%, 36.3% versus 18.1%) at week 13. Most treatment-emergent adverse events (TEAE) in HSK16149 groups were mild to moderate, and the most frequent TEAEs were dizziness and somnolence, which were always transient and needed no additional treatment. Conclusions: HSK 16149 rapidly improved analgesia without titration and was efficacious in relieving pain in Chinese DPNP patients, and well tolerated. Disclosure X.Guo: None. T.Zhang: None. G.Yuan: None. L.Yukun: None. J.Ma: None. L.Hong-mei: None.

A Cross-Sectional Web Survey of Satisfaction with Treatment for Pain in Participants with Suspected Diabetic Peripheral Neuropathic Pain in Both Feet.

IntroductionDiabetic peripheral neuropathic pain (DPNP), a symptom of diabetic polyneuropathy (DPN), is underdiagnosed in people with diabetes. To date, no studies have determined the relationship between diagnosis of DPN and satisfaction with treatment for pain. Additionally, the factors that influence satisfaction with treatment for pain remain unknown. This questionnaire study was conducted to understand satisfaction with treatment for pain among participants with diabetes who experienced bilateral pain or numbness in their feet.MethodsThis cross-sectional, observational, web-based questionnaire study for participants with diabetes and suspected DPNP was conducted in Japan. Potential respondents were registered in the INTAGE Disease Panel or the Rakuten Insight Disease Panel. The primary endpoint was the number and percentage of participants who were satisfied with their DPNP treatment. Secondary endpoints included participant opinions regarding treatment-related efficacy, side effects, and economic burden, and factors affecting satisfaction with treatment.ResultsThe questionnaire was accessed by 7565 potential participants; 777 met the eligibility criteria (final analysis set). Satisfaction with treatment for bilateral foot pain was low (satisfied, 27.9%; neither satisfied nor unsatisfied, 42.2%; unsatisfied, 23.4%; very unsatisfied, 6.4%). Participants were somewhat more satisfied with treatment side effects than with treatment efficacy and economic burden. Satisfaction with treatment mainly differed by improvement in actions in daily life, improvement in quality of life, and communication with doctors. The diagnostic testing rate for DPN was low, and diagnosis was more common in participants who complained of symptoms of pain and numbness (any visit) versus those who did not.ConclusionParticipants with diabetes who experience bilateral foot pain or numbness reported a low level of satisfaction with treatment for pain.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01810-x.

MiR-590-3p Alleviates diabetic peripheral neuropathic pain by targeting RAP1A and suppressing infiltration by the T cells.

MicroRNAs play a crucial role in diabetic peripheral neuropathic pain (DPNP). miR-590-3p is a novel miRNA and involved in multiple diseases. However, the pathological mechanism of miR-590-3p in DPNP needs to be elucidated. The db/db mice and db/m mice were selected to mimic diabetes and control, respectively, for in vivo studies. The miR-590-3p agomir was injected into db/db mice and pain-related behavioral tests were performed. The interaction of miR-590-3p with target gene was confirmed by dual-luciferase reporter assay. The expression of target gene was determined by qRT-PCR and western blot assay. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). miR-590-3p was down-regulated in diabetic peripheral neuropathy mice. More importantly, miR-590-3p agomir alleviated pain-related behavior, reduced TNF-α, IL-1β and IL-6 concentrations, and inhibited neural infiltration by immune cells in db/db mice. Interestingly, RAP1A was predicted to be the target of miR-590-3p by Targetscan, and was actually regulated by miR-590-3p. Finally, the rescue experiments proved that overexpression of RAP1A partially abrogated the suppressive impact of miR-590-3p on T cells proliferation and migration. miR-590-3p ameliorates DPNP via targeting RAP1A and inhibiting T cells infiltration, indicating that exogenous miR-590-3p may be a potential candidate for clinical treatment of DPNP.

Propofol ameliorated diabetic peripheral neuropathic pain via modulating miR-150/EPHB2 axis

Diabetic peripheral neuropathic pain (DPNP) is a kind of common diabetic chronic complications and affects life quality of patients. Given the protective function of propofol in multiple diseases, the aim of this study is to investigate the mechanism of propofol in DPNP. The streptozocin (STZ)-induced DPNP rat models were established for in vivo study and the high glucose (HG)-induced astrocytes were used for in vitro study, which was isolated from spinal cord of control rats. The paw withdraw thermal latency and mechanical withdrawal threshold were measured. The expression of pro-inflammatory cytokines containing tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) was determined by qRT-PCR assay. The interaction between miR-150 and EPBH2 was detected by luciferase activity assay. We demonstrated that propofol alleviated the STZ-induced DPNP in vivo. More importantly, propofol was proven to inhibit pro-inflammatory cytokine in DPNP rats, including TNF-α, IL-1β, and IL-6. Similarly, propofol suppressed HG-induced pro-inflammatory cytokine in astrocytes. Mechanically, propofol enhanced miR-150 expression in vivo and in vitro; furthermore, EPHB2 was confirmed as a direct target of miR-150 and was modulated by miR-150. In rescue experiments, propofol alleviated the impact of HG treatment via up-regulating miR-150 expression. These findings concluded that propofol could inhibit pro-inflammatory cytokine expression and promote the activation of astrocytes, and then ameliorated DPNP by modulating miR-150/EPHB2 axis in vivo and in vitro, which might provide a potential clinic strategy for DPNP treatment.

Changes in expression of Kv7.5 and Kv7.2 channels in dorsal root ganglion neurons in the streptozotocin rat model of painful diabetic neuropathy

Diabetic peripheral neuropathic pain (DPNP), the most debilitating complication of diabetes mellitus, is resistant to current therapy. The pathogenesis of DPNP is still elusive, but several mechanisms have been proposed including abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. The underlying molecular mechanisms of such aberrant hyperexcitability are incompletely understood. Using the streptozotocin (STZ) rat model of DPNP, we have recently provided evidence implicating neuronal Kv7 channels that normally exert a powerful stabilizing influence on neuronal excitability, in the abnormal hyperexcitability of DRG neurons and in pain hypersensitivity associated with DPNP. In the present immunohistochemical study, we sought to determine whether Kv7.2 and/or Kv7.5 channel expression is altered in DRG neurons in STZ rats. We found 35 days post-STZ: (1) a significant decrease in Kv7.5-immunoreactivity in small (<30 μm) DRG neurons (both IB4 positive and IB4 negative) and medium-sized (30−40 μm) neurons, and (2) a significant increase in Kv7.2-immunoreactivity in small (<30 μm) neurons, and a non-significant increase in medium/large neurons. The decrease in Kv7.5 channel expression in small and medium-sized DRG neurons in STZ rats is likely to contribute to the mechanisms of hyperexcitability of these neurons and thereby to the resulting pain hypersensitivity associated with DPNP. The upregulation of Kv7.2 subunit in small DRG neurons may be an activity dependent compensatory mechanism to limit STZ-induced hyperexcitability of DRG neurons and the associated pain hypersensitivity. The findings support the notion that Kv7 channels may represent a novel target for DPNP treatment.

Results of Mirogabalin Treatment for Diabetic Peripheral Neuropathic Pain in Asian Subjects: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Study.

IntroductionAlmost one-quarter of Asian patients with diabetes experience diabetic peripheral neuropathic pain (DPNP), which may be associated with moderate or severe levels of pain, insomnia, mood disorders, and worsened quality of life. Current treatments are generally ineffective and may be poorly tolerated. We evaluated mirogabalin as a treatment for DPNP in Asian subjects.MethodsThis phase 2, randomized, double-blind, controlled study was conducted in Japan, South Korea, and Taiwan. Subjects (n = 450) with DPNP were randomized (1:1:1:1:1) to treatment with 5, 10, or 15 mg twice-daily (BID) mirogabalin, 150 mg BID pregabalin, or placebo. The primary endpoint was change from baseline in average daily pain score (ADPS) at week 7; secondary endpoints included responder rates, Short-Form McGill Pain Questionnaire (SF-MPQ), Patient Global Impression of Change (PGIC), average daily sleep-interference score (ADSIS), and incidence of treatment-emergent adverse events (TEAEs).ResultsA greater improvement was noted for each mirogabalin treatment group for change from baseline in ADPS at week 7 compared with both placebo and with pregabalin, although these improvements were not statistically significant. The percentage of 30, 50, and 75% responders and subjects with PGIC improvements was greater in each mirogabalin group versus placebo. Mirogabalin 15 mg BID significantly improved the SF-MPQ sensory (p = 0.0313) and visual analog scale scores (p = 0.0093), and ADSIS (p = 0.0002), versus placebo. Treatment was generally well tolerated; the most frequently reported TEAEs in the mirogabalin groups were somnolence (14.7%) and dizziness (11.0%), and most AEs were mild or moderate even at the highest dose.ConclusionsIn Asian subjects with DPNP, mirogabalin (5, 10, and 15 mg BID) was well tolerated. Although no significant differences were observed in the primary endpoint, there was a tendency toward improvement of pain with mirogabalin treatment, and this trend was also observed in the secondary endpoints.Trial RegistrationClinicalTrials.gov identifier, NCT01504412.Electronic supplementary materialThe online version of this article (10.1007/s40122-020-00156-6) contains supplementary material, which is available to authorized users.

PND29 COST-EFFECTIVENESS OF MIROGABALIN FOR THE TREATMENT OF DIABETIC PERIPHERAL NEUROPATHIC PAIN IN TAIWAN

The objective of this study was to assess the cost-effectiveness of mirogabalin versus no treatment or pregabalin in patients with diabetic peripheral neuropathic pain (DPNP) from the third-party perspective in Taiwan. A Markov model, informed by a pragmatic literature review, was developed with cycles of 2 weeks and a time horizon of 1 year. The model consisted of three health states: ‘mild’, ‘moderate’ and ‘severe’ pain. Average daily pain score (ADPS) is assessed at the end of each 2-week cycle. All patients entered the model in the 'moderate' (4 ≤ ADPS <7) or 'severe' (7 ≤ ADPS ≤ 10) pain health states. At the end of each 2-week cycle, patients remained in their assigned health state or transitioned to a different health state according to the change in their pain scores. Efficacy data was informed by the pivotal clinical trial, J303, or by a network meta-analysis (NMA). Utility values for each health state were obtained from published literature. Resource use and cost data were obtained from Taiwanese clinical experts and the Taiwan National Health Insurance Administration. Probabilistic analysis was conducted to test the robustness of results. Results from the head-to-head analysis show that mirogabalin 30mg is a cost-effective treatment option versus no treatment for DPNP in Taiwan. The deterministic analysis estimated a QALY gain of 0.02 at an incremental cost of NT$9,697 (US$323) versus no treatment with an ICER of NT$489,310 (US$15,860). In the analyses using NMA efficacy data, mirogabalin 30mg was cost-effective when compared to pregabalin 300mg with an ICER of NT$18,476 (US$600). Results from sensitivity and scenario analyses confirmed these results. Results from this economic analysis suggest that mirogabalin 30mg, a potent and selective αlpha-2-delta ligand, is a cost-effective treatment option for DPNP in Taiwan with an ICER below the willingness-to-pay threshold.

Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial

BackgroundThe number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP.Methods/designA multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway.DiscussionThe study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment.Trial registrationISRCTN17545443. Registered on 12 September 2016.

Suboptimal Treatment of Diabetic Peripheral Neuropathic Pain in the United States.

Approximately one third of patients with diabetic peripheral neuropathy (DPN) also experience neuropathic pain, resulting in a significant health care burden, and reduced quality of life. Pregabalin, duloxetine, and tapentadol extended-release are approved for treating diabetic peripheral neuropathic pain (DPNP), but many other medications are commonly used "off-label" with various degrees of success. We examined US health insurance claims to determine the current DPNP treatment patterns. This retrospective analysis used the MarketScan claims database to identify adults with continuous health plan enrollment for 12 months pre- and postindex who were initially diagnosed with DPN between 2006 and 2011 and were provided a prescription for a medication reported to be beneficial for treating DPNP (anticonvulsants, antidepressants, opioids, or topical agents). We evaluated the frequency and types of medication dispensed within 1 year after first diagnosis, treatment adherence, and patterns of treatment alteration. Overall, 12,074 patients met inclusion criteria, with 66.6% initiating an anticonvulsant (gabapentin 45.0%; pregabalin 21.6%), and 5.2% initiating duloxetine. Patients commonly received less than the recommended dose of prescribed medication, and adherence was suboptimal for all treatments. It is estimated that up to 50% of patients discontinued their initial treatment within 3 months of initiation. Newly diagnosed patients with DPNP are most commonly prescribed anticonvulsants. Many patients receive lower than recommended dosages, potentially resulting in poor outcomes. Initial treatments are frequently discontinued, indicating low levels of satisfaction and/or poor tolerability. New therapies with improved efficacy and better tolerability are urgently needed for DPNP.

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

BackgroundDuloxetine 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.MethodsThis 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.ResultsOf 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).ConclusionsDuloxetine-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.

Effectiveness of Duloxetine Compared With Pregabalin and Gabapentin in Diabetic Peripheral Neuropathic Pain

This study aimed to compare the effectiveness of duloxetine (DLX) and the anticonvulsants pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP) in routine clinical care. Data from a 6-month, noninterventional study involving 2575 patients in whom treatment of DPNP was initiated with or changed to DLX, PGB, or GBP (n=1523) were analyzed post hoc; patients treated with other medications or combinations were excluded from this analysis. Propensity scoring was used to compare patient groups, assessing Brief Pain Inventory (BPI), Clinical and Patient Global Impression (CGI/PGI), the Hospital Anxiety and Depression Scale (HADS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 12). Mean median daily dosage over 6 months was 53.9 mg for DLX (N=931), 173.5 mg for PGB (N=248), and 727.8 mg for GBP (N=351). BPI average pain severity (last observation carried forward, mean [SD]) decreased by 2.3 [2.30] points for DLX patients, and by 1.9 [2.22] in PGB, and 1.1 [2.15] in GBP patients. This difference remained statistically significant (DLX vs. PGB: P=0.029; DLX vs. GBP: P<0.001) after adjustment by propensity scores. Similar findings were also seen for the BPI interference score, CGI and PGI, the HADS anxiety score, the HADS depression score. When compared with DLX, the low doses of PGB and GBP used in this noninterventional study might have contributed to the lower effectiveness found for both anticonvulsants in the treatment of patients with DPNP.

Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain.

The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared. A 12-week, randomized, open-label study confirming the non-inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability. Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p = 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end-point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 ± 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (-2.39 ± 0.04 and -1.06 ± 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p = 0.01). Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP.

Patient Expectations in the Treatment of Painful Diabetic Polyneuropathy: Results from a Non-Interventional Study

Pain control is the main objective when treating patients with painful diabetic peripheral neuropathic pain (DPNP). However, DPNP is associated with further substantial patient burden that often is not appropriately addressed. Our study identified patients' needs and asked patients what they expected from DPNP treatment. Baseline data were collected in a German prospective, non-interventional study in patients with DPNP starting or switching pain medication at the discretion of the investigator. DPNP severity was evaluated using Brief Pain Inventory (BPI) and Clinician/Patient Global Impression-Severity (CGI-S/PGI-S). Primary objective of this study was to evaluate for which interference item of the BPI DPNP patients expected most to improve due to DPNP therapy. We enrolled 2,576 patients with DPNP from 307 outpatient centers (mean [standard deviation {SD}] age: 65.8 years [11.5], 51.2% female). Mean (SD) CGI-S and PGI-S at baseline were 4.4 (0.91) and 4.5 (1.05), respectively. BPI average pain score was 5.1 (2.04). The BPI interference score was 4.8 (2.18); items most impaired at baseline were walking ability 5.5 (2.60) and general activity 5.4 (2.37). The most frequently chosen BPI interference items expected to improve as a result of the pain treatment were: General activity (29.3%; 95% confidence interval [CI] 27.5-31.0%) and walking ability (24.4%; 95% CI 22.8-26.1%), followed by sleep (14.7%), enjoyment of life (13.6%), mood (8.3%), normal work (7.7%), and relations with other people (1.9%). The majority of patients identified "general activity" and "walking ability" as most relevant BPI interference items for which they expect improvement from DPNP treatment.

Randomized, Placebo-Controlled Comparison of Amitriptyline, Duloxetine, and Pregabalin in Patients With Chronic Diabetic Peripheral Neuropathic Pain

OBJECTIVEChronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP.RESEARCH DESIGN AND METHODSThis was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period.RESULTSAll medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group.CONCLUSIONSThere was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.

Population pharmacokinetic/pharmacodynamic models for duloxetine in the treatment of diabetic peripheral neuropathic pain

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor approved for the treatment of diabetic peripheral neuropathic pain (DPNP). The current analyses aimed to identify and evaluate the effect of any significant covariates on DPNP treatment response, via the development of a continuous descriptive Pharmacokinetics/Pharmacodynamics (PK/PD) model for pain score reduction and a proportional odds PK/PD model describing the proportion of patients achieving pain relief. A total of 1139 patients received placebo, 20, 60 or 120 mg duloxetine daily for 12 weeks. The primary efficacy measure was 24-h pain scores collected on the 11-point categorical numerical rating scale averaged over a week. PK/PD models were fitted using non-linear mixed-effects models. Baseline pain severity was found to be an important factor in both PK/PD models. Larger drops in pain scores were observed for patients with more severe pain. The proportional odds PK/PD model used an a priori definition for adequate pain relief, which was a decrease in two points from baseline. Simulations showed that approximately 70% of patients in the highest dose groups would obtain pain relief at week 12, although placebo response was relatively high at 40%. The proportion of patients who obtained pain relief was slightly lower in those with mild pain compared to those with more severe pain. Patients with more severe pain at study entry had larger treatment responses and were more likely to achieve clinically meaningful pain relief with similar amounts of drug, compared to patients with milder pain.

Duloxetine in the management of diabetic peripheral neuropathic pain.

Diabetic neuropathy affects up to 70% of diabetics, and diabetic peripheral neuropathic pain (DPNP) is the most common and debilitating of the diabetic neuropathies. DPNP significantly reduces quality of life and increases management costs in affected patients. Despite the impact of DPNP, management is poor with one-quarter of patients receiving no treatment and many treated with medications having little or no efficacy in managing DPNP. Duloxetine is one of two drugs approved by the United States Food and Drug Administration for DPNP management. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) proven safe, effective, and cost-saving in reducing DPNP symptoms at a dose of 60 mg/day. Duloxetine doses greater than 60 mg/day for DPNP management are not recommended since they are no more efficacious and associated with more side effects; addition of pregabalin or gabapentin for these patients may be beneficial. Side effects of duloxetine are generally mild and typical for the SNRI class including nausea, dizziness, somnolence, fatigue, sweating, dry mouth, constipation, and diarrhea. Given its other indications, duloxetine is a particularly good choice for DPNP treatment in patients with coexisting depression, anxiety, fibromyalgia, or chronic musculoskeletal pain. Duloxetine treatment had no clinically significant effect on glycemic control and did not increase the risk of cardiovascular events in diabetes patients. However, duloxetine use should be avoided in patients with hepatic disease or severe renal impairment. Given its safety, efficacy, and tolerability, duloxetine is an excellent choice for DPNP treatment in many patients.

Comparative safety of duloxetine versus pregabalin versus duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain

A 12-week, phase IV, open-label, randomized study confirmed the noninferiority of duloxetine (D) monotherapy compared to pregabalin (P) monotherapy and to the combination of D plus gabapentin (D+G) among patients with diabetic peripheral neuropathic pain (DPNP). In this study, the safety and tolerability of the three therapies were assessed. Study participants had previously been treated with a stable dose of gabapentin (≥900 mg/day for ≥5 weeks) and had an inadequate response (defined as a weekly mean 24-hour average pain score ≥4 on an 11-point Likert scale). Patients were randomly assigned to D (N=138), P (N=134), or D+G (N=135). Completion rates did not differ significantly between the groups (D, 63.0%; P, 71.6%; D+G, 73.3%). Discontinuation due to adverse events (AEs) was significantly greater in the D group (19.6%) versus P group (10.4%) (p<.05); significance was not observed in comparisons of D+G (13.3%) versus P (p=.573) or D+G versus D (p=.193). With regard to AEs, nausea, insomnia, hyperhydrosis, and decreased appetite were reported significantly more frequently by patients in the D group versus the P group (p≤.001); insomnia was reported significantly more frequently for the D group versus the D+G group (p<.05); peripheral edema was reported more frequently in P versus D (p≤.001); nausea, hyperhydrosis, decreased appetite, and vomiting were reported more frequently in the D+G group versus the P group (p<.05). During the study patients in the P group gained weight (1.0 kg) while patients in the D+G and D groups lost weight (-1.06 and -2.39 kg, respectively); the between-group differences for P were significant (p<.001 each), as well as for D versus D+G (p<.05). In conclusion, D, D+G, and P were found to be safe and tolerable for the treatment of DPNP. The AE profiles for these therapies are consistent with previous reports. A 12-week, phase IV, open-label, randomized study confirmed the noninferiority of duloxetine (D) monotherapy compared to pregabalin (P) monotherapy and to the combination of D plus gabapentin (D+G) among patients with diabetic peripheral neuropathic pain (DPNP). In this study, the safety and tolerability of the three therapies were assessed. Study participants had previously been treated with a stable dose of gabapentin (≥900 mg/day for ≥5 weeks) and had an inadequate response (defined as a weekly mean 24-hour average pain score ≥4 on an 11-point Likert scale). Patients were randomly assigned to D (N=138), P (N=134), or D+G (N=135). Completion rates did not differ significantly between the groups (D, 63.0%; P, 71.6%; D+G, 73.3%). Discontinuation due to adverse events (AEs) was significantly greater in the D group (19.6%) versus P group (10.4%) (p<.05); significance was not observed in comparisons of D+G (13.3%) versus P (p=.573) or D+G versus D (p=.193). With regard to AEs, nausea, insomnia, hyperhydrosis, and decreased appetite were reported significantly more frequently by patients in the D group versus the P group (p≤.001); insomnia was reported significantly more frequently for the D group versus the D+G group (p<.05); peripheral edema was reported more frequently in P versus D (p≤.001); nausea, hyperhydrosis, decreased appetite, and vomiting were reported more frequently in the D+G group versus the P group (p<.05). During the study patients in the P group gained weight (1.0 kg) while patients in the D+G and D groups lost weight (-1.06 and -2.39 kg, respectively); the between-group differences for P were significant (p<.001 each), as well as for D versus D+G (p<.05). In conclusion, D, D+G, and P were found to be safe and tolerable for the treatment of DPNP. The AE profiles for these therapies are consistent with previous reports.

Factors associated with pain medication selection among patients diagnosed with diabetic peripheral neuropathic pain: a retrospective study

Objective:To assess the demographic and clinical characteristics associated with initiation of duloxetine therapy compared with other pharmacologic therapies for treatment of diabetic peripheral neuropathic pain (DPNP).Methods:This study used administrative claims databases for commercially-insured individuals aged 18–64 years to examine factors associated with treatment among DPNP patients who initiated duloxetine versus tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, or opioids between 7/1/2005 and 12/31/2007. Treatment initiation was defined as no pill coverage of the same medication over the previous 90 days. Multiple logistic regression models were estimated to assess factors associated with initiating duloxetine versus each of the other DPNP therapies.Results:The study included 11,060 DPNP patients with average age of 55 years old. Cardiovascular disease (63–70%), cerebrovascular/peripheral vascular disease (26–33%), low back pain (24–39%), and osteoarthritis (17–26%) were the most common diabetes- and pain-related comorbidities. Controlling for demographic and clinical characteristics, patients who received duloxetine or pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other DPNP treatment cohorts, except for those in the pregabalin cohort, were more likely to re-initiate the same prior therapy than begin treatment with duloxetine (all p < 0.05). A history of anxiety disorder was significantly associated with initiation of all DPNP treatments other than duloxetine (all p < 0.05), except for TCAs. Patients with low back pain were more likely to initiate duloxetine than TCAs or venlafaxine, but less likely to initiate duloxetine than pregabalin or opioids. Patients with infections related to diabetes were less likely to initiate duloxetine than venlafaxine, gabapentin, or opioids.Limitations:Because a retrospective administrative claims database was used, this study is subject to selection bias due to unobservable confounders, inability to measure prescriber preferences or characteristics or disease severity.Conclusions:Among commercially-insured DPNP patients, those with prior use of duloxetine or pregabalin were more likely to initiate duloxetine than other treatments. The presence of select comorbidities was also associated with specific medication initiation.

Safety and Efficacy Review: Lacosamide for the Treatment of Diabetic Neuropathic Pain

Objectives To provide background information on diabetic peripheral neuropathic pain (DPNP), current treatment options for DPNP, and information about lacosamide. To determine the safety and efficacy of lacosamide as a treatment option for DPNP. Methods A literature search was performed in order to describe DPNP, locate pertinent information about lacosamide, and determine the safety and efficacy of lacosamide for the treatment of DPNP in various trials. A search was also performed to review the effects of other medications on DPNP for the education of the reader as well as to make a comparison to lacosamide. Results DPNP is a common occurrence in patients with diabetes. Options for the treatment of DPNP include anti-depressants, anti-convulsants, opiates, and other alternative medications. One of the most recently studied drugs for DPNP is lacosamide, an anti-convulsant usually prescribed for the adjunct treatment of partial onset seizures. Three RCTs using lacosamide and an extension to one of the trials was found and reviewed. Rauck et al found that lacosamide titrated up to 400 mg divided twice daily to treat DPNP caused 60% of patients to have a significant decrease of 3.11 on the Likert Pain Scale as compared to 50.8% of patients in the placebo group having a decrease of 2.21 on the Likert Pain Scale from the beginning of treatment until conclusion of the trial. Shaibani et al performed an extension to the trial performed by Rauck et al and determined that the effects of lacosamide used for DPNP were maintained over a 2.5 year period. Wymer et al reproduced the results of the study done by Rauck et al by using 200 mg, 400 mg, and 600 mg of lacosamide divided twice daily and comparing them to placebo to see the difference in the Likert Pain Scale scores from the beginning of the trial to conclusion of the trial. The Likert Pain Scale differences were 1.8, 1.9, 2.5, and 2.0 for the placebo, 200 mg, 400 mg, and 600 mg dosage groups, respectively. In the 400 mg lacosamide daily group, 58% of subjects experienced a significant decrease in the Likert Pain Scale score. The 200 mg and 600 mg dosage groups showed no difference in the Likert Pain Scale scores. Ziegler et al studied the changes in pain scores from baseline to the last four weeks of maintenance therapy using lacosamide 400 mg and 600 mg versus placebo. No significant changes were seen in either group. The 400 mg and 600 mg groups lowered the pain scores -0.40 and -0.36 points below placebo, respectively. However, when broken into sections, the trial did show significant changes in pain scores. There were no significant differences in adverse effects across all trials using the 400 mg dose of lacosamide. No trials were found that compared lacosamide to any other drug for the treatment of DPNP. Conclusion Mixed results do show that lacosamide has the potential to effectively and safely lower pain scale scores in individuals with DPNP. However, due to a lack of consistent results and comparison studies with more established and accepted treatments, lacosamide cannot be recommended first line.

Advances in the management of diabetic peripheral neuropathy

Over the past 5 years there have been significant advances in the pathogenesis and management of diabetic peripheral neuropathic pain (DPNP) and this review attempts to summarize these. Recent research has shown that in addition to poor glucose control, traditional cardiovascular risk factors for macrovascular disease, are independent-risk factors for incident diabetic peripheral neuropathy (DPN). In contrast, the risk factors for DPNP are not known although data from the EURODIAB cohort suggest that female sex may be an independent-risk factor. The pathogenisis of pain in DPNP is also not clear although differences in sural nerve epineurial blood flow, foot skin microcirculation and intraepidermal nerve fibre density (IENF), and thalamic magnetic resonance spectroscopy have been demonstrated between individuals with DPNP and painless neuropathy.Pharmacological treatment of DPNP includes tricyclic compounds (TCAs), selective serotonin noradrenaline reuptake inhibitors (SNRIs), anticonvulsants, opiates, membrane stabilizers, the antioxidant alpha lipoic acid, capsaicin etc. Current first-line therapies for DPNP are a TCA, SNRI (such as duloxetine) or anticonvulsants (such as pregabalin or gabapentin), taking into account patient comorbidities and cost. There has recently been a consensus document suggesting an evidence-based protocol for the management of DPNP and this report is highlighted.