Exploring the therapeutic potential of L-arginine in chronic anal fissure management: a comprehensive review

Abstract

Anal fissure causes pain and bleeding during or after bowel movements, significantly impacting individuals’ quality of life. Current treatments aim to interrupt this cycle but have associated risks and limitations. The emergence of arginine, crucial for protein creation and nitric oxide (NO) production, presents an intriguing therapeutic avenue by the impact on reducing anal sphincter pressure and enhancing anoderm blood flow, due to its roles in vasodilation, anti-inflammatory responses, and collagen synthesis, which can promote wound healing and highlighting its potential as an alternative therapy. However, the effectiveness of oral supplementation remains debated, indicating the need for further elucidation of its mechanisms. Its multifaceted mechanisms can present an exciting avenue for nuanced treatments, urging further exploration to refine its role in chronic anal fissure management. This review comprehensively explores the therapeutic landscape of L-arginine in chronic anal fissure management, integrating recent research studies and clinical investigations.

Introduction

An anal fissure is a distressing clinical scenario characterized by anodermal linear tear commonly located the in posterior midline, with notably excruciating pain and bright red bleeding during or following bowel movements. This condition markedly disrupts the quality of life of affected individuals (Lock and Thomson 1977). The pathophysiology of anal fissures often involves a combination of local trauma and decreased blood flow to the area, rendering the mucosal lining susceptible to injury. Trauma to the anal canal in case of passing hard stool or severe diarrhea can cause splitting in the lining of the canal. However, only 25% of cases have reported a preexisting chronic constipation or diarrhea before developing the fissure (Lock and Thomson 1977). A chronic anal fissure (CAF) is defined as a fissure that fails to heal after 6 weeks (Goligher 1960). Following the initial trauma, the fundamental pathology underlying chronicity of anal fissures is often associated with increased anal resting pressure This condition is primarily caused by the hypertonicity of the internal anal sphincter and the consequent ischemia (Gibbons and Read 1986; Acheson and Scholefield 2005; Nelson 2010). The resulting tension is thought to trigger more spasm in the sphincter, worsening constipation, and creating a harmful cycle. Management of anal fissures aims to alleviate pain, promote healing, and prevent recurrence. Initial treatment often includes conservative measures such as stool softeners, dietary modifications to increase fiber intake, and the use of topical analgesics or nitroglycerin ointments to enhance blood flow to the anal area. The typical treatment, involving anal dilation and internal sphincterotomy, aims to interrupt this cycle by interfering with the internal anal sphincter (Klosterhalfen et al. 1989).

Arginine, a vital amino acid essential for protein creation and nitric oxide (NO) production, is found naturally in dairy, red meat, fish, and poultry. Additionally, it’s accessible in pill, cream, or powder formats from various commercial sources (Shi et al. 2007). Its significance lies in aiding healing through two distinct mechanisms. Firstly, being the sole substance for NO production it facilitates the NO pathway, thereby inducing vasodilation and anti-inflammatory responses. Secondly, it promotes ornithine production, which is vital element for collagen synthesis and wound repair (Albaugh et al. 2017). Recently, there has been increased interest in L-arginine’s therapeutic potential for treating CAF. This interest is supported by a growing body of research highlighting its various physiological roles, including vasodilation and modulation of smooth muscle tone. Furthermore, L-arginine’s role extends to enhancing immune function and modulating inflammatory responses, which can be particularly beneficial in the context of chronic inflammatory conditions like CAF (Lind et al. 2009; Liu et al. 2019).

This review aims to clarify and consolidate the evolving role of L-arginine in CAF management, based on recent research and clinical studies.

Overview of CAF treatment

Surgical treatment

Traditionally, surgical intervention has stood as the standard treatment in addressing CAF, offering a route towards symptom alleviation. Surgical options for treating CAF involve various methods such as anal dilatation, and posterior and lateral internal sphincterotomy. Among these methods, lateral sphincterotomy is widely accepted as the preferred treatment for CAFs due to its superiority over posterior sphincterotomy, as indicated by multiple studies (Abcarian 1980; Jensen et al. 1984).

The evolution of surgical techniques has introduced procedures like local flaps such as VeY advancement and rotation flaps, along with fissurectomy, fissurotomy, and sphincterolysis techniques. Lateral internal sphincterotomy is the most prominent recommendation for treating anal hypertonia, providing lasting relief from symptoms and successful healing of CAFs while minimizing complications (Nelson et al. 2011; Acar et al. 2019).

However, despite its efficacy, surgical procedures carry inherent risks, with anal incontinence among the potential complications up to 30% of cases (Khubchandani and Reed 1989; Prins et al. 2005). This risk has brought forth the quest for alternative nonsurgical modalities that promise efficacy without compromising bowel control of patients.

Non-surgical treatment

Topical medications like calcium channel blockers, botulinum toxin and nitrates can help decrease the hypertonia in the anal area and support the healing process of the fissure (Jost and Schimrigk 1993; Lund and Scholefield 1997; Carapeti et al. 2000).

Botulinum toxin

Botulinum toxin injection exhibits notable benefits with an impressive healing rate, potential for repetition if necessary, and eliminates the requirement for patient compliance. Nevertheless, its use is associated with costliness,, and there have been reports regarding temporary incontinence (Simms et al. 2004).

Nitric oxide donors

Nitric oxide (NO) donors are substances that release NO either within or outside the body. NO has various functions, including stimulating prostanoid release, inhibiting platelet aggregation, affecting angiogenesis, and producing oxygen free radicals. Small levels of NO support cell survival and encourage cell division. Conversely, elevated concentrations of NO might trigger apoptosis and accelerate cell aging. This function plays a pivotal part in immune response, inflammation control, and minimizing free radicals (Luiking et al. 2012; Kelly and Pearce 2020). Commonly used NO donors in clinical and basic research include organic nitrates (e.g., nitroglycerin, glyceryl trinitrate, isosorbide-5-mononitrate) (Beltrán et al. 2000; Hobbs et al. 2002; Miller and Megson 2007).

Glyceryl trinitrate (GTN) is a recognized NO donor and has demonstrated effectiveness across various studies. Its mechanism involves the release of nitric oxide, which subsequently activates soluble guanylyl cyclase, thereby elevating intracellular cyclic GMP levels (Chakder and Rattan 1993). Topical glyceryl trinitrate is effective in only 60–70% of patients, and many report severe headaches due to systemic absorption from the perianal area (Lund and Scholefield 1997). In a study involving 80 patients with CAF, a trial using 0.2% glyceryl trinitrate ointment twice daily demonstrated a significant healing rate of 68% within eight weeks, compared to an 8% healing rate in the placebo group. Healing was associated with reduced pain, lowered pressure in the anal area, and improved blood flow. Though there was an 8% relapse rate after four months, retreatment with glyceryl trinitrate ointment successfully resolved these cases without further relapse. Most patients (58%) experienced headaches, but no incontinence was reported. Mean resting anal pressure (MRAP) returned to normal levels after glyceryl trinitrate cessation (Lund and Scholefield 1997).

Consequently, a theory emerges suggesting that l-arginine as a main NO donor in the body, may enhance wound healing and heightened blood flow to the anal region, potentially relieving anal fissures by lowering internal sphincter pressure with at least causing adverse side effects.

L-arginine

Previous studies suggest that L-arginine supplementation aids in wound healing by enhancing collagen synthesis, fibroblast proliferation, increased NO synthesis, and growth hormone release, while also improving various bodily functions and reducing lesions (Cantürk et al. 2001). Arginine’s vital role in wound healing has been extensively explored across various research models (Wu et al. 2000; Witte and Barbul 2002). Animal studies showcased that an arginine-deficient diet resulted in increased postoperative complications and reduced wound strength compared to diets containing arginine (Seifter et al. 1978). Conversely, supplementing rats with additional arginine significantly improved wound healing (Barbul 1986). Clinical studies on healthy human volunteers corroborated these findings, revealing that arginine supplementation notably enhanced collagen deposition in superficial skin defects (Barbul et al. 1990; Sax 1994).

L-arginine role in NO synthesis

Previous studies suggest that L-arginine is the primary substrate for nitric oxide synthase (NOS) enzymes, playing a crucial role in NO synthesis, which is involved in functions like mucosal integrity, gastric protection, and ulcer healing (Knowles and Moncada 1994). Moreover, NO significantly influences endothelial function by facilitating the relaxation of vascular smooth muscle, leading to subsequent dilation (Bailey et al. 2012; McNeal et al. 2016; Figueroa et al. 2020).

NO plays a pivotal role in inducing muscle relaxation through the cyclic guanosine monophosphate (cGMP) signaling pathway (Katsuki et al. 1977). When NO is produced in response to various physiological stimuli, it diffuses into adjacent smooth muscle cells, particularly in blood vessels or the gastrointestinal tract. Inside these cells, NO activates the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) to cGMP (Barthó and Lefebvre 1995). The increased levels of cGMP then activate protein kinase G (PKG), leading to a cascade of events that ultimately result in muscle relaxation. PKG phosphorylates specific target proteins, including ion channels and contractile proteins, causing a reduction in intracellular calcium levels. Lower calcium concentrations impede the interaction between actin and myosin, the fundamental process in muscle contraction (Ignarro et al. 1999) (Fig. 1).

Fig. 1.

A possible route for wound healing (fissure) in the anal region is L-arginine to NO pathway by increasing vasorelaxation and angiogenesis which can increase blood flow in damaged tissue; also, increase cell growth and decrease inflammation which can help to improve ulcers. On the other hand, NO increases smooth muscle relaxation by reducing intracellular calcium concentration, which can decrease sphincter tonicity and the possibility of wound formation after defecation. On the other hand, converting L-arginine to L-ornithine by arginase can produce proline and polyamine for collagen formation and cell proliferation, respectively. Also, L-arginine with both pathway of NO and Agmatine reduces inflammation by inhibition of NF-kB signaling and cytokine secretion, can alleviate excessive inflammation. AD: arginine decarboxylase; cGMP: cyclic guanosine monophosphate; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; ODC: ornithine decarboxylase; OAT: ornithine aminotransferase

In 2002, Griffin et al. (Griffin et al. 2002) conducted the first study on the effect of administering topical L-arginine on maximum anal resting pressure (MARP). The results revealed that 400 mg topical L-arginine gel can decrease rapidly and significantly in MARP within five minutes, sustaining for over two hours, with a 46% reduction from the maximal value. Unlike GTN, no reported side effects or headaches were associated with L-arginine, even after using 400 mg topical L-arginine gel/five times a day for three days. However, the study was done on healthy volunteers. Then, Gosselink et al. (Gosselink et al. 2005) designed a similar study in 2005 on 15 patients with CAF with long-term intervention. For participants who used 400 mg topical L-arginine gel/five times a day for at least 12 weeks, 62% demonstrated fissure healing after 18 weeks, accompanied by decreased anal pain and resolution of perianal skin irritation. The application of L-arginine notably reduced anal resting pressure and increased anodermal blood flow.

Following the success of these studies in increasing anodermal blood flow and decreasing the tonicity of the anal sphincter, a hypothesis was raised whether oral arginine can have similar effects. In 2005, Prins et al. (Prins et al. 2005) carried out a study with high dose oral L-arginine supplementation (15 g/day) for seven days in healthy volunteers. The results suggested limited effectiveness for anal fissures, as higher oral doses did not significantly impact anal resting pressure or anodermal blood flow. In contrast, a double-blind, randomized, placebo-controlled study in 2019 by Khalighi et al. (Khalighi Sikaroudi et al. 2023) showed oral L-arginine supplementation with doses 1 g/three times a day in CAF patients had superior improvements in fissure size, bleeding, wound healing, and pain compared to the placebo group. Resting anal sphincter pressure notably decreased in the L-arginine group, suggesting potential therapeutic benefits. A detailed interpretation of the studies is demonstrated in Table 1.

Table 1.

Summary characteristics of studies that evaluated the effect of L-Arginine on anal resting pressures

Author, Year (refs)	Type of study	Participants	Arginine dosage and administration	Duration	Data gathering tools	Results
Griffin et al. 2002 (Griffin et al. 2002)	CT (cross-over)	25 Healthy Both sex 26 years old	400 mg Topical L-Arginine gel/ five times daily	3 days (14 days washout)	Anorectal manometry Adverse reaction	↓ anal resting pressures No side effects
Acheson et al. 2003 (Acheson et al. 2003)	In vitro	Sheep and human anal canal tissue	1 mmol/l to 100 mmol/l L-Arginine hydrochloride 100 mmol/l L-Arginine free (highest concentration)	0 to 60 min	Myogenic tone	Dose-dependent myogenic tone
Gosselink et al. 2005 (Gosselink et al. 2005)	CT (without control group)	15 CAF Both sex 36 years old	400 mg Topical L-Arginine gel/ five times daily	360 days	VAS Anal manometry Laser Doppler flowmetry	↓ Pain ↓ anal resting pressures ↑ Anodermal blood flow
Prins et al. 2005 (Prins et al. 2005)	CT (without control group)	8 Healthy Both sex 30 years old	15 g oral L-Arginine/ Divided in 3 sachets	7 days	Level of plasma Arginine Anorectal manometry Laser Doppler flow	↑ Arginine level ↔ Anodermal blood flow ↔ anal resting pressures
Khalighi et al. 2022 (Khalighi Sikaroudi et al. 2023)	RCT (parallel)	66 CAF Both sex 39.79 years old	3000 mg Cap L-Arginine/ 1000 mg three times a day	30 days	VAS Balloon pain score General health survey-SF-36 Anorectal manometry HADs	↓ Bleeding ↓ Fissure size ↓ Pain ↑ QoL ↓ anal sphincter pressure ↔ Anxiety and depression

CAF: chronic anal fissure; Cap: capsule; CT: clinical trial; HADs: Hospital anxiety and depression scale; QoL: quality of life; RCT: randomized clinical trial; SF-36: short form‑36; VAS: visual analog scale.

This notion posits that the vasodilatory effects of NO, mediated by l-arginine (either orally or topically), facilitate increased perfusion of the tissues surrounding the anal area. Enhanced blood flow may contribute not only to the acceleration of tissue repair but also to the alleviation of pain associated with fissures. By potentially relaxing the internal anal sphincter, it is conceivable that l-arginine promotes a state of reduced tension, thereby ameliorating symptoms and fostering a more conducive environment for healing.

L-arginine role in collagen synthesis

The precise mechanisms behind the positive effect of arginine on wound healing are not fully understood. Although arginine constitutes a small portion of the collagen molecule, its supplementation potentially provides precursor substrates for crucial pathways involved in wound healing. This hypothesis gains support from observations indicating a localized arginine-deficient state within wounds during healing stages characterized by increased fibroplasia (Albina et al. 1988). Experimental studies supplementing ornithine, an arginine precursor, demonstrated similar positive effects on wound healing as arginine supplementation. Ornithine’s conversion to Proline, an essential component in wound repair, has been estimated to occur at varying rates in different experimental setups, highlighting the complexity of this pathway (Smith and Phang 1978).

Collagen is rich in amino acids, particularly proline and hydroxyproline, which are essential for its structure and stability. L-arginine serves as a precursor for the synthesis of these amino acids. Through a series of enzymatic reactions, L-arginine is converted into ornithine, which is subsequently transformed into proline and hydroxyproline. These amino acids are critical components of collagen molecules, contributing to their stability and cross-linking (Karna et al. 2020) (Fig. 1).

Moreover, L-arginine plays a role in regulating gene expression related to collagen synthesis. It influences the activity of transcription factors and signaling pathways involved in collagen gene expression. For example, L-arginine can modulate the activity of the mammalian target of rapamycin (mTOR) pathway, which regulates protein synthesis and cell growth, including collagen production. Additionally, L-arginine may impact the expression of specific collagen genes by influencing the activity of transcription factors such as SP1 and AP-1. By modulating gene expressions, L-arginine contributes to the regulation of collagen synthesis at the molecular level (Yuan et al. 2015).

Also, Acheson et al. (Acheson et al. 2003) investigated the impact of L-arginine on myogenic tone in the internal anal sphincter (IAS) using tissue samples from sheep and humans. While L-arginine alone didn’t affect sheep IAS, it reduced neurogenic contractions when combined with L-NAME. The study suggested the potential role of L-arginine in conditions involving anal hypertonia, with its relaxation effects being independent of nitric oxide pathways. Another study by Williams et al. (Williams et al. 2002) conducted a separate study on elderly volunteers, finding that oral administration of arginine, Beta-hydroxy‐beta‐methylbutyrate (HMB), and glutamine increased collagen deposition in implanted tubes, offering a safe nutritional approach to enhance wound repair.

L-arginine role in inflammation

Inflammation is the initial stage of wound healing, crucial for protecting the body from pathogens. During this process, nitric oxide (NO) produced from arginine serves as a signaling molecule to regulate immune cell functions, including those of macrophages and neutrophils (Starikova et al. 2023). These immune cells, when activated, may increase their uptake of arginine, and utilize it to produce more NO, contributing to the resolution of inflammation. As the inflammatory phase wanes, other critical processes begin, including the transition to the proliferative phase of wound healing, where that same NO now plays a dual role by promoting angiogenesis and fibroblast proliferation. However, any disturbance in the control of inflammation leads to chronic non-healing wounds, thereby delaying healing (Wang et al. 2022).

Some studies suggest that L-arginine supplementation alleviates gut mucosal injury and reduces inflammation in certain conditions (Liu et al. 2008; Zhang et al. 2018, 2020; Huang et al. 2020), while other studies show no effect on inflammation (Neilly et al. 1995; Parlesak et al. 2007) or even increased inflammation in some cases. L-arginine can regulate immune status, primarily through the NO pathway (Barbul et al. 1990; Nieves and Langkamp-Henken 2002). Moreover, L-arginine serves as a substrate to produce polyamines and agmatine, both of which are involved in cellular processes related to inflammation. Polyamines such as spermidine and spermine not only play essential roles in cell proliferation, differentiation, and apoptosis, but also exert protective roles against oxidative stress, which often accompanies inflammation.

Agmatine, another important metabolite derived from L-arginine, arises through the decarboxylation of arginine by the enzyme arginine decarboxylase. Agmatine has gained attention for its anti-inflammatory properties, and studies have suggested its ability to modulate various aspects of the inflammatory response (Molderings and Haenisch 2012). Agmatine’s anti-inflammatory effects are partly attributed to its role in inhibiting the activation of nuclear factor-kappa B (NF-κB), a transcription factor crucial for the expression of pro-inflammatory genes. NF-Κb can induce inflammation through several pathways, most importantly encoding inflammatory cytokines by expression of related pro-inflammatory genes. Moreover, NF-κB can increase the activity of inflammatory cells such as T cells and innate immunity cells (Daniels et al. 2023). By interfering with NF-κB signaling, agmatine helps to downregulate the production of inflammatory mediators, such as cytokines and chemokines (Milosevic et al. 2022). This anti-inflammatory action of agmatine contributes to its potential therapeutic relevance in conditions characterized by excessive inflammation. Additionally, L-arginine can modulate the activity of immune cells, such as macrophages, by influencing the balance between pro-inflammatory M1 and anti-inflammatory M2 phenotypes (Matos et al. 2021). Polyamines synthesis and degradation are tightly controlled, with dysregulation potentially exacerbating inflammatory diseases.

In the context of inflammation, the interplay between L-arginine, polyamines, and agmatine is intricate. Polyamines are linked to cellular proliferation and repair, while agmatine seems to offer anti-inflammatory effects by inhibiting inflammatory signaling pathways. The balance and dynamic regulation of these metabolites in response to inflammatory stimuli are crucial for maintaining immune homeostasis (Satriano 2003) (Fig. 1). Therefore, L-arginine, as a precursor to both polyamines and agmatine, plays a significant role in modulating the inflammatory response.

Regulatory effect of arginine on balancing between inflammatory activation and inhibition of immune system led to prevent excessive inflammation in the wound region of anal. By dual action of L-arginine in reducing inflammation while simultaneously supporting tissue regeneration positions by facilitating the production of nitric oxide, it aids in improving blood flow and oxygen delivery to tissues, thereby promoting healing processes. Consequently, L-arginine is known as a promising candidate in both preventive and therapeutic strategies against CAF.

Conclusion

L-arginine shows promise in managing CAF by enhancing anodermal blood flow and reducing anal sphincter tension through increased nitric oxide levels, collagen production, and decreased inflammation in the wound area. While previous studies have shed light on L-arginine’s mechanisms in CAF treatment, their limitations must be recognized. To better understand L-arginine’s role in wound healing for CAF patients and its therapeutic potential, longer-term, larger-scale studies with appropriate control groups are recommended.

Abbreviations

CAF

Chronic anal fissure

cGMP

Cyclic guanosine monophosphate

GTN

Glyceryl trinitrate

GTP

Guanosine triphosphate

MARP

Maximum anal resting pressure

MRAP

Mean resting anal pressure

NF-κB

Nuclear factor-kappa B

NO

Nitric oxide

NOS

Nitric oxide synthase

PKG

Protein kinase G

Author contributions

Conceptualization: Mohsen MasoodiSupervision: Shahram AgahData curation, Investigation: Nikta MasoodiOriginal draft; and Writing: Nogol Motamed-GorjiVisualization: Masoumeh Khalighi Sikaroudi.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.