Natural menopause, specifically, is confirmed after 12 consecutive months of amenorrhea in the absence of any obvious, pathologic cause.1 These 12 months of amenorrhea and beyond, characterize a woman as postmenopausal. This can further be divided into early postmenopause (4 years after the FMP) and late postmenopause (>5 years since the FMP)

1. Desvenlafaxine Succinate: Is it a New Promise and Hope for
Management of Vasomotor Symptoms in Postmenopausal
Women?

2. Review Article
Desvenlafaxine succinate: Is it a new promise and hope for
management of vasomotor symptoms in postmenopausal
women?
Kavita Krishna a,
*, Vandana Nimbargi b
, Bijoy Panda c
a
Professor, Department of Medicine, Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune, Maharashtra, India
b
Associate Professor, Department of Obstetrics & Gynaecology, Bharati Vidyapeeth Deemed University Medical College and Hospital,
Pune, Maharashtra, India
c
Assistant Professor, PharmD Program, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India
a r t i c l e i n f o
Article history:
Received 13 August 2012
Accepted 18 February 2013
Available online 21 April 2013
Keywords:
Menopause
Vasomotor symptoms treatment
Hot flushes and night sweats
Desvenlafaxine succinate
a b s t r a c t
Background: Desvenlafaxine succinate (DVS) is one of several serotoninenorepinephrine
reuptake inhibitors (SNRIs) and has been approved by the US Food and Drug Administra-
tion (FDA) for the treatment of major depressive disorder (MDD) and trials are being per-
formed further to extend its approval in management of vasomotor symptoms in
postmenopausal women.
Objective: To review the published trials that evaluated the role of serotoninenorepinephrine
reuptake inhibitors (SNRIs), especially desvenlafaxine succinate, on vasomotor symptoms
(VMS).
Methods: PubMed (the web-based version of MEDLINE) was searched using term “desven-
lafaxine succinate AND vasomotor symptoms”. Trials examining the efficacy and safety of
desvenlafaxine succinate in VMS were considered for critical review.
Results: Recently, a program of clinical trials with desvenlafaxine (a salt from the major
metabolite of venlafaxine) has been developed for VMS. Currently, there are seven ran-
domized, double blind clinical trials published, showing a significantly higher efficacy of
desvenlafaxine versus placebo on VMS. There were also increased minor side effects with
desvenlafaxine, especially nausea, at the beginning of the treatment.
Conclusions: A non-hormonal alternativeddesvenlafaxine succinate may be useful and is
indicated for VMS in some but not most, cases. There was also an increase in minor side
effects, especially nausea, at the beginning of the treatment. Studies comparing des-
venlafaxine to other available treatment options relative to efficacy and safety are
lacking, with the exception of only one trial where the comparative option was tibolone.
The lack of head-to-head trials with the nonhormonal treatments, in particular, leaves
practitioners with numerous choices. Larger and longer studies are warranted to prove
its long-term efficacy and safety.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
* Corresponding author.
E-mail address: kavitakrishna2006@gmail.com (K. Krishna).
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.02.010

3. 1. Introduction
Natural menopause, specifically, is confirmed after 12
consecutive months of amenorrhea in the absence of any
obvious, pathologic cause.1
These 12 months of amenorrhea
and beyond, characterize a woman as postmenopausal. This
can further be divided into early postmenopause (1e4 years
after the FMP) and late postmenopause (>5 years since the
FMP).2,3
Surgical menopause results following surgical
removal of the ovaries. In either instance, one result of the
declining estrogen concentrations is the occurrence of
vasomotor symptoms (VMS) that include hot flushes and
night sweats, which occurs in, as many as 68.5% of women as
a result of menopause. While the median duration of these
symptoms is 4 years, approximately 10% of women continue
to experience VMS as many as 12 years after their final
menstrual period. As such, VMS have a significant impact on
the quality of life and overall physical health of women
experiencing VMS, leading to their pursuance of treatment to
alleviate these symptoms.4
Management of VMS includes lifestyle modifications, some
herbal and vitamin supplements, hormonal therapies
including estrogen and tibolone,5e9
and nonhormonal thera-
pies including clonidine, gabapentin, and some of the sero-
tonin and serotoninenorepinephrine reuptake inhibitors.10,11
The latter agents, including desvenlafaxine, have been the
focus of increased research as more is discovered about the
roles of serotonin and norepinephrine in the thermoregula-
tory control system. Desvenlafaxine succinate (DVS) is one of
several serotoninenorepinephrine reuptake inhibitors
(SNRIs). Others are venlafaxine hydrochloride, milnacipran,
and duloxetine. DVS has been approved by the US Food and
Drug Administration (FDA) for the treatment of major
depressive disorder (MDD) based on a number of randomized,
placebo controlled clinical trials. This critical review of various
published data in a standard scientific database will focus on
the role of desvenlafaxine as a treatment option for vasomotor
symptoms (VMS) management in postmenopausal women.
2. Materials and method
2.1. Search strategy
The following database was used to identify studies for this
review: PubMed (the web-based version of MEDLINE) using
term “desvenlafaxine succinate AND vasomotor symptoms”
with certain limits (“O-desmethylvenlafaxine”[Supple-
mentary Concept] OR “O-desmethylvenlafaxine”[All Fields]
OR “desvenlafaxine succinate”[All Fields]) AND (vasomotor[All
Fields] AND (“diagnosis”[Subheading] OR “diagnosis”[All
Fields] OR “symptoms”[All Fields] OR “diagnosis”[MeSH
Terms] OR “symptoms”[All Fields])) AND (“humans”[MeSH
Terms] AND (Randomized Controlled Trial[ptyp] OR Clinical
Trial[ptyp] OR Meta-Analysis[ptyp] OR Comparative Study
[ptyp] OR Review[ptyp] OR Case Reports[ptyp] OR Clinical
Conference[ptyp] OR systematic[sb] OR Editorial[ptyp]) AND
English[lang]). This search strategy was developed according
to Biondi-Zoccai.12
The language restriction was enforced to
English and the search strategy was set to an end on month of
July 2012.
2.2. Inclusion criteria
Study design criteria for inclusion in this review were: Clinical
Trial, Comparative Study, Controlled Clinical Trial, Evaluation
Studies, Multicenter Study, Randomized Controlled Trials
(RCTs).
2.3. Data extraction and analysis
All titles and abstracts were screened independently by the
reviewers and irrelevant studies were discarded. The full text
of the remaining studies ware assessed to determine if the
inclusion criteria were met. The included studies were
assessed for trial characteristics and outcome, by the re-
viewers, without blinding to author or source. Any discrep-
ancies in outcome assessment were resolved in discussion.
3. Results
3.1. Literature search
Nearly, 7 randomized controlled trials (RCTs) having followed
up data was included. There was no disagreement between
the reviewers regarding inclusion of trials. All the trials were
double blinded and placebo controlled. Out of which 4 trials
were multicentric and amongst that, one trial was a compar-
ative trial where standard drug was tibolone. Fig. 1 briefly
mentions the search strategy through the database.
3.2. Study characteristics and outcome assessment
The characteristics and outcome assessment of the 7 RCTs are
shown in Tables 1 and 2 respectively. All the trials were double
blinded and healthy postmenopausal women with 50
moderate-to-severe hot flushes per week were enrolled as the
main criteria. Nearly, 3295 participants were followed for
atleast 12 weeks and the efficacy and safety of the drug was
evaluated with primary end point such as average number of
reductions in hot flushes and reduction in nighttime awak-
enings. Few of the trials utilized standardized scoring tools
like Profile of Mood States (POMS), Greene Climacteric Scales
(GCS), Discontinuation-Emergent Signs and Symptoms (DESS)
Score and Menopausal Symptom Treatment Satisfaction
Questionnaire (MS-TSQ) scores. Safety parameters were pre-
dicted in terms of incidences of uterine bleeding, laboratory
values, vital signs and any adverse events reported during the
trial period.
4. Discussion
In nonhormonal prescription therapy, neuroactive agents
have been studied mostly in women with breast cancer or
who are at risk for breast cancer for their effectiveness at
relieving VMS. Increased serotonergic activity within the CNS
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 147

4. Fig. 1 e Search strategy adopted for the review.
Table 1 e Characteristics of trials using desvenlafaxine succinate (DVS) in postmenopausal women with vasomotor
symptoms (VMS).
(Ref)
Study Population No. of
patients (n)
Drug and doses given to
respective groups (mg)
Follow up
19
Cheng Multicentre 2012 Postmenopausal women
with 50 moderate
or severe hot flushes per week
458 Desvenlafaxine: 100 mg/day,
150 mg/day or placebo
12 weeks
18
Bouchard Multicentre,
comparative 2012
Postmenopausal women
with 50 moderate
or severe hot flushes per week
485 Desvenlafaxine: 100 mg/day, Tibolone:
2.5 mg/day or placebo
12 weeks
14
Archer 2009 Postmenopausal women
with 50 moderate
or severe hot flushes per week
567 Desvenlafaxine: 100 mg/day, 150 mg/day
or placebo
26 weeks
15
Archer Multicenter 2009 Postmenopausal women
with 50 moderate
or severe hot flushes per week
458 Desvenlafaxine: 100 mg/day, 150 mg/day
or placebo
12 weeks
16
Speroff Multicenter 2008 Postmenopausal women
with 50 moderate
or severe hot flushes per week
707 Desvenlafaxine: 50 mg/day, 100 mg/day,
150 mg/day and 200 mg/day or placebo
52 weeks
17
Wyrwich Multicenter 2008 Postmenopausal women
with 50 moderate
or severe hot flushes per week
620 Desvenlafaxine: 50 mg/day, 100 mg/day,
150 mg/day and 200 mg/day or placebo
12 weeks
20
Gallagher 2012 [Abstract] Postmenopausal women
with 50 moderate
or severe hot flushes per week
e Desvenlafaxine 100 mg/d (no titration),
50 mg/d, 25 mg/d (4 days) then 50 mg/d
(3 days), or desvenlafaxine 25 mg/d.
Participants then received open-label
desvenlafaxine 100 mg/d for 15 weeks.
In the 2-week taper phase, participants
received placebo, desvenlafaxine 50 mg/d
then placebo (7 days each), desvenlafaxine
50 mg/d then 25 mg/d (7 days each), or
desvenlafaxine 50 mg/d every other day
2 weeks
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1148

5. appeared to reduce hot flushes, possibly through an effect on
attenuation of central opioid peptide withdrawal or through
noradrenergic activity. Studies have included selective sero-
tonin reuptake inhibitors and serotoninenorepinephrine re-
uptake inhibitors (venlafaxine and desvenlafaxine).10,11,13
Most studies of non-hormonal prescription therapies have
required women to have 2 hot flushes for the day or 14/week
at baseline prior to study enrollment, which differ from the
FDA industry requirement of 50 or more hot flushes per week.
In our critical review of various RCTs focusing manage-
ment of vasomotor symptoms by desvenlafaxine found have
enrolled healthy postmenopausal women experiencing 50
moderate-to-severe hot flushes/week. Few studies have
considered nighttime awakening and climacteric conditions.
This confirms all the RCTs have enrolled participants ac-
cording to the FDA industry requirements.
Desvenlafaxine, a metabolite of venlafaxine was demon-
strated in RCTs14e16
at 100 mg and 150 mg per day to signifi-
cantly reduce the number of hot flushes compared with
placebo at weeks 4 and 12 (all p 0.012) with 65.4 and 66.6%
reduction from baseline at 12 weeks respectively, compared
with placebo at 50.8%. Hot flushes severity and number of
nighttime awakenings were significantly reduced at both time
points ( p 0.048). More adverse events were reported during
week 1 than placebo, with no difference in discontinuations.
Dose titration appears to improve initial tolerability and
decrease adverse event reporting.
Another placebo controlled trial utilized the criteria of
efficacy and treatment satisfaction design, where the in-
vestigators first identified the treatment satisfaction
thresholds for interpreting treatment related changes in
VMS and then determined the doses of DVS that effectively
provide relief VMS. The tool used to assess this was a
Menopause Symptom Treatment Satisfaction Question-
naire. Greater percentages of participants in DVS group re-
ported being “satisfied” or “extremely satisfied” with
daytime and nighttime control of hot flushes compared
with placebo. Amongst the various doses the 100 and
150 mg/day dose of DVS met both the important VMS
change thresholds.17
A recent randomized placebo and active controlled study
evaluated the safety and efficacy of DVS vs. Tibolone (2.5 mg/
day) or placebo. Reduction of the average daily number of
moderate and severe hot flushes at week 12 was found to be
non-significant where as time to 50% reduction was achieved
at week 4 ( p ¼ 0.006). Adverse drug events were consistent
with the known safety profile of DVS and significantly more
women who received tibolone experienced episodes of
Table 2 e Outcome assessment of trials using desvenlafaxine succinate (DVS) in postmenopausal women with vasomotor
symptoms (VMS).
(Ref)
Study Blinding? Measurement of outcome Outcome
19
Cheng
Multicentre 2012
Double blind Secondary outcomes of mood, climacteric symptoms,
and treatment satisfaction change from baseline in Profile
of Mood States (POMS) total mood disturbance, Greene
Climacteric Scale (GCS), and Menopausal Symptoms
Treatment Satisfaction Questionnaire (MS-TSQ) scores
Desvenlafaxine treatment
improved mood and
climacteric symptoms and
participants were satisfied
with this compared to placebo.
18
Bouchard
Multicentre,
comparative 2012
Double blind Primary endpoints: Reduction in the average daily number
of moderate-to-severe hot flushes at weeks 4 and 12
Safety Assessments: Incidence of uterine bleeding, adverse
events, laboratory values, and vital signs
Participants achieved 50%
reduction of hot flushes than
placebo and tibolone. Tibolone
group experienced episodes of
bleeding compared with women
who received desvenlafaxine or
placebo.
14
Archer 2009 Double blind Primary endpoints: Change from baseline in average daily
number of moderate-to-severe HFs and average daily HF
severity were compared with placebo at weeks 4, 12, and 26
Desvenlafaxine (DVS) is an
effective treatment for
menopausal hot flushes
15
Archer
Multicenter 2009
Double blind Primary endpoints: Hot flush number and severity were
assessed at weeks 4 and 12
Safety Assessments: Adverse events, laboratory values,
and vital signs
Desvenlafaxine (DVS) is an
effective treatment for
menopausal hot flushes
Dose titration improves initial
tolerability
16
Speroff
Multicenter 2008
Double blind Primary endpoints: Change from baseline in average daily
number of moderate-to-severe hot flushes and in daily hot
flush severity score at weeks 4 and 12
Desvenlafaxine (DVS) is an
effective treatment for
menopausal hot flushes
17
Wyrwich
Multicenter 2008
Double blind Primary endpoints: Number and severity of hot flushes and
number of nighttime awakenings were recorded in daily
diaries for 12 weeks of treatment. At week 12, responses to
the Menopause Symptoms Treatment Satisfaction Questionnaire
Significant satisfaction
thresholds were achieved in
participants with
desvenlafaxine (DVS)
100 mg/day
20
Gallagher 2012
[Abstract]
Double blind Primary endpoints: Nausea incidence during the first 2 weeks
of treatment and Discontinuation-Emergent Signs and Symptoms
(DESS) Checklist total scores after taper weeks 1 and 2
Taper regimens of
desvenlafaxine (DVS)
50 mg/d-placebo or 50/25-mg/d,
were better tolerated than
abrupt discontinuation
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 149

6. bleeding (23% vs 12%, p 0.024). Nausea was the most com-
mon adverse event observed in DVS group.18
A 12-week multicenter, double blind and placebo
controlled trial was performed to assess the effects of DVS in
secondary outcomes of mood, climacteric symptoms and
treatment and treatment satisfaction in postmenopausal
women with moderate-to-severe VMS. Change from baseline
in Profile of Mood States (POMS)-total mood disturbance
(POMS-TMD) and Green Climacteric Scale (GSC) scores re-
flected significant improvement ( p 0.001) respectively at a
dose of DVS 100 mg/day. Even all the sub-domains of the
POMS-TMD and GCS were significant ( p 0.05). Additionally,
the elements of Menopausal Symptoms Treatment Satisfac-
tion Questionnaire (MS-TSQ) score was significant (all
p 0.042) which finally stated that more women were satisfied
with DVS treatment than with placebo.19
A placebo controlled trial was performed to predict its
tolerability by titrating up and tailoring down desvenlafax-
ine succinate in postmenopausal women with vasomotor
symptoms (VMS). In the 1-week titration phase, participants
received desvenlafaxine 100 mg/d (no titration), desvenla-
faxine 50 mg/d, desvenlafaxine 25 mg/d (4 days) then 50 mg/
d (3 days), or desvenlafaxine 25 mg/d. Participants then
received open-label desvenlafaxine 100 mg/d for 15 weeks.
In the 2-week taper phase, participants received placebo,
desvenlafaxine 50 mg/d then placebo (7 days each), des-
venlafaxine 50 mg/d then 25 mg/d (7 days each), or des-
venlafaxine 50 mg/d every other day. Primary endpoints
included nausea incidence during the first 2 weeks of
treatment and Discontinuation-Emergent Signs and Symp-
toms (DESS) Checklist total scores after taper weeks 1 and 2.
Titration regimens improved tolerability of desvenlafaxine
100 mg/d in postmenopausal women with VMS. Taper reg-
imens of desvenlafaxine 50 mg/d-placebo or 50/25 mg/d,
were better tolerated than abrupt discontinuation or des-
venlafaxine 50 mg given every other day taper regimen.20
Limitations of the trials include the study duration, the
lack of ethnic diversity, and neglecting to evaluate the pres-
ence of VMS risk factors among the study participants. The
efficacy endpoints used in all of the trials were evaluated at
12 weeks and 26 weeks, which is a rather short duration.
Trials evaluating the efficacy and safety of desvenlafaxine
over an extended time are warranted.
5. Conclusion
Desvenlafaxine is a viable option for the treatment of VMS in
postmenopausal women where 100 and 150 mg/day regimen
can effectively reduce the frequency of moderate-to-severe
hot flushes and number of nighttime awakenings. Individu-
alized dose titration may improve initial tolerability and
decrease adverse events. Studies comparing desvenlafaxine
to other available treatment options relative to efficacy and
safety are lacking, with the exception of the one trial
comparing it to tibolone. The lack of head-to-head trials with
the nonhormonal treatments, in particular, leave practi-
tioners with numerous choices, as one medication has not
been shown to be superior. Larger studies with longer dura-
tions, inclusive of more diversity among subject ethnicity, and
with a focus that includes reporting the impact on overall
QOL, are warranted to evaluate the long-term safety and ef-
ficacy of desvenlafaxine for VMS treatment and improve the
generalizability of the results.
Conflicts of interest
All authors have none to declare.
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