Clinical trials on pain lowering effect of ginger: A narrative review

Ginger has a pain‐reducing effect and it can modulate pain through various mechanisms: inhibition of prostaglandins via the COX and LOX‐pathways, antioxidant activity, inibition of the transcription factor nf–kB, or acting as agonist of vanilloid nociceptor. This narrative review summarizes the last 10‐year of randomized controlled trials (RCTs), in which ginger was traditionally used as a pain reliever for dysmenorrhea, 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 activity. 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 consensus about the dosage of ginger useful for long‐term therapy.

Patients suffering from diseases associated with chronic inflammation are turning to alternative compounds for relief of their symptoms 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 beginning 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 proinflammatory cytokines and LPS-activated macrophages antigen presentation (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 dosedependent 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 production, 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 generation 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 inflammation is now generally accepted.
6-gingerol displayed anti-inflammatory activity by decreasing inducible NO synthase and TNF-α expression through the suppression of I-kBα phosphorylation, NF-kB nuclear activation, and PKC-α translocation. 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).
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 receptors 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 demonstrated 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 traditionally used in order to control pain, such as: dysmenorrhea, delayed onset muscle soreness (DOMS), knee osteoarthritis, chronic low back pain (CLBP), and migraine.

| 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 compared with a placebo or active treatment in diseases. The analysis was carried out in the form of a narrative review (Figure 1).  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 sample 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 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 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 developing future pain (Berkley & McAllister, 2011;Vincent et al., 2011). Dysmenorrhea is conventionally treated with nonsteroidal antiinflammatory drugs (NSAIDs) or oral contraceptive pills (OCPs) (Dawood, 2006), the efficacy of which are supported by research evidence (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 alternative treatments for dysmenorrhea is warranted. Ginger is one of the most commonly used natural products among women with dysmenorrhea. 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 suppresses the synthesis of prostaglandin (through inhibition of cyclooxygenase) and leukotrienes, which are involved in dysmenorrhea 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 demonstrating 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.

| 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 Double-blind, randomized placebo-controlled trial. Twenty Non-weight trained partecipants allocated in two groups.
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).  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). Inflammatory 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 damage (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 exercises, massage, and nutritional supplementation. Non-steroidal antiinflammatory 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).

| 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 (  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 effective 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 treatments 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 concern 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-

| 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

| 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 disabling 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 acetaminophen/aspirin/caffeine combination products and non-steroidal anti-inflammatory medications (Wenzel, Sarvis, & Krause, 2003), and prescription products, such as triptans and non-steroidal anti- 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, or acting as agonist of vanilloid 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 dysmenorrhea, DOMS, knee AO, CLBP, and migraine.
Regarding dysmenorrhea, six eligible studies suggest a promising effect of oral ginger. As concerns DOMS, the four eligible RCTs suggested a reduction of inflammation after oral and topical ginger administration. Regarding knee AO, eight RCTs agree in stating that oral and topical use of ginger seems to be effective 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 a reduction in pain.
The most of the included trials were conducted in Asia.
Pharmacogenetics and outcome expectancy regarding ginger intervention 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 heterogeneity 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.