Pain is described as an unpleasant sensory and emotional experience associated with actual or potential tissue damage (Bode and Dong, 2011; Desai et al., 2012; Simon, 2012). There are two common types of pain, acute pain and chronic pain. Basically, acute pain is crucial in alerting an individual to withdraw from a harmful situation while chronic pain could be constitute of serious, separate disease entity (Desai et al., 2012). For more detailed information, chronic pain is highly prevalent, affecting over 1.5 billion people worldwide (National Center for Health Statistics, 2007; Medeiros and Winsler, 2014). It is noteworthy that chronic pain affects more people than other chronic conditions such as diabetes, heart disease and cancer (Simon, 2012). The annual costs of chronic pain in the United States (including the total incremental cost of health care and cost of lost productive time) are estimated to be at least USD 560 billion (Medeiros and Winsler, 2014). As suggested by studies, chronic pain has a huge detrimental effect on the quality of life of patients (National Center for Health Statistics, 2007; Medeiros and Winsler, 2014). Undeniably, chronic pain is a significant healthcare issue, as it poses an enormous burden on patients, society and the healthcare system (Medeiros and Winsler, 2014).

In particular, neuropathic pain is a major form of chronic pain. Neuropathic pain results from dysfunction or lesions in the central and peripheral nervous system (Bridges et al., 2001; Campbell and Meyer, 2006; Treede et al., 2008; Nickel et al., 2012). Neuropathic pain conditions include HIV neuropathy (neurological complication of HIV) and postherpetic neuroglia (Derry et al., 2013). Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster ophthalmicus (HZO), commonly known as shingles, especially in elderly patients (Bucci et al., 1988). Besides, it is estimated that 10–15% of patients who have shingles will experience PHN (FDA, 2009). In particular, this disease is characterized by a distinctive syndrome—a painful skin rash mainly caused by reactivation of varicella zoster virus (VZV), especially if there is immunity to VZV drops due to aging or immunosuppression (Johnson and Whitton, 2004). Unfortunately, current treatment modalities such as tricyclic antidepressants and anticonvulsants are largely unsuccessful (due to adverse effects, poor tolerability and slow onset of action) (Bucci et al., 1988; Backonja et al., 2008). Unlike nociceptive pain, neuropathic pain such as PHN cannot be relieved by conventional analgesics such as paracetamol (Bridges et al., 2001). To make the scenario even worse, the prolonged and unresolved excruciating pain resulting from PHN often leads to depression, and in extreme cases suicide (Bucci et al., 1988).

Over the last three millennia, human civilization has relied on natural products derived from plants, animals and microbial origins to alleviate and cure sickness (Tan et al., 2015a,b; Tang et al., 2016; Yuan et al., 2016). From as far back as 60,000 years ago, in the Middle Paleolithic Age, there is evidence that humans were using plants as medicines (Fabricant and Farnsworth, 2001). The use of plants in traditional medical systems such as Ayurveda, Unani, Kampo and traditional Chinese medicine have flourished for 1000s of years (Fabricant and Farnsworth, 2001; Tan et al., 2016a,b). Although medical science views such systems as lacking credibility and scientific logic, it is notable that a lot of plant-originated drugs in current clinical medicine were derived from traditional medicine and serve as platforms for modern drug development. Most importantly, those products have become resources for developing new lead compounds and scaffolds (Fabricant and Farnsworth, 2001; Chan et al., 2016; Tan et al., 2016c). Given that over one-third of the world’s population, mainly in rural areas, lacks regular access to affordable modern medicines, the majority of people from countries in Africa, Asia and Latin America largely rely on traditional medicine, which is widely available to help meet some of their primary health care needs (Zhang, 2004; Verma and Singh, 2008).

Plants are reported to have been traditionally used as analgesics or resources for compounds with pain-relieving effects (Hamilton and Baskett, 2000; Tan et al., 2015a; Chan et al., 2016). For instance, opiate receptor agonists from poppy seeds and cyclooxygenase inhibitors from willow bark are widely used to alleviate pain in ancient medicine (Brownstein, 1993; Thun, 2000). Chili is also one of the sources for analgesic medications derived from plants. The ‘chili’ or ‘chili pepper’ plant, which is categorized under the genus Capsicum, belongs to a dicotyledonous group of flowering plants. The taxonomic position of Capsicum can be represented as follows: Kingdom – Plantae; Division – Magnoliophyta; Class – Magnoliopsida; Order – Solanales; Family – Solanaceae; Genus – Capsicum; Species – chinense/annuum/pubescens/etc. (Basu and Krishna, 2003).

Since ancient times, chili has been recognized for its broad range of therapeutic properties, and has been used for centuries to remedy pain. Several external and internal applications have been reported in various streams of traditional medicine (Khan et al., 2014; Maji and Banerji, 2016). Externally, it is used to treat different types of pain including rheumatism (joint pain), lumbago (lower back pain) and neuralgia (pain spread through nerves) (Khare, 2004). It can also be used as a local stimulant, counter-irritant, and rubefacient (Iwu, 1993; Panda, 1999). Internally, chili is used to treat dyspepsia, loss of appetite, flatulence, atherosclerosis, stroke, heart disease, and muscle tension (Panda, 1999; Khare, 2004). In Unani medicine, chili is utilized to prevent colds, sinus infections and sore throats, and to improve digestion and blood circulation (Khare, 2004). In folk medicine, it is suggested to treat cancer, asthma, bronchitis and cough. In addition, its regular consumption is also believed to be beneficial for anorexia, hemorrhoids, liver congestion, and varicose veins (Duke and DuCellier, 1993).

The broad traditional usage of chili has prompted the identification of capsaicin as the main active component of a variety of chili peppers such as habaneros and jalapeños. Capsaicin is responsible for causing the ‘hot’ and sharp pungent sensation (Bode and Dong, 2011). Those properties have been suggested to act through counter-irritation, which results in analgesic effects. Modern usage of capsaicin focuses on the treatment of various types of pain (Cortright et al., 2007). In fact, capsaicin has been studied clinically as a topical treatment for the pain of rheumatoid and osteoarthritis (Persson et al., 2016), psoriasis, diabetic neuropathy, and postherpetic neuralgia (Srinivasan, 2015). However, the efficacy of capsaicin in the treatment of these chronic pain disorders is still elusive.

In order to have a better understanding of the various action of capsaicin, studies have focused on the mechanism of capsaicin in pain induction (Cortright et al., 2007). It is known as a selective TRPV1 receptors ligand. The burning sensation is triggered upon the binding of capsaicin to the receptors. It is believed that the analgesic effect of capsaicin is due to its ability to cause reversible desensitization or defunctionalization, where the TRPV1-containing sensory axons become unresponsive to stimuli during the long-lasting refractory period (Bode and Dong, 2011; Derry et al., 2013). As a result, after repeated exposure to capsaicin, pain transmission is prevented and the pain response is reduced (Derry et al., 2013). As such, it is different from other naturally occurring irritant components. This feature of capsaicin has been exploited for therapeutic use for many years. Other than that, its ability to cause reversible nerve-fiber degeneration also contributes to the analgesic effect (Bode and Dong, 2011; Derry et al., 2013).

Conventionally, topical capsaicin has been used in pain management in numerous neuropathic pain conditions. FDA (2009), the Qutenza patch, a pure, synthetic capsaicin-containing prescription drug, was approved by the Food and Drug Administration (FDA) for long-term pain relief for PHN patients. In spite of that, its safety has been much debated. This is mainly because capsaicin is associated with some severe side effects such as capsaicin-induced dermal pain and contact dermatitis (human hand) (Bode and Dong, 2011). Topical capsaicin products such as Qutenza may cause a significant rise in blood pressure, necessitating the need for blood-pressure monitoring by health care professionals (FDA, 2009). Emerging evidence has also suggested that long-term application of topical capsaicin may be harmful. As mentioned previously, capsaicin exerts its therapeutic action by the desensitization process. Therefore, prolonged use of topical capsaicin may lead to persistent desensitization. Furthermore, multiple epidemiology studies have suggested that capsaicin may have carcinogenic properties. Its effectiveness has also not been fully established (Bode and Dong, 2011). Additionally, the effectiveness of topical capsaicin varies among patients with different conditions. It also seems to have inconsistent effectiveness across neuropathic pain conditions.

At the same time, there is a lack of comprehensive reviews on the effectiveness of capsaicin on PHN. Furthermore, earlier reviews have not included recent evidence (from research conducted using more rigorous and stringent standards). There is a need to conduct a literature review that includes the recent studies. By doing so, we will be able to investigate the effectiveness and safety of topical capsaicin using recent evidence.

The PICO framework is utilized to develop the main question (Gray, 2003). By referring to the relevant review articles and papers, the research question is further refined. The research question is: ‘Is topical capsaicin efficacious and safe (compared to a placebo) to be used as a first-line treatment in the management of chronic neuropathic pain (particularly PHN) in adult and elderly patients?’ By critically appraising the included studies, we will investigate the efficacy and safety of topical capsaicin in pain management. Topical capsaicin is usually prescribed as a third-line treatment or adjunctive treatment (Argoff, 2011). Based on the findings, we will evaluate its risk-benefit ratio and explore the feasibility of using topical capsaicin as a first-line treatment in PHN (Figure 1). It could potentially be used as a first-line option if it shows adequate efficacy and safety.

A systematic literature search was performed using databases including PubMed, Medline, Embase, Science Direct and Google Scholar. Cochrane Library and Wiley Library were also used to retrieve related papers.

Initially, a total of 109 records were identified using the search string (105 were found from Pubmed and Cochrane databases). There were 41 results remaining after duplicate results were removed. After screening the results using the inclusion and exclusion criteria described earlier, 34 results were excluded. The eliminated results include six reviews, two integrated studies, two short articles, one case series, one letter to an editor, four studies published only as abstract, one study that directly compared the efficacy of two agents, one preliminary study, two open label studies and a number of randomized controlled trials that were out of the research scope. Watson et al. (1993), which consists of both the double-blind phase and the long-term open-label phase, was included. However, only the results from the double-blind phase were analyzed. By further analyzing the full text of the seven remaining papers, only six fulfilled all the inclusion and exclusion criteria and were included in the review for qualitative analysis. Backonja et al. (2010), whose study lasted only 4 weeks, was excluded. All studies were included in quantitative analysis except Bernstein et al. (1989), due to the limited quantitative data.

Due to the limited number of recent studies, publications dated from 1989 to 2010 were included. However, most of the included studies are recent studies. The process of the literature search is depicted in the PRISMA flow chart attached (Figure 2).

Management of neuropathic pain such as PHN is more challenging than other types of pain (Park and Moon, 2010). In general, patients with neuropathic pain have higher pain scores than patients with non-neuropathic pain (Park and Moon, 2010). In addition, patients with neuropathic pain are reported to have a lower quality-adjusted life-year (QALY) and a higher risk of depression (Bucci et al., 1988; Park and Moon, 2010). They also experience less pain relief with the standard treatment, so they usually need multiple drugs and adjunctive treatments for adequate pain management (Smith et al., 2007; Park and Moon, 2010).

For PHN patients, good adherence to medicine is particularly important for adequate pain management. Patients need to continuously reapply capsaicin cream throughout the day due to the low concentration of the active ingredient (0.025–0.075%) (Das et al., 2013). The four-times-daily application may threaten medication compliance (Jorge et al., 2011).

While capsaicin cream (which requires frequent application) may reduce adherence, a capsaicin patch could potentially improve a patient’s adherence, as such a patch only needs to be reapplied every 3 months (Das et al., 2013). This could be accounted for by the down-regulation of TRPV-1 receptors (Jorge et al., 2011). The use of a capsaicin patch allows the medication regimen to be simplified and hence improves medicine adherence. The use of topical capsaicin in place of tricyclic antidepressants and anticonvulsants (which are commonly used to treat PHN) also eliminates the need to titrate doses, thus minimizing the risk of side effects or withdrawal symptoms.

Besides, topical capsaicin does not have systemic effects (e.g., CNS effects). As reported in one study, CNS impairment is the least acceptable side effect of pain-relieving medicines among chronic pain patients (Jorge et al., 2011). Hence, topical capsaicin would be better received than other conventional treatment options (which have significant systemic effects). The increased patient acceptance of medicine could significantly improve adherence and eventually lead to better pain management.

As topical capsaicin is able to provide efficient pain relief with fewer central nervous system effects and a minimal drug regimen burden, it seems to be an ideal candidate as a first-line agent in the management of PHN (Bernstein et al., 1989; Jorge et al., 2011). However, in practice, topical capsaicin is not commonly used as first-line treatment in chronic pain management (NICE, 2013). In fact, it is not advisable to use topical capsaicin (capsaicin patch) for initial treatment. For the initial treatment of PHN, the recommended first- and second-line agents are gabapentin, a lidocaine patch, opioid analgesics, and tricyclic antidepressants (Dworkin et al., 2003). Like the cream formulation, capsaicin patches may cause a burning sensation (Das et al., 2013). As placement of the patch can be quite painful, a local topical anesthetic or opioid pain relievers must be used concurrently during application (FDA, 2009). A capsaicin patch may also increase blood pressure during initial application (Das et al., 2013). In fact, the FDA recommends blood-pressure monitoring for at least an hour after the application of a capsaicin patch. In general, the role of topical preparations in patient adherence remains unclear, as there is a lack of compliance studies that compare traditional routes (e.g., oral) and topical treatment in chronic pain management (Jorge et al., 2011).

It should be noted that some of the studies, including Backonja et al. (2008) and Webster et al. (2010a,b), are funded or sponsored. This could be a potential source of bias, as inappropriate influence of funders is often regarded as a risk of bias (Higgins and Green, 2011; Lexchin, 2012). There may be potential conflicts of interest.

Blinding of outcome assessors can be especially important for assessment of subjective outcomes, such as degree of pain. All studies are adequately described as double-blind, but maintenance of blinding is not well-described in some studies (e.g., Bernstein et al., 1989). Besides, blinding may have been broken if the participants correctly guessed which group they were in. In that case, the participants may not be truly blinded. Generally, blinding is considered to be broken if more than 50% of guesses are correct. To ensure adequate blinding, low-concentration capsaicin is used in the control group instead of an inert placebo in studies such as Webster et al. (2010a,b) and Irving et al. (2011). However, this may confound the results of the studies. For example, in Webster et al. (2010b), spontaneous resolution of postherpetic neuralgia may have resulted in better reduction of pain in the control group. Additionally, a data review has shown that there may be a difference in pain score reporting (PGIC) between genders. This could be a potential source of bias. Hence, a gender-stratified analysis is required. In studies where an NPRS score was not assessed (Bernstein et al., 1989; Watson et al., 1993), a VAS score was instead used as a primary outcome.

Capsaicin, the main component in chili peppers, has immense ethnopharmacological potential, and has served as one of the main adjunctive treatments for neuropathic pain such as PHN. The current review aimed to compile and investigate the efficacy and safety of topical capsaicin in management of chronic pain caused by PHN. Based on a literature search, all the six included studies suggest that topical capsaicin is efficacious but at the same time is associated with a higher incidence of side effects. This prompted the need for a meta-analysis study. Based on the analysis, five of the included studies indicated the treatment with capsaicin has better efficacy compared to a vehicle-controlled placebo. However, the results of two studies involving 298 out of the 1415 total pooled population are not statistically significant. Unfortunately, the answer to the research question remains inconclusive. Therefore, it is still unclear whether or not topical capsaicin should be used as a first-line treatment. Further evidence is required to determine the risk-benefit ratio and support the use of capsaicin as a first-line treatment.

YY, LT, LM contributed to the literature database search, data collection, data extraction, data analysis, and writing of the manuscript. TK, K-GC, B-HG, and L-HL performed data analysis and rationalization of the results. The topic was conceptualized by B-HG, L-HL, and TK.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.