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作者：Pam Harrison  
出處：WebMD醫學新聞

　　February 9, 2010 — 長期難治型複雜性區域疼痛症候群(complex regional pain syndrome，CRPS)病患的一篇小型隨機研究顯示，低劑量靜脈注射免疫球蛋白(IVIG)可減少疼痛和改善長期難治型CRPS病患的自律肢體症狀。
　　
　　第一作者、英國利物浦大學的Andreas Goebel博士等人，在2月的內科醫學誌(Annals of Internal Medicine)中報告指出，治療效果方面有清楚的證據，後續14天的IVIG輸注之後，疼痛分數比生理食鹽水控制組平均低1. 55單位，且沒有嚴重不良事件(P < .001)。
　　
　　最初的13名隨機分組的病患中，有3人的疼痛強度在以IVIG治療之後，比生理食鹽水控制組減少50%以上。
　　
　　Goebel博士向Medscape Neurology表示，我們無法以標準治療好好地治療這些病患，使用IVIG時所見的疼痛分數降低代表著相當好的疼痛緩解，更重要的是，2個病患超過30%的緩解、3個有超過50%的疼痛緩解。
　　
　　【疼痛強度】
　　為了進行研究，在一個11分的數字量表中，疼痛強度超過4分、且有CRPS達6-30個月、標準治療方式難以控制的13名研究對象，被隨機指派到活性治療組或生理食鹽水控制組，之後給予不同的輸注，每種輸注給予連續2天，有12名病患完成試驗。
　　
　　研究作者們指出，我們要求所有病患需曾經嘗試使用乙醯胺酚、非類固醇抗發炎藥物、鴉片類藥物、三環抗憂鬱藥物、gabapentin或pregabalin、以及物理治療，但是不滿意結果，病患們在研究期間接受標準藥物治療，但不使用新的止痛藥物。
　　
　　隨機分派到活性治療組的病患接受的免疫球蛋白總劑量為每公斤體重0.5g，研究者表示這比一般用於其他情況的劑量低，初步結果認為這種劑量對於CRPS有效且副作用最少。如同研究作者們報告指出的，5個病患(該世代的42%)在以IVIG治療後疼痛中位數分數比對照組減少至少2分。
　　
　　有趣的是，一名病患在以生理食鹽水治療之後的疼痛中位數分數比IVIG組減少2分，研究作者們指出，4名病患(3名IVIG組以及1名生理食鹽水對照組)在初次輸注之後有持續的疼痛緩解，1名病患持續2週，其他持續3週，因而延遲了第二次的輸注，第二次輸注接受IVIG的病患，2名在輸注之後28天報告指出疼痛「改善許多」或「相當改善」。
　　
　　每個治療期間測量肢體症狀的11名病患中，1名病患指出在以活性藥物和安慰劑輸注之後有一些改善，3名病患在任何輸注之後都認為沒有改善，其他7名病患指出在IVIG輸注之後有改善、生理食鹽水輸注之後則無(P = .016)。
　　
　　【意外發現的觀察】
　　Goebel博士指出，使用IVIG作為治療CRPS的觀念是來自幾年前的意外觀察，當時有一名慢性疼痛病患需要IVIG治療其他狀況，結果在輸注之後發現有顯著的疼痛緩解。
　　
　　他觀察發現，我們現在知道，CRPS有一些免疫問題，但是我們當時並不知道，在該次觀察發現之後，研究者指出，CRPS至少有一部份是受到神經元表面的病原性自體抗體調節。
　　
　　藉由輸注IVIG，這些自體抗體如果不完全消除，也可以被中和，研究作者們也指出，長期的CRPS只有一些醫療介入方式有效，但是所有的療法在給藥上相當麻煩且有嚴重不良反應；迄今，沒有發現實用的疼痛緩解藥物治療方法。
　　
　　研究作者們結論表示，就我們所知，這是首次顯示低劑量IVIG可減少長期難治型CRPS病患之疼痛，且少有不良反應的方法。IVIG可以作為難治型疾病之有效且安全的新療法選項，不過還需要確認試驗。
　　
　　【自體抗體有關】
　　CRPS研究的佼佼者、德國Hessen Giessen大學的Franz Blaes醫師向Medscape Neurology表示，2004年時，他和研究夥伴辨識在神經細胞表面的自體抗體，而這些自體抗體與CRPS有關。
　　
　　他向Medscape Neurology表示，許多自體免疫疾病對IVIG有反應，所以，我們開始以IVIG治療慢性CRPS病患看看是否有效，雖然研究者並未完全確定IVIG如何在自體免疫疾病中發揮效果，給予高劑量時，它可以藉由和自體抗體作用且中和它們而降低某些免疫細胞功能。
　　
　　Blaes醫師也解釋，至少在CRPS的急性期時，它看起來更像是一種發炎疾病，有許多水腫、四肢發熱且腫脹，急性期的自體抗體值相當高。
　　
　　因此認為IVIG在急性CRPS時可能更有效，因為自體抗體值很高，Blaes醫師等人目前正研究IVIG是否在早期CRPS更有效，急性期CRPS病患被納入一個前溯、隨機安慰劑控制交叉研究。
　　
　　英國與愛爾蘭麻醉科醫師協會、倫敦大學院Trustees醫院、CSL-Behring公司支持本研究。Goebel醫師與 Blaes醫師皆宣告沒有相關財經關係。


IVIG Improves Symptoms in Refractory Complex Regional Pain Syndrome

By Pam Harrison
Medscape Medical News

February 9, 2010 — Low-dose intravenous immunoglobulin (IVIG) reduces pain and improves autonomic limb symptoms in patients with long-standing, refractory complex regional pain syndrome (CRPS), a small but randomized study of long-standing, refractory CRPS patients shows.

Published in the February issue of the Annals of Internal Medicine, researchers under lead study author Andreas Goebel, MD, PhD, from University of Liverpool, United Kingdom, found "clear evidence" for a treatment effect, with an average decrease of 1.55 units in pain scores vs saline after IVIG infusion during the subsequent 14 days, with no serious adverse events (P < .001).

For 3 of the 13 initially randomized participants, pain intensity was 50% lower or better after IVIG treatment compared with saline controls.

"We can't treat these patients very well with standard therapy, and the reduction in pain scores we saw with IVIG is an indication of very strong pain relief," Dr. Goebel told Medscape Neurology. "Most importantly, 3 patients had over 50% pain relief and 2 had over 30% relief.”

Pain Intensity

For the study, 13 participants with a pain intensity greater than 4 on an 11-point numerical rating scale and with CRPS for 6 to 30 months refractory to standard treatment were randomly assigned to active therapy or saline followed by the alternative infusion, each infusion given for 2 consecutive days. Twelve patients completed the trial.

"We required all patients to have tried acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, tricyclic antidepressants, gabapentin or pregabalin, and physiotherapy with an unsatisfactory outcome," the study authors note. Patients received standard medical therapy during the study but no new analgesic drugs were allowed.

... the reduction in pain scores we saw with IVIG is an indication of very strong pain relief.

Patients randomized to active therapy received a total immunoglobulin dose of 0.5 g/kg — a lower dose than that commonly used for other conditions, investigators observe, because preliminary findings indicated that this dose was still effective in CRPS but had minimal adverse events. As the study authors report, 5 patients or 42% of the cohort achieved median pain scores that were at least 2 points lower after IVIG treatment than with saline.

Interestingly, 1 patient reported a median pain score that was 2 points lower after saline administration than after IVIG. "Ongoing pain relief after the first infusion required delay of the second infusion in 4 patients (3 patients after IVIG and 1 patient after saline)," the investigators add. Two patients who received IVIG as the second infusion reported "much improved" or "very much improved" pain 28 days after the second infusion, 1 patient for 2 weeks and the other for 3 weeks.

Of the 11 patients with limb-symptom measurements for each treatment period, 1 patient reported some improvement after both active and placebo infusion, whereas 3 patients reported no improvement after either infusion. The remaining 7 patients reported an improvement after IVIG infusion but not after saline (P = .016).

Serendipitous Observation

The idea of using IVIG as a treatment for CRPS arose from a serendipitous observation a number of years ago, Dr. Goebel notes, when a patient with chronic pain who required IVIG treatment for an unrelated condition reported significant pain relief after the infusion.

"We know now that there are immune problems in CRPS, but we did not know this at the time," he observes. Subsequent to that observation, researchers have reported that CRPS at least in part appears to be mediated by pathogenic autoantibodies on the surface of neurons.

By infusing IVIG, these autoantibodies could be neutralized, if not entirely eliminated. The study authors also point out that in long-standing CRPS only a few medical interventions are effective, but all are cumbersome to administer and associated with serious adverse reactions; to date, no drug treatment has been found to provide viable pain relief.

"To our knowledge, we have shown for the first time that low-dose IVIG reduces pain in patients with long-standing, refractory CRPS, with few adverse reactions," the investigators conclude. IVIG may "emerge as an effective and safe novel clinical treatment option for otherwise refractory disease, [although] confirmatory trials are required."

Autoantibody Implicated

A leading researcher in CRPS, Franz Blaes, MD, from the University of Giessen, Hessen, Germany, told Medscape Neurology that in 2004 he and his colleagues identified autoantibody on the surface of nerve cells and that these autoantibodies had been implicated in CRPS.

“A lot of autoimmune diseases respond to IVIG, so we started to treat chronic CRPS patients with IVIG to see if it worked,” he told Medscape Neurology. Although researchers are not entirely sure how IVIG functions in autoimmune disease, given in high doses, it may downregulate some immune cell function by reacting with these autoantibodies and neutralizing them.

it looks more like an inflammatory disease...

As Dr. Blaes also explained, at least in the acute phase of CRPS, "it looks more like an inflammatory disease — there is a lot of edema, the limb is hot and swollen, and levels of autoantibodies are higher in the acute states."

Thinking that IVIG may well be more effective in acute CRPS when autoantibody levels are high, Dr. Blaes and colleagues are currently investigating whether IVIG may be even more effective in patients with early-stage CRPS, and acute-phase CRPS patients are currently being enrolled in a prospective, randomized, placebo-controlled, crossover study.

The study was supported by the Association of Anaesthetists of Great Britain and Ireland, the University College London Hospitals Trustees, and CSL-Behring. Dr. Goebel and Dr. Blaes have disclosed no relevant financial relationships.

Ann Intern Med. 2010;152:152-158.