帶狀泡疹(皰疹)神經痛 1. Postherpetic Neuralgia-StatPerls

2023-09-16 中午 12:01
資料來源 Postherpetic Neuralgia-StatPearls [Internet].
(在uptodate上面關於 PHN的治療內容太龐大,另外寫一篇筆記(帶狀泡疹(皰疹)神經痛 2. Postherpetic Neuralgia from Uptodate)

下面中文是google翻譯

簡介
帶狀皰疹後神經痛 (PHN) 是水痘帶狀皰疹病毒 (VZV) 重新激活（也稱為人類皰疹病毒 3 (HHV-3)）最常見的長期並發症。[1] [2]這種休眠 VZV 的重新激活稱為帶狀皰疹或帶狀皰疹。VZV 是兒童水痘（俗稱水痘）的病原體。在 20 世紀 90 年代末和 2000 年代初疫苗接種出現之前，超過 90% 的美國成年人的水痘帶狀皰疹病毒血清檢測呈陽性。[3]雖然在下一代中繼續患帶狀皰疹和 PHN 的成年人數量和百分比可能會減少，但 PHN 目前是一個具有臨床重要性的話題。

PHN 的標誌是單側皮節模式的刀割樣/燒灼樣疼痛，這種疼痛在帶狀皰疹 (HZ) 爆發後持續三個月或更長時間。[4] HZ 的兩個普遍接受的危險因素是年齡增長和免疫抑制，並且由於 HZ 是 PHN 發生的先決條件，因此老年人和體弱者通常受到影響。[2]最成功的治療是多模式的，一些研究人員/臨床醫生專注於高危人群的預防而不是治療，因為 PHN 在本已脆弱的患者群體中具有使人衰弱且往往難治的性質。[5]



病原學
VZV 是一種雙鏈 DNA 病毒。水痘發作消退後（通常在青年時期），它會在某些外周和中樞神經的神經節中休眠，宿主的免疫系統會消滅體內大部分部位的病毒。[2]年齡增長加上免疫能力下降，通常伴隨著心理或身體壓力，可能會導致休眠/潛伏的 VZV 重新激活為帶狀皰疹。[2]病毒複製並沿著軸突傳播，直到到達皮膚，出現水皰、紅斑和局部炎症。[1]



流行病學
帶狀皰疹後神經痛發生在患有急性帶狀皰疹發作的人群中。急性帶狀皰疹發作進展為 PHN 的明確危險因素包括年齡、嚴重的免疫抑制、前驅期的存在、帶狀皰疹爆發期間的劇烈疼痛、異常性疼痛、眼部受累和糖尿病。[3]

2016 年發表的一項針對 PHN 發生危險因素的薈萃分析指出，年齡大於或等於 50 歲的帶狀皰疹患者中約有 13% 會發生 PHN。[3]發病率隨著年齡的增長而增加，這強調了免疫能力的重要性，因為帶狀皰疹患者可能已經存在細胞介導的免疫力下降。年齡增長與 PHN 之間存在顯著關聯。[6]根據一些研究，60歲時，約60%的帶狀皰疹患者會出現帶狀皰疹後神經痛，70歲時，這一比例上升至75%。

帶狀皰疹發病後1個月，9%至14.3%的患者出現帶狀皰疹後神經痛，三個月後，這一比例變為5%。一年後，3% 的患者仍然感到劇烈疼痛。

家族史也被認為是帶狀皰疹的危險因素。Hicks 等人在一項由 504 名患者和 523 名對照者組成的病例對照研究中發現，患者的血親比對照組更容易患帶狀皰疹（39% vs. 11%，p < . 001）。此外，在多個血親患有帶狀皰疹的患者中，這種風險比單個血親患有帶狀皰疹的患者更顯著。[7]

冰島的一項研究報告了不同年齡組的帶狀皰疹後神經痛風險的差異。50歲以下的患者在任何時候都沒有發現劇烈疼痛。在 60 歲以上的患者中觀察到嚴重疼痛：發病後 1 個月內有 6% 的患者出現劇烈疼痛，3 個月內有 4% 的患者出現嚴重疼痛。[8]

帶狀皰疹後神經痛沒有性別差異。



病理生理學
將自限性帶狀皰疹爆發與帶狀皰疹後神經痛區分開來的確切生理學尚不完全清楚。對 PHN 患者相關外周和中樞神經組織的組織學檢查顯示，在某些情況下，髓磷脂和軸突缺乏以及背角萎縮。[9]一項研究比較了患有 PHN 的患者和患有自限性帶狀皰疹的患者之間表皮軸突密度的差異。[10]在大多數情況下，患有 PHN 的人相關皮區的軸突比非患者少得多。[10]因此，解剖結構紊亂可能至少是 PHN 發生的部分原因。一些人認為，神經元水平上不受控制的炎症反應是 PHN 最終發展的主要原因，特別是通過減少中樞介導的傷害性輸入抑制以及通過受損的傷害性感受器促進外周敏化。[11]


病史和體格 與
其他神經病不同，帶狀皰疹後神經痛的診斷相對簡單，而不是排除性的。[11]如前所述，帶狀皰疹發作是 PHN 的先決條件。因此，可以建立皮節型水皰皮疹病史。很少會發現特徵性皮疹。[12]皮疹區域或附近的持續（超過或等於 3 個月）刺痛/燒灼痛、異常性疼痛、感覺異常、瘙癢、感覺遲鈍和/或痛覺過敏是 PHN 的特徵。[11]

帶狀皰疹可以在亞臨床狀態下重新激活，但不會出現皮疹。[13]這種情況稱為帶狀皰疹，比較複雜。它在多個層面影響中樞神經系統，並引起顱神經病、脊髓炎、多發性神經炎或無菌性腦膜炎。[14]

帶狀皰疹後神經痛患者的體格檢查可能會揭示以下信息： 先前帶狀皰疹區域的皮膚疤痕證據 受
影響區域的感覺改變，要么過敏，要么感覺減退
疼痛是由非傷害性刺激產生的，例如輕觸，稱為異常性疼痛
自主功能障礙，例如相關區域出汗過多

評估
帶狀皰疹後神經痛幾乎都是根據病史和體格診斷的。然而，實驗室測試和一些有針對性的成像可能會提供一定程度的實用性。它們對於 PHN 的非典型表現（如帶狀皰疹或喉部帶狀皰疹）具有更大的價值。儘管敏感性和特異性不太理想，但可以進行 VZV IgG 和 IgM 滴度的血清學檢測。四倍的上升已用於診斷亞臨床帶狀皰疹（帶狀皰疹）。然而，這種滴度的上升可能是也可能不是繼發於病毒暴露或重新激活。相比之下，囊泡刮片的免疫熒光以高度特異性和靈敏的方式檢測 VZV 抗原。同樣，PCR 對於 VZV DNA 的檢測也非常敏感。[15]

61% 的患者腦脊液 (CSF) 分析結果異常。通常可以看到細胞增多、蛋白質升高和水痘帶狀皰疹病毒 (VZV) DNA。病毒培養或免疫熒光染色有助於區分單純皰疹和帶狀皰疹。

小規模研究表明，磁共振成像 (MRI) 可能有望用於診斷具有挑戰性的 PHN 病例並區分 PHN 和 HZ。Haanpaa 等人的一項研究。報導稱，MRI 顯示 9 名患者 (56%) 的頸髓和腦幹有 HZ 病變。帶狀皰疹發病後三個月，5 名 MRI 異常的患者 (56%) 出現 PHN。在 MRI 上，七名沒有帶狀皰疹病變的患者沒有出現殘餘疼痛。[16]



治療/管理
帶狀皰疹後神經痛可考慮三種基本治療方法。第一個是預防，重點是識別有感染帶狀皰疹風險的人群並接種疫苗。第二是早期識別和治療急性帶狀皰疹感染，因為延遲可能會增加發生帶狀皰疹病毒性神經炎的機會。第三種方法是通過多模式藥物治療和介入治療進行 PHN 症狀管理。關於這些方法有效性的證據多種多樣，但正在迅速發展，並且某些方法似乎比其他方法更成功。許多人主張預防，因為 PHN 一旦建立，可能難以治療，儘管採用多模式治療，仍有大量患者只能暫時和/或適度減輕症狀嚴重程度。[17]

由於多種原因，PHN 很難治療。症狀完全緩解的情況很少見。2014 年的一項研究得出結論，不到一半的 PHN 患者症狀得到顯著減輕。[5]患者群體通常年老體弱，患有多種合併症。因此，干預措施的副作用特徵變得更加重要。[4]比較治療方法及其結果的相關研究通常設計得不夠理想。沒有一種更好的治療方案；然而，專家共識表明多模式治療可能是最好的方法。最後，許多提倡的方法通常治療慢性神經性疼痛，而不是針對 PHN。

傳統的非侵入性治療包括口服藥物和局部藥物。美國神經病學學會(AAN)、神經性疼痛特別興趣小組(NeuPSIG) 和歐洲神經學會聯合會(EFNS) 均推薦口服三環類抗抑鬱藥(TCA)、普瑞巴林和5% 利多卡因貼劑作為一線藥物療法。[18]必須考慮 TCA 的抗膽鹼能、抗組胺能和 α 受體阻斷副作用，因為老年人更容易受到影響。[19]因此，最初開具加巴噴丁類藥物並滴定是很常見的，請記住，腎功能下降的患者應以較低劑量開始，並更緩慢地增加滴定。儘管缺乏令人信服的證據支持這種策略，但一些臨床醫生將加巴噴丁和普瑞巴林結合使用。使用阿片類藥物來對抗 PHN 是有爭議的，因為關於什麼構成適當使用的情況正在發生變化，而且考慮到濫用、成癮和死亡率的流行，政府對其管理重新產生了興趣。[20]上述三個醫學會推薦阿片類藥物作為一線或二線治療，這強調了此類藥物的減輕疼痛的能力。[21]

還有其他幾種藥理學方式需要考慮。多項研究已證實 5% 利多卡因貼劑的短期和長期療效。[22]該貼劑還有一個額外的好處，即副作用小，主要限於應用部位反應。貼劑和乳膏配方中的辣椒素製劑也可用，但不像利多卡因貼劑那樣得到充分研究。[19] [23]停止使用辣椒素治療的主要原因是施用部位的疼痛和刺激，幾乎所有使用者都會遭受這種疼痛，其程度與辣椒素濃度成比例。該霜的辣椒素濃度較低，需要全天多次塗抹才能達到治療效果。相反，辣椒素貼劑的配方為 8%，只需一次塗抹即可提供治療劑量。[24]然而，通常需要在應用部位使用口服鎮痛藥和局部麻醉劑進行預處理，以避免疼痛刺激。總體疼痛減輕程度一般低於利多卡因5%貼劑。然而，令人鼓舞的病例報告和其他文獻表明，干預措施值得考慮和進一步研究。

其他藥物類別包括非 TCA 抗抑鬱藥和 NMDA 拮抗劑，但支持其有用性的證據有限。例如，涉及SNRI（5-羥色胺-去甲腎上腺素再攝取抑製劑）和SSRI（選擇性5-羥色胺再攝取抑製劑）的大型研究並未顯示出比TCA 更好的結果，並且這兩類藥物都具有相關副作用，儘管通常不如TCA 嚴重。[19]最近氯胺酮輸注診所的激增以及用於治療從神經性疼痛到抑鬱症等多種疾病的相關研究也引起了人們對 NMDA 拮抗劑在治療 PHN 中的作用的新興趣。[25]

有傳聞稱氯胺酮可能有益，一些小型研究也支持這一發現，但長期數據和大規模研究尚不存在。利多卡因輸注也已被考慮。1999 年的一項雙盲研究表明，靜脈注射利多卡因可為 PHN 患者提供具有臨床意義的短期疼痛緩解。[26]一般來說，小型研究和病例報告已經證實，新療法與其他輔助療法相結合可能對某些 PHN 患者有用。PHN 的病理生理學很複雜，有時個體化的非傳統方法可能對特定患者有益。

侵入性療法包括肉毒桿菌毒素注射、局部麻醉劑交感神經阻滯、硬膜外/鞘內註射和脊髓刺激。肉毒桿菌注射操作簡單且副作用有限。[27]然而，需要進行更多的研究來評估其功效。提到的其他侵入性療法可能會帶來顯著的圍手術期風險和/或副作用。根據病例報告，硬膜外類固醇注射和神經調節（脊髓和周圍神經刺激）產生的結果好壞參半，但很有趣，前者充其量只能帶來有限的短期改善，而後者有時會導致長期症狀完全緩解。 。最近開發的用於治療局灶性皮節神經病理性疼痛的背根神經節刺激器理論上對於 PHN 來說是有希望的。2008 年來自中國的一項研究表明，CT 引導下的背根神經節射頻消融術可能會顯著減輕 PHN 的症狀，有時甚至完全消融。但樣本量較小，該技術可能導致氣胸，且缺乏重複研究。鞘內給藥也顯示出前景。2000 年的一項 270 人參與的研究調查了鞘內註射甲基潑尼松龍和利多卡因治療 PHN，通過兩年的隨訪，對 90% 的患者產生了顯著的鎮痛效果。



鑑別診斷
神經性疼痛是一個總稱，描述了許多疾病和病症常見的疼痛類型。然而，先前帶狀皰疹皮疹區域或附近的皮節模式中的單側神經性疼痛對於帶狀皰疹後神經痛具有高度特異性。然而，在極少數情況下應考慮其他神經性疾病。例如，至少有一例 CRPS 影響三個月前受帶狀皰疹感染的皮節的病例報告。神經性疼痛的位置將有助於做出鑑別診斷；如果出現在面部，則可能考慮三叉神經痛和貝爾麻痺。胸部皮區看似 PHN 的情況很少見，可能是闌尾炎、膽石症或結腸炎。[28]在 PHN 診斷不清楚的特殊情況下，VZV 血清學研究可能會有所幫助。



預後
帶狀皰疹後神經痛的治療具有挑戰性。症狀可能持續數年，有時甚至一生。隨著成人疫苗接種和新開發的非活疫苗配方的出現，預防成為大多數易感美國人群的現實目標。[3]當無法預防帶狀皰疹時，建議及時治療，因為疼痛的持續時間和嚴重程度被認為是 PHN 的危險因素。不幸的是，一旦出現 PHN，保守的一線治療很少能解決症狀，並且不能提供持久的緩解。因此，應考慮專家共識推薦的多模式治療方法。有限但發人深省的證據表明，某些非常規技術，無論是侵入性還是非侵入性，都是有希望的，值得進一步研究。

並發症
根據帶狀皰疹後神經痛的持續時間和疼痛程度，患者可能會出現以下並發症：抑鬱、疲勞、睡眠
不安
、
食慾不振、
注意力不集中、


威懾和患者教育，
預防的主要措施是接種帶狀皰疹病毒疫苗。[3] 2005年《NEJM》發表的一項大型（n = 38,000）雙盲研究表明，老年人接種疫苗可將帶狀皰疹的發病率降低51%，PHN的發病率降低66%。此外，即使在患有 PHN 的人中，疾病負擔也減少了約 61%。必須注意的是，疫苗接種的增強免疫效果並不持久，需要間隔重新接種以維持其功效。[3]此外，目前的疫苗配方是減毒活病毒，理論上能夠在免疫功能低下的個體中引起感染，因此限制了其在該人群中的使用。[3]然而，2017 年底，FDA 諮詢委員會批准了一種亞單位非活疫苗在美國用於50 歲以上的個體。它可用於免疫功能低下的個體，並針對帶狀皰疹和帶狀皰疹病毒提供更好的保護在所有患者群體中，其感染率均高於原始減毒活病毒。對高危人群進行預防性疫苗接種可能最終被證明是解決與 PHN 相關的重大發病率的最安全、最有效的方法。

另一種方法是嘗試阻止帶狀皰疹進展為帶狀皰疹後遺症（PHN），但要認識到帶狀皰疹發作的嚴重程度是帶狀皰疹後遺症（PHN）的危險因素。不幸的是，支持該技術的現有證據絕不是可靠的，並且現有的調查研究針對所討論的終點進行了次優設計。因此，雖然抗病毒藥物、糖皮質激素給藥和/或侵入性操作在某些情況下可能會降低帶狀皰疹發作的嚴重程度，但沒有明確的證據表明這些方法單獨或聯合使用可以降低PHN 的發生率。需要更高質量的研究來確定明確的立場。

提高醫療團隊的成果
考慮到帶狀皰疹後神經痛治療難度大且結果多變，預防至關重要。因此，初級保健醫生和老年病學家的任務是為高危人群接種疫苗。當預防措施失敗或從未採取時，應諮詢具有該病症經驗和多模式治療技術的疼痛管理領域專家。採用跨專業方法來治療帶狀皰疹後神經痛患者是最好的方法
Introduction
Postherpetic neuralgia (PHN) is the most common long-term complication of varicella-zoster virus (VZV) reactivation, also known as human herpesvirus-3 (HHV-3).[1][2] This reactivation of the dormant VZV is known as herpes zoster or shingles. VZV is the causative agent for the childhood condition varicella, colloquially known as chickenpox. Before the advent of vaccination in the late 1990s and early 2000s, upward of 90% of American adults would test seropositive for VZV.[3] Although this number and the percentage of adults who go on to develop herpes zoster and PHN may decrease in the coming generations, PHN is currently a topic of clinical importance.

The hallmark of PHN is a lancinating/burning pain in a unilateral dermatomal pattern that persists for three or more months after the onset of a herpes zoster (HZ) outbreak.[4] Two universally accepted risk factors for HZ are increasing age and immunosuppression, and because HZ is a prerequisite for the development of PHN, the elderly and infirm are commonly afflicted.[2] The most successful treatments are multi-modal, with some researchers/clinicians focusing on prevention in high-risk populations rather than cure because of the debilitating and often refractory nature of PHN in already fragile patient populations.[5]



Etiology
The VZV is a double-stranded DNA virus. It lays dormant in the ganglia of certain peripheral and central nerves after an episode of varicella resolves, generally in youth, with the immune system of the host eradicating the virus in most locations within the body.[2] Advancing age combined with a decrease in immunocompetence, usually accompanied by a psychological or physical stressor, may result in reactivation of the dormant/latent VZV as HZ.[2] The virus replicates and travels down axons until it reaches the skin, where blistering, erythema, and local inflammation occur.[1]



Epidemiology
Postherpetic neuralgia occurs in a subset of the population suffering from an episode of acute HZ. Well-established risk factors for an acute HZ episode progressing to PHN include age, severe immunosuppression, the presence of a prodromal phase, severe pain during zoster outbreak, allodynia, ophthalmic involvement, and diabetes mellitus.[3]

A meta-analysis of the risk factors for the development of PHN published in 2016 noted that approximately 13% of patients older than or equal to 50 years of age with HZ would develop PHN.[3] The incidence increases with advancing age, which underscores the importance of immunocompetence, as a decrease in cell-mediated immunity is likely already present in those with HZ. The association between increasing age and PHN is significant.[6]According to some studies, at age 60, around 60% of patients with shingles develop postherpetic neuralgia, and at age 70, this percentage rises to 75%.

One month after the onset of shingles, 9 to 14.3% of patients develop postherpetic neuralgia, and at three months, this percentage becomes 5%. At one year, 3% of patients continue to have severe pain.

Family history has also been considered a risk factor for herpes zoster. In a case-control study by Hicks et al., comprising 504 patients and 523 controls, it was observed that the blood relatives of patients were more likely to have herpes zoster than the control group (39% vs. 11%, p< .001). Moreover, this risk was more significant in patients with multiple blood relatives having herpes zoster than those with a single blood relative having herpes zoster.[7]

A study from Iceland reported variations in the risk of postherpetic neuralgia associated with various age groups. Patients younger than 50 years were not found to have severe pain at any time. Severe pain was observed in patients older than 60 years: 6% at one month and 4% at three months from the onset.[8]

There is no sex predilection for postherpetic neuralgia.



Pathophysiology
The exact physiology that separates a self-limited zoster outbreak from postherpetic neuralgia is not fully understood. Histological examinations of relevant peripheral and central nervous tissue from sufferers of PHN reveal myelin and axon deficiency and atrophy of the dorsal horn in certain instances.[9] One study compared the difference in epidermal axon densities between patients who suffered from PHN and those who had a self-limited occurrence of HZ.[10] Those afflicted with PHN had, in most instances, far fewer axons in the relevant dermatomes than non-sufferers.[10] Therefore, an anatomical derangement is likely at least partially responsible for the development of PHN. Some suggest that an unchecked inflammatory response at the neuronal level is the main culprit of the eventual development of PHN, specifically via the reduction of centrally-mediated inhibition of nociceptive input and the promotion of peripheral sensitization via damaged nociceptors.[11]


History and Physical
Unlike other neuropathic conditions, the diagnosis of postherpetic neuralgia is relatively straightforward and not one of exclusion.[11] As mentioned, an episode of herpes zoster is a prerequisite for PHN. Therefore, a history of rash with blisters in a dermatomal pattern could be established. Rarely the characteristic rash will not be found.[12] Persistent (more than or equal to 3 months) lancinating/burning pain, allodynia, paresthesias, pruritus, dysesthesias, and/or hyperalgesia at or near the area of the rash is characteristic of PHN.[11]

Herpes zoster can reactivate subclinically with no rash.[13] This condition is called zoster sine herpete and is more complicated. It affects the central nervous system at multiple levels and causes cranial neuropathies, myelitis, polyneuritis, or aseptic meningitis.[14]

Physical examination of a patient with postherpetic neuralgia may reveal the following:Evidence of cutaneous scarring on an area of previous herpes zoster
Altered sensation in the affected areas, either hypersensitivity or hypoesthesia
Pain is produced by non-noxious stimuli, such as a light touch, known as allodynia
Autonomic dysfunction, such as excessive sweating over the involved area

Evaluation
Postherpetic neuralgia is almost universally diagnosed based on history and physical. However, laboratory tests and some targeted imaging may provide a degree of utility. They are of greater value in atypical presentations of PHN, such as zoster sine herpete or herpes zoster of the larynx. Serological testing for VZV IgG and IgM titers is available, although the sensitivity and specificity are less than ideal. A four-fold rise has been used to diagnose subclinical HZ (zoster sine herpete). However, this rising titer may or may not be secondary to viral exposure or reactivation. Comparatively, immunofluorescence of vesicle scrapings detects VZV antigens in a highly specific and sensitive manner. Similarly, PCR is exquisitely sensitive for the detection of VZV DNA.[15]

Results of cerebrospinal fluid (CSF) analysis are abnormal in 61% of patients. Pleocytosis, elevated protein, and varicella-zoster virus (VZV) DNA are usually seen. Viral culture or immunofluorescent staining helps distinguish herpes simplex from herpes zoster.

Small-scale studies suggest that magnetic resonance imaging (MRI) may hold promise for diagnosing challenging PHN cases and differentiating between PHN and HZ. A study by Haanpaa et al. reported that MRI revealed lesions attributable to HZ in the cervical cord and the brain stem in 9 patients (56%). At three months after the onset of HZ, PHN developed in 5 patients (56%) who had an abnormal MRI. On MRI, seven patients with no HZ lesions did not develop residual pain.[16]



Treatment / Management
Three fundamental treatment approaches may be considered for postherpetic neuralgia. The first is prevention, which focuses on identifying populations at risk for contracting HZ and administering a vaccine. The second is early recognition and treatment of an acute HZ infection, as delay may increase the chance of developing PHN. The third approach is symptom management of PHN via multimodal medication regimens and interventional procedures. The evidence regarding the efficacy of these methods is mixed but rapidly evolving, and certain approaches appear to be more successful than others. Prevention is advocated by many because, once established, PHN can be refractory to treatment, with a substantial number of sufferers achieving only a temporary and/or modest reduction in symptom severity despite multimodal therapy.[17]

PHN is notoriously difficult to treat for many reasons. Complete resolution of symptoms is rare. A 2014 study concluded that less than half of patients with PHN achieve significant symptom reduction.[5] The patient population is usually old and frail with multiple comorbidities. Therefore side effect profiles of interventions take on greater importance.[4] Relevant studies comparing treatments and their outcomes are often suboptimally designed. There is no one superior treatment regimen; however, expert consensus suggests that multimodal therapy is likely the best approach. Lastly, many of the advocated approaches treat chronic neuropathic pain in general and are not specific to PHN.

Traditional non-invasive treatments include oral and topical medications. The American Academy of Neurology (AAN), Special Interest Group on Neuropathic Pain (NeuPSIG), and European Federation of Neurological Societies (EFNS) all recommend an oral tricyclic antidepressant (TCA), pregabalin, and the lidocaine 5% patch as first-line therapies.[18] The anticholinergic, antihistaminergic, and alpha receptor-blocking side effects of TCAs must be considered, as the elderly are more susceptible.[19] As a result, it is commonplace to initially prescribe and titrate a gabapentinoid, keeping in mind that patients with reduced renal function should be started at a lower dose and up-titrated more slowly. Some clinicians combine gabapentin and pregabalin despite a lack of compelling evidence that supports this tactic. The use of opioids to combat PHN is controversial because of the changing landscape regarding what constitutes appropriate use and also renewed governmental interest in their administration given the epidemic of abuse, addiction, and mortality.[20] The above three medical societies recommend opioids as either first or second-line treatments, which underscores the pain-reducing capability of this medication class.[21]

There are several other pharmacologic modalities to consider. Multiple studies have confirmed the short and long-term efficacy of the lidocaine 5% patch.[22] This patch also has the additional benefit of a small side effect profile that is mostly limited to application site reactions. Capsaicin preparations in the patch and cream formulations are also available but not as well-studied as the lidocaine patch.[19][23] The leading cause of discontinuing capsaicin treatment is pain and irritation at the application site, suffered by almost all users in proportion to the capsaicin concentration. The cream has a low concentration of capsaicin, requiring multiple applications to achieve a therapeutic effect throughout the day. Conversely, the capsaicin patch is available in an 8% formulation, delivering a therapeutic dose in just one application.[24] However, pre-treatment with oral analgesics and local anesthetic at the application site is often necessary to avoid painful irritation. The degree of overall pain reduction is generally less than the lidocaine 5% patch. Nevertheless, encouraging case reports and other literature suggest the intervention warrants consideration and further study.

Other medication classes include non-TCA antidepressants and NMDA antagonists, but limited evidence supports their usefulness. For example, larger studies involving SNRIs (serotonin-norepinephrine reuptake inhibitors) and SSRIs (selective serotonin reuptake inhibitors) have not shown better outcomes than TCAs, and both classes possess concerning side effect profile, though typically less severe than TCAs.[19] The recent explosion of ketamine infusion clinics and related studies for treating a wide range of ailments, from neuropathic pain to depression, has also resulted in renewed interest in the role of NMDA antagonism in treating PHN.[25]

There are anecdotal reports that ketamine may prove beneficial, and a few small studies support this finding, but long-term data and large-scale studies are non-existent. Lidocaine infusions have also been considered. One double-blind study in 1999 showed that an intravenous lidocaine infusion provided clinically significant short-term pain reduction in patients with PHN.[26] In general, small studies and case reports have established that novel therapies may be useful in certain PHN sufferers when combined with other adjuncts. The pathophysiology of PHN is complex, and sometimes an individualized non-traditional approach may prove beneficial for a particular patient.

Invasive therapies include botulinum toxin injections, sympathetic blockade with local anesthetics, epidural/intrathecal injections, and spinal cord stimulation. Botox injections are simple to perform and have a limited side effect profile.[27] However, more studies need to be conducted to evaluate their efficacy. The other invasive therapies mentioned carry the potential for significant peri-procedural risk and/or side effects. Epidural steroid injections and neuromodulation (both spinal cord and peripheral nerve stimulation) produce mixed results but are intriguing, with the former resulting in limited short-term improvement at best and the latter sometimes resulting in complete long-term symptom resolution, according to case reports. The recent development of the dorsal root ganglion stimulator to treat focal dermatomal neuropathic pain conditions is theoretically promising for PHN. One study originating from China in 2008 suggests that CT-guided radiofrequency ablation of the dorsal root ganglion may result in a significant reduction in symptomatology and sometimes complete resolution of PHN. However, the sample size was small, the technique may cause a pneumothorax, and repeat studies are lacking. Intrathecal medication administration also demonstrates promise. One 270-person study in 2000 investigated the use of intrathecal methylprednisolone with lidocaine for the treatment of PHN, resulting in a significant analgesic effect in ninety percent of patients through two years of follow-up.



Differential Diagnosis
Neuropathic pain is an umbrella term that describes a type of pain common to many diseases and conditions. Nevertheless, unilateral neuropathic pain in a dermatomal pattern at or near the area of a previous HZ rash is highly specific for postherpetic neuralgia. However, there are rare instances where other neuropathic conditions should be considered. For example, there is at least one case report of CRPS affecting dermatomes afflicted by HZ just three months prior. The location of neuropathic pain will assist in the development of a differential diagnosis; if present in the face, trigeminal neuralgia and Bell’s palsy may be considered. What appears to be PHN in the thoracic dermatomes may infrequently be appendicitis, cholelithiasis, or colitis.[28] In the exceptional case where PHN diagnosis is unclear, serological studies for the VZV may be beneficial.



Prognosis
Postherpetic neuralgia is challenging to treat. Symptoms may continue for years, sometimes whole life. With the advent of adult vaccination and the newly developed non-live vaccine formulation, prevention looms as a realistic goal for most of the susceptible American population.[3] When prevention of HZ is not possible, timely treatment is advisable, as duration and severity of pain are considered risk factors for PHN. Unfortunately, once PHN is established, conservative first-line treatment rarely results in symptom resolution and does not offer long-lasting relief. Therefore, multimodal therapeutic approaches recommended by expert consensus should be considered. Limited but thought-provoking evidence suggests that certain unconventional techniques, both invasive and non-invasive, are promising and merit further investigation.

Complications
Depending on the duration of postherpetic neuralgia and how painful it is, the following complications can arise in patients:Depression
Fatigue
Disturbed sleep
Lack of appetite
Impaired concentration


Deterrence and Patient Education
The mainstay of prevention is the vaccination against HZV.[3] A large (n = 38,000) double-blind study published in the NEJM in 2005 showed that vaccination in the elderly reduced the incidence of HZ by 51% and PHN by 66%. Moreover, even among those who developed PHN, the burden of illness was reduced by approximately 61%. It must be noted that the immune-boosting effect of the vaccination is not long-lasting, and interval re-vaccination is necessary to maintain its efficacy.[3] Additionally, the current formulation of the vaccine is a live-attenuated virus, theoretically capable of causing infection in immunocompromised individuals, therefore limiting its use in this population.[3] However, in late 2017, the FDA Advisory Committee approved a subunit, non-live vaccine for use in the United States for individuals over the age of 50. It may be used in immunocompromised individuals and confer greater protection against HZ and PHN than the original live-attenuated virus in all patient populations. Preventative vaccination of at-risk populations may ultimately prove to be the safest and most efficacious approach to addressing the significant morbidity associated with PHN.

The other approach is to attempt to prevent the progression of HZ to PHN, with the understanding that the severity of an HZ episode is a risk factor for PHN. Unfortunately, the available evidence supporting this technique is by no means robust, and existing investigatory studies are suboptimally designed for the endpoint in question. Therefore, while antiviral drugs, glucocorticoid administration, and/or invasive procedures may reduce the severity of an HZ episode in certain instances, there is no clear evidence that these methods, alone or in combination, result in a reduced incidence of PHN. Higher-quality studies are needed for a definitive stance.

Enhancing Healthcare Team Outcomes
Considering that postherpetic neuralgia is difficult to treat and outcomes are variable, prevention is of paramount importance. Therefore, primary care physicians and geriatricians are tasked with administering vaccinations to at-risk populations. When preventative measures fail or are never instituted, experts in the field of pain management who have experience with the condition and multimodal treatment techniques should be consulted. An interprofessional approach to managing patients with postherpetic neuralgia is the best way forward.