Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: A randomized,double‐blind study

Seven published, randomized, placebo‐controlled clinical trials with pregabalin have shown robust efficacy for relief of neuropathic pain from DPN and PHN. An investigation of the efficacy and safety of twice daily pregabalin enrolled 395 adults with painful DPN for ≥1 year in a 12‐week, double‐blind, placebo‐controlled trial. Patients were randomized to placebo, 150, 300, or 600mg/day pregabalin (n=96, 99, 99, and 101). Primary efficacy measure was change from baseline in endpoint mean pain score from patients’ daily pain diaries. Secondary efficacy measures included pain‐related sleep‐interference scores, Patient and Clinical Global Impressions of Change (PGIC, CGIC), and the EuroQOL Health Utilities Index (EQ‐5D). Statistically significant reduction in pain was observed in patients receiving pregabalin 600mg/day, and 46% of patients treated with 600mg/day pregabalin reported ≥50% improvement in mean pain scores from baseline (vs 30% of placebo patients, p=0.036). Number needed to treat to achieve such response was 6.3. Pregabalin 600mg/day was significantly superior to placebo in improving pain‐related sleep‐interference scores (p=0.003), PGIC (p=0.021), and CGIC (p=0.009). (Neither pregabalin 150 nor 300mg/day separated from placebo on these measures, largely because of an atypically large placebo response in one country representing 42% of patients.) All pregabalin dosages were superior to placebo in improving EQ‐5D utility scores (all p≥0.0263 vs placebo). Pregabalin was well tolerated at all dosages; adverse events were generally mild to moderate. Number needed to harm (discontinuation because of adverse events) was 10.3 for pregabalin 600mg/day.     

Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens

Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation.     

普瑞巴林治疗痛性糖尿病周围神经病变的效果观察

目的探讨普瑞巴林治疗痛性糖尿病周围神经病变的效果。方法50例痛性糖尿病周围神经病变的患者,随机平分为两组,治疗组选用普瑞巴林150mg／d,无效时加量至300mg／d;对照组选用卡马西平200mg／d,无效时加量至600mg／d。疗程8周,评价两组的疗效及治疗前、后VAS评分。结果服药1周时疗效评估治疗组优于对照组（U=2．028,P=0．046）,服药8周时疗效评估治疗组优于对照组（U=3．540,P〈0．001）,差异均有统计学意义。服药1周时治疗组VAS评分低于对照组[（5．13±1．76）、（6．74±1．52）分,P〈0．05）];服药8周时治疗组VAS评分低于对照组[（1．13±0．45）、（3．27±1．04）,P〈0．05]。治疗组有5例（20％,5／25）患者出现不良反应,对照组有10例（40％,10／25）患者出现不良反应。结论普瑞巴林治疗痛性糖尿病周围神经病变具有良好的疗效。     

A Randomized,Controlled Trial of Oxycodone Versus Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin

The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain.PerspectivePeripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in ～40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.     

Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders

BACKGROUND: The US Food and Drug Administration (FDA) approved pregabalin in December 2004 for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is the first drug approved in the United States and in Europe for both conditions. In June 2005, pregabalin was approved as an adjunctive treatment in adults with partial-onset seizures. The FDA currently is considering the approval of pregabalin as adjunctive therapy in adults with generalized anxiety disorder (GAD) or social anxiety disorder (SAD). OBJECTIVES: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of pregabalin; review its approved uses in the management of neuropathic pain and refractory partial-onset seizures; and investigate its potential use in patients with GAD or SAD. METHODS: Relevant English-language literature was identified through a search of MEDLINE (1993-June 2006) and International Pharmaceutical Abstracts (2000-June 2006). The search terms included pregabalin, Lyrica, S-(+)-3 isobutyl-gaba, PN, DPN, diabetic peripheral neuropathy, PHN, postherpetic neuralgia, partial seizures, epilepsy, generalized anxiety disorder, and CI-1008. RESULTS: In 4 clinical trials in a total of 1068 patients with diabetic peripheral neuropathy, the patients receiving pregabalin 300 to 600 mg/d had significantly greater improvement in mean pain scores than placebo recipients (P < or = 0.01). Patients with postherpetic neuralgia receiving pregabalin 450 to 600 mg/d had significantly greater improvement in relief of pain and pain-related sleep interference than placebo recipients (P < or = 0.002). Patients with refractory partial-onset seizures who received pregabalin 150 to 600 mg/d (divided into 2 or 3 doses) concomitantly with antiepileptic drugs had significantly fewer seizures than placebo recipients (P < or = 0.001). In the 3 studies that evaluated the efficacy of pregabalin in patients with GAD or SAD, the patients receiving pregabalin 200 to 600 mg/d (divided into 2 or 3 daily doses) had a significantly greater reduction in mean pain scores on the Hamilton Anxiety Scale than placebo recipients (P < or = 0.01). Across all the reviewed clinical trials, the most commonly reported adverse effects (AEs) were those affecting the central nervous system, including somnolence (< or =50%), dizziness (< or =49%), and headache (< or =29%). AEs resulted in withdrawal from the study in < or =32% of patients. CONCLUSIONS: Pregabalin appears to be an effective therapy in patients with diabetic peripheral neuropathy, postherpetic neuralgia, and adults with refractory partial-onset seizures. The available data suggest that pregabalin may be beneficial as an adjunctive therapy in adult patients with GAD or SAD.     

Effectiveness and time to onset of pregabalin in patients with neuropathic pain

BACKGROUND: The data from a previously published 12-week randomised, double-blind, placebo-controlled multicentre study on the efficacy and safety of pregabalin were analyzed for time to onset of analgesic action with neuropathic pain. PATIENTS AND METHODS: A total of 338 patients with postherpetic neuralgia or painful diabetic peripheral neuropathy were treated with flexible or fixed regimens of pregabalin at daily doses of up to 600 mg/day (n=141 and 132, respectively) or placebo (n=65). RESULTS: Under fixed dose treatment, a decrease of one full point on the 11-point numerical rating pain scale was reached on day 1, two full points on day 13, and three full points on day 23 (under flexible dose pregabalin: on days 6, 17 and 30). In both treatment arms, pain reduction was statistically significant (P=0.001, P=0.002 vs placebo, respectively). CONCLUSION: In patients with chronic neuropathic pain, the analgesic effect of both pregabalin treatment regimens was high and associated with a rapid time to onset.     

Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen

The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600 mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150 mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P = 0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain.     

A prospective,open‐label,multicentre study of pregabalin in the treatment of neuropathic pain in Latin America

Aims: The objective of this study was to evaluate the safety and efficacy of pregabalin at flexible doses of 150–600 mg/day in Latin American patients with neuropathic pain. Methods: A prospective, multicentre, open‐label, non‐comparative study included patients age ≥ 18 years diagnosed with neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy‐induced peripheral neuropathic pain (PNP), or human immunodeficiency virus‐related PNP. Eligible patients (N = 121) had a score of ≥ 40 mm on the visual analogue scale and a daily pain rating scale (DPRS) score of ≥ 4 throughout screening. Patients received flexible‐dose pregabalin (150–600 mg/day) for 12 weeks, which included a 4‐week dose‐adjustment phase. The primary efficacy measure was change from baseline to end of treatment/last observation carried forward (EOT/LOCF) in weekly mean pain score on the DPRS. Secondary efficacy measures included pain, anxiety, sleep interference, treatment satisfaction and Patient and Clinician Global Impression of Change. Results: Pregabalin significantly reduced the weekly mean pain score on DPRS from baseline to EOT/LOCF [–3.8 (95% CI: ?4.2 to ?3.3); p < 0.0001]. Reductions from baseline to EOT/LOCF were observed for all secondary efficacy outcomes (p < 0.0001). Pain and sleep interference were significantly improved compared with baseline across all weeks of the study, as early as 1 week after initiation of pregabalin (p < 0.0001). The most common adverse events (AEs) were somnolence, dizziness, weight gain and peripheral oedema. Nine (7.4%) patients discontinued the study because of AEs and 25 (20.7%) temporarily stopped or reduced their pregabalin dose because of AEs. Conclusions: Flexible‐dose pregabalin (150–600 mg/day) significantly reduced pain and anxiety and improved sleep and was generally well tolerated in Latin American patients with neuropathic pain.     

Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score ≥40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of ≥4 (11-point numerical pain rating scale [0=no pain, 10=worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n=70) or pregabalin 300 mg/day (n=76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P<0.0001); mean sleep interference scores (P<0.0001); total SF-MPQ score (P<0.01); SF-36 Bodily Pain subscale (P<0.03); PGIC (P=0.001); and Total Mood Disturbance and Tension–Anxiety components of POMS (P<0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P<0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.     

Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial

This study was designed to assess the efficacy and safety of pregabalin-a novel alpha(2)-delta ligand with analgesic, anxiolytic, and anticonvulsant activity-for treating neuropathic pain in patients with post-herpetic neuralgia (PHN). Two hundred and thirty-eight patients were randomised into this multicentre, doubleblind, placebo-controlled trial to receive 150 (n=81), 300 mg/day (n=76) pregabalin, or placebo (n=81) for 8 weeks. Among the exclusion criteria was failure to respond to previous treatment for PHN with gabapentin at doses > or =1200 mg/day. Endpoint mean pain scores were significantly reduced in patients receiving 150 or 300 mg/day pregabalin compared with placebo. Efficacy was observed as early as week 1 and was maintained throughout the study. Significantly more patients in both pregabalin groups (150 mg, 26%; 300 mg, 28%) were responders (> or =50% decrease in mean pain score from baseline to endpoint) than in the placebo group (10%). Additionally, by week 1 and for the study's duration, 150 and 300 mg/day pregabalin significantly reduced weekly mean sleep interference scores. More pregabalin-treated patients than placebo-treated patients reported that they were 'much improved' or 'very much improved'. Health-related quality-of-life (HRQoL) measurements using the SF-36 Health Survey demonstrated improvement in the mental health domain for both pregabalin dosages, and bodily pain and vitality domains were improved in the 300 mg/day group. The most frequent adverse events were dizziness, somnolence, peripheral oedema, headache, and dry mouth. Pregabalin efficaciously treated the neuropathic pain of PHN. Additionally, pregabalin was associated with decreased sleep interference and significant improvements in HRQoL measures.     

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.     

Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses

OBJECTIVE—To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODS—Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.RESULTS—Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P ≤ 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P ≤ 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (≥30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.CONCLUSIONS—Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.The prevalence of diabetic neuropathy is as high as 50% in patients who have had diabetes for 25 years (1), and painful diabetic peripheral neuropathy (DPN) occurs in up to 26% of all people with diabetes (2). Symptoms range from mild dysesthesias to severe unremitting pain that can profoundly impact patients’ lives (3,4).Medications of several different classes are used to treat painful DPN with varying degrees of efficacy, safety, and tolerability. The antiepileptic agents gabapentin and pregabalin have attained widespread use in the treatment of painful DPN. These agents bind to the auxiliary α2-δ subunit of the voltage-sensitive calcium channel, thereby decreasing Ca²⁺ influx at nerve terminals and modulating neurotransmitter release (5).There are seven double-blind, randomized, placebo-controlled trials in painful DPN with pregabalin (6–12), five of which are published in full (7–11). The effective dosing range for treatment of neuropathic pain syndromes is 150 to 600 mg/day, administered either three times daily (TID) or twice daily (BID). Among the seven trials, dosages of 150, 300, and 600 mg/day were used, but only one trial included all three of these dosages. Thus, individually, the seven trials present an incomplete picture of the effective dosing range. In addition, TID dosing was used in the first four trials, whereas the three most recent trials of pregabalin in painful DPN used BID dosing.The objective of the current report is to use the pooled data from these seven trials to evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range. We also use these data to determine differences in the efficacy of TID and BID dosing schedules. Finally, we use a time-to-event analysis of the pooled data to determine the time to onset of a sustained therapeutic effect across the range of doses.     

Efficacy and Safety of Carisbamate in Patients with Diabetic Neuropathy or Postherpetic Neuralgia: Results from 3 Randomized,Double‐Blind Placebo‐Controlled Trials

The results of 3 proof‐of‐concept studies to evaluate carisbamate's efficacy and safety in treating neuropathic pain are presented. In studies 1 (postherpetic neuralgia, n = 91) and 2 (diabetic neuropathy, n = 137), patients received carisbamate 400 mg/day or placebo for 4 weeks and then crossed over to the other treatment for 4 weeks. In study 3 (diabetic neuropathy, higher carisbamate doses), patients (n = 386) were randomized (1:1:1:1) to receive either carisbamate 800 mg/day, 1200 mg/day, pregabalin 300 mg/day or placebo for 15 weeks. Primary efficacy end point was the mean of the last 7 average daily pain scores obtained on days the study drug was taken, for all 3 studies. Least square mean (95% CI) differences between carisbamate and placebo groups on the primary end point were as follows: study 1: ?0.512 (?1.32, 0.29) carisbamate 400 mg/day; study 2: ?0.307 (?0.94, 0.33) carisbamate 400 mg/day; and study 3: ?0.51 (?1.10, 0.08), carisbamate 800 mg/day; ?0.55 (?1.13, 0.04), carisbamate 1200 mg/day; and ?0.43 (?1.01, 0.15), pregabalin 300 mg/day. Neither carisbamate (all 3 studies) nor pregabalin (study 3) significantly differed from placebo, although multiple secondary end points showed significant improvement in efficacy with carisbamate in studies 1 and 2. Dizziness was the only treatment‐emergent adverse event occurring at ≥10% difference in carisbamate groups versus placebo (study 1: 12% vs. 1%; study 3: 14% vs. 4%; study 2: 1% vs. 2%). Carisbamate, although well tolerated, did not demonstrate efficacy in neuropathic pain across these studies, nor did the active comparator pregabalin (study 3).     

Lacosamide in Painful Diabetic Neuropathy: An 18-Week Double-Blind Placebo-Controlled Trial

The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patient's Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain.PerspectiveThis study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.     

Pregabalin for neuropathic pain based on recent clinical trials

Pregabalin is a ligand for the α-2-δsubunit of voltagegated calcium channels with anticonvulsant, analgesic, and anxiolytic properties. It has predictable absorption across the gastrointestinal tract, is neither metabolized nor protein-bound, and has minimal drug-drug interactions. It is effective with two or three-times daily dosing in a dose range of 150 to 600 mg daily. Seven published prospective, randomized clinical trials in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN) demonstrate pain relief, decreased sleep interference, and improvements in several secondary outcome measures. The 50% responder rates for PHN and DPN compare favorably with other first-line agents for neuropathic pain. Pregabalin is well tolerated in most patients with infrequent severe adverse effects. Pregabalin is an important addition to the treatment armamentarium for neuropathic pain.     

A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy

Pregabalin has anticonvulsant, antihyperalgesic, and anxiolytic properties. In this study we evaluated the control of pain after perioperative administration of pregabalin 300 or 600 mg, compared with diazepam 10mg. Altogether 91 women scheduled for laparoscopic hysterectomy were randomized to receive diazepam 10mg (D10), pregabalin 150 mg (P300) or 300 mg (P600) for premedication, and the dose was repeated after 12h, except for the D10 group, in which the patients received placebo. Up until the 1st postoperative morning, analgesia was provided by oxycodone using patient controlled analgesia. The visual analogue scale scores for pain and side effects, and the amounts of the analgesics were recorded for three days after surgery. The doses of oxycodone during hours 0-12 after surgery were similar in the three groups, whereas the dose of oxycodone during hours 12-24 after surgery was smaller in the P600 group than in the P300 group (0.09 vs. 0.16 mg kg(-1); P=0.025). The total dose of oxycodone (0-24h after surgery) was smaller in the P600 group than in the D10 group (0.34 vs. 0.45 mg kg(-1); P=0.046). The incidence of dizziness (70% vs. 35%; P=0.012), blurred vision (63% vs. 14%; P=0.002) and headache (31% vs. 7%; P=0.041) were higher in the P600 group than in the D10 group. In conclusion, perioperative administration of pregabalin 600 mg decreases oxycodone consumption compared with diazepam 10mg, but is associated with an increased incidence of adverse effects.     

Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin

This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.     

Pregabalin for Postherpetic Neuralgia: Placebo-Controlled Trial of Fixed and Flexible Dosing Regimens on Allodynia and Time to Onset of Pain Relief

Time to onset of pain relief and improvement in allodynia in 269 patients with postherpetic neuralgia was examined in a 4-week randomized trial comparing flexibly dosed pregabalin (150–600 mg/d), fixed-dose pregabalin (300 mg/d), and placebo. For each patient with clinically meaningful pain reduction (≥30%) at end point, onset of pain relief was defined as the first study day on which a patient reported ≥1-point reduction in pain relative to baseline. Average dose achieved was 396 mg/d in the flexible-dose group compared with 295 mg/d in the fixed-dose group. Median pain relief onset times were 3.5 days (flexible-dose), 1.5 days (fixed-dose), and >4 weeks (placebo). Compared with placebo, significantly more patients in both pregabalin treatment groups achieved ≥30% and ≥50% pain reduction at end point. Almost 95% of patients had brush-evoked allodynia, with 68% having moderate to severe allodynia (≥40/100 mm). At baseline, pain and allodynia were highly correlated. Independent of treatment assignment, improvement in pain and improvement in allodynia were significantly correlated. Allodynia could serve as a useful surrogate outcome measure in future studies. Pregabalin was significantly better than placebo in alleviating allodynia (flexible-dose reduction, 26 mm; fixed-dose, 21 mm; placebo, 12 mm). Discontinuation rates due to adverse events were more frequent in the fixed-dose group.PerspectiveA flexible-dose regimen reduces discontinuations, facilitates higher final doses, and results in a slightly greater pain relief. Allodynia (touch-evoked pain) can be of disabling severity and is present in nearly all patients with postherpetic neuralgia. Allodynia severity is correlated with pain severity and improvement in allodynia is correlated with clinical response.     

Safety and efficacy of pregabalin in patients with central post-stroke pain

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ?18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = -0.2; 95% CI = -0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.     

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.