作者：Allison Gandey
出處：WebMD醫學新聞
October 1, 2009 — 研究者尋找難治型神經痛的新治療方法，認為併用gabapentin與nortriptyline有效。他們提議將一個抗憂鬱藥物加上解痙攣劑用於治療難治型的神經痛。研究發現線上登載於9月30日的The Lancet期刊。
第一作者、加拿大安大略皇后大學Ian Gilron醫師在訪問中向Medscape Neurology表示，神經疼痛相當具有挑戰性，經常需使用多種藥物。但是許多併用方式沒有效果，我們希望在合理且有證據基礎下研究併用方式。
本試驗由加拿大健康研究中心發起且提供支持。Gabapentin(商品名Neurontin，輝瑞藥廠)是γ-胺基丁酸的一種3-烷基化相似物。原本發展用於治療癲癇，但是已經普遍用於緩解疼痛。
Nortriptyline (商品名Pamelor，諾華藥廠)是amitriptyline的代謝物，據報告可以阻斷正腎上腺素、血清素再吸收、鈉通道、以及N-甲基-D-天(門)冬氨酸麩胺酸鹽受體。
丹麥Aarhus大學醫院的Troels Jensen醫師與Nanna Brix Finnerup醫師在評論中表示，本研究頗受歡迎，因為我們極需改善此類慢性疼痛病患的治療。
神經疼痛影響了大約3%的人口，統合分析顯示，獲得適當疼痛緩解的病患不到三分之二(Pain 2005；118:289–305)。
在最近的美國疼痛醫學院年會中，專家進行有關難治型疼痛之挑戰性的討論。會議主持人、鹽湖城猶他大學醫學院的Perry Fine醫師強調，目前的治療可以完成的有限。
【治療神經痛的挑戰】
Jensen醫師與Finnerup醫師在文章中指出，一般而言，現有的藥物缺乏分子特定性，而只作為抗痛覺敏感。現在已經在發展針對體覺皮質區特定部份的藥物，可以在發生神經可塑型變化之前及早治療。
不過，一旦已經發生慢性疼痛，因其相關的生物、生理與社會影響，Jensen醫師與Finnerup醫師認為，單靠一、兩種針對特定機轉的藥物仍可能無法治癒病患。
在這個雙盲、雙虛擬交叉研究中，研究對象有56名病患；研究對象有糖尿病型多發性神經病變或者帶狀疱疹後神經痛，每日疼痛分數在0-10分的量表中至少4分。
研究者隨機將病患以1:1:1的比率進行分派。研究對象分別接受每天口服gabapentin或nortriptyline或併用兩種。在治療期間，研究者每6週調整藥物，以達最大耐受劑量。
試驗的主要結果是在最大耐受劑量時的平均每日疼痛分數，採取治療意向分析。
Gilron醫師等人發現，併用治療組的疼痛顯著低於單用gabapentin (-0.9；95%信心區間[CI]為 -1.4 至 -0.3; P = .001)或nortriptyline (-0.6；95% CI，-1.1至-0.1；P = .02) 。
【最大耐受劑量的疼痛】
治療 | 平均每日疼痛分數 | 95% CI |
Gabapentin | 3.2 | 2.5 – 3.8 |
Nortriptyline | 2.9 | 2.4 – 3.4 |
併用 | 2.3 | 1.8 – 2.8 |
研究者報告指出，試驗中沒有任何病患有嚴重副作用；最常見的一般副作用為口乾，gabapentin組的病患體重增加較多。
Gilron醫師表示，併用治療減少疼痛、也減少睡眠干擾且沒有增加副作用。他也承認，這些效果還需要由其他中心研究驗證。
Jensen醫師與Finnerup醫師指出，Gilron醫師等人的試驗結果來自研究者發起的兩種神經痛常用藥物的初步研究。可惜的是，這類研究很少見，因為多數藥物研究是接受藥廠資助、許多機構參與，以及大樣本的研究。
現在這個研究的缺點是，研究者經費有限而限制了研究對象人數；他們使用交叉研究設計，每個病患也是自己的對照組。
研究者也沒有提供比較相繼使用與同時使用的效果的資料。Jensen醫師與Finnerup醫師指出，在臨床實務，相繼使用比較常見，但是在Gilron醫師等人的研究中，同時給予了併用藥物。
加拿大健康研究中心支持該研究。第一作者、Ian Gilron醫師與資深作者、Robyn Houlden醫師皆宣告接受輝瑞藥廠的財務支持。編輯Troels Jensen醫師宣告接受輝瑞、Eli Lilly以及Grunenthal等的資助。編輯Nanna Brix Finnerup醫師宣告接受UCB Nordic的研究支持。
Lancet. 線上發表於2009年9月30日。
Combination Gabapentin and Nortriptyline May Ease Neuropathic Pain
By Allison Gandey
Medscape Medical News
October 1, 2009 — Researchers looking for new ways to treat refractory neuropathic pain suggest that combining gabapentin with nortriptyline may be beneficial. They propose that adding an antidepressant to an anticonvulsant used for pain relief may ease difficult-to-treat neuropathic pain. Exploratory findings were published online September 30 in the Lancet.
"Given the challenges of neuropathic pain, polypharmacy is frequently used," lead investigator Ian Gilron, MD, from Queen's University in Kingston, Ontario, Canada, said during an interview. "But many combinations are not beneficial. We wanted to study this combination in a rational and evidence-based way," Dr. Gilron told Medscape Neurology.
 |
| Dr. Ian Gilron |
The trial was investigator initiated and was supported by the Canadian Institutes of Health Research. Gabapentin (
Neurontin, Pfizer) is a 3-alkylated analogue of γ aminobutyric acid. It was originally developed for the treatment of epilepsy but is widely used as a pain reliever.
Nortriptyline (
Pamelor, Novartis) is a metabolite of amitriptyline and reportedly blocks norepinephrine, serotonin uptake, sodium channels, and N-methyl-D-aspartate glutamate receptors.
"This study is most welcome because improved treatment for patients with chronic types of pain is urgently needed," Dr. Troels Jensen and Dr. Nanna Brix Finnerup, from the Aarhus University Hospital in Denmark, said in an accompanying comment.
Neuropathic pain affects an estimated 3% of the general population, and a meta-analysis showed that less than two thirds of patients obtain sufficient pain relief (
Pain 2005;118:289–305).
At the recent American Academy of Pain Medicine annual meeting, experts discussed the challenges of refractory neuropathic pain. Session moderator Perry Fine, MD, from the University of Utah School of Medicine, Salt Lake City, emphasized the limits to what can be accomplished with current therapies.
Challenge of Treating Neuropathic Pain
"Generally, available drugs lack molecular specificity and simply act as antihyperalgesics," Dr. Jensen and Dr. Finnerup add in their article. Drugs that target specific parts of somatosensory processing are now in development and could be used for early treatment before neuroplastic changes have taken place.
However, once chronic pain has set in, with all of its associated biological, psychological, and social effects, Dr. Jensen and Dr. Finnerup suggest that 1 or even 2 drugs that target a specific mechanism are unlikely to cure the patient.
In this double-blind, double-dummy, crossover trial, investigators studied 56 patients. Participants had diabetic polyneuropathy or postherpetic neuralgia and a daily pain score of at least 4 on a scale of zero to 10.
Investigators randomly assigned patients in a 1:1:1 ratio. Participants received 1 of 3 sequences of daily oral gabapentin, nortriptyline, and a combination of both. During each 6-week treatment period, investigators titrated the drugs toward the maximum tolerated dose.
The primary outcome for the trial was mean daily pain at maximum tolerated dose. Analysis was by intention to treat.
Dr. Gilron and his team found that pain with combination therapy was significantly lower than with gabapentin (?0.9; 95% confidence interval [CI], ?1.4 to ?0.3;
P = .001) or nortriptyline (?0.6; 95% CI, ?1.1 to ?0.1;
P = .02) alone.
Pain at Maximum Tolerated Dose
| Therapy | Mean Daily Pain | 95% CI |
| Gabapentin | 3.2 | 2.5 – 3.8 |
| Nortriptyline | 2.9 | 2.4 – 3.4 |
| Combination | 2.3 | 1.8 – 2.8 |
Investigators report no serious adverse events for any patients during the trial. The most common adverse effect was dry mouth, and the participants reported more weight gain in the gabapentin group.
"Combination therapy decreased pain, but it also decreased sleep interference without increasing side effects," Dr. Gilron said. He acknowledged that these promising results will need to be replicated at other centers.
"Gilron and colleagues' trial benefits from being an investigator-initiated study of 2 commonly used drugs for neuropathic pain," note Dr. Jensen and Dr. Finnerup. "This type of study is unfortunately rare because most drug studies are based on large sample sizes from many sites and financed by drug companies."
A drawback of the current study was that the investigators had to keep costs down and thus limited the number of participants. They used a crossover design in which each participant served as his or her own control.
The investigators also provide no data on the benefits of sequential vs simultaneous combination treatment. "In clinical practice, sequential treatment is most common," Dr. Jensen and Dr. Finnerup point out, "but in Gilron and colleagues' study, drugs in combination were given simultaneously."
This study was supported by the Canadian Institutes of Health Research. Lead author Dr. Ian Gilron and senior author Dr. Robyn Houlden have disclosed receiving financial support from Pfizer. Editorialist Dr. Troels Jensen has disclosed that he has received funding from Pfizer, Eli Lilly, and Grunenthal. Editorialist Dr. Nanna Brix Finnerup has disclosed receiving research support from UCB Nordic.
Lancet. Published online September 30, 2009.
