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REVIEW
Clinical trials on pain lowering effect of ginger: A narrative
review
Mariangela Rondanelli
1,2
| Federica Fossari
3
| Viviana Vecchio
3
|
Clara Gasparri
3
| Gabriella Peroni
3
| Daniele Spadaccini
3
|
Antonella Riva
4
| Giovanna Petrangolini
4
| Giancarlo Iannello
5
|
Mara Nichetti
3
| Vittoria Infantino
6
| Simone Perna
7
1
IRCCS Mondino Foundation, Pavia, Italy
2
Department of Public Health, Experimental
and Forensic Medicine, University of Pavia,
Pavia, Italy
3
Endocrinology and Nutrition Unit, Azienda di
Servizi alla Persona “Istituto Santa Margherita”,
University of Pavia, Pavia, Italy
4
Research and Development Unit, Indena SpA,
Milan, Italy
5
General Management, Azienda di Servizi alla
Persona “Istituto Santa Margherita”, Pavia,
Italy
6
Department of Biomedical Science and
Human Oncology, University of Bari Aldo
Moro, Bari, Italy
7
Department of Biology, College of Science,
University of Bahrain, Zallaq, Bahrain
Correspondence
Vittoria Infantino, Department of Biomedical
Science and Human Oncology, University of
Bari, Azienda di Servizi alla Persona “Istituto
Santa Margherita,”Pavia, 27100 Italy.
Email: viriainfantino@hotmail.it
Ginger has a pain-reducing effect and it can modulate pain through various mecha-
nisms: inhibition of prostaglandins via the COX and LOX-pathways, antioxidant activ-
ity, inibition of the transcription factor nf–kB, or acting as agonist of vanilloid
nociceptor. This narrative review summarizes the last 10-year of randomized con-
trolled trials (RCTs), in which ginger was traditionally used as a pain reliever for dys-
menorrhea, delayed onset muscle soreness (DOMS), osteoarthritis (AO), chronic low
back pain (CLBP), and migraine. Regarding dysmenorrhea, six eligible studies suggest
a promising effect of oral ginger. As concerned with DOMS, the four eligible RCTs
suggested a reduction of inflammation after oral and topical ginger administration.
Regarding knee AO, nine RCTs agree in stating that oral and topical use of ginger
seems to be effective against pain, while other did not find significant differences.
One RCT considered the use of ginger in migraine and suggested its beneficial activ-
ity. Finally, one RCT evaluated the effects of Swedish massage with aromatic ginger
oil on CLBP demonstrated a reduction in pain. The use of ginger for its pain lowering
effect is safe and promising, even though more studies are needed to create a con-
sensus about the dosage of ginger useful for long-term therapy.
KEYWORDS
chronic low back pain, dysmenorrhea, ginger, knee osteoarthritis, myalgia, pain
1|INTRODUCTION
Zingiber officinale Roscoe (Zingiberaceae family), commonly known
as ginger is a climbing perennial plant, indigenous to southeastern
Asia. Ginger extract is a mixture of many biologically active constitu-
ents (Grzanna, Lindmark, & Frondoza, 2005). These compounds are
numerous and vary depending on the place of origin and whether
the rhizomes are fresh or dry (Ali, Blunden, Tanira, &
Nemmar, 2008).
More than 400 chemical substances have been isolated and iden-
tified in ginger rhizomes extracts, and new ones are still being discov-
ered (Charles, Garg, & Kumar, 2000; Jolad, Lantz, Solyom, &
Chen, 2004; Ma, Jin, Yang, & Liu, 2004). At present, only a few of
them have been evaluated for their pharmacological properties
(Grzanna et al., 2005).
Carbohydrates, lipids, terpenes, and phenolic compounds are
between the ones that already have been identified (Peter, 2016;
Prasad & Tyagi, 2005). From the chemical point of view, isolated
Received: 28 August 2019 Revised: 8 April 2020 Accepted: 23 April 2020
DOI: 10.1002/ptr.6730
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2020 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.
Phytotherapy Research. 2020;1–14. wileyonlinelibrary.com/journal/ptr 1
zingiber's principles are categorized into pungent and flavoring com-
pounds. Pungent ones including gingerols, shogaols, zingerones,
gingerdiols, gingerdione, and paradols are known to play a major role
in various pharmacological actions (Jolad et al., 2004; Mashhadi
et al., 2013; Peter, 2016; Prasad & Tyagi, 2005).
Patients suffering from diseases associated with chronic inflam-
mation are turning to alternative compounds for relief of their symp-
toms or to take advantage of natural drug properties as prophylactic
treatments. A complex interplay of inflammatory cells and a large
range of chemical mediators are normally associated with the begin-
ning of the inflammatory response, recruiting, and activating other
immune cells to the site to subsequently solve it.
Several studies indicate that many different compounds in ginger
are active in lowering chronic inflammatory diseases' symptoms:
•Inhibition of prostaglandins via COX and LOX pathways
The traditional use of ginger infusions to alleviate rheumatism and
arthritis have pushed researchers to investigate the anti-inflammatory
pathways of secondary metabolites of the plant (Baliga et al., 2011;
Zahedi, Fathiazad, Khaki, & Ahmadnejad, 2012). Some authors attributed
6-gingerol's anti-inflammatory activity to the inhibition of pro-
inflammatory cytokines and LPS-activated macrophages antigen presen-
tation (Setty & Sigal, 2005; Tripathi, Tripathi, Kashyap, & Singh, 2007).
Dugasani et al. demonstrated that shogaols and all gingerols
inhibit NO production in LPS-stimulated RAW 264.7 cells in a dose-
dependent manner (Dugasani et al., 2010). Moreover, with their
experiments they showed that stimulation of RAW 264.7 cells with
LPS (1 g/ml) for 24 hr induced a dramatic increase in PGE2 produc-
tion, four times the basal level (Dugasani et al., 2010).
•Antioxidant activity on free radical scavenging cascade
Zingiber officinale active ingredients like gingerols, shogaols,
zingerone, and so on exhibit antioxidant activity. Ginger inhibits an
enzyme, namely xanthine oxidase, which is mainly involved in the gen-
eration of reactive oxygen species (ROS) (Ahmad et al., 2015).
•Inhibition of the transcription factor, nuclear NF-kB
Grzanna and his group demonstrated for the first time that ginger
inhibits the transcription factor nuclear NF-kB (Grzanna et al., 2005).
Nuclear NF-kB is the principal regulator of pro-inflammatory gene
expression. Activated NF-kB can be detected at sites of inflammation,
and a link among NF-kB activation, cytokine production, and inflam-
mation is now generally accepted.
6-gingerol displayed anti-inflammatory activity by decreasing
inducible NO synthase and TNF-αexpression through the suppression
of I-kBαphosphorylation, NF-kB nuclear activation, and PKC-αtrans-
location. The compound was also found to control TLR-mediated
inflammatory responses. It inhibited NF-kB activation and COX-2
expression by inhibiting the LPS-induced dimerization of TLR4 (Ahn,
Lee, & Youn, 2009).
•Vanilloid nociceptor agonist
Vanilloid nociceptor agonists are known to be potent analgesics.
The moderate pungency of ginger has been attributed to the mixture
of gingerol derivatives in the oleoresin fraction of processed ginger.
Gingerols possess the vanillyl moiety which is considered important
for activation of the VR1 receptor expressed in nociceptive sensory
neurones (Dedov et al., 2002).
Dedov reported that gingerols act as agonists at vanilloid recep-
tors suggesting an additional mechanism by which ginger may reduce
inflammatory pain (Dedov et al., 2002). This finding has added
gingerols and zingerone to the list of vanilloid receptor agonists.
Moreover, the presence of VR1 receptors throughout the
brainstem (Mezey et al., 2000), where the nausea center is located,
may conceivably be associated in part with the common use of ginger
as antiemetic medicine (Dedov et al., 2002).
In summary, current evidence in vitro and in animal models dem-
onstrated that many different compounds of ginger have been shown
to posses antioxidative and anti-inflammatory activities that may be
active in lowering chronic inflammatory disease symptoms, in
particular pain.
However, human studies that were carried out to assess whether
oral or topic ginger has a positive effect by reducing pain are not
numerous; furthermore, in these studies different dosages and
methods of administration were used, as well as disparate products'
formulations and different study designs.
Given this background, the aim of this narrative review was to
assess the state of the art randomized clinical trials on pain lowering
effect of ginger, considering the pathologies in which ginger is tradi-
tionally used in order to control pain, such as: dysmenorrhea, delayed
onset muscle soreness (DOMS), knee osteoarthritis, chronic low back
pain (CLBP), and migraine.
2|MATERIALS AND METHODS
This narrative review was written after a PubMed and SCOPUS
research performed with these keywords: “Ginger,”“pain”with the
use of Boolean AND operator to establish the logical relation between
them. The research was conducted by four skilled operators from July
to September 2018 and followed Egger's criteria (Egger, Smith, &
Altman, 2001; Moher, Liberati, Tetzlaff, Altman,, & PRISMA
Group, 2009). The research was time limited (from 2008 to 2018) and
restricted to English and humans randomized controlled trial (RCT).
The keywords were pain, ginger, primary dysmenorrhea, DOMS, knee
pain, osteoarthritis (AO), CLBP, and migraine. They were combined
with “AND”to search related articles. Furthermore, we selected trials
with oral ginger used as a primary, sole or combined therapy and com-
pared with a placebo or active treatment in diseases. The analysis was
carried out in the form of a narrative review (Figure 1).
Standard datacoding tables were developed for extracting data
from individual trials, key characteristics, and the level of evidence of
each study (“Oxford Centre for Evidence-based Medicine - Levels of
2RONDANELLI ET AL.
Evidence (March 2009)—CEBM,”2009). The following data were
extracted: participant characteristics, sample size, form and dosage of
ginger, control group, assessment of adherence, outcome measures,
methods for statistical analysis, study findings, and adverse events
reported.
3|RESULTS AND DISCUSSION
3.1 |Dysmenorrhea
This review summarizes evidence from six clinical trials
(687 patients) evaluating the efficacy of oral ginger use for dys-
menorrehea (Table 1). Among the six eligible studies, five were con-
ducted in Iran (Jenabi, 2013; Kashefi et al., 2014; Ozgoli, Goli, &
Simbar, 2009; Rahnama et al., 2012; Shirvani et al., 2017) and one
in India (Halder, 2012). Participants were either college or high
school students. Five of the six studies included only women with
moderate to severe symptoms (Jenabi, 2013; Kashefi et al., 2014;
Ozgoli, Goli, & Simbar, 2009; Rahnama et al., 2012). Five studies
specified the inclusion of women with primary dysmenorrhea only,
excluding women with secondary dysmenorrhea (Jenabi, 2013;
Kashefi et al., 2014; Ozgoli, Goli, & Moattar, 2009; Rahnama et al.,
2012; Shirvani et al., 2017); however, it is unclear how secondary
dysmenorrhea was defined/diagnosed. Across the studies, the sam-
ple sizes of the ginger group ranged from N=25 to N= 61. The
daily dose of powdered ginger ranged from 750 to 2,000 mg. The
most common duration and timing of ginger treatment was 3 days
(the first 3 days of menstruation) (Halder, 2012; Jenabi, 2013;
Ozgoli, Goli, & Simbar, 2009).
FIGURE 1 Flow chart of literature research [Colour figure can be viewed at wileyonlinelibrary.com]
RONDANELLI ET AL.3
TABLE 1 Summary of articles about effect of ginger on dysmenorrhea
Author, year Study design Study population Type of intervention Results
Evidence
level
Rahnama, Montazeri,
Huseini, Kianbakht,
& Naseri, 2012
Double blind,
placebo-controlled
and parallel-group
study with balanced
randomization [1:1]
for the two groups.
one hundred twenty
female students living
in the dorms in Iran:
age (>18), were
randomly assigned to
two equal groups: (a)
ginger, (b) placebo
Zingiber officinale R.
rhizomes. Five
hundred milligram
ginger powder for
capsule and the others
were placebo
capsules, three times a
day in two different
treatment protocols.
Both treatment
protocols were given
at monthly intervals.
Ginger may be an
effective and safe
therapy for relieving
pain in women with
primary dysmenorrhea
if administered at the
onset and 3 days
earlier it needs
revision.
Level IB
Shirvani,
Motahari-Tabari, &
Alipour, 2017
Randomized clinical trial One hundred
twenty-two female
students living in the
dorms in Iran: age
(21.62 ± 2.0), were
randomly allocated to
two interventional
groups: (a) ginger, (b)
mefenamic groups.
Zingiber officinal roscoe.
Two hundred fifty
milligram capsule of
ginger powder
(Zintoma): in the
mefenamic group
every 8 hr, and in the
ginger group every
6 hr from the onset of
menstruation until
pain relief lasted
2 cycles.
No significant difference
in pain severity was
found between ginger
and mefenamic.No
significant difference
in pain duration was
found between ginger
and mefenamic acid.
Level IB
Kashefi, Khajehei,
Tabatabaeichehr,
Alavinia, &
Asili, 2014
A placebo-controlled
randomized trial
One hundred fifty high
school students
(15–18 age) in Iran,
were randomly
assigned to three
study groups. (a) zinc
sulfate (n= 48), (b)
ginger (n= 56), (c)
placebo (n= 46)
Ginger: The relative
capsules were filled
with 250 mg ginger
powder. The capsules
was filled with 220 mg
zinc sulfate, and the
placebo capsules were
filled with lactose.
The severity of pain was
significantly different
between, before, and
after the intervention
in both the ginger and
the zinc sulfate
groups.
Level IB
Compared with the
placebo receiving
group, participants
receiving ginger and
zinc sulfate reported
more alleviation of
pain during the
intervention.
The severity of
dysmenorrhea was
not significantly
different among the
three groups before
the intervention.
Halder, 2012 Clinical trial Seventy-five nursing
students in India.
Participants were
divided into three
groups: experimental
group 1, experimental
group 2 and control
group again by lottery
method, 25 in each
group.
The first experimental
group was
administered
Jacobson's
progressive muscle
relaxation exercise
once a day; the
second experimental
group was
administered ginger
powder 1 g per dose
twice a day with warm
water after meal.
Main outcome measures
were the severity of
selected symptoms of
dysmenorrhoea, which
were analysed using
MANOVA.
Level IIA
4RONDANELLI ET AL.
Dysmenorrhea is characterized by low abdominal or pelvic pain
occurring before or during menstruation (Morrow &
Naumburg, 2009). Better management of dysmenorrhea may not only
improve women's quality of life, but also reduce their risk of develop-
ing future pain (Berkley & McAllister, 2011; Vincent et al., 2011). Dys-
menorrhea is conventionally treated with nonsteroidal anti-
inflammatory drugs (NSAIDs) or oral contraceptive pills (OCPs)
(Dawood, 2006), the efficacy of which are supported by research evi-
dence (Wong, Farquhar, Roberts, & Proctor, 2009). However, NSAIDs
and OCPs have limitations: some women with dysmenorrhea do not
respond to NSAIDs or OCPs (with an estimated failure rate of >15%
for NSAIDs) (Dawood, 2006); some cannot use these medications
because of contraindications or adverse effects; some prefer not to
use any medications. Therefore, investigation of complementary alter-
native treatments for dysmenorrhea is warranted. Ginger is one of the
most commonly used natural products among women with dysmenor-
rhea. The exact mechanism of action of ginger in pain relief remains to
be elucidated; however, some evidence suggests that the constituents
of ginger have anti-inflammatory and analgesic properties (Ali
et al., 2008). Furthermore, preclinical research shows that ginger sup-
presses the synthesis of prostaglandin (through inhibition of
cyclooxygenase) and leukotrienes, which are involved in dysmenor-
rhea pathogenesis (Dawood, 2006; Committee on Herbal Medicinal
Products (HMPC), 2013).
The available data suggest a promising pattern of oral ginger
(750 to 2,000 mg for the first 3 days of menstruation) as a potentially
effective treatment for pain in dysmenorrhea. All RCTs agree in dem-
onstrating that ginger is more effective for pain relief than placebo,
and no significant difference was found between ginger and NSAIDs
(Halder, 2012; Jenabi, 2013; Kashefi et al., 2014; Ozgoli, Goli, &
Moattar, 2009; Rahnama et al., 2012). These findings, however, need
to be interpreted with caution due to the small number of studies,
poor methodological quality, and high heterogeneity across the trials.
Moreover, all of the included trials were conducted in Asia.
3.2 |Delayed onset muscle soreness
This review summarizes evidence from four randomized clinical trials
(194 subjects) evaluating the efficacy of oral or topic ginger use for
DOMS (Table 2). Three RCT suggested an effective reduction of
inflammation due to exercise-induced muscle damage after daily
TABLE 1 (Continued)
Author, year Study design Study population Type of intervention Results
Evidence
level
Pre-test post-test
control group design
was selected.
In treating symptoms of
dysmenorrhoea,
ginger powder has
efficacy superior to
progressive muscle
relaxation.
Jenabi, 2013 Randomized clinical trial Seventy college students
in Iran, were allocated
to two groups: (a)
Ginger group (n= 35),
(b) Placebo group
(n= 34), aged
21.33 ± 1.16/
21.54 ± 1.78 years
Ginger versus placebo,
both in capsule form
for 3 days in first
menstruation cycles.
In the ginger group, 29
subjects reported an
improvement in
nausea symptoms,
compared with 16 in
the placebo group.
Ginger is effective in
minimising the pain
severity in primary
dysmenorrhoea.
Level IB
Five hundred milligram
of it was filled in each
capsule.
Ozgoli, Goli, &
Moattar, 2009
Double-blind
comparative clinical
trial
One hundred fifty
college students (>18)
in Iran living in the
dorm, were allocated
to three groups: (a)
ginger, (b) mefenamic
acid, (c) ibuprofen.
Ginger powder versus
placebo: The ginger
group took 250 mg
capsules of ginger
rhizome powder four
times a day for 3 days
from the start of their
menstrual period.
Members of the other
groups received
250 mg mefenamic
acid or 400 mg
ibuprofen capsules,
respectively, on the
same protocol.
No significant difference
in pain severity was
found between ginger,
ibuprofen, and
mefenamic acid.
Level IIA
RONDANELLI ET AL.5
TABLE 2 Summary of articles about effect of ginger on DOMS
Author, year Study design Study population Type of intervention Results
Evidence
level
Matsumura, Zavorsky, &
Smoliga, 2015
Double- blind, randomized
placebo-controlled trial.
Twenty Non-weight trained
partecipants allocated in two groups.
(a) Intervention group: n= 10 (5F,
5 M); aged 32 ± 9 years. (b) Placebo
group: N= 10 (5F, 5 M);
27 ± 5 years.
Zingiber officinale roscoe (4 g) once
daily for 5 days.
Four gram of ginger supplementation
may be used to accelerate recovery
of muscle strength following intense
exercise but does not influence
indicators of muscle damage
(DOMS).
Level IB
Manimmanakorn
et al., 2016
Double- blind, randomized
placebo-controlled trial.
Seventy-five healthy untrained
volunteers (47F, 28 M), aged
18–60 years, allocated in three
groups. (a) 14% Plai cream: n=25
(15F, 10 M); aged 28.7 ± 13.7 years.
(b) 7% Plai cream: n= 25 (16F, 9 M);
aged 31.3 ± 16.7 years. (c) Placebo
group: n= 25 (16F, 9 M); aged
26.2 ± 12.0 years.
Zingiber cassumunar: 2 g of the cream
(strips of 5-cm long) were rubbed
into the quadriceps muscles for
5 min immediately following the
exercise and every 8 hr thereafter for
7 days in all groups.
Using 14% Plai cream over a 7-day
period substantially reduced muscle
soreness symptoms compared to 7%
Plai cream or a placebo cream.
Level IB
Black & O'Connor, 2008 Double blind crossover design Twenty-five participants (15F, 10 M)
aged 23.2 ± 4.2 years.
Six capsules, for a total of 2 g of ground
ginger or 2 g of flour (placebo),
administered 30 min before cycling
on an ergometer at an intensity of
60% of VO
2peak,
enough to stimulate
mild to moderate quadreceps muscle
pain.
Ginger exhibited no hypoalgesic effect
on quadriceps pain intensity
compared with placebo.
Level IIA
Black, Herring, Hurley, &
O'Connor, 2010
Double- blind, randomized
placebo-controlled trial
Study 1: N= 34 allocated in two
groups: (a) Raw ginger: n= 17 (14F,
3 M), aged 21.1 ± 0.7 years. (b)
Placebo: n= 17 (14F, 3 M), aged
20.9 ± 0.6 years.
Six capsules, for a total of 2 g of raw or
heated ginger or 2 g of placebo, all
administered within 1 min, before
performing 18 eccentric actions of
the nondominant elbow flexors at an
intensity of 120% of their concentric
1-RM.
Raw and heat-treated ginger resulted in
similar pain reductions 24 hr after
eccentric exercise compared to
placebo.
Level IB
Study 2: N= 40 allocated in two
groups: (a) Heated ginger: n=20
(13F, 7 M), aged 20.6 ± 0.6 years. (b)
Placebo: n= 17 (13F, 7 M), aged
21.4 ± 0.8 years.
6RONDANELLI ET AL.
consumption of 2 g of raw and heat-treated ginger (Black et al., 2010;
Manimmanakorn et al., 2016). A useful alternative seems to be the
topical administration of Zingiber cassumunar in 14% concentration
(Manimmanakorn et al., 2016). Finally, 4 g of ginger supplementation
is the suggested dose to be used to accelerate recovery of muscle
strength following intense exercise (Matsumura et al., 2015).
DOMS indicated by muscle pain and tenderness typically occurs
after a strenuous workout or undertaking unaccustomed exercise
(Gulick & Kimura, 1996). The underlying causes of DOMS are related
to exercise-induced muscle damage, including sarcomere disruption,
and the ensuing secondary inflammatory response
,
(Gleeson
et al., 1995; Warren, Hayes, Lowe, Prior, & Armstrong, 1993). Inflam-
matory processes stimulate prostaglandin E2 release which sensitizes
type III and IV pain afferents, and leukotrienes to attract neutrophils,
which produce free radicals that further exacerbate muscle cell dam-
age (Connolly, Sayeres, & McHugh, 2003). DOMS after eccentric
exercise may result in reduction of muscle performance of athletes
(Cheung, Hume, & Maxwell, 2003). Numerous methods to prevent
and reduce DOMS have been suggested, including stretching exer-
cises, massage, and nutritional supplementation. Non-steroidal anti-
inflammatory drugs (NSAIDs) have been used in an attempt to reduce
DOMS by reducing inflammation and pain and improving function.
Ginger and several of its constituents inhibit activity of COX-1
and COX-2, block leukotriene synthesis, and block the production of
interleukins and tumor necrosis factor alpha in activated macrophages
(Black et al., 2010). Thus, these antiinflammatory actions that may
help reduce inflammation, such as exercise-induced muscle damage,
are recognized as a product of participating in unfamiliar or strenuous
physical activity.
Given that ginger has antinflammatory and analgesic properties, it
follows that it may be used to reduce the damage and consequent
DOMS following high-intensity exercise. (Black et al., 2010; Black &
O'Connor, 2008).
3.3 |Knee osteoarthritis
This review summarizes evidence from nine randomized clinical trials
(964 patients) evaluating the efficacy of oral or topical ginger, sole or
in combination with other botanicals, use for knee OA (Table 3). The
three RCTs that considered the efficacy of oral ginger (powder supple-
mentation of 1 g/day) on pain in knee OA demonstrated that efficacy
of ginger on knee pain seemed not to have a unique position. Two
studies suggested that the use of ginger in subjects with knee pain
could decrease pain (Mozaffari-Khosravi et al., 2016; Naderi
et al., 2016) while other did not find significant differences (Naderi
et al., 2016; Niempoog et al., 2012). The two RCT that assessed the
efficacy of the topical use of ginger considered an aromatic essential
oil (1% Zingiber officinale and 0.5% Citrus sinesis) (Yip & Tam, 2008)
and 4% ginger gel (Niempoog et al., 2012) and agree in stating that
the topical use of ginger seems to have potential as an alternative
method for short-term knee pain relief. Finally, all the four studies that
considered the ginger supplementation in combination with other
botanicals agree in demonstrating that these combinations are effec-
tive in order to decrease knee pain (Chopra et al., 2013; Drozdov
et al., 2012; Nieman et al., 2013).
Osteoarthritis Osteoarthritis (OA) is a joint disease characterized
by degeneration of cartilage, pain, inflammation, impaired mobility,
and dysfunction, especially in older populations (Heidari, 2011).
Current treatment for OA is palliative and is focused on pain relief
and improving mobility, including a combination of nonpharmacologic
and pharmacologic measures. However, when these therapeutic treat-
ments fail to improve symptoms, a variety of surgical interventions
can be used (Haghighi, Tavalaei, & Owlia, 2006). With respect to some
commonly-used treatments, such as NSAIDs, there is increasing con-
cern that long-term consumption may cause gastrointestinal bleeding
and cardiovascular risks, mainly hypertension and thrombotic events
(Dingle, 1999; Mamdani, 2005). Thus, an interest in research has been
conducted to find care treatments that have negligible adverse effects
while offering significant improvements in the symptoms (Zakeri
et al., 2011).
Ginger is thought to have anti-inflammatory effects and may
modulate the concentration and activity of inflammatory mediators in
OA (Ahmad et al., 2015).
Only one RCT, that considered the efficacy of oral ginger (powder
supplementation of 1 g/day) on pain in knee OA, did not find signifi-
cant changes (Niempoog et al., 2012). These difference in the results
between the study by Niempoog et al. and the study by Mozaffari-
Khosravi H, although the dosage used was the same (1 g/day), could
be due to numerous reasons: the type of administration (non-
encapsulated powder vs. encapsulated powder), the duration of treat-
ment (2 vs. 3 months), the parameters studied (symptoms and daily
activities vs. inflammatory cytokines), number of patients evaluated
(30 vs. 120 subjects) (Mozaffari-Khosravi et al., 2016; Niempoog
et al., 2012).
3.4 |Chronic low back pain
As shown in Table 4, one RCT was sourced using topical ginger. No
RCT studies were found regarding oral ginger supplementation and
pain in patients with low back pain.
CLBP is defined as a chronic condition of lower back pain lasting
for at least 3 months or longer (Andersson, 1999; Bogduk, 2004).
Non-pharmacologic interventions for CLBP are recommended when
patients do not show improvement with standard treatment (Deyo,
Mirza, & Martin, 2006).
Ginger has been used as an anti-inflammatory and anti-rheumatic
for musculoskeletal pain (Altman & Marcussen, 2001;
Therkleson, 2010). Although CLBP predominantly affects older peo-
ple, only one study has specifically investigated the effects of Swedish
massage with aromatic ginger oil in order to evaluate if improve the
level of disability.
The objective of Sritoomma et al. was to investigate the effects
of Swedish massage with aromatic ginger oil (SMGO) on CLBP and
disability in older adults compared with traditional Thai massage
RONDANELLI ET AL.7
TABLE 3 Summary of articles about effect of ginger on knee AO
Author, year Study design Study population Type of intervention Results Evidence level
Zahmatkash & Vafaeenasab,
2011
A double-blind randomized
controlled trial study.
Ninety-two participates with
the mean age of 52.2 (+/−
12.4) years, allocated to two
groups: (a) Ginger, (b)
Salicylate
Ginger versus salicylate: 2 g of
topical ointment for three
times a day, applied with
massage for 1 min, for
6 weeks, twice a day.
Treatment group applied
herbal ointment and control
group used salicylate
ointment.
It seems that using this herbal
combination is clinically
effective for patients
suffering from knee AO in
order to decrease their pain,
morning stiffness and limited
motion; its effect is
comparable with salicylate
ointment. The severity of pain
were measured using Visula
analog pain scale.
Level IB
Niempoog, Siriarchavatana, &
Kajsongkram, 2012
A double-blind, randomized,
controlled trial.
Fifty participates, male and
female, allocated to two
groups: (a) Treatment
(Plygersic) gel, (b) Diclofenac
gel
Zingiber officinale Zingiber
cassumunar versus
diclofenac: The combination
of 4% ginger and plai extract
in a gel (Plygersic gel) as
compared with a 1% solution
of diclofenac sodium gel.
Both Plygersic gel and
diclofenac gel could
significantly improve knee
joint pain, symptoms, daily
activities, sports activities and
quality of life measured by
KOOS following 6 weeks of
treatment. In the ANOVA fo
repeated measures, there
were no differences in the
results between the Plygersic
and diclofenac gel groups.
Level IB
Gels were applied as 1 g
solution for four times a day
for 2 months
The efficacy of the drugs was
monitored by using KOOS
(knee injury and AO outcome
score) score.
Mozaffari-Khosravi, Naderi,
Dehghan, Nadjarzadeh, &
Fallah Huseini, 2016
A randomized double-blind
placebo-controlled trial
One hundred twenty
participates, aged
50–70 years, allocated to two
groups: (a) Ginger group (GG),
(b) Placebo group (PG).
GG group: 500 mg of ginger
powder, while PG participants
received capsules filled with
500 mg starch.
At baseline proinflammatory
cytokine (TNF-alfa and IL-1 g)
concentrations did not differs
in the groups. At 3 months,
both cytokines decreased in
the GG relative to the PG
group.
Level IB
Partecipants were treated twice
daily for 3 months.
The results of this study
indicate that ginger
supplementation may have a
promising benefits for knee
AO.
Naderi, Mozaffari-Khosravi,
Dehghan, Nadjarzadeh, &
Huseini, 2016
Double blind randomized
placebo controlled clinical
trial.
One hundred twenty patients
with moderate painful knee
OA, aged 50–70 years, Male
Two capsules of 500 mg per
day for 3 months.
At the beginning of the study
there were no significant
difference between the two
groups in terms of C-reactive
Level IB
Capsules of ginger and placebo
look the same and contains
8RONDANELLI ET AL.
TABLE 3 (Continued)
Author, year Study design Study population Type of intervention Results Evidence level
and female, allocated to two
groups: (a) Ginger, (b) Placebo
protein and nitric oxide. After
12 weeks the concentration
of these markers declined
more in the ginger group.
Ginger supplementation at
this dosage can reduce
inflammatory markers in
patients with knee AO
ginger and starch powder,
respectly
Niempoog et al., 2012 A double-blind randomized
controlled trial.
Sixty patients, allocated to two
groups: (a) Treatment group
(n= 30), (b) Placebo group,
aged 48.88 years (male);
49.09 years (female),
allocated to two groups: (a)
Ginger, (b) Placebo
Zingiber officinale (rhizome)
versus placebo: 500 mg
powered ginger in one
capsule, twice a day for
2 months vs the same looking
capsule of placebo twice a
day.
The present study showed that
1 g per day of powdered
ginger could not relieve joint
pain and improve symptoms
and the quality of life during
8 weeks of treatment of AO
of the knee compared with
the placebo.
Level IB
Nieman et al., 2013 Placebo-controlled, randomized,
double-blind clinical trial.
One hundred men and women,
ages 50–75 years with a
history of join pain
>3 months, allocated to two
groups: (a) Instaflex, (b)
Placebo
InstaflexTM is a joint pain
supplement containing
glucosamine sulfate,
methylsufonlylmethane
(MSM), white willow bark
extract (15% salicin), ginger
root concentrate, boswella
serrata extract (65% boswellic
acid), turmeric root extract,
cayenne, and hyaluronic acid
(4.0 mg).
Results from this support the
use of the Instaflex dietary
supplement in alleviating joint
pain severity in middle-aged
and older adults, with
mitigation of difficulty
performing daily activities
most apparent in subjects
with knee pain.
Level IB
Treatment: 1 gel capsule for
three times a day for 8 weeks
for INSTAFLEX and placebo.
Chopra et al., 2013 Randomized, double-blind,
parallel-efficacy, four-arm,
multicentre equivalence drug
trial.
Four hundred forty eligible
patients suffering from
symptomatic knee OA were
enrolled and monitored as per
protocol. Age > 55, four
groups: Ayurvedic groups
(two shunthi-guduchi
formulations, SGCG and
SGC), vs glucosamine sulfate
or celecoxib
Ayurvedic formulations SGCG
and SGC (without Boswelia
Serrata) are extracts of
Tinospora cordifolia
(73.33 mg), Zingiber officinale
(33.33 mg), Emblica officinalis
(166.66 mg), Boswellia serrata
(100 mg). Two capsules for
three times a day with palin
water after a meal or snack.
Ayurvedic drugs were found
equivalent to oral
glucosamine sulfate and
celecoxib in reducing knee
pain and improving knee
function.
Level IB
Glucosamine sulphate (2 g daily)
and celecoxib (200 mg daily)
for 24 weeks.
(Continues)
RONDANELLI ET AL.9
TABLE 3 (Continued)
Author, year Study design Study population Type of intervention Results Evidence level
Yip & Tam, 2008 Double-blind,
placebo-controlled clinical
trial
Of the 59 participants enrolled
in this study, 53 (89.8%)
participants completed both
post 1-week and 4-week
follow-up. The majority of the
53 participants were women
(79%) and the mean age was
73.59 years old
(S.D. = 5.42 years). Their
mean knee joint pain history
was 9.71 years (S.D.
= 7.05 years). Partecipants
were allocated to groups: (a)
Intervention group (IG), (b)
Placebo control group (PG),
(c) Control group (CG).
Ginger oil versus orange oil:
Ginger essential oil (1% ginger
and 0.5% Citrus sinensis oil in
olive oil as the base lubricant)
and conventional treatment.
0.5% orange essential oil
(Citrus aurantium).
The intervention group reported
a reduction in knee pain
rating (at the 4-week
follow-up period. No
significant differences were
reported in mean change in
stiffness intensity for
betweengroup comparison at
thepost 1-week follow-up or
post 4-week follow-up.
Level IB
Sessions of 30–35 min of aroma
massage on both lower imbs,
six times witin 2–3 weeks.
Drozdov, Kim, Tkachenko, &
Varvanina, 2012
Randomized clinical trial. Forty-three patients (35F, 8 M),
aged 55.1–3.1 years, with an
average disease duration of
7.1–1.3 years, were allocated
to two groups: (a) Ginger, (b)
Diclofenac
The ginger group received a
specific ginger combination
daily (340 mg EV.EXT 35
Zingiber officinalis extract) for
4 weeks. The diclofenac
group received 100 mg
diclofenac daily for the same
period. Both groups also
received 1,000 mg
glucosamine daily.
The ginger group showed a
slight but significantly
decreased upper SODA pain
intensity by the 28th day of
treatment with p= .05. SODA
dyspepsia did not change
significantly during the
treatment and the dyspepsia
index remains the same with
p= .6. EGDS showed
significantly increased levels
of PGE1, PGE2, and PGF2a in
the stomach mucosa. The
diclofenac group showed
increased SODA pain and
dyspepsia values with a
corresponding significant
decrease of stomach mucosa
prostaglandins and general
negative stomach mucosa
degeneration.
Level IB
The ginger group with 21
patients (17F, 4 M) and. The
diclofenac group (positive
control) of 22 patients (18F,
4M)
10 RONDANELLI ET AL.
(TTM). This study demonstrated that SMGO was more effective than
TTM in reducing pain and improving disability at short- and long-term
assessments. It's important to note that there might be a lack of meth-
odology in this study, because the difference might be due to the type
of massage not to the use of ginger. Moreover, it is not clear if the
benefit of low back pain is due to the massage and ability of the oper-
ator itself or the medical principle of ginger drug in the aromatic oil.
3.5 |Migraine
One single RCT (Cady et al., 2011) on humans could be considered as
the first effort to elucidate the use of ginger in this frequently dis-
abling disease that is present in a large slice of the adult population.
This multi-center RCT on feverfew/ginger use seems to suggest an
effective treatment to migraine.
Migraine is a complex neurological disease characterized by episodic
periods of disabling physiological dysfunction typically recurring over
decades of an individual's lifetime (Cady, Schreiber, & Farmer, 2004).
Treatment needs for migraine vary considerably from patient to
patient and indeed, from attack to attack for the same patient.
Pharmacologically, many over the counter and prescription products
are effective on treatment in acute migraine (Monteith &
Goadsby, 2011). Commonly employed acute treatments approved for
migraine can be classified as over the counter products, such as acet-
aminophen/aspirin/caffeine combination products and non-steroidal
anti-inflammatory medications (Wenzel, Sarvis, & Krause, 2003), and
prescription products, such as triptans and non-steroidal anti-
inflammatories (Ng-Mak, Hu, Chen, & Ma, 2008). Various opioid and
butalbital-containing analgesics are also commonly prescribed, but most
do not have Food and Drug Administration approval for migraine, and
are generally avoided by physicians because of their propensity to pro-
duce medication overuse headache (Bigal, Rapoport, Sheftell, Tepper, &
Lipton, 2004; Snow, Weiss, Wall, & Mottur-Pilson, 2002).
The main limitation of this review is represented by searching just
two databases and only English literature.
4|CONCLUSION
Current evidence in vitro and in animal models demonstrated that
many different compounds of ginger have been shown to posses
TABLE 4 Summary of articles about effect of ginger on migraine and low back pain
Author, year Study design Study population Type of intervention Results
Evidence
level
Sritoomma,
Moyle, Cooke,
&O’Dwyer,
2014
Randomized controlled
trial
One hundred sixty-four
patients were screened;
140 were eligible, and
randomized to two
groups: (a) Swedish
massage with aromatic
ginger oil (SMGO)
(n= 70), (b) TTM
(n= 70). Female and
male, aged 60 years.
Aromatic ginger oil used
for Swedish massage in
SMGO group contains
10 ml of jojoba oil and
2% of aromatic ginger
oil for massaging.
Traditional Thai Total
sample massage (TTM).
Both SMGO and TTM led
to significant
improvements in pain
intensity (p< .05) and
disability (p< .05)
across the period of
assessments, indicating
immediate, short- and
long- term
effectiveness. SMGO
was more effective
than TTM in reducing
pain (p= .04) and
improving disability at
short- and long-term
assessments (p= .04).
Level IB
Cady et al., 2011 A double-blind
placebo-controlled
pilot study
Sixty patients, female and
male, aged 12–60 years
with migraine, were
randomized allocated
3:1 into two groups: (a)
feverfew/ginger, (b)
placebo.
Forty-five subjects for a
total of 208 attcks of
migraine over 1 month,
Were treated with
feverfew/ginger:
2 units dose
applications. If any
headache pain persists
at 1 hr, a second
treatment of 2 units
could be administred.
Sublingual formulation of
feverfew/ginger
appears safe and
effective as a first-line
abortive treatment for
a population of
migraineurs who
frequently experience
mild headache prior to
the onset of moderate
to severe headache.
Level IIB
Fifteen subjects of the
placebo group treated
58 attacks with a
sublingual placebo
preparation.
RONDANELLI ET AL.11
antioxidative and anti-inflammatory activities that may be active
in lowering chronic inflammatory disease symptoms, in particular,
pain. This pain-reducing effect of ginger has been modulated
through various mechanisms: inibition of prostaglandins via the
COX and LOX-pathways, antioxidant activity, inibition of the
transcription factor nf–kB,oractingasagonistofvanilloid
nociceptor.
However, human studies that were carried out to assess whether
oral or topic ginger has a positive effect by reducing pain are not
numerous; furthermore, in these studies different dosages and
methods of administration were used, as well as different study
designs.
This narrative review summarizes the last 10-year of RCT, in
which ginger was traditionally used as a pain reliever for dysmenor-
rhea, DOMS, knee AO, CLBP, and migraine.
Regarding dysmenorrhea, six eligible studies suggest a prom-
ising effect of oral ginger. As concerns DOMS, the four eligible
RCTs suggested a reduction of inflammation after oral and topi-
cal ginger administration. Regarding knee AO, eight RCTs agree
in stating that oral and topical use of ginger seems to be effec-
tive against pain, while others did not find significant differences.
One RCT considered the use of ginger in migraine and suggested
its beneficial activity. Finally, one RCT evaluated the effects of
Swedish massage with aromatic ginger oil on CLBP demonstrated
areductioninpain.
The most of the included trials were conducted in Asia.
Pharmacogenetics and outcome expectancy regarding ginger inter-
vention could differ across cultures and ethnicities, and therefore, it is
necessary to confirm the promising effects in the worldwide
population.
In conclusion, the use of ginger for its pain lowering effect is safe
and promising, even if more studies are needed to create a consensus
about the amount of ginger useful for long-term therapy. The positive
health benefits need to be interpreted with caution due to the small
number of studies, poor methodological quality, and high heterogene-
ity across the trials. Therefore, new studies, possibly multi-center RCT
in different continents, with an adequate number of patients and with
standardized ginger formulations, are necessary to confirm the results
of this review.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
ORCID
Mariangela Rondanelli https://orcid.org/0000-0001-8336-4851
Clara Gasparri https://orcid.org/0000-0002-1088-6648
Gabriella Peroni https://orcid.org/0000-0002-1632-1787
Daniele Spadaccini https://orcid.org/0000-0001-6413-9253
Antonella Riva https://orcid.org/0000-0003-2819-943X
Giovanna Petrangolini https://orcid.org/0000-0001-6681-7329
Mara Nichetti https://orcid.org/0000-0003-1902-817X
Vittoria Infantino https://orcid.org/0000-0001-8172-5182
Simone Perna https://orcid.org/0000-0002-2720-1473
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How to cite this article: Rondanelli M, Fossari F, Vecchio V,
et al. Clinical trials on pain lowering effect of ginger: A
narrative review. Phytotherapy Research. 2020;1–14. https://
doi.org/10.1002/ptr.6730
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