Postherpetic neuralgia: clinical manifestations

Postherpetic neuralgia (PHN) is nerve pain, persisting beyond four months from the initial onset of the herpes zoster (shingles) rash. Postherpetic neuralgia represents a potentially debilitating, and often undertreated, form of neuropathic pain that disproportionately affects vulnerable populations. The earlier shingles is diagnosed and treatment initiated, the greater the chance of relieving the pain of postherpetic neuralgia. At present there is no cure for postherpetic neuralgia, but available treatments can help reduce the debilitating symptoms. Management includes a pharmacological approach, using anticonvulsants, antidepressants, opioids and topical agents, along with a non-pharmacological approach using transcutaneous electrical nerve stimulation (TENS) and acupuncture.

Herpes zoster

Herpes zoster (shingles) is a transient, self-limiting illness, resulting from reactivation of the varicella-zoster virus which is acquired during primary varicella (chickenpox) infection. While varicella is usually a disease of childhood, herpes zoster is more common in adulthood. Herpes zoster is a sporadic disease, with an estimated lifetime incidence of 10-20%. The incidence of herpes zoster appears to increase with age, roughly doubling in each decade past the age of 50.¹

Types of herpetic neuralgia

Acute herpetic neuralgia refers to the pain preceding or accompanying the eruption of the herpes zoster rash that persists up to 30 days from its onset. Subacute herpetic neuralgia refers to the pain that persists beyond healing of the rash but which resolves within four months of onset. Pain persisting beyond four months from the initial onset of the rash is known as postherpetic neuralgia. Postherpetic neuralgia is classified as a type of neuropathic pain (NP), defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.”^2,3

Postherpetic neuralgia is reported to develop in 9-34% of individuals following herpes zoster. It can be a very debilitating complication of herpes zoster infection, disproportionately affecting vulnerable populations, including older people and the immunocompromised, and can considerably impact on an individual’s psychosocial functioning, resulting in impaired sleep, decreased appetite and reduced overall quality of life.^4,5

Studies suggest that peripheral and central demyelination is involved, along with neuronal destruction.⁶ Several clinical and laboratory parameters have been suggested and evaluated as risk factors predicting the development of postherpetic neuralgia.^7,8

Risk factors

• Advanced age (>50 years)
• Female sex
• Compromised cell-mediated immunity
• Presence of prodrome
• Severe or disseminated rash
• Severe pain at presentation
• Polymerase chain reaction detectable varicella-zoster virus viraemia.

Clinical manifestations of postherpetic neuralgia

Herpes zoster is characterised by a dermatomal rash, which is typically unilateral and localised to a single dermatome of a single sensory ganglion. The thoracic, cervical and trigeminal nerves are most commonly affected by herpes zoster and postherpetic neuralgia. The diagnosis of postherpetic neuralgia is essentially clinical. Thorough investigation of other possible causes of neuralgia (eg. neoplastic, toxic and compressive) should be carried out. The pain of postherpetic neuralgia is frequently intermittent and patients often describe the character of the pain as ‘burning’.^3,4 The pain is mild to moderate in most cases, but can be severe in some. 

The majority of patients with postherpetic neuralgia will also have allodynia, defined as pain evoked by normally non-painful stimuli, such as light touch.⁹ Patients with postherpetic neuralgia frequently describe areas of anaesthesia, along with deficits of thermal, tactile, pinprick and vibration sensation within the affected dermatomes.⁹  These sensory deficits may extend beyond dermatomal margins.

Signs and symptoms of postherpetic neuralgia

• Occasional burning, shooting, stabbing pain
• Constant burning, throbbing, aching pain
• Sensitivity to touch
• Sensitivity to temperature change
• Itching
• Numbness
• Hypersensitivity of the skin in the affected area (allodynia).

Management of postherpetic neuralgia

Evidence suggests that early antiviral therapy initiated for acute herpes zoster may help to reduce the duration of postherpetic neuralgia, although they do not prevent it occurring.^10,11,12 Options include acyclovir, valaciclovir and famciclovir. All three appear to be equally effective. The optimum window seems to be within seven hours of appearance of the rash, but treatment outside three days may be of benefit. Evidence also suggests that tricyclic antidepressants (TCADs) used for the acute phase of herpes zoster may reduce the prevalence of postherpetic neuralgia.¹³ Spontaneous resolution of pain is common in patients with postherpetic neuralgia of less than six months duration and there is little evidence to guide treatment decisions in such patients.¹⁴

Once postherpetic neuralgia develops, there is no cure, but a variety of medications can be employed to minimise the pain while waiting for the condition to resolve. For postherpetic neuralgia of longer duration, a complex regime of oral and topical agents may be required in order to achieve effective pain relief. The choice of medication for each patient depends on a number of factors, including the potential for adverse effects, treatment of comorbidities (eg. depression and sleep disturbances), drug interactions, risks of misuse and abuse, and cost.¹⁵

While many people with postherpetic neuralgia make a full recovery within a year of developing the condition, occasionally, the nerves do not heal completely and symptoms can last for several years or can become permanent.

General approach to postherpetic neuralgia management 

Initial management of postherpetic neuralgia involves making a thorough assessment of the pain and associated symptoms:

• Identify and treat relevant comorbidities
• Initiate pharmacological treatment, if appropriate, starting as monotherapy with low doses and titrating to effect. Other medications with different mechanisms of action may be added as necessary
• Evaluate the patient for non-pharmacological treatment options and initiate if appropriate
• Frequently reassess pain and effect of the treatments commenced. Particular care should be taken with older patients on other medications, as adverse effects and drug interactions may be more common.

Pharmacological options

Antidepressants

TCADs are effective agents in the treatment of postherpetic neuralgia and are often thought of as the mainstay of therapy, with many studies demonstrating the efficacy of nortriptyline and amitriptyline.^14,16 These agents work through the reuptake of noradrenaline and serotonin in the central nervous system. TCADs are limited by a slow onset of action (analgesia in days to weeks), anticholinergic side-effects, (eg. dry mouth, blurred vision and urinary retention), and potential cardiac toxicity. They are, however, inexpensive and have the convenience of being administered once daily. TCADs should be started at low doses and titrated to effect, and caution should be exercised when used in older people. Abrupt withdrawal should be avoided.

Selective serotonin-noradrenaline reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine, have also been used in the management of postherpetic neuralgia and offer efficacy for both pain and depression, with fewer reported adverse effects.¹⁷

Anticonvulsants

While sodium-channel blockers such as carbamazepine and sodium valproate were formally used in the treatment of postherpetic neuralgia, newer agents such as gabapentin and pregabalin acting via calcium-channels appear to be more effective and have a better adverse-effect profile; thus, are more commonly used.^18,19 Pregabalin is also effective in improving sleep in patients with postherpetic neuralgia. Pregabalin is dosed on a twice daily schedule but may require three times daily dosing similar to gabapentin. Both gabapentin and pregabalin appear similar in terms of adverse effects, actions and efficacy. Dose-related dizziness and sedation are adverse effects of both that can be ameliorated by starting with low doses and titrating cautiously.²⁰ Both require dose reduction in patients with renal insufficiency.¹⁵

Opioids

A number of studies have confirmed the efficacy of opioids in patients with postherpetic neuralgia.^18,21 In one study, treatment with morphine, methadone or TCADs (desimipramine or nortriptyline) for eight weeks was significantly better than placebo, with a trend towards greater pain relief with opioids and more patients preferring opioids over TCADs.²¹ The use of opioids is associated with fewest cardiac adverse effects and they may also help with any associated sleep disturbance. As with all agents used in the management of postherpetic neuralgia, the response to opioids may be incomplete and the extent to which pain responds varies, depending on both patient and pain characteristics.²² Common opioid adverse effects include constipation, nausea and sedation. Initiating treatment with low doses and titrating gradually can reduce nausea and sedation. Individualised dose titration must be employed. 

Tramadol, an atypical opioid analgesic, has also been shown to improve pain in postherpetic neuralgia.²³

Topical agents

The topical application of capsaicin, a natural chemical isolated from red peppers, appears to be effective in the management of postherpetic neuralgia.^14,24 One study showed a 21% reduction in pain scores in those receiving capsaicin when applied four times per day, versus a 6% reduction in those receiving placebo.²⁵ Capsaicin can cause burning, stinging and erythema, which can be intolerable to a number of patients. Mixing the capsaicin with EMLA cream or GTN paste may help. Topical 5% lidocaine, a local anaesthetic agent applied as a patch, has also been shown to be effective in the management of postherpetic neuralgia and allodynia.^26,27 The patch is applied to the area over which the pain is experienced, in a 12 hours on, 12 hours off regimen. Given the low systemic drug exposure, adverse events with topical agents are generally limited to application-site reactions. Adverse effects are frequently mild and transient with topical lidocaine, but may involve treatment-limiting discomfort with capsaicin. Lidocaine 5% gel is also effective in postherpetic neuralgia and allodynia.^26,27 Other topical agents that can be applied for the treatment of postherpetic neuralgia are currently under review with promising results.

Combination therapy

In randomised controlled trials assessing efficacious medications for neuropathic pain, typically less than 50% of patients experience satisfactory pain relief.²⁰ Burdensome adverse effects (including inability to tolerate treatment) are also common.^¹⁵ Monotherapy may be desirable for both ease of administration and reduction of potential adverse effects, but this approach may not achieve satisfactory analgesic control. A combination of medications may provide greater analgesia than monotherapy. The combination of two or more agents with different mechanisms of action at lower doses to achieve synergistic pain efficacy is not uncommon. Involvement of clinicians with expertise and experience in postherpetic neuralgia is prudent. In particular, it is important to screen patients for risk of addiction and drug diversion, agree treatment plans and goals, monitor usage regularly and be vigilant for problems.

Non-pharmacological options

General measures such as loose-fitting clothing may help to reduce the irritation of the affected area. Ice cubes wrapped in a plastic bag or having a cool bath may also aid in cooling the affected area. Non-drug options, including transcutaneous electrical nerve stimulation (TENS) and acupuncture, have also been evaluated in postherpetic neuralgia and are reported to be effective.²⁸

Prevention of herpes zoster and postherpetic neuralgia

Of late, much research has been conducted on the use of a vaccine against herpes zoster.^29,30 Recent evidence suggests that among immunocompetent adults aged 60 years and older, receipt of the herpes zoster vaccine is associated with a lower incidence of herpes zoster.^³⁰ Evidence has also suggested lower incidence of postherpetic neuralgia following vaccination.²⁹ The vaccine is not recommended for immunocompromised individuals.³¹

Conclusion

Herpes zoster and postherpetic neuralgia are common conditions, particularly in older people and immunocompromised patients. The treatment of postherpetic neuralgia can be challenging. Symptom control is often unsatisfactory in a proportion of patients, especially those with many comorbidities and intense pain at herpes zoster presentation. Therapeutic options have improved over recent years, presenting the clinician with many treatment choices. 

Many patients respond to medications, such as TCADs, anticonvulsants, opioid analgesics, which can be prescribed to reduce the pain. Effective management of postherpetic neuralgia may require several trials, using combinations of different types of analgesics before effective pain relief can be achieved. Further research into newer treatment options for postherpetic neuralgia is warranted.

References

1. Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and postherpetic neuralgia. Am Fam Physician 2000; 61(8): 2437-44: 47-48
2. Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70(18): 1630-1635
3. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996; 67(2-3): 241-51
4. Johnson RW, Bouhassira D, Kassianos G et al. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med 2010; 8: 37
5. Drolet M, Brisson M, Schmader KE et al. The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. CMAJ 2010; 182(16): 1731-1736
6. Christo PJ, Hobelmann G, Maine DN. Post-herpetic neuralgia in older adults: evidence-based approaches to clinical management. Drugs Aging 2007; 24(1):1-19
7. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004; 62(9): 1545-1551
8. Scott FT, Leedham-Green ME, Barrett-Muir WY et al. A study of shingles and the development of postherpetic neuralgia in East London. J Med Virol 2003; 70 Suppl 1: S24-S30
9. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment. Neurology 1995; 45(12 Suppl 8): S56-S57
10. Beutner KR, Friedman DJ, Forszpaniak C et al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39(7): 1546-1553
11. Tyring SK, Beutner KR, Tucker BA et al. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 2000; 9(9): 863-869
12. Wood MJ, Johnson RW, McKendrick MW et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994 Mar 31; 330(13): 896-900
13. 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(6): 327-331
14. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. J Fam Pract 2002; 51(2): 121-128
15. Dworkin RH, O’Connor AB, Audette J et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010; 85(3 Suppl): S3-S14
16. Wu CL, Raja SN. An update on the treatment of postherpetic neuralgia. J Pain 2008; 9(1 Suppl 1): S19-S30
17. Sampathkumar P, Drage LA, Martin DP. Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clin Proc 2009; 84(3): 274-280
18. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology  1991; 41(7): 1024-1028
19. Sabatowski R, Galvez R, Cherry DA et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004; 109(1-2): 26-35
20. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009; 122(10 Suppl): S22-S32
21. Raja SN, Haythornthwaite JA, Pappagallo M et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002; 59(7): 1015-1021
22. Watson CP, Watt-Watson JH, Chipman ML. Chronic noncancer pain and the long term utility of opioids. Pain Res Manag 2004; 9(1): 19-24
23. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain 2003; 104(1-2): 323-331
24. Bernstein JE, Korman NJ et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21(2 Pt 1): 265-270
25. Watson CP, Evans RJ, Watt VR. Post-herpetic neuralgia and topical capsaicin. Pain 1988; 33(3):333-340
26. Dworkin RH, O’Connor AB, Backonja M et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132(3) 237-251
27. Finnerup NB, Otto M, McQuay HJ et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005; 118(3): 289-305
28. Wareham DW, Breuer J. Herpes zoster. BMJ 2007; 334(7605): 1211-5
29. Oxman MN, Levin MJ, Johnson GR et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352(22): 2271-2284
30. Tseng HF, Smith N et al. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA 2011; 305(2): 160-6
31. Kimberlin DW, Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 2007; 356(13): 1338-1343