Eur Arch Otorhinolaryngol (2016) 273:3083–3090

DOI 10.1007/s00405-016-3927-3

OTOLOGY

Comparison of acyclovir and famciclovir for the treatment

of Bell’s palsy
Ho Joong Kim1 • Sang Hoon Kim1 • Junyang Jung2 • Sung Su Kim3 •

Jae Yong Byun1 • Moon Suh Park1 • Seung Geun Yeo1

Received: 23 August 2015 / Accepted: 4 February 2016 / Published online: 12 February 2016
Ó Springer-Verlag Berlin Heidelberg 2016

Abstract The relative effectiveness of acyclovir and effective than treatment with steroid plus acyclovir in
famciclovir in the treatment of Bell’s palsy is unclear. This patients with severe facial palsy. Famciclovir may be the
study therefore compared recovery outcomes in patients antiviral agent of choice in the treatment of patients with
with Bell’s palsy treated with acyclovir and famciclovir. severe facial palsy.
The study cohort consisted of patients with facial palsy
who visited the outpatient clinic between January 2006 and Keywords Bell’s palsy
Steroid
Acyclovir

January 2014. Patients were treated with prednisolone plus Famciclovir
Electroneurography
either acyclovir (n = 457) or famciclovir (n = 245).
Patient outcomes were measured using the House-Brack-
mann scale according to initial severity of disease and Introduction
underlying disease. The overall recovery rate tended to be
higher in the famciclovir than in the acyclovir group. The Bell’s palsy is the most common cranial nerve lesion, with
rate of recovery in patients with initially severe facial palsy an annual incidence of 20 per 100,000 individuals [1]. Its
(grades V and VI) was significantly higher in the famci- causes remain unknown, although many studies have sug-
clovir than in the acyclovir group (p = 0.01), whereas the gested that viral infection is primarily responsible. For
rates of recovery in patients with initially moderate palsy example, herpes simplex virus (HSV) has been detected in
(grade III–IV) were similar in the two groups. The overall human geniculate ganglions and the HSV genome in
recovery rates in patients without hypertension or diabetes endoneural fluid of patients with Bell’s palsy, strongly
mellitus were higher in the famciclovir than in the acy- suggesting that HSV infection can cause Bell’s palsy [2, 3].
clovir group, but the difference was not statistically sig- The mechanism by which HSV infection can cause neu-
nificant. Treatment with steroid plus famciclovir was more ropathy may start with cytotoxic edema caused by neuronal
inflammation [4, 5]. Ischemia may result from obstructing
the microcirculation, followed by neural edema in the
H. J. Kim and S. H. Kim contributed equally to this work. narrow fallopian canal [6]. These hypotheses have led to
& Seung Geun Yeo
the treatment of these patients with corticosteroids and/or
yeo2park@gmail.com antiviral agents. Corticosteroids have been shown effective
in the treatment of Bell‘s palsy and are administered to all
1
Department of Otohinolaryngology, H & N Surgery, School patients with this condition [7]. Many studies and Cochrane
of Medicine, Kyung Hee University, #1 Hoegi-dong,
Dongdaemun-gu, Seoul 130-702, Korea
reviews analyzing the efficacy of antiviral agents in Bell’s
2
palsy have concluded that there is no benefit from the
Department of Anatomy, School of Medicine, Kyung Hee
combination of antivirals with corticosteroids when com-
University, Seoul, Korea
3
pared with corticosteroids alone or placebo [8].
Department of Biochemistry and Molecular Biology, Medical
More recently, however, the combination of a steroid
Science and Engineering Research Center for Bioreaction to
Reactive Oxygen Species, BK-21, School of Medicine, with an antiviral agent has been reported to be more
Kyung Hee University, Seoul 130-701, Korea effective than steroid therapy alone in the treatment of

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patients with Bell’s palsy [1, 9]. Three antiviral agents are paralysis plus gross asymmetry at rest). HB grade B2 was
available for these patients, with acyclovir being the most defined as a good outcome or complete recovery and
frequently used, although famciclovir and valacyclovir grade [2 as incomplete recovery. The degree of recovery
have been tested in various clinical trials. Famciclovir has of facial paralysis was assessed through 6 months [12].
several important advantages in virostatic therapy, includ- Patients were assessed by electroneurography (ENoG;
ing excellent oral bioavailability and a longer intracellular Nicolet Viking Select; Madison, WI, USA) 5–14 days after
half-life of its active metabolite than acyclovir in cells the onset of facial weakness, with all evaluations per-
infected with varicella zoster virus (VZV) [9, 10]. Less is formed by a single highly experienced examiner. ENoG
known about the comparative effectiveness of these anti- was performed first on the healthy side and subsequently
viral agents in patients with Bell’s palsy. This clinical trial on the affected side. The facial nerve in the area around the
therefore compared the therapeutic effects of famciclovir stylomastoid foramen was stimulated with a bipolar surface
and acyclovir in patients with Bell’s palsy. electrode, and compound muscle action potential was
measured. ENoG results were reported as the maximal
amplitude of the affected site divided by the maximal
Materials and methods amplitude of a healthy site (%).

The study cohort consisted of patients with facial palsy Statistical analysis
who visited the outpatient clinic of the Department of
Otolaryngology at Kyung Hee Medical Center between Groups were compared using the Chi square test and meta-
January 2006 and January 2014. Bell’s palsy was diag- analysis, as applicable. All statistical analyses were per-
nosed when the facial paralysis was peripheral, and no formed using SPSS (18.0, SPSS Inc, Chicago IL), with
obvious cause was identified in the patient’s medical his- statistical significance defined as a p value \0.05. A ran-
tory, or during physical, serologic or radiologic examina- dom effects meta-analysis was performed to obtain a
tions. Exclusion criteria included presentation [7 days combined estimate for the success rate and to calculate the
after onset of symptoms, lack of knowledge of previous odds ratios for the effects of treatment.
medications, traumatic facial palsy, postsurgical facial
palsy, presence of definite neurologic diseases, middle ear
diseases or a defined lesion on the cerebellopontine angle Results
or central nervous system by brain MRI and temporal MRI/
temporal bone CT. The study protocol was approved by our Of the 702 patients with facial palsy included in the study;
Institutional Review Board, with all patients providing 457 were treated with acyclovir and 245 with famciclovir.
written informed consent. The acyclovir group consisted of 212 males (46.4 %) and
Baseline and follow-up demographic and clinical data, 245 females (53.6 %), whereas the famciclovir group
including diagnoses of hypertension and diabetes mellitus, consisted of 110 males (44.8 %) and 135 females (55.2 %).
were obtained by reviewing patients’ medical histories. All Mean initial HB grade at admission was 3.67 ± 0.99 in the
patients were treated with oral prednisolone plus either fam- acyclovir group and 3.53 ± 0.97 in the famciclovir group
ciclovir or acyclovir. Prednisolone was administered for (p = 0.14), and final HB grades 6 months after treatment
12 days, 80 mg/day for the first 4 days, 60 mg/day on days 5 were 1.92 ± 1.21 and 1.70 ± 0.70, respectively. ENoG
and 6, 40 mg/day on days 7 and 8, 20 mg/day on days 9 and results in the two groups showed no difference in the ratio
10, and 10 mg/day on days 11 and 12. Children, adolescents, of peak-to-peak amplitudes on the affected relative to the
and low-weight adults were started at a dose of 1 mg/kg/day, unaffected side. The two groups included 336 (73.5 %) and
with doses proportionately tapered as above. Patients were 184 (75.1 %) patients without diabetes or hypertension,
also treated with acyclovir (1000–2400 mg/day) for 5 days or respectively; 88 (19.2 %) and 44 (17.9 %), respectively,
famciclovir (750 mg/day) for 7 days. with hypertension alone; 47 (10.2 %) and 34 (13.8 %),
Initial and final facial nerve function was reported using respectively, with diabetes alone; and 14 (3.06 %) and 17
the House-Brackmann (HB) scale [11], which categorizes (6.9 %), respectively, with both conditions (Table 1).
patients based on the degree of facial function under sev- Severe facial palsy (HB grade C5) was observed in 85
eral conditions (at rest, forehead wrinkling with maximal patients (20.8 %) in the acyclovir and 47 (19.9 %) in the
effort, eye closure with maximal effort, and raising mouth famciclovir group. HB grading after 6 months showed that
angle with maximal effort). The HB grading system assigns 371 patients (81.1 %) in the acyclovir group and 209
facial function to six categories, ranging from grade I (85.3 %) in the famciclovir group had achieved complete
(normal function in all facial areas), to grade VI (complete remission.

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Table 1 Baseline
Total patients Steroid ? acyclovir Steroid ? famciclovir p value
characteristics and outcome
measurements of patients with No. of patients (%) 702 457 (65.0 %) 245 (35.0 %) –
Bell’s palsy
Age 48.8 ± 15.5 50.8 ± 19.5 47.2 ± 18.3
Male:female 322:380 212:245 110:135
(%) (45.8:54.2) (46.3:53.7) (44.8:55.2)
Initial H-B grade 3.54 ± 0.97 3.67 ± 0.99 3.53 ± 0.97 0.248
Final H-B grade 1.86 ± 1.07 1.92 ± 1.21 1.70 ± 0.70 0.215
Electroneurography
ENoG C10 % (%) 645 (91.8 %) 413 (90.4 %) 226 (92.2 %) 0.157
ENoG \10 % (%) 57 (8.11 %) 44 (9.6 %) 19 (7.8 %) 0.185
No number, H-B grade House-Brackmanngrade, ENoG electroneurography, HTN hypertension, DM dia-
betes mellitus

Of patients with mild to moderate facial palsy (HB Discussion

grade B4), 310 (83.3 %) in the acyclovir and 172 (86.8 %)
in the famciclovir group recovered completely To date, there is no consensus about the definitive treat-
(p = 0.072). In contrast, recovery from severe facial palsy ment for patients with idiopathic facial palsy, especially
(HB grade C5) was observed in 61 (71.7 %) patients in the Bell’s palsy, owing to the high spontaneous recovery rate
acyclovir and 37 (78.7 %) in the famciclovir group and unknown etiologic factors. In about 15 % of patients
(p = 0.01) (Table 2). with Bell’s palsy, however, some degree of muscle weak-
Evaluation of patients with hypertension showed that 64 ness remains; in some individuals, this weakness can per-
(86.5 %) in the acyclovir group and 23 (85.2 %) in the manently change the functioning of facial muscles and
famciclovir group recovered completely (p = 0.34). Of affect the appearance of the person’s face. Thus, proper
patients with diabetes, 27 (81.8 %) in the acyclovir and 14 treatment is important for these patients.
(82.4 %) in the famciclovir group recovered completely Viruses such as VZV and the Epstein-Barr virus (EBV),
(p = 0.65). Assessment of patients with both hypertension both herpes viruses, are thought to establish a persistent or
and diabetes showed that 11 (78.5 %) in the acyclovir and latent infection without symptoms in some individuals.
13 (76.5 %) in the famciclovir group recovered completely Reactivation of an existing or dormant viral infection may
(p = 0.75), whereas, of patients without hypertension and therefore cause acute Bell’s palsy [3]. Antiviral agents are
diabetes, 270 (80.3 %) and 159 (86.4 %), respectively, therefore prescribed for these patients, although combina-
recovered completely (p = 0.21) Thus therapeutic results tions of antiviral agents and steroids are relatively inef-
were not affected by the presence or absence of hyper- fective in patients with new-onset Bell’s palsy, improving
tension and diabetes (Table 3). facial function recovery \7 % [7]. The antiviral agents

Table 2 Comparison of
Initial severity Steroid ? acyclovir Steroid ? famciclovir p value
recovery rates in patients with
Bell’s palsy according to initial Mild to moderate 310/372 (83.3 %) 172/198 (86.8 %) 0.072
severity
Severe 61/85 (71.7 %) 37/47 (78.7 %) 0.01*
Total 371/457 (81.1 %) 209/245 (85.3 %) 0.176
* p \ 0.05

Table 3 Recovery rates in

Complete recovery
Bell’s palsy patientsaccording
to underlying disease Steroid ? acyclovir Steroid ? famciclovir p value

Hypertension (HTN) 64/74 (86.5) 23/27 (85.2) 0.34

Diabetes mellitus (DM) 27/33 (81.8) 14/17 (82.4) 0.65
HTN ? DM 11/14 (78.5) 13/17 (76.5) 0.75
None 269/336 (80.1) 158/184 (85.9) 0.16
Total 371/457 (81.2) 209/245 (85.3) 0.21

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acyclovir, famciclovir, and valaciclovir have been used to prednisolone and placebo, although a similar study found
treat patients with Bell’s palsy, particularly those at high no difference between these two treatment regimens [12,
risk of herpes zoster infection. Our study compared the 26, 28, 29] (Table 4; Fig. 1).
therapeutic effects of acyclovir and famciclovir, finding Age has been reported to significantly influence final
significantly better outcomes with famciclovir in patients recovery [30], with increased age thought to reduce the
with idiopathic severe facial palsy. Recovery rates were not likelihood of satisfactory recovery because of peripheral
affected by the co-occurrence of hypertension and/or dia- vascular degeneration [31]. In contrast, another study
betes mellitus. reported that age [50 years did not significantly influence
Many antiviral agents are unable to destroy viruses the long-term prognosis of patients with Bell’s palsy [32],
that have already replicated, because these drugs prevent with a trend test showing no significant correlation between
viral replication by interfering with viral DNA poly- age and recovery [33]. In this study, there was no differ-
merase. Thus, antiviral agents, such as acyclovir, fam- ence in age between the two groups.
ciclovir and valacyclovir, must be taken early during the ENoG is a neurophysiologic method used to evaluate the
course of the disease [13–15]. Combination therapy with degree of injury to facial nerves and to predict patient
a steroid plus acyclovir showed better outcomes than prognosis. It can accurately compare the palsied and nor-
oral steroid therapy alone [15–18]. Outcomes are mal sides and uses low electric current, thereby enhancing
dependent on the antiviral agent, its dosage, its time patient compliance. Although about 98 % of patients with
relative to the onset of the disease, and the duration of ENoG [25 % on the palsied side within 10 days of
therapy. Acyclovir has low oral bioavailability of 20 % symptom onset have been reported to recover [34], other
and must be administered five times per day, reducing studies have found that this may be an overestimate [35].
patient compliance [19]. The systemic availability of Our study found similar rates of ENoG \10 % after onset
acyclovir, already low in the fasted state, is further of symptoms in the acyclovir and famciclovir groups (9.6
compromised if taken with food. Even if study patients vs. 7.8 %).
are well instructed, the correct administration is difficult The effects of diabetes and hypertension on the fre-
to monitor. Valaciclovir is a prodrug of acyclovir and quency of Bell’s palsy are unclear. Hypertension has been
has a higher bioavailability (54 %) than orally adminis- reported to improve the prognosis of these patients [36],
tered acyclovir [20]. Famciclovir, the most recent acy- although another study found that hypertension had no
clovir analogue, exhibits excellent oral bioavailability effect on prognosis [33]. Similarly, diabetes has been
(60–75 %) and is not affected by concurrent food intake. reported to be unrelated to the prognosis of patients with
Its active metabolite, penciclovir triphosphate, has a Bell’s palsy [37], whereas other studies have found that
much longer intracellular half-life in VZV-infected cells diabetes worsens prognosis [38, 39]. The percentage of
than acyclovir. Therefore, famciclovir offers important diabetics among patients with Bell palsy is similar to the
advantages in virostatic therapy [21, 22]. percentage in the general population [40–42]. We therefore
It is known that Bell’s palsy is also caused by various investigated the effects of acyclovir and famciclovir on
virus such as Herpes simplex, Epstein-Barr virus, cyto- recovery rates in patients with and without hypertension
megalovirus, or Varicella zoster virus. Recent study and/or diabetes. Recovery rates differed in patients with
showed a high value of HHV-6 DNA in saliva of Bell’s hypertension and diabetes who received combination
palsy patients [23]. There are many types of viruses that therapy. These rates were slightly higher in patients with-
caused Bell’s palsy. The antiviral activity could be differ- out than with hypertension, although the difference was not
ent according to the type of virus and antiviral agent. statistically significant. Recovery rates also tended to be
This study showed that a considerable percentage of higher in patients without than with both hypertension and
patients with severe Bell’s palsy benefited from combina- diabetes. The greater effectiveness of antiviral agents in
tion treatment with famciclovir and a steroid, similar to treating Bell’s palsy in patients without than with hyper-
previous findings [24, 25]. The combination of prednisone tension and diabetes may be due to the associations
with valaciclovir showed better clinical outcomes only in between these conditions and microangiopathy, inasmuch
elderly patients [19, 26]. Improvements in patients with HB as Bell’s palsy may be caused by microcirculatory failure
grade IV or higher were found to be more frequent in of the vasa nervosum [43]. Disorders of the microcircula-
patients receiving prednisone plus valaciclovir than pred- tion appear to attenuate the effects of antiviral agents in
nisone alone (29.4 vs. 11.9 %), with complete recovery in patients with hypertension and/or diabetes. Other causes of
patients with HB grade V or VI being significantly more Bell’s palsy may include an entrapment neuropathy
frequent with combination treatment than with prednisone resulting from inflammation, edema, and strangulation of
alone [26]. A recent large study found that the combination the facial nerve, as shown by perioperative and magnetic
of valaciclovir and prednisolone was superior to resonance imaging studies, as well as the corticosteroid

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 Table 4 The outcome of combination therapy with antiviral agents in Bell’s palsy
Study type Age FU time Number of Antiviral dose Recovery Outcome
(month) patients rate

Combination therapy with acyclovir

Adour et al. [18] RCT (double blind) 43 4 53 Acyclovir 2000 mg/day for 10 days 49 (92.4 %) FPRI score C8
De Diego et al. [16] Participants randomly – 3 54 Acyclovir 2400 mg/day for 10 days 42 (77.7 %) HB grade BII
assigned FPRI score C8
Eur Arch Otorhinolaryngol (2016) 273:3083–3090

Inanli et al. [17] Participants randomly 42 3 20 Acyclovir 2400 mg/day for 10 days 18 (90.0 %) HB grade BI
assigned
Sullivan et al. [14] RCT (double blind) 44 3, 9 124 Acyclovir 2000 mg/day for 10 days 115 HB grade BI
(92.7 %)
Yeo et al. [15] RCT (double blind) 41 2, 6 44 Acyclovir 2400 mg/day for 5 days 41 (93.1 %) HB grade BII
Combination therapy with famciclovir
Minnerop et al. [24] RCT (not blinded) 42.6 3, 5, 7–12 50 Famciclovir 250 mg/day for 7 days 37 (74 %) HB grade BI
[12
Shahidullah et al. RCT (not blinded) NA 1, 3 34 Famciclovir 750 mg/day for 5 days 33 (97.1 %) HB grade BI
[24]
Combination therapy with Valaciclovir
Antunes et al. [28] RCT (double blind) 39 6 15 Valaciclovir 1500 mg/day for 14 (93.3 %) HB grade BII
7 days Sunnybrook score 100
Hato et al. [13] RCT (single blind) 50 6 114 Valaciclovir 1000 mg/day for 110 Yanagihara score [36 points,
5 days (96.4 %) No facial contracture or synkinesis
Kawaguchi et al. Random allocation – 6 84 Valaciclovir 100 mg/day for 5 days 76 (90.4 %) Yanagihara score [36 points
[26]
Engstrom et al. [27] RCT (double blind) 40 12 206 Valaciclovir 3000 mg/day for 164 HB grade BII, Sunnybrook score
10 days (79.6 %) 100
RCT randomized controlled trial, HB House-Brackmann, FPRI Facial paralysis recovery index
3087

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3088 Eur Arch Otorhinolaryngol (2016) 273:3083–3090

Fig. 1 Forest plots comparing steroid with steroid and anti-viral agents. a Steroid versus steroid plus acyclovir. b Steroid versus steroid plus
famciclovir. c Steroid versus steroid plus valaciclovir

administration having a significantly better outcome than prednisolone and famciclovir may be superior to pred-
placebo [44]. nisolone and acyclovir in patients with severe Bell’s palsy.
Although these findings suggested that antiviral treat-
Compliance with ethical standards
ment may be effective in patients with Bell’s palsy, treat-
ment with antiviral agents alone without steroids was not Conflict of interest No potential conflict of interest relevant to this
effective [45]. Rather, combinations of prednisolone with article was reported. Acknowledgments: This work was supported by
acyclovir and famciclovir have been found effective in the National Research Foundation of Korea(NRF) Grant funded by
patients with Bell’s palsy [7, 24], although other studies the Korea government(MSIP) (No. 2011-0030072).
have shown a lack of effect [1, 12]. In conclusion, the Financial disclosure None of the authors reported financial
present findings suggest that combined treatment with disclosures.

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Eur Arch Otorhinolaryngol (2016) 273:3083–3090 3089

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