帶狀泡疹(皰疹)神經痛 2. Postherpetic Neuralgia from Uptodate

2023-09-16 中午12:12
另一篇參考資料(帶狀泡疹(皰疹)神經痛 1. Postherpetic Neuralgia-StatPerls)太龐大.
本來想把兩篇文章寫在同一篇筆記. 但實在不好閱讀. 還是切割開來

這裡只列出在 uptodate 上面關於治療的部分. 其他部分請自己看原文(沒有附)
下面中文是google翻譯. 第一段自動沒有翻譯, google翻譯的程式邏輯還有缺陷
治療這段的英文原文在筆記最下面

初始治療 —臨床試驗和薈萃分析發現，加巴噴丁類藥物（即加巴噴丁和普加巴林）和三環類抗抑鬱藥 (TCA) 對 PHN 有效且普遍耐受性良好[ 40-44 ]。與 TCA 相比，加巴噴丁類藥物因不良反應而停藥的風險可能較低，但尚未直接比較這些藥物對 PHN 的影響。我們使用患者變量（包括藥物副作用、合併症和症狀嚴重程度）來幫助選擇初始治療。例如，加巴噴丁或普瑞巴林可能是患者的首選，以幫助共同治療癲癇症或避免與 TCA 相關的認知障礙風險。阿米替林或其他 TCA 可能是患者首選，以幫助共同治療抑鬱症。

加巴噴丁類藥物用於大多數中度或重度疼痛患者 — 對於大多數中度至重度疼痛患者，我們建議加巴噴丁類藥物（加巴噴丁或普加巴林）作為初始治療[ 45 ]。加巴噴丁和普瑞巴林是γ-氨基丁酸（GABA）的結構類似物，已被美國食品和藥物管理局（FDA）批准用於治療PHN。兩者通常都具有良好的耐受性，並且不會改變其他藥物的藥代動力學，因為兩者都不與血漿蛋白結合[ 46,47 ]。我們通常從加巴噴丁開始，因為成本更低且耐受性更好[ 43]。然而，根據療效，普瑞巴林也是治療 PHN 的合理初始選擇，因為沒有與加巴噴丁的直接比較。

●加巴噴丁-加巴噴丁通常以低劑量開始，以盡量減少因不良反應而停藥的風險。每日劑量逐漸調整至有效，對於大多數患者來說，通常為 1800 至 3600 毫克。我們建議的加巴噴丁速釋製劑治療 PHN 的初始滴定劑量為：


• 第 1 天 300 mg
• 第 2 天 300 mg，每天兩次
• 第 3 天 300 mg，每天 3 次
• 此後，根據需要每三天增加300 mg每日 3 次，最多 600 毫克

對於在初始滴定過程中報告中等劑量緩解或不良反應的患者，可以使用較低劑量或減慢滴定速度。

對於每日總劑量 1800 mg 一個月後報告症狀緩解甚微或無緩解的患者，我們改用 TCA。


對於每日總劑量為 1800 mg 時疼痛部分緩解但不充分的患者，加巴噴丁可根據需要進一步增加，並可耐受，每週最多 600 mg，分三次給藥，最大劑量為 3600 mg。加巴噴丁



緩釋製劑根據相同的時間表使用每日總劑量進行滴定，以確定每日一次的劑量。速釋製劑和緩釋製劑都需要針對腎功能損害進行調整，並且不建議在嚴重腎功能損害（例如肌酐清除率<30 mL/分鐘）的患者中使用緩釋製劑。有中等質量的證據支持加巴噴丁的功效



對於 PHN，但一些試驗未能顯示加巴噴丁緩釋製劑的益處，並且超過 12 週的益處尚不確定 [ 43,48 ]。在一項薈萃分析中，對2200 多名PHN 引起的中度至重度疼痛患者進行了8 項試驗，每天服用1200 毫克或更高劑量加巴噴丁的患者更有可能報告獲益（疼痛強度至少降低50% ）或“明顯改善”疼痛）比接受安慰劑的患者（32% 對 17%）[ 49 ]。



加巴噴丁通常耐受性良好。在一項針對多種類型神經性疼痛的 37 項試驗的不良反應匯總分析中，由於不良反應，患者比安慰劑更有可能停用加巴噴丁（11% 對 8%）[49 ]。最常見的不良反應是嗜睡或嗜睡（14% vs 5%）、頭暈（19% vs 7%）、外周水腫（7% vs 2%）以及共濟失調或步態障礙（14% vs 3%） 。兩組的嚴重不良反應發生率均為 3%。●普瑞巴林-普瑞巴林


的速釋製劑每天服用兩到三次。我們基於效果和耐受性的滴定方案是：• 75 毫克，每天兩次，持續一周，然後• 150 毫克，每天兩次，持續一到三週，然後• 300 毫克，每天兩次





緩釋製劑也可供每日一次給藥。滴定方案與速釋製劑相同；然而，起始劑量為每天 165 毫克，最大劑量為每天 660 毫克。

停藥時，普瑞巴林應在一周內逐漸減量，以降低戒斷症狀的風險[ 50 ]。

速釋製劑和緩釋製劑都需要針對腎損傷進行調整；不建議患有嚴重腎功能不全（例如肌酐清除率<30 mL/分鐘）的患者使用緩釋製劑。普瑞巴林在美國被指定為第五類管制物質，因為據報導它會引起欣快感。

普瑞巴林治療神經性疼痛的系統評價確定了 8 項試驗，其中包括 2300 多名 PHN 患者[ 51 ]。在四項PHN 患者試驗中對732 名患者進行的薈萃分析中，接受普瑞巴林的患者比接受安慰劑的患者更有可能出現劑量反應和疼痛顯著減輕（至少50%）：150 mg（24 % vs 13%） 、300 毫克（32% 對 13%）和 600 毫克（41% 對 15%）。與普瑞巴林給藥相關的常見副作用包括嗜睡（300 mg，16%；600 mg，25%）和頭暈（300 mg，29%；600 mg，35%）。其他副作用包括口乾、外周水腫和體重增加。

如果加巴噴丁類藥物無效或不耐受，則使用三環類抗抑鬱藥物 — 對於不耐受加巴噴丁類藥物或對加巴噴丁類藥物沒有反應的患者，我們建議使用 TCA。它們經常用於治療抑鬱症或其他類型的神經性疼痛，對 PHN 也有效，但耐受性低於加巴噴丁類藥物 [ 52,53 ]。對於大多數使用 TCA 的患者，我們通常從阿米替林開始；然而，對於有抗膽鹼能症狀風險的患者和有阿米替林不良反應的患者，去甲替林或地昔帕明可能是首選。

●阿米替林開始劑量為每晚 10 毫克。劑量可根據需要和耐受性在 4 週內增加，直至每晚 50 毫克。對於服用 50 毫克一個月後報告症狀緩解甚微或無緩解的患者，我們改用另一種藥物（參見下文“替代療法”）。對於那些在 50 mg 劑量下報告部分但不充分緩解的患者，可以每 4 週進一步增加劑量，直至每日最大劑量 150 mg，並監測不良反應。

●去甲替林通常從每晚 10 mg 開始，每週增加 10 至 20 mg，以達到耐受的效果，每日最大劑量為 150 mg。

●地昔帕明通常從每晚 25 毫克開始，每週增加 25 毫克，以達到耐受的效果，每日最大劑量為 150 毫克。

TCA 抑制中樞神經系統去甲腎上腺素和血清素的再攝取。它們被認為可以增強對來自外周的傷害性信號的抑制[ 54,55 ]。

抗膽鹼能副作用（主要是鎮靜和口乾）限制了 TCA 的耐受性（表 1）[ 56]]。由於 TCA 具有抗膽鹼能作用，老年患者尤其是患有認知障礙或癡呆的患者應謹慎使用 TCA。我們還避免對患有心髒病、癲癇或青光眼的患者使用 TCA。通過緩慢滴定可以減少不良反應；然而，在 TCA 開始減輕疼痛之前延遲起效（最多三週）可能會導致過早停藥。可能需要以目標劑量進行至少一個月的治療試驗來評估 TCA 的療效。在一項研究中，症狀緩解與阿米替林和活性代謝物的血清水平相關[ 57 ]。儘管血清水平為 100 ng/mL 至少三週，但報告沒有獲益的患者被認為 TCA 治療失敗。

2015 年的一項系統評價發現中等質量的證據支持 TCA 對 PHN 的療效[ 43 ]。TCA 中阿米替林的療效最為明確，多項短期研究發現阿米替林可有效緩解至少中度疼痛，通常劑量為每日 65 至 75 毫克 [57,58 ]。在一項針對 33 名 PHN 患者的小型交叉試驗中，去甲替林比阿米替林具有更好的耐受性 [ 59 ]。大約三分之二的患者報告這兩種藥物的反應良好，但阿米替林比去甲替林更常見導致停藥的不良反應（48% vs 30%）。研究規模較小限制了這些結果的普遍性。地昔帕明似乎是第一代 TCA 中副作用最少的，並且在一項小型試驗中以平均每天 165 毫克劑量對 PHN 有效 [ 60,61 ]。近一半的人表示服用地昔帕明效果良好。然而，對該試驗的方法學批評限制了這些結論的確定性[ 62 ]。

對症狀較輕的患者進行局部治療 — 對於輕度至中度局部疼痛的患者以及喜歡局部用藥的患者，我們建議使用辣椒素。對於那些不耐受辣椒素的人，我們改用利多卡因貼劑。

●辣椒素——辣椒素被配製成乳膏、凝膠、乳液或高濃度貼劑。

我們用對於大多數 PHN 患者，可使用辣椒素乳膏（0.025 至 0.075%），並為對辣椒素乳膏有部分反應且更喜歡長效配方的特定患者保留高濃度辣椒素（8%）貼劑。

•辣椒素霜每天最多可塗抹在患處四次。

•高濃度辣椒素貼劑單次使用60 分鐘。三個月後可以重複申請。它必須由醫療保健專業人員進行，並且治療後對患者進行長達兩個小時的監測。為了控制施用辣椒素引起的局部疼痛，通常用局部麻醉劑（例如局部利多卡因）預處理皮膚，一些研究還使用治療後口服鎮痛藥，例如羥考酮，持續時間長達五天[ 63 ]。需要進一步的研究來確認高濃度辣椒素貼劑的長期有效性和耐受性。

有限的數據表明局部應用標準濃度辣椒素對 PHN 有效[ 41 ]。在一項小型試驗中，143 名 PHN 患者被分配每天四次辣椒素乳膏（0.075%），持續六週，與接受安慰劑的患者相比，疼痛明顯緩解（21% vs 6%）[64 ]。接受辣椒素和安慰劑的患者皮膚不良反應發生率相似。

2013 年的一項系統回顧確定了四項隨機對照試驗，這些試驗評估了 1272 名 PHN 受試者，使用一次高濃度辣椒素貼劑或標準濃度辣椒素進行治療。所有四項試驗報告的唯一共同終點是，與基線相比，八週時疼痛強度降低≥30%，高濃度辣椒素貼片的效果顯著更高（43% vs 34%；相對效益1.3，95 % CI 1.1-1.5） [ 65 ]。

高濃度辣椒素貼劑經 FDA 批准用於治療 PHN。然而，辣椒素會引起灼燒感、刺痛感和紅斑，因此在臨床研究中很難實現真正的致盲。實際上，多達三分之一的患者無法忍受辣椒素的應用。

●利多卡因 —利多卡因貼劑 (5%) 可以短期緩解 PHN。每天最多可在受影響區域塗抹 3 片貼劑，持續時間長達 12 小時。

小規模試驗和開放標籤研究的數據表明，局部利多卡因（5%）可能有助於緩解 PHN 患者的疼痛[ 66]。利多卡因貼劑已獲得 FDA 批准用於 PHN。然而，2014 年對局部利多卡因治療神經性疼痛的系統評價（包括280 名PHN 患者）發現，由於數量少、結果評估不完整以及療效結果測量不充分，局部利多卡因療效的證據質量非常低[67 ]。

替代療法 — 對於不能耐受初始治療或對初始治療無反應的患者，我們改用替代藥物（流程 1）。對於初始治療反應部分但未達最佳的患者，我們通過添加替代藥物進行聯合治療。我們利用患者偏好和醫療合併症來幫助選擇選項。

抗驚厥藥物 — 對於一些對初始藥物選擇沒有反應或不能耐受的患者，試用一種（非加巴噴丁類）抗驚厥藥物可能有用。治療決策應根據患者特徵、合併症、副作用和藥物相互作用進行個體化。抗驚厥藥的益處部分基於其對其他神經性疼痛病症（如三叉神經痛和糖尿病神經病變）的療效，以及 PHN 的低質量和軼事證據。PHN 的選項和典型每日目標劑量包括：

●丙戊酸，每日 500 至 1000 毫克
●卡馬西平，每日 200 至 1200 毫克
●奧卡西平，每日 600 至 1200 毫克
●拉莫三嗪每天 100 至 300 mg


這些藥物治療 PHN 的劑量、滴定和監測與三叉神經痛的治療方案相似，通常比達到抗驚厥作用的劑量要低。(參見“三叉神經痛”，關於‘藥物治療’一節)

在一項對48 名PHN 患者進行的為期八週的試驗中，接受雙丙戊酸鈉治療（每天1000 mg）的患者與接受雙丙戊酸鈉治療的患者相比，更有可能報告疼痛至少有中度改善。分配給安慰劑（58% 對 15%）[ 68 ]。丙戊酸治療其他神經性疼痛的小型試驗結果好壞參半[ 69 ]。在三叉神經痛患者的短期試驗中，卡馬西平奧卡西平比安慰劑更能減輕疼痛，但這兩種藥物都沒有在 PHN 患者中進行測試 [ 70,71 ]。拉莫三嗪可能比卡馬西平具有更好的耐受性，但尚未針對神經性疼痛進行廣泛研究。

5-羥色胺-去甲腎上腺素再攝取抑製劑 — 根據疼痛性多發性神經病的療效數據，5-羥色胺-去甲腎上腺素再攝取抑製劑 (SNRI) 可能對某些 PHN 患者有用 [43 ]。這些藥物可能對患有抑鬱症的患者有用。對於 PHN 患者，我們使用度洛西汀或文拉法辛。

●度洛西汀通常從每天 30 毫克開始。典型的每日劑量為 60 至 120 毫克。可以每週增加劑量以達到效果並在耐受範圍內。高劑量時更常見的不良反應包括噁心、口乾、頭暈和失眠。

●文拉法辛可以每天 75 mg 開始，每兩週增加一次，直至達到耐受的效果。典型的每日劑量為 150 至 225 毫克。青光眼患者和服用抗凝劑的患者應謹慎使用文拉法辛。常見的不良反應包括噁心、頭暈和嗜睡。

SNRIs 的初始滴定和給藥詳見其他專題。(參見“5-羥色胺-去甲腎上腺素再攝取抑製劑：藥理學、給藥方法和副作用” )

度洛西汀和文拉法辛等 SNRI 藥物對 PHN 患者的有效性基於其他類型神經性疼痛患者的數據。對 8 項試驗（包括 4084 名患者）的系統評價發現，度洛西汀對患有疼痛性糖尿病神經病變的患者有益 [ 72 ]。一項針對 244 名患有疼痛性糖尿病多發性神經病患者的短期試驗發現文拉法辛有效 [ 73 ]。接受 150 至 225 mg 文拉法辛治療的患者比接受安慰劑治療的患者更有可能報告至少 50% 的疼痛減輕（50% 對 27%）。然而，2015 年對 6 項試驗（包括 460 名神經性疼痛患者）進行的系統回顧發現，文拉法辛僅具有中等療效的低質量數據。74 ]。SNRIs 對糖尿病神經病變的療效詳見其他專題。(參見“糖尿病神經病變的治療”，關於‘給藥方法和療效’一節)

輔助選擇— 對於先前治療難治性症狀的患者，可以嘗試或添加輔助選擇和其他介入治療，如肉毒毒素注射(流程1 ) 。這些包括口服或透皮阿片類鎮痛藥和鞘內糖皮質激素注射劑。這些藥物的選擇取決於患者個體的偏好和合併症。

阿片類藥物 — 阿片類藥物可能對某些在初始或替代療法滴定期間患有頑固性疼痛的患者有益。它們可以與非阿片類藥物同時給藥以實現短期緩解。如果使用的話，應以低劑量開始，並在等待非阿片類藥物治療獲益的同時逐步調整以提供緩解，此時應逐漸減少阿片類藥物的用量。

阿片類藥物有短效或長效製劑（表 2和表 3）。我們首先為未使用過阿片類藥物的患者提供短效選擇，並使用最低有效劑量。PHN 患者開始和長期使用阿片類藥物的策略與其他非癌性疼痛患者相似，將單獨更詳細地討論。（看“使用阿片類藥物治療慢性非癌症疼痛”。）

小型試驗支持阿片類鎮痛藥對 PHN 的療效[ 75-79 ]。在一項涉及 76 名 PHN 患者的交叉試驗中，嗎啡（平均每日劑量 91 mg）或美沙酮（平均每日劑量 15 mg）或 TCA 治療八週比安慰劑更有效[ 77 ]。阿片類藥物有更好地緩解疼痛的趨勢，但這些結果的確定性受到樣本量較小的限制。

應避免使用阿片類藥物治療慢性 PHN。由於存在身體依賴性、耐受性、成癮性和過量服用的風險，阿片類藥物治療慢性非癌性疼痛仍然存在爭議。由於這些風險，阿片類藥物被視為三線治療選擇，通常僅供 PHN 的短期輔助使用[ 38,43,80 ]。阿片類藥物治療包括 PHN 在內的神經性疼痛的現有試驗並未解決濫用和成癮問題 [ 81 ]。藥物警戒對於在任何人群中使用阿片類藥物至關重要（表 4）。(參見“阿片類藥物使用障礙：流行病學、臨床特徵、健康後果、篩查和評估” )

椎管內輸注糖皮質激素 — 鞘內註射糖皮質激素可能對經過初始治療或替代治療後仍存在頑固性疼痛的患者有益。這些注射對於三叉神經分佈區的疼痛沒有作用。

用於治療 PHN 的鞘內糖皮質激素通常是每週注射一次，持續 4 週 [ 82 ]。鞘內註射糖皮質激素的技術將單獨更詳細地討論。(參見“脊髓麻醉：技術” )

鞘內註射糖皮質激素與不確定但可能較低風險的嚴重不良事件相關，包括無菌性腦膜炎、橫貫性脊髓炎、馬尾綜合徵、腰神經根炎、頭痛、尿瀦留和蛛網膜炎[ 83,84 ]。

一些 [ 40,82,85 ] 但並非所有 [ 86 ] 研究發現鞘內注射甲潑尼龍對 PHN 患者有益。最大的試驗評估了 277 名頑固性 PHN 患者，他們被分配到三個治療組之一：鞘內註射甲基強的松龍加利多卡因，每週一次，持續四個星期，鞘內註射利多卡因，每週一次，持續四個星期，或不治療[ 82]。甲基強的松龍組中超過 90% 的患者在 4 週後報告疼痛緩解效果良好或良好，而利多卡因組和無治療組中這一比例分別為 6% 和 4%。這些結果在兩年的隨訪中得以維持。沒有與註射相關的嚴重不良事件。在一項對 25 名 PHN 患者進行的小型試驗中，發現鞘內註射

甲基潑尼松龍比硬膜外注射更有效[ 85 ]。

難治性症狀的治療 — 對於對其他治療無反應的難治性症狀患者，我們保留其他介入和手術方法，例如肉毒毒素注射、冷凍療法和神經調節（流程圖 1 ））。此類療法的益處已在小型試驗和觀察性研究中得到證實；需要更大規模的研究來更好地確定它們對 PHN 患者的作用。

肉毒桿菌毒素 — 肉毒桿菌毒素注射治療 PHN 尚未得到廣泛研究，但觀察性研究和小型試驗的證據表明它是有效的[ 87-90 ]。一項試驗評估了 30 名患有 PHN 的成年人，他們持續疼痛至少三個月[ 87 ]。分配至 A 型肉毒毒素 ( onabotulinumtoxinA)的患者與接受安慰劑注射的患者相比，注射安慰劑更有可能在兩週內實現 ≥50% 的疼痛減輕（15 名患者中有 13 名患者 [87%]，而 15 名患者中沒有一人）。獲益持續時間中位數為 16 週。在一項對 60 名 PHN 患者進行的比較研究中，與接受利多卡因注射的患者相比，接受肉毒桿菌毒素A 注射的患者在7 天時報告疼痛減輕幅度更大（4.5 分與2.6 分） [ 88 ]。這些發現持續了三個月。據報導，肉毒桿菌毒素組的睡眠有所改善，阿片類藥物的使用也有所減少。

肉毒毒素注射應由具有這種治療經驗的臨床醫生進行[ 91-93]。小型研究未發現安全問題[ 87,88 ]。然而，肉毒桿菌毒素可能會引起局部或全身不良反應，包括瘀傷、虛弱、疼痛或頭痛，並且可能對某些患者是禁忌的。更大規模、更長期的研究將有助於進一步闡明這種治療 PHN 的安全性和有效性。

神經調節和神經刺激 — 脊髓刺激和周圍神經刺激等侵入性神經調節策略被認為是實驗性的。這些技術針對周圍神經，被認為可以調節神經元信號傳導或炎症過程[ 94 ]。對 PHN 患者顯示出一些益處的技術包括：

●經皮神經電刺激 (TENS) [95 ]
●脈衝射頻[ 96-100 ]
●脊髓刺激[ 101,102 ]

據報導，在病例報告和病例係列中，這些技術對大約一半的患者有效[ 103 ]。它們應該由經驗豐富的臨床醫生在具有專業知識的中心進行。

認知和行為治療 — 一些 PHN 患者即使採用聯合藥物治療也只能部分緩解。對於其他患者來說，藥物治療的功效受到不良反應的限制。非藥物方法，包括認知行為療法（CBT），可能對一些患有難治性 PHN 疼痛或情緒、睡眠或其他生活質量領域相關損害的患者有用。104，105 ]。在一項對 40 名接受普瑞巴林治療的 PHN 患者進行的小型試驗中，被分配接受 CBT 的患者報告疼痛強度和情緒症狀比單獨接受普瑞巴林的患者有更大的改善 [ 106 ]。治療慢性疼痛的認知和行為療法將單獨詳細討論。(參見“成人慢性非癌性疼痛的治療方法”，關於‘心理治療’一節)

療效不確定或有限的治療

●NMDA 受體拮抗劑——動物數據表明興奮性氨基酸神經遞質在維持疼痛中發揮作用。神經損傷引起的慢性疼痛 [ 107,108]。N-甲基-D-天冬氨酸（NMDA）受體拮抗劑已被證明可以緩解人類的神經性疼痛[ 109 ]。

最廣泛使用的 NMDA 受體拮抗劑是氯胺酮和右美沙芬。靜脈注射氯胺酮可適度緩解 PHN 患者的疼痛，但劑量會導致鎮靜、煩躁和解離發作 [ 110 ]。在一項交叉試驗中，服用右美沙芬或安慰劑的患者六週後的疼痛緩解情況相似[ 111 ]。

●靜脈注射利多卡因 – 小型試驗未能發現靜脈注射利多卡因與安慰劑相比對 PHN 患者有持續的益處 [ 40,112]。輸注後立即測量的任何暫時的疼痛變化似乎不會持續四個星期[ 40,112-116 ]。局部利多卡因

治療 PHN的作用將單獨討論。(參見上文‘症狀較輕患者的局部治療’ ) ●手術消融和其他介入手術–冷凍療法是一種涉及冷凍周圍神經的消融技術。一項針對面部疼痛的冷凍療法的小型非盲研究未能顯示出對 PHN 患者有顯著益處 [ 117

]。作者沒有提供納入標準、伴隨療法或如何評估反應的信息。相比之下，第二項試驗報告稱，14 名接受冷凍治療的 PHN 患者中，有 11 名患者的肋間神經得到“顯著”緩解 [ 118 ]。然而，在大多數情況下，根據調查問卷評估，緩解持續時間不到兩週。

包括丘腦中樞電刺激、前外側皮質切除術消融和背根電凝術在內的手術干預措施存在造成永久性神經功能缺損的巨大風險。對難治性 PHN 患者的外科手術進行的系統評價報告稱，手術消融手術可減輕疼痛，但常常伴有嚴重的並發症，包括神經肌肉無力。119 ]。

●簡單的鎮痛藥——阿司匹林或其他非甾體類抗炎藥等鎮痛藥對於急性帶狀皰疹神經痛或PHN患者的價值有限[ 38,120 ]。
Postherpetic neuralgia from uptodate TREATMENT
Multiple medications have shown benefit in reducing PHN symptoms. However, PHN can be difficult to treat, and some patients require multimodal therapy to manage symptoms. The choice among treatments for PHN should be individualized according to the severity and location of pain, comorbid conditions, medication side effect profile, treatment cost and availability, and patient values and preferences (algorithm 1). Because the pain of PHN may be chronic, long-term therapy is often required [38]. However, the long-term benefits of most therapies are uncertain, and side effects are common [39].

Initial therapies — Both gabapentinoids (ie, gabapentin and pregabalin) and tricyclic antidepressants (TCAs) have been found to be effective and generally well tolerated for PHN in clinical trials and meta-analyses [40-44]. Gabapentinoids may have a lower risk of discontinuation due to adverse effects than TCAs, but these agents have not been compared directly for PHN. We use patient variables including medication side effect profile, comorbid conditions, and symptom severity to help select initial therapy. As examples, gabapentin or pregabalin may be preferred for patients to help co-treat a seizure disorder or to avoid the risk of cognitive impairment associated with TCAs. Amitriptyline or other TCAs may be preferred for patients to help co-treat depression.

Gabapentinoids for most patients with moderate or severe pain — For most patients with moderate to severe pain, we suggest a gabapentinoid (gabapentin or pregabalin) as initial therapy [45]. Gabapentin and pregabalin are structural analogs of gamma-aminobutyric acid (GABA) and have been approved by the US Food and Drug Administration (FDA) for PHN. Both are generally well tolerated and neither alters the pharmacokinetics of other medications because neither binds to plasma proteins [46,47]. We typically start with gabapentin because of lower cost and more favorable tolerability [43]. However, pregabalin is also a reasonable initial choice for PHN based on efficacy because there are no direct comparisons with gabapentin.

●Gabapentin − Gabapentin is typically started at a low dose to minimize the risk of discontinuation from adverse effects. The daily dose is titrated to effect, for most patients typically from 1800 up to 3600 mg. Our suggested initial titration of the immediate release formulation of gabapentin for PHN is:


•300 mg on day 1
•300 mg twice daily on day 2
•300 mg three times daily on day 3
•Thereafter, increase as needed by 300 mg every three days up to 600 mg three times daily

Lower doses may be used or the titration may be slowed for patients who report relief or adverse effects at intermediate doses during the initial titration.

For patients who report minimal or no relief after one month at a total daily dose of 1800 mg, we switch to a TCA.


For patients who report partial but inadequate pain relief at a total daily dose of 1800 mg, gabapentin may be further increased as needed and tolerated by up to 600 mg each week to a maximum of 3600 mg given in three divided doses.



The extended-release formulation of gabapentin is titrated according to the same schedule using the total daily dosage to determine the once-daily dosing. Adjustment for kidney impairment is required for both immediate- and extended-release formulations, and use of the extended-release formulation is not recommended in patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute).



There is moderate-quality evidence supporting the efficacy of gabapentin for PHN, but some trials have failed to show a benefit with the extended-release formulation of gabapentin, and benefits beyond 12 weeks are uncertain [43,48]. In a meta-analysis including eight trials of more than 2200 patients with moderate to severe pain due to PHN, patients receiving gabapentin at a daily dose of 1200 mg or higher daily were more likely to report benefit (at least 50 percent reduction in pain intensity or "very much improved" pain) than those receiving placebo (32 versus 17 percent) [49].



Gabapentin is generally well tolerated. In a pooled analysis of adverse effects including 37 trials for multiple types of neuropathic pain, patients were more likely to discontinue gabapentin than placebo due to adverse effects (11 versus 8 percent) [49]. The most common adverse effects reported were somnolence or drowsiness (14 versus 5 percent), dizziness (19 versus 7 percent), peripheral edema (7 versus 2 percent), and ataxia or gait disturbance (14 versus 3 percent). The rate of serious adverse effects was 3 percent for both groups.


●Pregabalin − The immediate-release formulation of pregabalin is given two or three times daily. Our titration regimen based on effect and tolerability is:

•75 mg twice daily for one week, then
•150 mg twice daily for one to three weeks, then
•300 mg twice daily

An extended-release preparation is also available for once-daily dosing. The titration schedule is the same used for the immediate-release formulation; however, the starting dose is 165 mg daily and the maximum dose is 660 mg daily.

When stopping the drug, pregabalin should be tapered over a week to reduce the risk of withdrawal symptoms [50].

Adjustment for kidney impairment is required for both the immediate- and extended-release formulations; the extended-release formulation is not recommended for patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute). Pregabalin is designated as a schedule V controlled substance in the United States because it has been reported to cause euphoria.

A systematic review of pregabalin for neuropathic pain identified eight trials including more than 2300 patients with PHN [51]. In the meta-analysis of 732 patients in four trials of patients with PHN, a dose response and significant reduction in pain (at least 50 percent) was more likely for patients receiving pregabalin than those receiving placebo: 150 mg (24 versus 13 percent), 300 mg (32 versus 13 percent), and 600 mg (41 versus 15 percent). Common side effects associated with pregabalin dosing included somnolence (300 mg, 16 percent; 600 mg, 25 percent) and dizziness (300 mg, 29 percent; 600 mg, 35 percent). Other side effects are dry mouth, peripheral edema, and weight gain.

Tricyclic antidepressants if gabapentinoids ineffective or not tolerated — For patients who do not tolerate or respond to a gabapentinoid, we suggest a TCA. They are frequently used for depression or other types of neuropathic pain and are also effective for PHN but have a lower tolerability than gabapentinoids [52,53]. For most patients using a TCA, we typically start with amitriptyline; however, nortriptyline or desipramine may be preferred for patients at risk for anticholinergic symptoms and those with adverse effects from amitriptyline.

●Amitriptyline is started at 10 mg each night. The dose may be uptitrated as needed and tolerated over four weeks up to a dose of 50 mg each night. For patients who report minimal or no relief after one month at 50 mg, we switch to an alternative agent (see 'Alternative therapies' below). For those who report partial but inadequate relief at a dose of 50 mg, the dose may be further uptitrated every four weeks up to a maximum daily dose of 150 mg, monitoring for adverse effects.

●Nortriptyline is typically started at 10 mg each night and increased by 10 to 20 mg each week to effect as tolerated, with a maximum daily dose of 150 mg.

●Desipramine is typically started at 25 mg each night and increased by 25 mg each week to effect as tolerated, with a maximum daily dose of 150 mg.

TCAs inhibit the reuptake of norepinephrine and serotonin in the central nervous system. They are thought to increase the inhibition of nociceptive signals from the periphery [54,55].

Anticholinergic side effects (principally sedation and dry mouth) limit the tolerability of TCAs (table 1) [56]. Because of their anticholinergic effects, TCAs should be used cautiously in older patients, particularly those with cognitive impairment or dementia. We also avoid TCAs in patients with heart disease, epilepsy, or glaucoma. Adverse effects may be reduced by using a slow titration; however, delayed onset of efficacy (up to three weeks) before TCAs begin to reduce pain may lead to premature discontinuation. A treatment trial of at least one month at a target dose may be needed to assess the efficacy of TCAs. In one study, symptom relief correlated with serum levels of amitriptyline and active metabolites [57]. Patients who reported no benefit despite serum levels of 100 ng/mL for at least three weeks were considered to have failed TCA therapy.

A 2015 systematic review found moderate-quality evidence supporting the efficacy of TCAs for PHN [43]. Efficacy among TCAs is best established for amitriptyline, which was found effective in producing at least moderate pain relief in multiple short-term studies, typically at doses of 65 to 75 mg daily [57,58]. Nortriptyline was better tolerated than amitriptyline in a small crossover trial of 33 patients with PHN [59]. Approximately two-thirds of patients reported a good response with either medication, but adverse effects leading to discontinuation were more common with amitriptyline than nortriptyline (48 versus 30 percent). The small study size limits generalizability of these results. Desipramine appears to have the fewest side effects of the first-generation TCAs and was effective for PHN in a small trial at mean dose 165 mg per day [60,61]. Almost half reported good response with desipramine. However, methodologic criticisms of this trial limit the certainty of these conclusions [62].

Topical therapy for patients with milder symptoms — For patients with mild to moderate and localized pain and for those who prefer a topical agent, we suggest capsaicin. We switch to lidocaine patches for those who do not tolerate capsaicin.

●Capsaicin – Capsaicin is formulated as a cream, gel, lotion, or a high-concentration patch.

We use capsaicin cream (0.025 to 0.075%) for most patients with PHN and reserve the high-concentration capsaicin (8%) patch for selected patients with partial response to capsaicin cream who prefer a longer acting formulation.

•Capsaicin cream may be applied to the affected area up to four times each day.

•High-concentration capsaicin patches are administered as a single 60-minute application. The application may be repeated after three months. It must be administered by a health care professional, and patients are monitored for up to two hours after treatment. To manage local pain from capsaicin application, the skin is usually pretreated with a local anesthetic such as topical lidocaine, and some studies also used post-treatment oral analgesics such as oxycodone for up to five days [63]. Further study is needed to confirm long-term effectiveness and tolerance of the high-concentration capsaicin patch.

Limited data suggest that topical application of standard-concentration capsaicin is effective for PHN [41]. In one small trial, 143 patients with PHN assigned to capsaicin cream (0.075%) four times per day for six weeks were likelier to report significant pain relief than those assigned to placebo (21 versus 6 percent) [64]. The rate of adverse skin reactions was similar in patients receiving capsaicin and placebo.

A 2013 systematic review identified four randomized controlled trials that evaluated 1272 subjects with PHN treated with one application of either high-concentration capsaicin patch or standard-concentration capsaicin. The only common endpoint reported by all four trials, a ≥30 percent pain intensity reduction at eight weeks compared with baseline, was significantly greater for high-concentration capsaicin patch (43 versus 34 percent; relative benefit 1.3, 95% CI 1.1-1.5) [65].

High-concentration capsaicin patches are approved by the FDA for the treatment of PHN. However, capsaicin can cause burning, stinging, and erythema, making it difficult to achieve true blinding in clinical studies. In practice, application of capsaicin is intolerable in up to one-third of patients.

●Lidocaine — Lidocaine patches (5%) may provide short term relief for PHN. Up to 3 patches may be applied over the affected area for up to 12 hours daily.

Data from small trials and open-label studies suggest that topical lidocaine (5 percent) may be beneficial for pain relief in patients with PHN [66]. Lidocaine patches have been approved by the FDA for PHN. However, a 2014 systematic review of topical lidocaine for neuropathic pain (including 280 patients with PHN) found only very low quality evidence of efficacy of topical lidocaine due to small numbers, incomplete outcome assessments, and modest outcome measures of efficacy [67].

Alternative therapies — For patients who do not tolerate or are unresponsive to initial therapy, we switch to an alternative agent (algorithm 1). For patients with a partial but suboptimal response with initial therapy, we use combination therapy by adding an alternative agent. We use patient preferences and medical comorbidities to help select among options.

Antiseizure medications — A trial of one of a (non-gabapentinoid) anticonvulsant agent may be useful for some patients who do not respond to or cannot tolerate initial medication options. Treatment decisions should be individualized based on patient characteristics, medical comorbidities, side effects, and drug interactions. The benefit of anticonvulsants is based in part on their efficacy in other neuropathic pain conditions such as trigeminal neuralgia and diabetic neuropathy and also on low-quality and anecdotal evidence for PHN. Options and typical target daily doses for PHN include:

●Valproic acid 500 to 1000 mg daily
●Carbamazepine 200 to 1200 mg daily
●Oxcarbazepine 600 to 1200 mg daily
●Lamotrigine 100 to 300 mg daily


The dosing, titration, and monitoring of these agents for PHN is similar to regimens used in trigeminal neuralgia and typically lower doses than those to achieve anticonvulsant effects. (See "Trigeminal neuralgia", section on 'Medical treatment'.)

In an eight-week trial of 48 patients with PHN, patients assigned to divalproex sodium (1000 mg per day) were likelier to report at least moderate improvement in pain than those assigned to placebo (58 versus 15 percent) [68]. Results of small trials of valproic acid in other neuropathic pain conditions were mixed [69]. In short-term trials in patients with trigeminal neuralgia, both carbamazepine and oxcarbazepine reduced pain more than placebo, but neither drug was tested in patients with PHN [70,71]. Lamotrigine may be better tolerated than carbamazepine but has not been studied extensively for neuropathic pain.

Serotonin-norepinephrine reuptake inhibitors — Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be useful for some patients with PHN based on efficacy data for painful polyneuropathy [43]. These medications may be useful for patients with comorbid depression. We use duloxetine or venlafaxine for patients with PHN.

●Duloxetine is typically started at 30 mg daily. Typical daily doses are 60 to 120 mg. The dose may be increased weekly to effect and as tolerated. Adverse effects including nausea, dry mouth, dizziness, and insomnia are more common at higher doses.

●Venlafaxine may be started at 75 mg daily and increased every two weeks to effect as tolerated. Typical daily doses are 150 to 225 mg. Venlafaxine should be used with caution in patients with glaucoma and in those taking anticoagulants. Common adverse effects include nausea, dizziness, and somnolence.

The initial titration and administration of SNRIs are presented in greater detail separately. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)

The effectiveness of SNRIs such as duloxetine and venlafaxine for patients with PHN is based on data for those with other types of neuropathic pain. A systematic review of eight trials and including 4084 patients found that duloxetine was beneficial for patients with painful diabetic neuropathy [72]. Venlafaxine was found to be effective in a short-term trial of 244 patients with painful diabetic polyneuropathy [73]. Patients assigned venlafaxine at 150 to 225 mg were likelier to report at least 50 percent pain reduction than those assigned placebo (50 versus 27 percent). However, a 2015 systematic review of six trials including 460 patients with neuropathic pain found only low-quality data of modest efficacy for venlafaxine [74]. The efficacy of SNRIs for diabetic neuropathy is presented in greater detail separately. (See "Management of diabetic neuropathy", section on 'Administration and efficacy'.)

Adjunctive options — For patients with symptoms refractory to prior therapies, adjunctive options and other interventional therapies such as botulinum toxin injections may be tried or added (algorithm 1). These include oral or transdermal opioid analgesics and intrathecal glucocorticoid injections. The selection of these agents depends on individual patient preferences and comorbidities.

Opioids — Opioids may be beneficial for selected patients with intractable pain during the titration of initial or alternative therapies. They can be administered simultaneously for short-term relief along with the nonopioid agents. They should be initiated at low doses if used and titrated to provide relief while awaiting benefit from nonopioid treatments, at which point opioids should be tapered off.

Opioids are available in short- or long-acting formulations (table 2 and table 3). We start with short-acting options for opioid-naïve patients and use the lowest effective dose. The strategies for initiation and chronic use of opioids for patients with PHN is similar to that of other patients with noncancer pain and is discussed in greater detail separately. (See "Use of opioids in the management of chronic non-cancer pain".)

Small trials support the efficacy of opioid analgesics for PHN [75-79]. In one crossover trial involving 76 patients with PHN, treatment with morphine (mean daily dose 91 mg) or methadone (mean daily dose 15 mg) or a TCA for eight weeks was more effective than placebo [77]. There was a trend toward greater pain relief with opioids, but certainty with these results is limited by small sample size.

The use of opioids for chronic PHN should be avoided. Opioids for chronic noncancer pain remains controversial due to the risk of physical dependence, tolerance, addiction, and overdose. Because of these risks, opioids are regarded as third-line treatment options and typically reserved for short-term, adjunctive use for PHN [38,43,80]. Available trials of opioids for neuropathic pain including PHN do not address the issues of abuse and addiction [81]. Pharmacovigilance is essential to using opioids in any population (table 4). (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

Neuraxial glucocorticoid infusion — Intrathecal glucocorticoid injections may be beneficial for patients who continue to have intractable pain despite initial or alternative therapies. These injections are not useful for pain in the distribution of the trigeminal nerve.

Intrathecal glucocorticoids for PHN are typically given as a single course of weekly injections over four weeks [82]. Techniques for intrathecal glucocorticoid infusion are discussed in greater detail separately. (See "Spinal anesthesia: Technique".)

Intrathecal glucocorticoid injections are associated with an uncertain but probably low risk of serious adverse events, including aseptic meningitis, transverse myelitis, cauda equina syndrome, lumbar radiculitis, headache, urinary retention, and arachnoiditis [83,84].

Some [40,82,85] but not all [86] studies have found a benefit with intrathecal methylprednisolone infusions for patients with PHN. The largest trial evaluated 277 patients with intractable PHN who were assigned to one of three treatment groups: intrathecal methylprednisolone plus lidocaine once per week for four weeks, intrathecal lidocaine alone once per week for four weeks, or no treatment [82]. More than 90 percent of patients in the methylprednisolone group reported excellent or good pain relief both at four weeks compared with 6 and 4 percent in the lidocaine and no treatment groups, respectively. These results were sustained at two-year follow-up. There were no serious adverse events associated with the injection.

Intrathecal administration of methylprednisolone was found more effective than administration in the epidural space in a small trial of 25 patients with PHN [85].

Therapies for refractory symptoms — We reserve other interventional and surgical approaches such as botulinum toxin injections, cryotherapy, and neuromodulation for patients with refractory symptoms who do not respond to other therapies (algorithm 1). The benefit of such therapies has been shown in small trials and observational studies; larger studies are needed to better define their role for patients with PHN.

Botulinum toxin — Botulinum toxin injection for PHN is not extensively studied, but evidence from observational studies and small trials suggests it is effective [87-90]. One trial evaluated 30 adults with PHN who had persistent pain for at least three months [87]. Patients assigned to botulinum toxin type A (onabotulinumtoxinA) injections were likelier to achieve ≥50 percent pain reduction at two weeks compared with those who received placebo injections (13 of 15 patients [87 percent] versus none of 15). The benefit persisted for a median of 16 weeks. In a comparative study of 60 patients with PHN, patients who received onabotulinumtoxinA injection reported a greater pain reduction at seven days when rated on the visual analog scale compared with those who received lidocaine injections (4.5 versus 2.6 points) [88]. These findings were sustained at three months. Improvement in sleep and reduction in opiate use were also reported in the botulinum toxin group.

Botulinum toxin injections should be performed by a clinician experienced with this treatment [91-93]. No safety concerns were identified in small studies [87,88]. However, botulinum toxin may cause localized or systemic adverse effects including bruising, weakness, pain, or headache and may be contraindicated for some patients. Larger and longer-term studies would be helpful to further clarify the safety and efficacy on this treatment in PHN.

Neuromodulation and nerve stimulation — Invasive neuromodulatory strategies such as spinal cord stimulation and peripheral nerve stimulation are considered experimental. These techniques target peripheral nerves and are thought to modulate neuronal signaling or inflammatory processes [94]. Techniques that have shown some benefit for patients with PHN include:

●Transcutaneous electrical nerve stimulation (TENS) [95]
●Pulsed radiofrequency [96-100]
●Spinal cord stimulation [101,102]

These techniques been reported to be effective in approximately half of patients in case reports and case series [103]. They should be performed by experienced clinicians and in centers with expertise.

Cognitive and behavioral therapies — Some patients with PHN achieve only partial relief even with combination pharmacotherapy. For other patients, the efficacy of pharmacotherapy is limited by adverse effects. Nonpharmacologic approaches, including cognitive-behavioral therapy (CBT), may be useful for some patients with refractory PHN pain or associated impairment in mood, sleep, or other quality-of-life domains [104,105]. In a small trial of 40 patients with PHN treated with pregabalin, patients who were assigned to also receive CBT reported a greater improvement in pain intensity and mood symptoms than those assigned to pregabalin alone [106]. Cognitive and behavioral therapies for the treatment of chronic pain are discussed in detail separately. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Psychological therapy'.)

Therapies of uncertain or limited benefit

●NMDA receptor antagonists – Animal data suggest a role for excitatory amino acid neurotransmitters in the maintenance of chronic pain due to nerve injury [107,108]. Antagonists of the N-methyl-D-aspartate (NMDA) receptor have been shown to relieve neuropathic pain in humans [109].

The most widely available NMDA receptor antagonists are ketamine and dextromethorphan. Intravenous ketamine induces modest pain relief in patients with PHN but at doses that cause sedation, dysphoria, and dissociative episodes [110]. In a crossover trial, pain relief after six weeks was similar in those taking dextromethorphan or placebo [111].

●Intravenous lidocaine – Small trials have failed to find sustained benefit of intravenous lidocaine compared with placebo in patients with PHN [40,112]. Any temporary changes in pain measured immediately after infusion do not appear to be sustained by four weeks [40,112-116].

The role of topical lidocaine for PHN is discussed separately. (See 'Topical therapy for patients with milder symptoms' above.)

●Surgical ablation and other interventional procedures – Cryotherapy is an ablation technique that involves freezing peripheral nerves. A small, unblinded study of cryotherapy for facial pain failed to show a significant benefit in patients with PHN [117]. The authors did not provide inclusion criteria, concomitant therapies, or information on how the response was assessed. By contrast, a second trial reported "considerable" relief in 11 of 14 patients with cryotherapy to the intercostal nerves for PHN [118]. In most cases, however, the duration of relief was less than two weeks as assessed by questionnaire.

Surgical interventions including central electrical stimulation of the thalamus, ablation by anterolateral cordotomy, and electrocoagulation of the dorsal root carry substantial risks of permanent neurologic deficits. A systematic review of surgical procedures for patients with refractory PHN reported the pain reduction with surgical ablation procedures was frequently accompanied by serious complications including neuromuscular weakness [119].

●Simple analgesics – Analgesic medications such as aspirin or other nonsteroidal anti-inflammatory drugs are of limited value in patients with either acute herpetic neuralgia or PHN [38,120].