Postherpetic neuralgia: New hopes in prevention with adult vaccination and in treatment with a concentrated capsaicin patch

Scandinavian Journal of Pain 3 (2012) 220–228

Contents lists available at SciVerse ScienceDirect

Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com

Topical review

Postherpetic neuralgia: New hopes in prevention with adult vaccination and in treatment with a concentrated capsaicin patch Ewa Gawecka a,b,∗ , Oddbjørn Viken a,b a b

Oslo University Hospital, Department of Pain Management and Research, Rikshospitalet, Oslo, Norway Oslo University Hospital, Department of Anaesthesiology and Intensive Care Medicine, Rikshospitalet, Oslo, Norway

a r t i c l e

i n f o

Article history: Received 10 May 2012 Accepted 10 May 2012 Keywords: Postherpetic neuralgia Varicella-zoster-vaccination Topical capsaicin Topical lidocaine Antidepressants Gabapentinoids

a b s t r a c t Background and purpose: Postherpetic neuralgia (PHN) is a complication of acute herpes zoster (HZ). The evidence base for management of PHN has increased by recent publications. Therefore, we reviewed incidence of HZ, prevalence, risk factors, and mechanism of PHN pain, prevention and treatment of PHN with special interest in studies on adult vaccination and topical application of lidocaine and concentrated capsaicin patch. Methods: We searched databases with an English language restriction: MEDLINE 1944–2011, EMBASE 1988–2011, PubMed, and the Cochrane Controlled Trial Register and Cochrane Library (2011). From retrieved publications, we selected studies focusing on our main goals, prevention and treatment of PHN in particular. The review was therefore systematic, but with a pragmatic approach to which studies to select for closer review. Results: From the large number of abstracts retrieved we selected 65 papers for closer review and as evidence base for our conclusions and recommendations for prevention and treatment of HZ and PHN. The incidence of HZ and risks of having PHN after HZ increases markedly with age above 60–70. Severity of symptoms and their impact on quality of life is a major health problem of persons above 70 years of age. Adult vaccination with the reinforced varicella virus vaccine reduces the incidence of HZ and PHN by about 50%. This is an important health and quality of life gain for the elderly. Antiviral drugs given early in an episode of HZ reduce pain and duration of HZ and decrease the risk of PHN. Pharmacological management of PHN are with nortriptyline (or amitriptyline in the younger patients), and or a gabapentinoid as first line drugs. Early treatment also is with topical lidocaine for immediate but short-lasting relief of burning hyperalgesia, and topical capsaicin relieving hypersensitivity for up to 12 weeks. A number of second and third line drugs have less evidence-base for effect, and often more adverse effects than the first line drugs: serotonin and noradrenaline uptake inhibitors (venlafaxin, duloxetin), antiepileptics (valproate), and opioid analgesics. Opioids are indicated for bridging in patients with severe PHN-symptoms while waiting for the more specific first line drugs to take effect. In these elderly patients, systemic pharmacological treatments are always a difficult balance between effects and adverse effects. It is important with close supervision of the patients, especially during start-up of systemically administered drugs, in order to prevent tragic complications from falls in sedated, dizzy, and confused elderly patients. Topical treatment with lidocaine and capsaicin patches does not have these problems. Conclusions: Prevention of this significant health problem of the increasing elderly population is now possible through adult vaccination against varicella zoster virus (VZV) reactivation, as well as vigorous and early antiviral treatment during acute HZ. The evidence -base supports the oral use of tricyclic antidepressants, gabapentinoids, and opioids for bridging till the first line drugs take effect. Topical therapy with lidocaine and capsaicin patches is effective and well supported by evidence. A number of second and third line drugs and treatments are available, but have less evidence-base. All drug treatments, except topical lidocaine and capsaicin, have adverse effects that are often problematic and can be dangerous in the elderly patients. Close supervision of the patients is mandatory. Implications: Recent advances in prevention and management of this serious health problem should be better known and implicated: Adult vaccination for prevention of varicella zoster virus reactivation, antiviral drugs and combinations of drugs can reduce the suffering from acute HZ and chronic PHN. Topical lidocaine and capsaicin are now evidence-based therapies that reduce suffering from hypersensitivity and hyperalgesia in patients with PHN. When properly applied, they have few complications. © 2012 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2012.07.003. ∗ Corresponding author at: Oslo University Hospital, Department of Pain Management and Research, Rikshospitalet, 0027 Oslo, Norway. Tel.: +47 95753273. E-mail addresses: [email protected], [email protected] (E. Gawecka). 1877-8860/$ – see front matter © 2012 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sjpain.2012.05.070

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

221

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Identification of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Definitions of PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Acute herpes zoster – shingles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Definition of pain phases of PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Acute herpetic neuralgia (AHN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Subacute herpetic neuralgia (SHN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Postherpetic neuralgia (PHN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Description of pain associated with PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Incidence of HZ and risk factors for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. The incidence of HZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Risk-factors for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Progression of PHN symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Pathology and possible mechanism of PHN pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Prevention of postherpetic neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1. Optimal treatment of the acute herpes zoster with antiviral drugs and analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2. Adding antihyperalgesic drugs to antiviral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.3. Adult varicella-zoster virus (VZV) vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Treatment of postherpetic neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.1. First line drugs for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.2. Second line drugs for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.3. Third line drugs for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.4. Procedures that are debated or not recommended for PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion and concluding summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Prevention of PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Treatment of chronic PHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Adverse effects of PHN-drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

221 221 221 222 222 222 222 222 222 222 222 222 222 222 222 222 222 223 223 223 223 224 224 224 226 226 226 226 227 227 227 227

Contents 1. 2.

3.

4.

5.

1. Introduction Varicella-zoster virus (VZV) is the causative agent of varicella, or “chickenpox,” and herpes zoster, or “shingles”. Acute herpes zoster (HZ) is an acute inflammation in the dorsal root ganglion, its peripheral nerves and dorsal horn of the spinal cord. The varicella-zoster viruses remain dormant in the neurons after a childhood chickenpox, and for some (unknown) reason have been reactivated later on in life. The cutaneous vesicles in the distribution of the affected peripheral nerve(s) are painful. The commonest sites for HZ and PHN are the mid-to-lower thoracic dermatomes (50%), the ophthalmic division of the trigeminal nerve (10–20%), and the cervical dermatomes (10–20%), but any dermatome can be affected. Women are more often affected than men, in a ratio of approximately 3:2 [1]. In immune-competent persons HZ is almost always unilateral and most cases are self-limiting. Very occasionally it may recur (1–8%), and this is mostly in the same site. The pain can cause significant suffering, particularly in the elderly. HZ and PHN have major impact on patients’ lives across all four health domains – physical, psychological, functional, and social. Symptoms may be severe enough to interfere with sleep, appetite, activities of daily life, and sexual function. The pain is often described as a constantly ongoing, burning, aching pain that is localized to the affected dermatome. In addition there are episodic breakthrough attacks of stabbing, electric shock-like, episodes of lancinating pain. Hyperesthesia and hyperalgesia are common. The most severe acute pain usually diminishes in the second or third week as the skin lesions begin to heal. Pain persisting for either longer than 3 months after complete healing of the acute herpes zoster skin lesions, or more than 4 months after appearance of the herpetic vesicles, is considered PHN [2], although the pain often decreases rapidly in some patients during the next three months. It

is an important observation that in many patients the pain gradually diminishes to less than bothersome pain during the following 1–3 years [3]. Pain of PHN is similar to the pain in the acute phase, however, dysaesthetic, allodynic sensations evoked by clothes or light touch may be more prominent. Diagnosis is clinical and based on the presence, or past presence, of vesicles. Occasionally the vesicles are few and transient, leaving no cutaneous evidence of an acute HZ; such zoster sine herpetes is a difficult diagnosis. The great variations in the intensity and course of the herpes zoster infection, makes finding proof of effect of any prevention or treatment in the acute or subacute phase of neuralgia difficult. New knowledge on prevention and management of these serious health problems of the elderly population is appearing. Therefore, the objectives of the present study were to review literature on epidemiology and management, focusing on recent studies on prevention and treatment of PHN. 2. Methods 2.1. Inclusion criteria This was a focused review on recent new knowledge about management of PHN and not a strict systematic review of all aspects of HZ and PHN. We used the definition of PHN as pain persisting for longer than 4 months after the appearance of the herpes zoster rash of an acute attack of HZ. We searched specifically for systematic reviews and for high quality, blinded and randomized clinical trials that examined outcome of adult patients with zoster-associated pain. Unpublished, letter and abstract-only studies were excluded as were studies where data for PHN were not analysed separately from other neuropathic pain syndromes.

222

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

2.2. Identification of studies The following databases were searched with an English language restriction: MEDLINE 1944–November 2011, EMBASE 1988–November 2011, PubMed, and the Cochrane (2011) databases. The CINAHL database was not used. Search terms used were: “herpes zoster*,” “postherpetic neuralgia”, “neuralgia”, “pain”, and “neuropathic” in combination with “study”, “trials”, “randomised”, “random”, “double-blind”, “controlled clinical trials”, “review”, “systematic review”, and similar search terms. References of retrieved studies and review articles were also searched for further trials. The following variables were the focus of interest: drug or treatment studied, number of patients, study design and duration, dosing regimen, outcome measures, pain-relief outcomes and adverse events. 3. Results From the large number of abstracts retrieved we selected 65 original trials and reviews for closer review and as evidence base for our conclusions and recommendations for prevention and treatment of HZ and PHN. 3.1. Definitions of PHN 3.1.1. Acute herpes zoster – shingles During the acute phase, pre-eruptive pain for up to 3 weeks has been described, although pain for more than 2–3 days before the rash is uncommon. There is no generally agreed definition of when acute herpes zoster becomes a postherpetic neuralgia (PHN), since symptoms are similar in the acute and chronic phase. Nevertheless, the persistence of pain for more than four months after the appearance of the herpes zoster rash indicates that the patient is at risk of being among the unlucky ones who may have a prolonged and troublesome pain condition. 3.2. Definition of pain phases of PHN Dworkin and Portenoy [3] defined three phases of the post herpes zoster pain: 3.2.1. Acute herpetic neuralgia (AHN) Acute herpetic neuralgia (AHN) refers to pain preceding or accompanying the eruption of a rash that persists up to 30 days from its onset. 3.2.2. Subacute herpetic neuralgia (SHN) Subacute herpetic neuralgia (SHN) refers to pain that persists beyond healing of the rash but which resolves within four months of onset. 3.2.3. Postherpetic neuralgia (PHN) Postherpetic neuralgia (PHN) refers to pain persisting beyond four months from the initial onset of the rash. 3.3. Description of pain associated with PHN AHN is often severe, there are generally no features of the pain unique to it, and it merges into PHN without a distinctive qualitative change. Two types of pain dominate: • A relentless ongoing pain in the affected dermatome that is burning, aching, tearing, sometimes with an itchy sensation. Occasionally the pruritus dominates over pain.

• Paroxysmal pain which is a stabbing, electric shock-like pain, also localized to the affected dermatomal area. The scars themselves tend to be hypoaesthetic, but hyperphenomena are common: brush or cotton induced allodynia, pinprick hyperalgesia, warm- and cold allodynia [4]. Pain is often provoked by clothes contact and skin stretching. These evoked sensations may constitute the most unbearable part of postherpetic neuralgia for many patients. 3.4. Incidence of HZ and risk factors for PHN 3.4.1. The incidence of HZ Any individual infected with varicella zoster virus (VZV) has the virus latent in ganglion cells and is at risk of reactivation of the VZV, causing an acute herpes zoster infection. This risk appears to be related to a declining VZV-specific cell-mediated immunity related to immunosenescence with advancing age [5]. The risk of HZ increases with the impairment of the immune system due to age, diseases such as cancer, immunosuppressive drugs of cancer therapy or organ transplantation, and steroid therapy [5]. In a general immune-competent population under the age of 20 years approximately 1 HZ occurs per 1000 person-years [6], 2 per 1000 person-years in those under the age of 50 years [7]. The incidence is 5–10 times greater for those older than 65–80 years, so that about 1 of every 100 persons older than 80 years will develop HZ every year [6]. 3.4.2. Risk-factors for PHN Most studies agree that PHN is rare in children and young adults. The major risk factors for PHN are older age, more severe prodromal and acute pain, and greater rash severity [2,8–10]. The risk of having PHN 4 months after start of acute HZ in adults below 60 years of age is less than 2% and about 10% in those above 60 years [8]. In patients who do develop PHN, advanced age is also associated with increasing severity and persistence of symptoms of PHN [11]. Data from patients in the placebo arm of antiviral trials of acute herpes zoster show that pain is present in approximately 10% of individuals 3–6 months after the acute HZ [12]. Also the placebo arm of a large randomized trial that evaluated adult vaccination against VZV, in 334 patients 60–69 years of age PHN occurred in almost 7%, and in almost 19% among the 308 patients older than 70 years when they developed acute HZ [13]. The risk of PHN after HZ is NOT increased in persons with compromised immune functions [14]. However, acute HZ is several times more common in patients with cancer or HIV infection [15]. 3.4.3. Progression of PHN symptoms In a few patients pain gradually worsened despite attempts at pain relief [16]. However, prospective studies have shown that pain usually decreases continuously during the first year after HZ. In one study evaluating pain in 100 patients after HZ, more than 90% of patients reported pain during the acute phase, PHN was then present in 25% of the patients at 4 months, and in 12% at 6 months [17]. Helgason et al. [8] following 400 patients found early PHN in less than 2% of patients younger than 60 years, but in 10% of older individuals; after 1 year none of the patients in the younger age group reported severe pain and in those above 60 years, only 3% had severe pain. 3.5. Pathology and possible mechanism of PHN pain The virus persists in the dorsal root ganglia of cranial or spinal nerves after resolution of the original chickenpox episode. The virus

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

is kept in a dormant, latent condition by cellular immunity. As cellular immunity wanes with age, or the patient is immuno-suppressed by drugs or disease, the virus is transported along peripheral nerves, producing an acute neuritis [18]. During the acute HZ there is a hemorrhagic inflammation of the peripheral nerve, dorsal root, and the dorsal root ganglion. Extension centrally into the dorsal horn of the spinal cord and leptomeninges (arachnoidea mater and pia mater) has also been described [19]. After resolution of the acute process, fibrosis occurs in the dorsal root ganglion, nerve root, and in the peripheral nerve [20]. The pain of acute herpetic neuralgia is probably produced both by the inflammation associated with the movement of viral particles from sensory nerves to skin and subcutaneous tissues, as well as by the damage and malfunctioning of nerve structures. Impulses from primary afferent neurons, that respond to tissue damage, cause changes in the dorsal horn neurons, sensitizing them to further input from non-nociceptive afferents, as well as causing spontaneous activity capable of maintaining ascending impulsetraffic in the pain modulating and transmission system [21]. This may cause perceptions of pain, in the absence of ongoing tissue damage [21,22]. Some have speculated that ongoing VZV replication might be responsible for PHN. However, a randomized, double-blind, placebo-controlled trial of intravenous and oral acyclovir for 56 days in 10 patients with severe PHN of at least six months’ duration failed to influence the course of PHN [23]. 3.6. Prevention of postherpetic neuralgia 3.6.1. Optimal treatment of the acute herpes zoster with antiviral drugs and analgesics Early antiviral therapy promotes more rapid healing of skin lesions, lessens the severity and duration of pain associated with acute neuritis, and reduces the incidence or severity of postherpetic neuralgia. The recommendations have been to provide antiviral therapy for patients above 50 years of age with uncomplicated herpes zoster infections who present within 72 h of debut of clinical symptoms [24,25]. Some prefer either famciclovir, the prodrug of penciclovir (500 mg three times daily) [26], or valacyclovir a prodrug of acyclovir (1000 mg three times daily for seven days). However, if cost is a major consideration, acyclovir is a good option (800 mg five times per day for seven to ten days) [12]. The benefit of antiviral therapy in younger patients is not as clear. All HIV-infected patients should be treated with antiviral therapy for episodes of uncomplicated herpes zoster, regardless of the age at onset, although they do not have an overall increased risk of PHN, as already stated [14]. Despite AHZ being several times more common in patients with cancer or HIV infection [15], these patients have the same overall risk of developing PHN with devastating effects on their quality of life. Intravenous acyclovir should be considered for more severe infections, such as disseminated disease or ophthalmic involvement. 3.6.2. Adding antihyperalgesic drugs to antiviral drugs Potent analgesic drugs and nerve blocks, including potent opioids, are often needed for the acute nociceptive and inflammatory pain at presentation of acute HZ. Antihyperalgesic drugs such as low-dose tricyclic antidepressants: Amitriptyline or nortriptyline 25 mg daily should be initiated within two days of rash onset [32]. Treatment should be continued for 90 days. Anticholinergic side effects (sedation, dizziness, dry mouth) and orthostatic hypotension may limit the utility of tricyclics, particularly amitriptyline in elderly patients who need these drugs the most. For patients who cannot tolerate amitriptyline or nortriptyline, gabapentin, or pregabalin for 90 days may

223

reduce the risk of PHN, an unproven hypothesis [27]. Doses of these drugs must be kept low in the most elderly: dose-related adverse effects, especially dizziness and sedation may increasing the risk of falls. Corticosteroids are shown not to decrease the risk of PHN [24]. Local anaesthetic blocks (e.g., paravertebral, epidural, stellate ganglion) relieve pain temporarily. Epidural injection therapy with glucocorticoids and local anaesthetics is commonly used in many countries to treat acute herpes zoster. One dose of epidural depot methylprednisolone and local anaesthetic reduced pain for one month [28], but the implications of this finding is markedly weakened by the study not being placebo controlled or blinded. Repeated epidural injections of local anaesthetic and depot methylprednisolone may decrease the risk of PHN [24]. But the risk of catheter tract infection progressing to an epidural infection, indicates that this cannot be used in most cases during the acute phase of HZ.

3.6.3. Adult varicella-zoster virus (VZV) vaccine 3.6.3.1. The efficacy and safety of adult VZV-vaccination. The adult varicella-zoster virus vaccine with live attenuated Oka/Merck VZV virus reduces the incidence of HZ and PHN [5]. The vaccination boosts the cell-mediated immunity to VZV after chickenpox in childhood, preventing re-activation of the VZV and HZ-outbreak. The large scale shingles-prevention-study randomized 38 546 adults aged 60 or older to receive either the VZV vaccine or a placebo [13]. Subjects reported in monthly follow-ups through an interactive automated telephone-response system. The median follow-up time was more than 3 years for more than 95% of the included individuals in both treatment arms. If any suspicion of a herpes zoster outbreak occurred, subjects were contacted the study site for an examination. Suspected cases of herpes zoster were confirmed by polymerase chain reaction (PCR) testing for DNA of VZV. Of the 957 confirmed cases of acute herpes zoster, 315 occurred in the vaccine group and 642 in the placebo group, a 51% reduction in HZ. PHN was defined as pain intensity of 3 or higher on a numerical 0–10 rating scale 90 days after onset of the rash. This was reduced by 67% [13]. Thus, the vaccination reduced both the incidence of herpes zoster and the risk of PHN. Overall, the vaccine reduced the incidence of herpes zoster from 11.12 per 1000 person-years in the placebo group to 5.42 per 1000 person-years in the vaccine group [13]. The vaccine also shortened the duration of pain and discomfort and the severity-of-illness score in subjects with confirmed cases of acute herpes zoster by 61%. The vaccine was well tolerated and adverse events consisted mainly of erythema, transient pain or tenderness, swelling, or pruritus (itch) at the injection site. Although there was a slight increase of serious adverse effects from 1.3% in the placebo group to 1.9 in the vaccine group, there was no clinically meaningful difference in outcome of these serious adverse events. Whereas the benefit of the vaccination persisted unabated for an observation period of over 5 years, it is clear that vaccination did not completely abolish herpes zoster outbreaks and subsequent PHN. Vaccination early in life is necessary to prevent the primary VZV infection, i.e. chickenpox (varicella). From about 1995 this has been part of the childhood vaccination programme in Australia, Canada, Germany, Israel, Japan, South Korea, and the USA. It is not likely that immunity based on childhood VZV vaccination persists longer than immunity after chickenpox. We will not know this until after several decades, but it is likely that booster adult vaccination will be needed in those vaccinated in childhood, in order to reduce the risk of HZ and PHN. In the Nordic countries VZV vaccination is not part of the child vaccination programme, based on the fact that chickenpox is usually a mild disease with few severe complications.

224

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

3.6.3.2. Should adult VZV vaccination become a requirement?. The adult VZV-vaccine was approved by the FDA in 2005. Considering the often devastating and prolonged loss of quality of life in healthy elderly persons who are struck by an acute HZ, we are convinced that there is a need for acceptance and wide use of the adult vaccination in the Nordic countries. In some countries, immunization to prevent herpes zoster and postherpetic neuralgia is already recommended for most adults 60 years and older [60]. The elderly population is increasing rapidly in the Nordic countries. Without the adult VZV-vaccination, the absolute number of elderly persons who will otherwise be susceptible to HZ will increase dramatically. The costs to health care budgets due to HZ and PHN will also increase significantly due to this, in part, preventable malady of the elders, unless a adult vaccination programme is instituted. Presently it is possible to get individual VZV-vaccine, at a cost of about US$ 150–200 per dose. This means that only the well-to-do and well educated with knowledge of this particular preventable health problem will benefit from vaccination. 3.7. Treatment of postherpetic neuralgia For treatment of established chronic, painful postherpetic neuralgia, a number of modalities have been documented to have some effect in some, not all, patients. These include antidepressants, anticonvulsants, opioids, topical capsaicin, topical and intravenous lidocaine, intrathecal glucocorticoids, and intravenous NMDA receptor antagonists. Cryotherapy, surgery, non-steroidal anti-inflammatory drugs (NSAIDs), and paracetamol are of limited value in patients with PHN. First line drugs for PHN are the best documented drugs for treatment of PHN. When first line drugs give little effect or intolerable side effects, second and third line drugs should be considered. Table 1 illustrates treatment options with additional information below. 3.7.1. First line drugs for PHN First line drugs are tricyclic antidepressant drugs (TCA) [27,29–33]. This was first demonstrated with amitriptyline in a study of 24 patients with PHN [31] and confirmed in 58 elderly patients with PHN who were randomized to receive amitriptyline (12.5–150 mg per day), lorazepam (0.5–6 mg per day) as an “active” placebo, or an inactive placebo [30]. A mean amitriptyline dose of 65 mg per day was achieved in 6 weeks. Despite a 2–3 weeks lag before TCAs begin to reduce pain, amitriptyline was significantly more effective than lorazepam and the inactive placebo in providing moderate relief of pain (47%, 15%, and 16%, respectively). A significant correlation between the degree of symptom relief and serum amitriptyline levels led the authors to conclude that serum levels of amitriptyline and active metabolites must be maintained at 100 ng/mL serum for at least three weeks before a patient is considered to have failed TCA therapy [30]. The central and peripheral anticholinergic side effects (somnolence and dry mouth) are not only bothersome; they also increase the risk of falls/fractures, periodontal infectious disease and loss of teeth. Nortriptyline is less sedative and better tolerated than amitriptyline, and nortriptyline is therefore recommended before amitriptyline in elderly patients [27]. Desipramine was found to be effective in relieving PHN in one small study with mean dose 165 mg per day (Table 1). Desipramine appears to have fewer side effects than amitriptyline, but it is not available in all Nordic countries any more. Anticonvulsant drugs that have been evaluated in sufficiently powered, randomized trials include gabapentin [27], pregabalin [25], and less so, valproic acid (Table 1) [35,36]. The efficacy of gabapentin was demonstrated in a randomized, double blind,

placebo-controlled study of 229 patients [38]. Gabapentin dose was titrated during a four-week period to a maximum dose of 3600 mg/day with maintenance of the maximum dose for another four weeks. Gabapentin resulted in significant reduction in the average daily pain score compared with placebo, while decreasing sleep interference by pain and improving mood and quality of life [38]. Pregabalin has similar effects and side effects as gabapentin, but a much shorter onset time, decreasing pain and improving sleep at doses of 150–600 mg daily within 1–2 weeks [25,27]. Common side effects are dizziness, somnolence, cognitive decline (transient), dry mouth, peripheral oedema, and weight gain. The recommended daily starting dose is 75–150 mg, divided in two or three doses, increasing to a total daily dose of 300–600 mg. In elderly patients and patients with renal impairment, the doses must be reduced, starting dose only 25 mg in the evening. When stopping the gabapentinoids, they should be tapered over a week, as withdrawal symptoms may occur on abrupt discontinuation of antiepileptic drugs. Topical lidocaine, especially application of a 5% lidocaine patch, is well documented to relieve mechanical allodynia, or touch evoked pain [34]. Topical capsaicin, the 8% concentrated capsaicin patch may soon be listed among the first line drugs in patients who have sever mechanical allodynia in a limited skin area. This drug does not help all patients with allodynia as part of the PHN, but for those in whom this drug is effective, a major part of their burden from PHN will be well relieved for 3 months or longer. And the treatment can then be repeated [42,63] – see under 2nd line drugs below. 3.7.2. Second line drugs for PHN 3.7.2.1. Opioid analgesic drugs. Opioids in oral depot or transdermal administration forms are useful in addition to first line drugs when pain is severe [39,40]. When the pain is excruciating, a potent opioid may give immediate relief and can serve as a “bridge” while waiting for the more slow-onset first line drugs to take effect. The opioid can subsequently be tapered and discontinued. Awareness is needed when starting any opioid analgesic in neuropathic pain conditions about the highly variable opioid sensitivity in these patients. Effects and tolerability of long-term treatment with opioids are similar to those of TCAs [39]. The burden of side effects is not negligible in elderly patients with any of the first or second line drugs. Close monitoring of effects and side effects are therefore mandatory during titration of the drugs as well as during long term follow up [25]. 3.7.2.2. Topical application of transdermal lidocaine 5% patch and capsaicin 8% patch. Lidocaine 5% patch relieves pain and discomfort in hypersensitive, allodynic, hyperalgesic skin areas [34,52]. It is a 1st line drug, but unfortunately the effect disappears after removal of the patch. Capsaicin 8% patch, on the other hand, can have prolonged effect on pain and hypersensitivity. Topical capsaicin has been around for several years in the form of a dilute (0.025%) cream. Capsaicin is an agonist at the transient receptor potential vanilloid 1 (TRPV1) receptor which is a ligand-gated ion channel receptor expressed on nociceptor neurons in the skin. The mechanism of action on pain was thought to be the depletion of substance P from the nerve endings of C-fibres, however, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate. Rather, topical capsaicin acts to attenuate hypersensitivity in the skin and reduces pain by a process best described as ‘defunctionalization’ of nociceptor fibres. This leads to temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

225

Table 1 Management of postherpetic neuralgia (PHN). Treatment

Effectiveness

Mechanism of action

References

1st line drugs Tricyclic antidepressants Nortriptyline Amitriptyline (if tolerated) Desipramine (if available)

May reduce ongoing pain and stimulus-dependent pain by ∼30%.

Inhibit reuptake of noradrenaline and serotonin at synapses in the CNS. Increase inhibition of transmission of nociceptive signals from the periphery. Anticholinergic adverse effects are numerous, nuisance – to serious; sedation and dizziness with increased risk of falling. Xerostomia aggravates periodontal disease → loss of teeth! Local anaesthetic block of peripheral nerves, and sub-anaesthetic, analgesic effects in spinal cord dorsal horn. Gabapentin and pregabalin act on presynaptic Ca2+ channels, anticonvulsants decrease general neuronal hyper-excitability.

Alper and Lewis [27] Dubner and Basbaum [29] Max et al. [30] Watson et al. [31,50,53] Bowsher [32,33] Kishore-Kumar et al. [56] Blackwell [55]

Lidocaine-patch

Suppresses stimulus-provoked pain and allodynia.

Anticonvulsants Gabapentin Pregabalin

May reduce paroxysmal and ongoing pain.

Valproic acid

3rd line drugs Intravenous lidocaine

Rice and Maton [48] Alper and Lewis [27] Dubinsky et al. [25] Rowbotham et al. [38] Dworkin et al. [54,58] Sabatowski et al. [59]

Effective, but more adverse effects?

2nd line drugs SSNRIs Venlafaxin Duloxetin ␣2 -agonists Clonidine Dexmedetomidine Opioids Codeine Tramadol Buprenorphine Morphine Oxycodone Oxycodone plus naloxone Methadone Capsaicin Topical application of capsaicin 0.025–0.075% cream Capsaicin 8% patch

Khaliq et al. [34] Hempenstall et al. [52]

Relieve ongoing pain.

Serotonin and noradrenaline reuptake-inhibitors. Effects in other types of neuropathic pain.

Relieve ongoing pain.

Clonidine and dexdetomidin are ␣2 -agonists that inhibit pain transmission in the CNS, potentiate effects of opioids in PHN. Agonists at opioid-receptors that reduce severe acute pain and suppress pain in PHN; add-on drugs to TCA and anticonvulsants. Opioid-induced-gastrointestinal dysfunctions are frequent in elderly patients. Problematic opioid use is infrequent in elderly persons. Tramadol also has serotonin and noradrenaline effects, may cause severe serotonin syndrome. Moderate relief (21%) when applied four times per day for 6 weeks.

Relieve acute severe pain. Additive analgesic effect to 1st line drugs.

Second line drug for severe hyper-phenomena.

Relieves ongoing, provoked, and paroxysmal pain.

Subcutaneous botulinum toxin

Relieves PHN pain compared to lidocaine and placebo.

Intrathecal glucocorticoids Methyl-prednisolone

Relieve PHN pain in refractory cases.

Swerdlow [35] Kochar et al. [36] Dworkin et al. [54] Hempenstall et al. [52] Max et al. [37]

Rowbotham et al. [41] Raja et al. [39] Hempenstall et al. [52]

Boureau et al. [40] Alper and Lewis [27] Watson et al. [49]

Topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process described as ‘defunctionalization’ of nociceptor fibres that lead to temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. 8% capsaicin patch once a day (after topical lidocaine) reduced pain more for 12 weeks than a low-concentration capsaicin (0.4%) patch.

Backonja et al. [42] Anand and Bley [63]

Lidocaine suppresses hyperexcitable neurons in the CNS and may provide benefit in patients who do not respond to other therapies. Subcutaneous injection of botulinum toxin causes a significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased subjects’ sleep times. Immunologically activated glia and astrocytes in spinal cord may be inactivated by the immune-suppressive effect of intra-thecal glucocorticoids. More than 90% of patients in the methylpredniso-lone group reported excellent or good pain relief and the areas of allodynia were reduced by more than 70% in the methyl-prednisolone group and only 25% in the lidocaine alone group. One study compared intrathecal with epidural methylprednisolone and found significantly greater improvements with the intrathecal route. Adverse effects on spinal cord and nerveroots are possible.

Rowbotham et al. [41] Baranowski et al. [51] Hempenstall et al. [52] Xiao et al. [61]

Kotani et al. [43]

Kikuchi et al. [44]

226

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

Table 1 (Continued) Treatment

Effectiveness

Mechanism of action

References

Bupivacaine sympathetic block

Reduce noradrenaline induced pain. Reduce ongoing and provoked pain.

Reduce sympathetically maintained pain. Effect in one trial. Antagonists of N-methyl-d-aspartate (NMDA) receptors inhibit pain transmission in CNS. Induce modest pain relief in patients with PHN, but at doses that cause sedation, dysphoria, and unpleasant dissociative phenomena.

Alper and Lewis [27] Hempenstall et al. [52] Kristensen et al. [45] Eide et al. [46] Nelson [47]

Failed to provide even modest analgesia in small study, act as a selective inhibitors of the reuptake of serotonin. Including electrical stimulation of the thalamus, anterolateral cordotomy, and electrocoagulation of the dorsal root, all had no consistent benefit, carry substantial risks of permanent neurologic deficits Neurolytic interventions (cryo-/RF-/phenol-/ethanol-blocks) are not recommended.

Dubner and Basbaum [29] Watson et al. [50] Kishore-Kumar et al. [57] Hempenstall et al. [52]

Intravenous NMDA receptor antagonists Ketaminedextro-methorphan

Drugs and procedures that are proven NOT to be effective SSRIs No effect on PHN pain. Serotonin specific reuptake inhibitors TENS No effect on PHN pain. Acupuncture Surgery Neurolytic procedures

hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervations, and collateral sprouting, all of which are defunctionalized by topical capsaicin [63]. The TRPV1 channel is highly calcium permeable, which allows significant amounts of calcium to flow down its steep electrochemical gradient into nerve fibres [63]. The capsaicin cream (0.025%) administration is demanding in that it causes severe pain unless the skin is well anaesthetized, and the cream needs to be applied 4 times a day for 6 weeks to take effect. This topical treatment tends to be “messy”, and compliance is low (Table 1) [49]. A renaissance for capsaicin is occurring with a concentrated capsaicin 8% patch [42]. Advantages of the highconcentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug–drug interactions. The skin must be well anaesthetized with topical lidocaine before the patch is put on areas of hyper-phenomena and left on for 30–60 min. The 8% capsaicin patch is not approved for application in the face. With this treatment pain is relieved for up to 3 months before the procedure has to be repeated [42,63]. 3.7.2.3. Other antidepressants and ˛2 -agonist. The serotonin and noradrenaline reuptake inhibitors (venlafaxin, duloxetin) are well documented for other types of neuropathic pain, but are still not well studied in PHN (Table 1). Clonidine is a second line drug for PHN, with moderate effect [37]. 3.7.3. Third line drugs for PHN These are intravenously infused NMDA-antagonists (mainly ketamine), subcutaneous injection of botulinum toxin, intravenous infusion of lidocaine and intrathecal methylprednisolone. Sympathetic block and spinal cord stimulation may also be considered [43–47] (Table 1). Subcutaneous injection of botulinum toxin has in a randomized, double-blind, placebo-controlled study been shown to have beneficial effects in postherpetic neuralgia. This recent study showed a significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months posttreatment. It also increased subjects’ sleep times [61]. Intravenous lidocaine does relieve the pain of some patients with severe PHN, but usually only transiently. Some patients can have their PHN pain kept reasonably under control with repeated intravenous lidocaine every 3–4 weeks [41,51]. Interventional treatments, such as intrathecal glucocorticoid injection and injections with local anaesthetic drugs, have an effect

on the acute pain but are of limited use in treating post-herpetic neuralgia [43,44]. When conservative treatment fails in providing satisfactory relief of post-herpetic neuralgia, a sympathetic block may be considered. Spinal cord stimulation may be considered as well [62]. 3.7.4. Procedures that are debated or not recommended for PHN We identified five trials that compared acute glucocorticoid therapy (given by oral, intramuscular, or intravenous routes) with no treatment or placebo; at six months after onset of herpetic rash, there was no significant difference between treatment and control groups in the presence of PHN [64]. There are potentially harmful effects of intrathecal glucocorticoid injections, and although studies report positive effects [43,44], we do not recommend this therapy. Any neuro-destructive procedure carries a considerable risk of aggravating the already complex pain condition of PHN. TENS, acupuncture, serotonin specific inhibitors, and serotonin agonists [57] have no effect. 4. Discussion and concluding summary Acute herpes zoster (HZ) is caused by a reactivation of latent varicella-zoster virus (VZV) in ganglion cells. The incidence of acute HZ increases with age and other causes of decreased cellular immunity. It is infrequent below 40 years, increasing to around 10 per 1000 person-years in those older than 65. The risk of PHN, i.e. pain persisting beyond 4 months after the appearance of rash, can be as high as one in five elderly after HZ. Post herpes zoster neuralgia (PHN) can be a devastating condition for elderly people who suffer an acute herpes zoster (HZ) infection, followed by PHN. This condition can ruin quality of life for the remaining years of the patient [65]. 4.1. Prevention of PHN There is a clear association between the severity of the rash and pain of HZ and the risk of suffering from chronic pain in the area affected. Relieving the acute pain is therefore important. Antiviral therapy started early in the acute phase of HZ, i.e. before 48–72 h after appearance of rash, reduces the severity and duration of the painful acute phase. Local anaesthetic blocks can abolish the acute pain for several hours. It is a long held, but unproven, conviction among experienced pain clinicians that paravertebral blocks or specific sympathetic ganglion blocks with local anaesthetics, will reduce the risk of an acute HZ infection progressing to a chronic PHN.

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228

Analgesic drugs, including opioids as needed, in addition to an early start of amitriptyline or nortriptyline, possibly also pregabalin (gabapentin is too slow in onset), as well as topical local anaesthetic (lidocaine 5% patch), will provide relief and reduce risk of chronic pain. Varicella virus vaccination of children may reduce the incidence of herpes zoster in elderly people, although we will not know this for a few decades yet because this vaccine was included in childhood vaccination programmes in some countries as late as 1995. A booster dose in adult life will most likely be needed. Adult varicella virus vaccination is effective in reducing the risk of shingles by more than 50% and postherpetic neuralgia by more than 60%. This vaccine is now becoming available in the Nordic countries, but may not be affordable to everybody. An awareness campaign is needed to make more lay people aware of this possibility to reduce the risk of having a severe pain condition during their retirement years. A tricyclic antidepressant (nortriptyline), a gabapentinoid, and an appropriate analgesic drug should be started early in the acute HZ and continued as long as needed. An opioid analgesic may be necessary and the risk of erroneous use and addiction are almost irrelevant in the elderly with an intensely painful severe acute HZ. In the subacute phase, i.e. two to three months following an acute HZ infection, there are inflammatory changes in the peripheral nerves and neurons in the posterior spinal ganglion, as well as in pain regulating mechanisms in the dorsal horn of the spinal cord. It is during this phase that the neuroinflammatory processes, activation of microglia and astrocytes may be important for the establishment of chronic, intractable PHN. Anti-inflammatory drugs reaching the CNS, may be useful during this phase, but this has not been confirmed.

4.2. Treatment of chronic PHN Tricyclic antidepressants (TCA), i.e. amitriptyline, nortriptyline (less adverse effects in the elderly), desimipramine (not available in all Nordic countries), and gabapentinoids are first line drugs. Local application of a local anaesthetic (lidocaine 5% patch) gives effective, but transient relief. If this treatment fails or gives inadequate pain relief with continuous detrimental effect on quality of life, second line drugs are indicated and include long acting opioids, SNRIs, clonidine, and capsaicin 8% patch. Third line drugs should be considered if 1st and 2nd line treatments have not provided adequate symptom control or cause intolerable side effects. Third line drugs are intravenous ketamine, subcutaneous botulinum toxin, intravenous lidocaine, sympathetic blocks, and spinal cord stimulation.

4.3. Adverse effects of PHN-drugs Most systemic drugs that relieve PHN-pain have side effects that limit their usefulness. A low initial dose with slow dose escalation under close supervision is mandatory in elderly, often frail patients due to increased risk of falling. Close supervision and monitoring of the patient is a must and often not easily accomplished without hospital treatment. Hospitalization is a good investment for the patient, her (most often an elderly lady who is going to live fore a while) quality of remaining life, and for society at large where prolonged direct and indirect health care expenses will otherwise ensue. In this connection, it is important that the concentrated capsaicin 8% patch, after pre-treatment with lidocaine 5% patch, relieves allodynic pain for around 3 months, has no systemic side effects, and it can be repeated as needed.

227

5. Implications Recent advances in prevention and management of this serious health problem should be better known and implicated: Adult vaccination for prevention of varicella zoster virus reactivation, antiviral drugs and combinations of drugs can reduce the suffering from acute HZ and chronic PHN. Topical lidocaine and capsaicin are now evidence-based therapies that reduce suffering from hypersensitivity and hyperalgesia in patients with PHN. When properly applied, they have few complications. Adult vaccination against virus reactivation, antiviral drugs, and topical treatment of hyperalgesia are high cost, but a very good investment for the health care budgets of society. They prevent the miserable effects of postherpetic neuralgia on the quality of life of a large number of elderly persons who may be in good general health, except for their painful “helvetesild” (in Norvegian), i.e. “fire of hell”. References [1] Watson CP, Evans RJ, Watt VR, Birkett N. Post-herpetic neuralgia: 208 cases. Pain 1988;35:289–97. [2] Dey D, Oaklander AL. Neuropathic pain syndromes. In: Ballantyne JC, editor. The Massachusetts General Hospital Handbook of Pain Management. 3rd ed. Lippincott Williams & Wilkins; 2006. p. 342–3. [3] Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67:241–51. [4] Scadding JW, Kolzenburg M. Painful peripheral neuropathies. In: McMahon SB, Koltzenburg M, editors. Textbook of pain. 5th ed. Edinburgh: Churchill Livingstone; 2006. p. 973–9. [5] Sanford M, Keating GM. Zoster vaccine (Zostavax): a review of its use in preventing herpes zoster and postherpetic neuralgia in older adults. Drugs Aging 2010;27:159–76. [6] Glynn C, Crockford G, Gavaghan D, Cardno P, Price D, Miller J. Epidemiology of shingles. J R Soc Med 1990;83:617–9. [7] Kost RG, Straus SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32–42. [8] Helgason S, Petursson G, Gudmundsson S, Sigurdsson JA. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. BMJ 2000;321:794–6. [9] Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62:1545–51. [10] Nagasako EM, Johnson RW, Griffin DR, Dworkin RH. Rash severity in herpes zoster: correlates and relationship to postherpetic neuralgia. J Am Acad Dermatol 2002;46:834–9. [11] Ragozzino MW, Melton III LJ, Kurland LT, Chu CP, Perry HO. Population-based study of herpes zoster and its sequelae. Medicine 1982;61:310–6. [12] Jackson JL, Gibbons R, Meyer G, Inouye L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. A meta-analysis. Arch Intern Med 1997;157:909–12. [13] Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84. [14] Balfour Jr HH. Varicella zoster virus infections in immunocompromised hosts: a review of the natural history and management. Am J Med 1988;85:68–73. [15] Rusthoven JJ, Ahlgren P, Elhakin T, Pinfold P, Reid J, Stewart L, Feld R. Varicellazoster infection in adult cancer patients: a population study. Arch Intern Med 1988;148:1561–6. [16] Watson CP, Deck JH, Morshead C, Van der Kooy D, Evans RJ. Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105–17. [17] Haanpää M, Laippala P, Nurmikko T. Allodynia and pinprick hypesthesia in acute herpes zoster, and the development of postherpetic neuralgia. J Pain Symptom Manage 2000;20:50–8. [18] Meier JL, Straus SE. Comparative biology of latent VZV and herpes simplex virus infections. J Infect Dis 1992;166(Suppl 1):S13–6. [19] Denny-Brown D, Adams RD, Fitzgerald PJ. Pathologic features of herpes zoster: a note on ‘geniculate herpes’. Arch Neurol Psychiatry 1944;77:337–49. [20] Zacks SI, Elliott FA, Langfitt TW. Herpetic neuritis: a light and electron microscopic study. Neurology 1964;14:744–50. [21] Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989;63:139–46. [22] Bennett GJ. Hypotheses on the pathogenesis of herpes zoster-associated pain. Ann Neurol 1994;35(Suppl.):S38–41. [23] Acosta EP, Balfour Jr HH. Acyclovir for treatment of postherpetic neuralgia: efficacy and pharmacokinetics. Antimicrob Agents Chemother 2001;45:2771–4. [24] Baron R, Wasner G. Prevention and treatment of postherpetic neuralgia. Lancet 2006;367:186–8. [25] Dubinsky RM, Kabbani H, El-Chami Z, Boutwell C, Ali H. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter:

228

[26]

[27] [28]

[29]

[30]

[31] [32] [33]

[34] [35] [36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

E. Gawecka, O. Viken / Scandinavian Journal of Pain 3 (2012) 220–228 treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004;63:959–65. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 1998;78(Suppl. 1):S76–86. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. J Fam Pract 2002;51:121–8. van Wijck AJ, Opstelten W, Moons KG, van Essen GA, Stolker RJ, Kalkman CJ, Verheij TJ. The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial. Lancet 2006;367:219–24. Dubner R, Basbaum AI. Spinal cord plasticity following tissue or nerve injury. In: Wall PD, Melzack R, editors. Textbook of pain. 3rd ed. Edinburgh: Churchill Livingstone; 1994. p. 225. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 1988;38:1427–32. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology 1982;32:671–3. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment. Neurology 1995;45:S56–7. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 1997;13:327–31. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev 2007. CD004846. Swerdlow M. Anticonvulsant drugs and chronic pain. Clin Neuropharmacol 1984;7:51–82. Kochar DK, Garg P, Bumb RA, Kochar SK, Mehta RD, Beniwal R, Rawat N. Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study. QJM 2005;98:29–34. Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in post-herpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharmacol Ther 1988;43: 363–71. Rowbotham M, Harden N, Stacey B, Bernstein P, iller Magnus-M.F L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837–42. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Gravison TG, Bockbrader H. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;59:1015–21. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain 2003;104: 323–31. Rowbotham MC, Reisner-Keller LA, Fields HM. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991;41:1024–8. Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan Jr P, Rauck R, Tobias J. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008;7:1106–12. Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514–9. Kikuchi A, Kotani N, Sato T, Takamura K, Sakai I, Matsuki A. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 1999;24:287–93.

[45] Kristensen J, Svensson B, Gordh T. The NMDA receptor antagonist CPP abolishes neurogenic “wind-up pain” after intrathecal administration in humans. Pain 1992;51:249–53. [46] Eide P, Jorum E, Stubhaug A, Bremnes J, Breivik H. Relief of postherpetic neuralgia with the N-methyl-d-aspartic acid receptor antagonist ketamine: a double-blind, crossover comparison with morphine and placebo. Pain 1994;58:347–54. [47] Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997;48:1212–8. [48] Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain 2001;94:215–24. [49] Watson CP, Evans RJ, Watt VR. Post-herpetic neuralgia and topical capsaicin. Pain 1988;33:333–40. [50] Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998;51:1166–71. [51] Baranowski AP, De Courcey J, Bonello E. A trial of intravenous lidocaine on the pain and allodynia of postherpetic neuralgia. J Pain Symptom Manage 1999;17:429–33. [52] Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005;2:e164. [53] Watson CP, Evans RJ. A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia. Pain 1985;23:387–94. [54] Dworkin HR, O’Connor AB, Bakonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmiko TJ, Portenoy RK, Rice ASC, Stacey BR, Treede R-D, Turk DC, Wallace MS. Pharmacological management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237–51. [55] Blackwell B. Adverse effects of antidepressant drugs. Part 1: Monoamine oxidase inhibitors and tricyclics. Drugs 1981;21:201–19. [56] Kishore-Kumar R, Max MB, Schafer SC, Meister B, Gracely RH, Smoller B, Dubner R. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther 1990;47:305–12. [57] Kishore-Kumar R, Schafer SC, Lawlor BA. Single doses of the serotonin agonists buspirone and m-chlorophenylpiperazine do not relieve neuropathic pain. Pain 1989;37:223. [58] Dworkin RH, Corbin AE, Young JP, Sharma U, LaMoreaux L, Bockbrader H, Garofalo EA, Poole RM. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003;60:1274–83. [59] Sabatowski R, Galvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, Versavel M. 1008-045 Study Group; pregabalin reduced pain and improved sleep and mood disturbances in patients with postherpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26–35. [60] Fashner J, Bell AL. Herpes zoster and postherpetic neuralgia: prevention and management. Am Fam Physician 2011;83:1432–7. [61] Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med 2010;11:1827–33. [62] van Wijck AJM, Wallace M, Mekhail N, van Kleef M. Evidence-based interventional pain medicine according to clinical diagnoses. 17. Herpes zoster and post-herpetic neuralgia. Pain Pract 2011;11:88–97. [63] Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011;107:490–502. [64] Chen N, Yang M, He L, Zhang D, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2010;12. CD005582. [65] Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med 2010;8:37.