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. 2023 Nov 24;102(47):e36268. doi: 10.1097/MD.0000000000036268

Efficacy and safety of TRPV1-related preparations in the treatment of inflammatory arthralgia

Xin Zhou a,*, Ziping Li a, Bingfeng Xing b
PMCID: PMC10681444  PMID: 38013379

Abstract

Background:

Currently, medications for the treatment of inflammatory arthralgia are limited. The role and safety of transient receptor potential vanilloid subtype 1 (TRPV1)-related preparations in reducing inflammatory arthralgia have not yet been fully established. Thus, we aimed to review the efficacy and safety of TRPV1-related preparations for the treatment of inflammatory arthralgia.

Methods:

We searched PubMed, Web of Science, Cochrane, and Embase databases for relevant studies, and the primary outcome was pain score (VAS, PI, NRS, and WOMAC).

Results:

Six randomized controlled trials involving 481 patients were analyzed. Patients with inflammatory arthralgia who received TRPV1-related preparations had lower pain scores after treatment than those who received placebo or nonsteroidal anti-inflammatory agents (standardized mean difference = –0.525; 95% confidence interval [CI], –0.789 to –0.261; P < .001). There was no significant difference in the incidence of total adverse reactions between the TRPV1-related preparations and control groups (relative risk = 1.225; 95% CI, 0.685 to 2.191; P = .494).

Conclusion:

TRPV1-related preparations are clinically safe and effective in the treatment of inflammatory arthralgia and are superior to placebo or nonsteroidal drugs. This may be the preferred treatment for patients with inflammatory arthralgia.

Keywords: inflammatory arthralgia, TRPV1-related preparations

1. Introduction

The incidence rate of inflammatory arthralgia, especially in the neck, waist, knee, and hip joints, increases with age, which causes significant burden to daily life. Controlling the progress of inflammation is an important means of protecting the normal shape and function of joints in inflammatory arthralgia. Some types of arthritis are associated with a high risk of disability. For example, the disability rate of knee osteoarthritis is as high as 50% within 2 years, which seriously affects the quality of life of patients and increases the economic pressure of family and society care and treatment.[1,2] Inflammatory arthralgia in the early and middle stages is mainly treated with anti-inflammatory and analgesic drugs, mainly oral nonsteroidal drugs. However, such drugs cause serious adverse effects to the gastrointestinal tract, are not suitable for long-term use, and have significant side effects.[3,4] However, recently, the use of cartilage repair as a target, such as chondroitin and glucosamine-containing formula drugs and intra-articular injection of viscous supplements (sodium hyaluronate, platelet-rich plasma), has also been controversial owing to the lack of evidence regarding its clinical efficacy.[5,6]

Pain that lasts longer than the healing time of joint tissue (approximately 3 months) is considered chronic inflammatory arthralgia[7] and is the most common reason for seeking advice from primary care units. In the United States alone, the estimated cost of chronic inflammatory arthralgia exceeds $600 billion annually.[3] It may originate from nerve injury (neuropathic pain) and is usually associated with changes in the plasticity of the peripheral nerve and central nervous system, leading to changes in the detection, transmission, processing, and regulation of pain.[8,9] Several meta-analyses have demonstrated that among the commonly used drugs for neuropathic pain, the potential benefits of cannabis-based drugs (herbal cannabis, plant-derived or synthetic tetrahydrocannabinol [THC], THC/cannabidiol oral mucosal spray) in chronic neuropathic pain may be offset by their potential hazards[10]; that pregabalin is only effective in postherpetic neuralgia and diabetes neuralgia,[11] and that its administration also significantly increases the risk of adverse events and drug withdrawal due to its adverse events.[12] Gabapentin also lacks clear evidence for its efficacy in the treatment of neuralgia.[13] At present, side effects and insufficient evidence of the efficacy of conservative medications for inflammatory arthralgia in different periods are limited.

In recent years, transient receptor potential vanilloid subtype 1 (TRPV1)-related preparations for the treatment of inflammatory arthralgia have shown therapeutic potential in clinical and animal experiments. TRPV1 is a pressure-sensitive Ca2 + channel protein that is widely distributed in various tissues of the human body. TRPV1 agonists can reduce pain mainly by destroying pain nerve conduction, and the local application of capsaicin in the joint cavity can lead to calcium toxicity in the afferent terminal nerve cells containing TRPV1, thus relieving arthralgia. However, the degree of damage depends on the dosage, and the effect of capsaicin is reversible.[14] The common TRPV1 agonists are mainly capsaicin, and the inhibitors are NEO6860 and mavatrep. The 2 preparations are currently widely used in clinical pain management. Current evidence shows that capsaicin has a better long-term pain reducing effect on chronic inflammatory arthralgia pain,[15–18] which can alleviate chronic neck, shoulder, knee, and hip pain, while TRPV1 inhibitors mainly alleviate knee joint pain.[19,20] Powerful TRPV1 agonists (such as resin toxins) can achieve long-term pain relief.[21] Other studies have focused on silencing or antagonizing TRPV1. By antagonizing TRPV1, the pain transmission in the terminal sensory nerve cells is blocked, reducing pain.[19] A recent study has demonstrated that activating TRPV1 on the synovium of joints can effectively delay the inflammatory progress of the synovium in arthritis.[22] Although TRPV1-related preparations have great therapeutic potential in relieving pain and improving the progress of inflammation, whether TRPV1 agonists or antagonists are used, there are certain risks. They may lead to calcium toxicity of normal cells or cause joint repair dysfunction. We speculate that the efficacy and side effects of TRPV1 in treating inflammatory arthralgia pain are significantly correlated with its concentration and mode of use. Therefore, it is necessary to analyze and review current clinical studies on TRPV1-related preparations. At present, there are no meta-analyses of randomized controlled trials (RCTs) that assess the role and safety of TRPV1-related preparations in the treatment of inflammatory arthralgia. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy and safety of TRPV1-related drugs for arthralgia.

2. Methods

2.1. Search strategy

All analyses were based on data from previously published studies. No ethical approval or patient consent was obtained. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.[23] The a priori protocol for this review was published in the International Prospective Register of Systematic Reviews. (CRD42022360217).

Two investigators independently searched the following electronic databases to identify relevant studies from January 2000 to March 2023: PubMed, Embase, Web of Science, and the Cochrane Library. Relevant journals, conference proceedings, and reference lists were manually searched for additional studies.

The research was performed using a combination of the following keywords on December 21, 2022: (arthralgia or osteoarthritis or arthritis) AND (TRPV1 antagonist or TRPV1 agonist). The search strategy for each database is presented in Figure 1. In addition, the literature was manually searched from the reference lists of articles identified from the search of electronic databases. The inclusion and exclusion criteria were based on the Population, Intervention, Comparison, Outcome method.[24,25] No Patient and Public Involvement statement since the study has no human participants.

Figure 1.

Figure 1.

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Meta-analyses flowchart for inclusion of eligible studies.

2.2. Eligibility criteria

RCTs regarding the effect of TRPV1-related preparations in patients with inflammatory arthralgia (physician or self-reported physician diagnosis along with matching items based on the American College of Rheumatology clinical criteria[26,27]) were included in this review. The included studies were published in English language. Articles were excluded if the study was a non-RCT or a nonclinical trial. Abstracts from meeting proceedings with no corresponding full article published in a peer-reviewed journal or no specific data provided, even after contacting the author, were excluded. All disagreements were resolved by consensus with the help of a third reviewer.

2.3. Data extraction and risk-of-bias assessment

Two authors independently extracted the data. Demographic and baseline characteristics, treatment design, and results were extracted from the eligible studies. Results were extracted as binary or continuous variables. We extracted the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, numerical rating scale (NRS), pain intensity(PI) and visual analog scale (VAS) scores, of patients with osteoarthritis (OA) and adverse reactions after treatment. If no data can be extracted, other RCT should be conducted. The difference between the data before and after treatment was used to calculate efficacy. The quality of the included trials was assessed using the risk-of-bias tool of the Cochrane Collaboration. Funnel plots and Begg and Egger tests were used to evaluate publication bias.

2.4. Data synthesis and analysis

Stata version 15.0 and Review Manager was used to analyze the data and draw forest, sensitivity analysis, and funnel maps. The pain outcome was a continuous variable, and there were differences in the pain evaluation methods included in the study. Therefore, the standardized mean difference (SMD) was used for statistics of the pain indicators combined with the effect amount, and its 95% confidence interval (CI) was calculated. The adverse reaction outcome was classified as a variable; thus, the combined effect was calculated by relative risk (RR) and 95% CI. If there was no special description, the Q test was used to analyze the heterogeneity of the included studies. When I2 was > 50% and P was < .1, there was a significant heterogeneity among the studies, and the random effects model was used. However, if there was no significant heterogeneity among the studies, the fixed effects model was used. The stability of the results was evaluated using the sensitivity analysis method of removing 1 document at a time. Funnel plots and Begg and Egger tests were used to evaluate publication bias. If there was no special description, the results were all bilateral tests, and P < .05 indicated a significant difference.

3. Results

3.1. Study characteristics

According to the inclusion criteria, 6 RCTs published from 2000 to 2022 were included in this study, and the data were extracted and analyzed. All studies were published in English language, and 481 patients were included, including 394 patients in the TRPV1 agonist test group[15–18] and 87 patients in the TRPV1 antagonist test group.[19,20] The pain sites of the subjects included the neck, knee, hip, shoulder, and hands. The routes of administration included oral, external, and intra-articular. The overall intervention time ranged from 1 to 104 days. The specific sample size, demographic characteristics, and WOMAC and NRS scores before and after treatment in each study are shown in the baseline (Table 1).

Table 1.

Demographic and clinical characteristics of included studies.

Research Country TG ADM CG Pain sites SS IT PA Mean age Mean BMI Female (%)
Cho, et al Korea Cap External p Neck 57 4W VAS 41.3 22.67 91.2
Arsenault, et al U.S.A NEO6860 Oral p Knee 54 1D PI 61.1 29.1 63.0
Persson, et al Britain Cap External I Knee 13 4w NRS 67.0 30.7 55.0
Stevens, et al U.S.A Cap Intraarticular p Knee 157 24W WOMAC 60.5 Not reported 78.3
McCleane, et al Britain Cap External p Knee/hip/shoulder/h-and 167 6W VAS 49.3 Not reported 53.3
Mayorga, et al U.S.A mavatrep Oral p Knee 33 1W NRS 52.3 30.1 33.3
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ADM = administration, Cap = capsaicin, CG = control group, D = day, I = ibuprofen, IT = intervention time, NRS = numerical rating scale, P = placebo, PA = pain assessment, PI = pain intensity, SS = sample size, TG = treatment group, VAS = visual analog scale, W = week, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

3.2. Efficacy outcomes

3.2.1. Effects of TRPV1-related preparations on inflammatory arthralgia.

Six articles compared pain-related indicators between the intervention and control groups. Two articles used NRS, 2 used VAS, 1 used pain PI and 1 used the WOMAC. The pain data in all articles were described by means (95% CI); thus, the data were converted to mean (standard deviation). In view of the heterogeneity of the study methods in the above 6 studies, the random effects model and SMD were used to describe the effect of pain indicators. The results showed that, compared with the control group, the use of TRPV1 agonists or antagonists could significantly lower the pain of patients, with a statistically significant difference (SMD = –0.525; 95% CI, –0.789 to –0.261; P < .001), and there was no significant heterogeneity between patients not receiving TRPV1 agonists or antagonists and those receiving TRPV1 agonists or antagonists (I2 = 43.6%, P = .114) (Fig. 2A). The analysis result had no significant change after removing one of the included literatures, indicating that the study result is robust (Fig. 2B). The results of Review Manager are similar to those of STATA. Compared with the control group, the use of TRPV1 agonist can significantly reduce the pain of patients, and the difference is statistically significant (SMD = −0.52, 95% CI: −0.78, −0.26; P < .001). The results are not significantly heterogeneous (I2 = 41%, P = .13) (Fig. 2C).

Figure 2.

Figure 2.

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(A–C) Comparison of pain relief efficacy of TRPV1-related preparations and placebo or ibuprofen. TRPV1 = transient receptor potential vanilloid subtype 1.

3.3. Adverse reactions

Among the included articles, 4 compared the adverse reactions between the intervention and control groups. A total of 346 patients were included, and the results showed a significant heterogeneity (I2 = 63.1%, P = .043) (Fig. 3A). Therefore, the random effects model was used for analysis. There was no significant difference in the incidence of total adverse reactions between the TRPV1 agonist or antagonist and control groups (RR = 1.225; 95% CI, 0.685 to 2.191; P = .494). After removing a single included study, the results showed that one study (Arsenault 2018) may have a potential effect on the results (Fig. 3B). Owing to the small number of studies, the random effects model was used. After excluding this study, the forest map results showed no significant difference in the total adverse reaction rate between the TRPV1 agonist or antagonist and control groups (RR = 0.938; 95% CI, 0.649 to 1.355; P = .732). However, the results showed no significant heterogeneity (I2 = 0, P = .882) (Fig. 3C), suggesting that the heterogeneity of adverse reactions of TRPV1 agonists or antagonists mainly originates from Arsenault study (2018). The results of Review Manager are the same as those of STATA. The results of the Review Manager are the same as those of the STATA. Excluding Arsenault 2018 literature, the results of the forest map show that there is still no significant difference in the incidence of total adverse reactions between the TRPV1 agonist and the control group (RR = 0.94, 95% CI: 0.65–1.36; P = .73), and there is no significant heterogeneity (I2 = 0, P = .88). (Fig. 3D).

Figure 3.

Figure 3.

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(A–D) Adverse reactions after treatment with TRPV1-related preparations. TRPV1 = transient receptor potential vanilloid subtype 1.

3.4. Quality assessment and publication bias

The Stata software risk-of-bias tool was used to assess potential publication bias risk. The funnel diagram was symmetrical on both sides (Fig. 4A) (Begg test, P = .851; Egger test, P = .677), indicating that there is no significant publication bias in the effect of TRPV1 agonists or antagonists on inflammatory arthralgia in this study. The results showed that the funnel plot was visually biased (Fig. 4B) (Begg test, P = .174; Egger test, P = .874), indicating that there is no significant publication bias in the adverse reactions in this study. Quality evaluation was performed from the perspectives of random allocation method, hidden allocation scheme, blind method, blinding of outcome assessment, data integrity, selective reporting, and other biases. The evaluation results are presented in Table 2 and Figure 5A and B. All studies were randomized, and 4 of these studies described the specific randomization method, 4 described specific allocation hiding methods, 4 adopted a double-blind design, and 2 adopted an open-label design. The results of all the literature data included were complete, without selective reporting or other potential biases.

Figure 4.

Figure 4.

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(A, B) The publication bias of the effects of TRPV1-related preparations on inflammatory arthralgia and adverse reactions. TRPV1 = transient receptor potential vanilloid subtype 1.

Table 2.

Included literature quality evaluation.

Study Random method Allocation concealment Blind method Detection bias Data integrity Selective reporting Other biases
Cho RNT Not reported Double blind No Complete No No
Arsenault RNT NOA Double blind No Complete No No
Persson Web random program NOA Public label No Complete No No
Stevens RNT NOA Double blind No Complete No No
McCleane Not reported envelope method Double blind No Complete No No
Mayorga Not reported Not reported Public label No Complete No No
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NOA = nonoperator assignment, RNT = random number table.

Figure 5.

Figure 5.

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(A, B) Included literature quality evaluation.

4. Conclusion

In this study, we conducted a new meta-analysis focusing on the efficacy and safety of TRPV1-related preparations for inflammatory arthralgia. TRPV1 agonist studys: In the study of Cho J-H,[15] Persson MSM,[16] and McClean,[18] the authors used capsaicin as a control with placebo; Stevens’ study[17] used different concentrations of capsaicin as a control with a placebo. TRPV1 inhibitor studys: Arsenault study[20] compared NEO6860, placebo, and naproxen; Mayorga[19] used Mavatrep as a control with a placebo. Six published high-quality RCTs involving 481 patients were analyzed. We found that both TRPV1 agonists and inhibitors could reduce the pain score of inflammatory arthralgia, which may be the preferred choice for patients experiencing the symptoms of inflammatory arthralgia. TRPV1 agonists or inhibitors were significantly more effective than placebo in reducing the inflammatory arthralgia scores. In terms of safety, we found no significant difference in the incidence of adverse reactions between TRPV1 agonists or inhibitors and the placebo.

For early- and middle-stage inflammatory arthralgia, resting or exercise pain is usually the primary complaint of patients, and effective and safe pain relief must be considered in treatment. There remains no conclusive evidence regarding the efficacy and safety of TRPV1 agonists and inhibitors for inflammatory arthralgia. A 2018 review pointed out that local capsaicin was safe and could significantly reduce the pain scores of the hands, knees, hips, or shoulders. None of the included articles used the standard blind method; therefore, the analysis value of the conclusions was limited.[28] In the same year, another meta-analysis that included 5 RCTs of topical capsaicin in the treatment of knee OA concluded that topical capsaicin was statistically superior to placebo only at the permitted dose and that there was no significant difference between topical nonsteroidal anti-inflammatory drugs and capsaicin in terms of pain relief. However, whether there was a difference in equivalence between individuals was unknown.[29] Only the TRPV1 agonist was included in the article, and its action pathway was single, which could not fully reflect the effect of TRPV1-related preparations on inflammatory arthralgia. From the perspective of clinical and basic studies, this review included articles assessing oral, external, and intra-articular injections of TRPV1-related preparations, which are more effective than placebo or nonsteroidal drugs, especially intra-articular injection.[17] The pain relief effect lasts for half a year only after a single injection, which is more compliant than other medication routes and has more lasting effects and no significant side effects. This is a new route for capsaicin medication, which deserves attention. The latest review on capsaicin mentioned 2 ongoing phase 2 clinical trials. The preliminary experimental result is that local application of 5% liquid capsaicin has a better continuous pain reducing effect and better tolerance than 1% liquid capsaicin,[30,31] which suggests that there is a dose–effect relationship in the clinical use of capsaicin, and future research and development trends may be to develop high-concentration sustained-release capsaicin intra-articular preparations with long-term pain relief.

Two studies on oral TRPV1 inhibitors also confirmed their significant efficacy and safety in relieving OA.[19,20] The disadvantages of these studies are that the evaluation time point after treatment is relatively short, and the long-term effects cannot be evaluated. In 2012, a meta-analysis of 3 phase 1 trials demonstrated that ABT-102, an antagonist of TRPV1, had good metabolic robustness in healthy human volunteer models,[32] showing that the TRPV1 antagonist has great potential in the clinical application of arthralgia and is worthy of further studies. However, attention should also be paid to joint repair disorders caused by excessive inhibition of TRPV1. In the future, emphasis should be placed on prolonging the pain-reducing effect of TRPV1 inhibitors and clarifying the specific dose–effect relationship. Simultaneously, TRPV1 agonists and inhibitors should not be antagonistic in the treatment of inflammatory arthralgia but should be cooperative and complementary. For example, TRPV1 inhibitors can be adjusted for use in some patients who have difficulty tolerating capsaicin adverse reactions, such as local pain and burning sensation.

This article discusses the role of TRPV1 related preparations in the treatment of inflammatory pain. Based on existing clinical evidence, although TRPV1 agonists and inhibitors have different pathways of action, they have good therapeutic effects on inflammatory joint pain, and no serious adverse reactions have been found. The author believes doctors can choose based on the patient pain level and the damage degree of sensory nerve. If the pain level is strong, TRPV1 inhibitors and high-dose agonists can control pain, especially for long-term control of chronic pain, with high-dose agonists performing better; If there is simultaneous severe sensory nerve damage, priority should be given to TRPV1 inhibitors to avoid the calcium toxicity of high-dose TRPV1 on sensory nerve cells.

The main limitation of this review is that only 6 RCTs were investigated, and the number of trials included was small. In addition, the 2 included studies did not have specific allocation concealment measures and were considered to have an ambiguous bias risk.[15,19] Therefore, although we found that TRPV1 agonists or inhibitors are effective and tolerable in the treatment of inflammatory arthralgia, the current results remain unreliable, considering the number and level of evidence. In order to enhance the credibility of the results, it is necessary to analyze more clinical trials of TRPV1 related preparations in the treatment of inflammatory arthralgia pain in the future, and if necessary, to increase the analysis of some animal experimental results, including the analgesic effects and adverse reactions of TRPV1 agonists and inhibitors. On the second hand, there are still no relevant reports on the adverse effects of long-term use of TRPV1 related preparations. The results of relevant studies should be paid attention to and guidance should be provided for further clinical applications. Based on existing evidence, there were no significant adverse reactions with the use of TRPV1 agonists (capsaicin) within 6 months and TRPV1 inhibitors (NEO6860 and Mavatrep) within 1 week.

Author contributions

Writing – original draft: Xin Zhou, Bingfeng Xing.

Writing – review & editing: Ziping Li, Bingfeng Xing.

Abbreviations:

NRS
numerical rating scale
OA
osteoarthritis
PI
pain intensity
RCTs
randomized controlled trials
RR
relative risk
SMD
standardized mean difference
TRPV1
transient receptor potential vanilloid subtype 1
VAS
visual analog scale
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index

The study has no material from other sources.

The datasets generated during and/or analyzed during the current study are publicly available.

The authors have no conflicts of interest to disclose.

This work was funded by Guangdong Administration of Traditional Chinese Medicine (20221069).

No ethical approval and patient consent required since the study has no human participants.

No Clinical trial registration required since the study has no human participants.

How to cite this article: Zhou X, Li Z, Xing B. Efficacy and safety of TRPV1-related preparations in the treatment of inflammatory arthralgia. Medicine 2023;102:47(e36268).

Contributor Information

Ziping Li, Email: lzip_008@163.com.

Bingfeng Xing, Email: 461450995@qq.com.

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