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Corticosteroids for preventing postherpetic neuralgia

  1. Ying Han1,*,
  2. Jingjing Zhang2,
  3. Ning Chen2,
  4. Li He2,
  5. Muke Zhou2,
  6. Cairong Zhu3

Editorial Group: Cochrane Neuromuscular Disease Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 16 APR 2012

DOI: 10.1002/14651858.CD005582.pub4


How to Cite

Han Y, Zhang J, Chen N, He L, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD005582. DOI: 10.1002/14651858.CD005582.pub4.

Author Information

  1. 1

    Xuanwu Hospital, Capital Medical University, Department of Neurology, Beijing, China

  2. 2

    West China Hospital, Sichuan University, Department of Neurology, Chengdu, Sichuan, China

  3. 3

    School of Public Health, Sichuan University, Epidemic Disease & Health Statistics Department, Sichuan, Chengdu, China

*Ying Han, Department of Neurology, Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China. sophiehanying@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 MAR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Clemmensen 1984

MethodsSingle centre RCT, double-blind, placebo-controlled, parallel-group study (methods not described).


Participants60 patients (33 males and 22 females) within 7 days of onset of HZ.

Age range: 16 to 86 years, 33 were 55 years or older. Among them 20 participants received intramuscular ACTH (Synacthen depot). 5 participants dropped out.

Exclusion criteria: (1) duration of symptoms (pain and/or cutaneous signs) beyond 7 days; (2) age under 16 years; (3) generalised HZ (more than 50 vesicles outside the affected dermatome); (4) history of, or current, malignant disease; (5) treatment with cytostatics and corticosteroids; (6) history or findings of peptic ulcer, psychosis, cardiac decompensation, hypertension, diabetes mellitus, adrenocortical disease or with symptoms of osteoporosis; (7) pregnancy.


InterventionsACTH: ACTH depot 1 mg intramuscularly 3 times a week (Monday, Wednesday, Friday) amounting to a total of 7 injections.
Prednisone: orally, 45 mg daily during the 1st week, 30 mg daily during the 2nd week, and 15 mg daily tapered to zero during the 3rd week.
Comparison treatment: placebo.


OutcomesPrimary outcome (mean duration of PHN: 4.2 months, which ranged from 1.5 to 10 months) and secondary outcomes (serious adverse events and non-serious adverse events) were available.


NotesConducted in Denmark


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomisation was not described.

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was stated that a "double-dummy" administration technique was used: matched oral and/or parenteral placebo was given to each participant. Placebo tablets or injections indistinguishable from the active medication.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Double-dummy" administration technique.

Incomplete outcome data (attrition bias)
All outcomes
Low risk5 participants dropped out, 1 in the prednisone group (because of increasing blood sugar), 1 in the placebo group (discontinued by the participant without specific reason), 3 in the ACTH group (2 participants developed uncomfortable dizziness and 1 participant moderate periorbital oedema).

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.

Other biasLow riskNo other potential bias was found.

Eaglstein 1970

MethodsSingle centre, randomised, double-blind, placebo-controlled parallel design.


Participants35 patients with early, severely painful HZ admitted to the dermatology inpatient service.

Age: from 21 to 91 years, 24 of them older than 59 years of age. One participant dropped out.
Exclusion criteria: hypertension, tuberculosis, lymphoma, leukaemia, bleeding peptic ulcers, diabetes, cardiac disease, or bacterial infections.


InterventionsUnmarked red capsules containing either 8 mg of triamcinolone or lactose, 2 capsules 3 times daily (48 mg/day) for 7 days, and 1 capsule 3 times daily (24 mg/day) for 7 days, and 1 capsule twice daily (16 mg/day) for 7 days.


OutcomesPrimary outcome (the presence of PHN six months after the onset of the acute herpetic rash) and secondary outcomes (serious adverse events and non-serious adverse events) were available.


NotesConducted in Miami, USA dermatology inpatient service


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers were used; each patient was assigned a different code number and distributed to a group in a random fashion.

Allocation concealment (selection bias)Low riskThe code for each participant was opened after a 3-year follow-up and evaluation.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were treated with unmarked red capsules prepared by the hospital pharmacy.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnmarked red capsules were prepared by the hospital pharmacy. Comment: a double-blind method was probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly one participant in the control group dropped out after five days because of a sudden increase in her BP.

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.

Other biasLow riskNo other potential bias was found.

Esmann 1987

MethodsMulticentre randomised, double-blind, placebo-controlled parallel design. Number of losses to follow up: all participants were evaluated at week 26 except for one from the prednisolone group, who was last seen at week 10. She had not had pain since day 5.


Participants84 patients (25 males and 53 females) within 4 days of onset of HZ.

Age at least 60 years, mean age: intervention group 72.8 years (SD 7.5); control group 71.4 (SD 8.1).
Exclusion criteria: immunocompromise, pituitary or adrenal dysfunction, diastolic BP > 105 mm Hg on entry day, signs of cardiac insufficiency, insulin dependent diabetes, bacterial infections, bleeding peptic ulcers, severe mental confusion, serum creatinine 150 mmol, receiving corticosteroid treatment.


Interventions800 mg aciclovir orally 5 times daily for 7 days and coded tablets containing either prednisolone or calcium lactate for 21 days. The dose of prednisolone was 40 mg daily for 7 days, 30 mg for 4 days, 20 mg for 3 days, 10 mg for 4 days, and finally 5 mg for 3 days.


OutcomesThe primary outcome (the presence of PHN six months after the onset of the acute herpetic rash) and secondary outcomes (serious adverse events and non-serious adverse events) were available.


NotesConducted in Aarhus and Copenhagen, Denmark


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomisation was not described.

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe trial report stated that double-blind method was used, and all participants were given coded tablets containing either prednisolone or calcium lactate.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind method was used.

Incomplete outcome data (attrition bias)
All outcomes
High riskSix participants were withdrawn, either because the inclusion criteria could not be upheld upon subsequent scrutiny or because of lack of compliance during the first 1-2 weeks. One of the six participants dropped out because of a possible side effect of prednisolone, and she could be included in the intention-to-treat analysis. But whether the lack of compliance of the other participants was due to inefficacy or side effects, and which group those five participants were firstly assigned to, were not specified.

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.

Other biasLow riskNo other potential bias was found.

Whitley 1996

MethodsMulticentre randomised, double-blind, placebo-controlled parallel study with a 2 x 2 factorial design.


Participants208 immunocompetent patients older than 50 years of age who had localised herpes zoster that developed less than 72 hours before study enrolment. Five randomly assigned participants were not included in this analysis because they never received study medication; no case record forms were submitted. Two other participants were proven to have herpes simplex virus infection and were not included in the analysis.

Of the 201 participants included in the analysis, 51 received aciclovir plus prednisone (24 males and 27 females, mean age 63), 48 received aciclovir plus prednisone placebo (21 males and 27 females, mean age 62), 50 received prednisone plus aciclovir placebo (26 males and 24 females, mean age 60), and 52 received aciclovir and prednisone placebo (25 males and 27 females, mean age 61). 32 participants were lost to follow-up.
Exclusion criteria: immunosuppressive therapy; cancer; women capable of conceiving and bearing a child; history of hypertension (diastolic BP >100 mm Hg) or receiving antihypertensive therapy; osteoporosis or insulin-dependent diabetes mellitus; receipt of other antiviral drugs or immunoglobulin products in the 4 weeks before the study began; history of glycosuria or hyperglycaemia.


InterventionsPrednisone or a matched placebo orally 60 mg/d for days 1 to 7, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21.

Aciclovir or a matched placebo orally as 800 mg 5 x daily, for 21 days. The four treatments regimens were aciclovir plus prednisone, aciclovir plus prednisone placebo, prednisone plus aciclovir placebo, and placebos for both aciclovir and prednisone.


OutcomesThe primary outcome (six-month evaluation of pain (time to cessation of zoster-associated pain)) and secondary outcomes (one-month evaluation of quality of life; serious adverse events and non-serious adverse events) were available.


NotesConducted in 15 university hospitals or affiliated clinics in USA.
Participants discontinued therapy because of influenza, conjunctivitis or iritis, nausea and vomiting, complete resolution of disease, cutaneous dissemination, hyperglycaemia, and bacterial pneumonia.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated randomisation code randomised participants to one of the four treatment groups.

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll research personnel remained blinded to drug assignment until the study was completed and the database was locked. All matched medications were identical in taste and appearance.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll research personnel remained blinded to drug assignment until the study was completed and the database was locked.

Incomplete outcome data (attrition bias)
All outcomes
Low risk32 participants dropped out: 7/51 in the aciclovir plus prednisone group, 6/48 in the aciclovir plus prednisone placebo group, 9/50 in the prednisone plus aciclovir placebo group, and 10/52 in the wholly placebo-treated group. Missing data were equal among the treatment groups, and an intention-to-treat analysis was performed.

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.

Other biasLow riskNo other potential bias was found.

Wood 1994a

MethodsMulticentre randomised, double-blind, placebo-controlled parallel study. Losses to follow up: 2 participants in 7-day aciclovir with corticosteroids; 3 participants in 7-day aciclovir without corticosteroids; 2 participants in 21-day aciclovir with corticosteroids; 3 participants in 21-day aciclovir without corticosteroids.


ParticipantsAdults over 18 years of age without immune dysfunction due to cancer or immunosuppressive therapy, who presented with a clinical diagnosis of HZ as confirmed by one of the investigators and had a rash for 72 hours or less and at least moderate pain.

400 participants enrolled and assigned to 4 groups:

aciclovir for 7 days with corticosteroids (99 participants, 37 males and 62 females, mean age 59); aciclovir for 7 days without corticosteroids (101 participants, 39 males and 62 females, mean age 58); aciclovir for 21 days with corticosteroid (99 participants, 39 males and 60 females, mean age 60); aciclovir for 21 days without corticosteroid (101 participants, 38 males and 63 females, mean age 59).

51 participants were withdrawn.
Exclusion criteria: pregnant women and women of childbearing potential who were not adequately protected by contraception; renal insufficiency (serum creatinine concentration, more than 1.8 mg per dL), hypertension (diastolic BP >110 mmHg), insulin-dependent diabetes, or random blood glucose > 216 mg/dL (12 mmol/L); history of peptic ulceration, severe psoriasis, or hypersensitivity to aciclovir; and patients receiving barbiturates, anticonvulsant drugs, systemic corticosteroids, rifampicin, or specific antiviral therapy for the present infection.


InterventionsAciclovir (800 mg orally) five times daily, beginning on day 0. The participants in the groups assigned to 7 days of aciclovir therapy (with or without corticosteroid) received matching placebo beginning on day 7.

Prednisolone (5 mg tablets) according to the following schedule: on days 0 to 6, 40 mg per day; days 7 to 10, 30 mg per day; days 11 to 14, 20 mg per day; days 15 to 18,10 mg per day; and days 19 to 21, 5 mg per day (total dose 535 mg).


OutcomesThe primary outcome (up to month six to assess PHN, and time to complete cessation of pain) and secondary outcomes (serious adverse events and non-serious adverse events) were available.


NotesConducted in 4 clinical centres in the United Kingdom.
51 participants were withdrawn:
14 in aciclovir for 7 days with corticosteroid group, 10 in aciclovir for 7 days without corticosteroid group, 13 in aciclovir for 21 days with corticosteroid group, 14 in aciclovir for 21 days without corticosteroid group.
Reasons were deviation from protocol, adverse events, loss to follow-up, no reason given, and death.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated randomisation code was used.

Allocation concealment (selection bias)Low riskThe randomisation code was stratified by study centre to assigned participants in blocks of eight to either group; it indicated that allocation concealment might be performed.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was stated that it was a double-blind study, and the participants in the groups not receiving corticosteroid received matching placebo tablets.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind method was used.

Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals of participants and the reasons were balanced equally across all groups.

Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported.

Other biasLow riskNo other potential bias was found.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Benoldi 1991RCT, but the control group was treated with carbamazepine.

Brusco 1993Confirmed not a true RCT.

Chang 2004PHN was defined as pain persisting at the site of shingles two weeks after the onset of acute rash.

Cui 2002Confirmed not truly randomised by contacting the study author.

Guo 2001The routine treatments were mismatched between two groups.

Hao 2002Confirmed not truly randomised by contact with study author.

Huang 2004Confirmed not truly randomised by contacting study author.

Huang 2010Confirmed not a true RCT.

Jiang 2005The routine treatments were mismatched between two groups.

Jiang 2008Confirmed not a true RCT, and the duration of herpes zoster was not specified.

Keczkes 1980The control group was treated with carbamazepine.

Li 2000Confirmed not a true RCT.

Li 2002Confirmed not truly randomised by contact with study author.

Liao 2005PHN was defined as pain persisting one week after total decrustation.

Lin 2002This trial exceeded our seven days to treatment criterion.

Lin 2005Confirmed not truly randomised by contact with study author.

Liu 2003PHN was defined as pain persisting at the site of shingles two weeks after the onset of acute rash.

Liu 2005PHN was defined as pain persisting at the site of shingles two weeks after the onset of acute rash.

Ma 2000Confirmed not a true RCT.

Ma 2002Confirmed not truly randomised by contacting study author.

Shi 2008Confirmed not a true RCT.

Song 2009Confirmed not a true RCT.

Tang 2004Confirmed not truly randomised by contacting study author.

Wang 2004This trial exceeded our seven days to treatment criterion.

Xu 1999This trial exceeded our seven days to treatment criterion.

Yang 2000The routine treatments were mismatched between two groups.

Yang 2002PHN was defined as pain persisting at the site of shingles two weeks after the onset of acute rash.

Yang 2010Confirmed not a true RCT, and PHN was not clearly defined. The duration of herpes of some participants was longer than seven days after the rash onset.

Yin 2004The routine treatments were mismatched between two groups.

Yin 2005The routine treatments were mismatched between two groups.

Zeng 2011Confirmed not a true RCT.

Zhang 2003Confirmed not truly randomised by contacting study author.

Zhang 2004The routine treatments were mismatched between two groups.

Zhang 2005This trial exceeded our seven days to treatment criterion.

Zheng 2004The routine treatments were mismatched between two groups.

Zhou 2000Confirmed not truly randomised by contacting study author.

Zhou 2008Not a true RCT.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Hu 2001

MethodsSingle centre, randomised controlled parallel trial.

Participants45 patients with confirmed herpes zoster and without contraindications to glucocorticosteroids were enrolled. They were randomly assigned to the aciclovir plus dexamethasone group (20 participants) or the aciclovir alone group (25 participants).

InterventionsIn the aciclovir plus dexamethasone group, participants were given 0.25 g aciclovir intravenously every 8 hours for a total of 10 days, and 5 mg dexamethasone intravenously daily. In the control group, aciclovir alone was administered in the same way as with the other group.

OutcomesTime to cessation of new herpes eruption, time to crusting, and the presence of PHN at one month after the rash onset.

NotesThe exact course of disease from onset of herpes zoster to receipt of treatment was not specified. We tried to contact the author, but have not yet received a reply.

 
Comparison 1. Corticosteroids versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 The presence of PHN six months after the onset of the acute herpetic rash2114Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.45, 1.99]

 2 The main effect of prednisone compared with no prednisone on six months evaluation of pain (generic inverse variance)1RR Ratios (Fixed, 95% CI)Totals not selected

 3 Serious adverse events5755Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.51, 5.29]

 4 Non-serious adverse events5755Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.90, 1.87]

 
Comparison 2. Subgroup analysis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 The presence of PHN six months after the onset of the acute herpetic rash2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Adults aged 50 years or more
2107Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.47, 2.04]

    1.2 Adults 49 years of age or less
16Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Corticosteroids for acute herpes zoster to prevent postherpetic neuralgia

Corticosteroids for acute herpes zoster to prevent postherpetic neuralgia

Patient or population: patients with acute herpes zoster to prevent postherpetic neuralgia
Settings: hospitals and clinics
Intervention: corticosteroids

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlCorticosteroids

Presence of PHN six months after the onset of the acute herpetic rash
Clinical manifestation
Follow-up: 6-23 months
193 per 1000183 per 1000
(87 to 384)
RR 0.95
(0.45 to 1.99)
114
(2 studies)
⊕⊕⊕⊝
moderate1

Serious adverse events
Clinical manifestation and laboratory examination
Follow-up: 6-23 months
8 per 100013 per 1000
(3 to 42)
RR 1.65
(0.38 to 5.29)
755
(5 studies)
⊕⊕⊕⊝
moderate1

Non-serious adverse events
Clinical manifestation and laboratory examination
Follow-up: 6-23 months
113 per 1000147 per 1000
(102 to 211)
RR 1.30
(0.9 to 1.87)
755
(5 studies)
⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 There is a high risk of bias due to inadequately addressed incomplete outcome data of the Esmann 1987 trial, in which six participants were withdrawn, but the reasons and assigned groups of five cases were not specified.