他喷他多缓释制剂可有效治疗慢性神经源性及伤害性疼痛

ROME (EGMN) – Tapentadol extended release, an investigational centrally acting analgesic, proved effective both for moderate to severe diabetic peripheral neuropathy and for similarly severe chronic nociceptive pain due to osteoarthritis or low-back injury in a series of five phase III clinical trials.

Tapentadol immediate release is approved for the treatment of moderate to severe acute pain. The investigational extended release formulation is a twice-daily drug for which a New Drug Application for marketing approval is now under review at the U.S. Food and Drug Administration.

The package of phase III studies included two 15-week, double-blind, multicenter trials totaling 2,010 patients with moderate to severe pain due to osteoarthritis of the knee. They were randomized to tapentadol extended release titrated to 100-250 mg b.i.d. or oxycodone controlled release titrated to 20-50 mg b.i.d. over the first 3 weeks or to placebo.

The tapentadol extended release group showed a significant reduction in mean pain intensity scores over the course of 15 weeks, compared with placebo in both trials. The oxycodone controlled release group was significantly better than placebo in only one trial, Dr. Christine Rauschkolb reported at the annual European Congress of Rheumatology.

The double-blind, 15-week, placebo-controlled diabetic peripheral neuropathy study included 389 patients. The placebo group showed significant worsening of average pain intensity over the 15 weeks. There was no change in pain intensity over time in the tapentadol extended release group, which signifies treatment efficacy, said Dr. Rauschkolb of Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey.

The double-blind, chronic low-back pain study was also 15 weeks in duration. It included 958 patients with moderate to severe pain who were randomized to tapentadol extended release, oxycodone controlled release, or placebo. Both the tapentadol and oxycodone groups experienced significantly reduced pain intensity from baseline through the end of the study, compared with placebo.

The 1-year-long safety study was an open-label trial conducted in 1,117 patients with osteoarthritis or low-back pain. They were randomized 4:1 to tapentadol extended release at 100-250 mg b.i.d. or oxycodone controlled release at 20-50 mg b.i.d. Mean pain intensity scores improved in the tapentadol extended release group from 7.58 at baseline to 4.37 at 1 year on an 11-point scale, and from 7.61 to 4.52 with oxycodone controlled release. Nausea, vomiting, and constipation were significantly more frequent in the oxycodone controlled release arm.

In a separate pooled analysis of three randomized, double-blind phase III studies involving 980 patients who received tapentadol extended release for moderate to severe osteoarthritis or low-back pain, 1,001 patients assigned to oxycodone controlled release, and 993 on placebo, the treatment discontinuation rate was highest by far in the oxycodone arm. The discontinuation rates were 40.6% with placebo, 43.5% with tapentadol extended release, and 61.7% with oxycodone controlled release, reported Dr. Bernd Lange of Grunenthal GmbH, Aachen, Germany.

The bottom line on this extensive randomized trial experience is that tapentadol extended release is at least as effective as oxycodone controlled release for the management of chronic pain at a ratio of approximately 5 mg of tapentadol extended release to 1 mg of oxycodone controlled release. But tapentadol extended release is better tolerated, Dr. Lange said.

Tapentadol has both mu-opioid receptor agonist and noradrenaline reuptake inhibitor actions.

Disclosures: All studies were funded jointly by Johnson & Johnson and Grunenthal GmbH. Dr. Rauschkolb is an employee of Johnson & Johnson, and Dr. Lange is an employee of Grunenthal.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

他喷他多速释制剂已获准用于治疗中重度急性疼痛。目前美国食品药品管理局(FDA) 正在对试验用他喷他多缓释制剂进行新药上市申请批准前的审查，该药为1日2次用药。

此系列III期临床试验包括2项为期15周的双盲、多中心试验，共纳入2,010例由膝部骨关节炎所致的中重度疼痛患者。这些受试者被随机分配他喷他多缓释制剂治疗组(100~250 mg，每日2次)或羟考酮控释制剂治疗组(20~50 mg，每日2次)，剂量调整于最初3周内完成，以及安慰剂处置。

在这两项试验，他喷他多缓释制剂治疗组在15周疗程中平均疼痛强度评分相对于安慰剂对照组显著降低。仅在一项试验中，羟考酮控释制剂的疗效显著优于安慰剂，Christine Rauschkolb博士在欧洲风湿病学年会(European Congress of Rheumatology)上报告称。

这项为期15周的双盲、安慰剂对照、糖尿病性周围神经病变研究纳入了389例患者。在15周的研究期内，安慰剂对照组平均疼痛强度显著加重。他喷他多缓释制剂治疗组疼痛强度随时间无变化，表明存在疗效，新泽西州拉里坦强生制药公司研发部Rauschkolb博士说。

另一项双盲、慢性腰背部疼痛研究同样历时15周，纳入985例中重度疼痛的患者，这些受试者被随机分入他喷他多缓释制剂治疗组、羟考酮控释制剂治疗组或安慰剂对照组。与安慰剂对照组相比，他喷他多治疗组与羟考酮治疗组的疼痛强度自基线至研究结束时显著减轻。

历时1年的安全性研究为开放式研究，其受试者为1,117例骨关节炎或腰背部疼痛的患者。这些患者按4:1的比例被随机分入他喷他多缓释制剂治疗组(100~250 mg，每日3次)或羟考酮控释制剂治疗组(20~50 mg，每日3次)。他喷他多缓释制剂治疗组的平均疼痛强度评分由基线时的7.58降至4.37(疼痛量表满分为11分)，而羟考酮缓释制剂治疗组由7.61降至4.52。羟考酮治疗组恶心、呕吐及便秘等不良反应明显偏多。

在对3项随机、双盲的III期研究单独进行的一项汇总分析中，受试者为980例接受他喷他多缓释制剂治疗中重度骨关节炎或腰背部疼痛的患者，有1,001例患者被安排接受羟考酮控释制剂治疗，有993例接受安慰剂处置，羟考酮治疗组治疗终止率最高。安慰剂对照组终止率为40.6%，他喷他多缓释制剂治疗组为43.5%，羟考酮控释制剂治疗组为61.7%，德国格兰泰(亚琛)有限公司的Bernd Lange博士报告称。

这项大规模的随机临床试验的结论为，他喷他多缓释制剂在处置慢性疼痛方面至少与羟考酮缓释制剂等效，其比例关系大致为5 mg他喷他多缓释制剂对等1 mg羟考酮控释制剂。但他喷他多缓释制剂的耐受性较优，Lange博士说。

他喷他多兼具μ阿片受体激动剂和去甲肾上腺素再摄取抑制剂的功能。

披露：所有研究均由强生制药公司和格兰泰公司联合资助。Rauschkolb博士任职于强生制药公司，而Lange博士任职于格兰泰公司。

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