Alternative pharmacological options to antivenom therapy in scorpion envenomation: an updated narrative review

Introduction

Background

Scorpion envenomation represents a significant public health concern across various regions of the world, particularly in Latin America, North Africa, the Middle East, and Asia (1). Mexico reports one of the highest documented national incidences of scorpion envenomation worldwide (241 cases per 100,000 inhabitants), exceeding rates reported in Brazil (90.48 per 100,000) and Algeria (99.98 per 100,000), although high regional burdens are also observed in North Africa and the Middle East, with a disproportionate burden on rural communities and areas with limited access to healthcare services (1,2).

The clinical presentation of scorpion stings is variable and depends on the species involved, the inoculated venom dose, and the patient’s physiological response. Manifestations may range from mild local symptoms to severe systemic involvement with life-threatening complications (3). Specific antivenom therapy—available in whole immunoglobulin G (IgG), F(ab')₂, or Fab fragment formulations—is the only intervention capable of directly neutralizing circulating venom toxins and significantly reducing mortality. Accordingly, timely administration of antivenom is generally advised in patients presenting with systemic manifestations or signs of severe envenomation, including neurological and cardiovascular complications (4). However, its limited availability in certain regions, along with challenges related to cost, distribution, and cold-chain requirements, occasionally forces healthcare providers to rely on alternative or adjunctive pharmacological options while antivenom becomes accessible (1,5).

Scorpion envenomation also represents a substantial public health burden, with an estimated 1.2–1.5 million cases annually and more than 3,000 deaths, although underreporting in rural and resource-limited regions likely underestimates the true magnitude of the problem (1,6). Updated epidemiological analyses continue to demonstrate marked regional variability and persistent mortality in endemic areas, particularly in Mexico, North Africa, the Middle East, India, and parts of South America (7,8). Mexico remains one of the most affected countries globally, with high-incidence states such as Guerrero, Morelos, Jalisco, and Guanajuato, where Centruroides species account for most medically significant cases (9,10). Clinical manifestations range from localized pain to severe systemic toxicity depending on species, venom composition, and host factors (11). Systemic envenomation is characterized by autonomic dysregulation resulting from massive catecholamine and neurotransmitter release, potentially leading to cardiopulmonary complications such as pulmonary edema, cardiogenic shock, and life-threatening hemodynamic instability, particularly in pediatric patients due to lower body mass and a higher venom-to-weight ratio (1,12,13).

Although specific antivenom therapy has significantly reduced mortality where broadly accessible (12,14-18), important challenges persist in resource-limited settings. Barriers include geographic and logistical constraints, cold-chain requirements for certain formulations, limited trained personnel, financial restrictions, and seasonal demand fluctuations, all of which may delay timely administration (5,6,15,16,19-24). These limitations create scenarios in which clinicians must rely on supportive or adjunctive pharmacologic measures while recognizing antivenom as the standard of care.

Rationale and knowledge gap

Over the years, various medications have been proposed to mitigate the autonomic, neuromuscular, or cardiovascular effects induced by scorpion venom. These include calcium channel blockers, sympatholytics (e.g., prazosin), benzodiazepines (BZDs), analgesics, antihistamines, and corticosteroids, among others. Evidence remains heterogeneous, limited, or in some cases contradictory. While some observational studies suggest potential hemodynamic benefit with prazosin in certain regional contexts, consistent improvement in clinically meaningful outcomes has not been uniformly demonstrated. Historically, several of these pharmacologic strategies were evaluated in specific epidemiologic and taxonomic contexts, particularly in regions where timely access to antivenom was limited (25). Many reports originate from Centruroides species in Mexico and Hottentotta tamulus in India, both belonging to the family Buthidae but differing in venom composition and clinical expression. Given the marked interspecies variability in toxin profiles and pathophysiological mechanisms, therapeutic findings derived from one genus or regional context should not be assumed to be universally applicable (1).

Given this scenario, a critical appraisal of the available literature regarding alternative or complementary pharmacotherapies to antivenom is warranted. Previous narrative reviews have examined pharmacological management strategies in scorpion envenomation, including autonomic and cardiovascular interventions (6). However, earlier analyses primarily focused on conventional treatment paradigms or antivenom-centered approaches and did not specifically synthesize alternative or adjunctive pharmacotherapies in scenarios of delayed or limited antivenom availability. The present review expands upon prior work by integrating updated evidence, mechanistic considerations, and practical implications for resource-constrained settings.

Objective

This review addresses the following clinical question: in patients with scorpion envenomation—particularly those affected by Centruroides species in resource-limited settings—which symptomatic or adjunctive pharmacologic treatments may be used to stabilize patients while awaiting antivenom, and which interventions should be avoided due to lack of efficacy or potential harm. Although this review draws substantially from data on Centruroides and other buthid genera such as Hottentotta, therapeutic considerations should be interpreted within the context of predominantly neurotoxic envenomation syndromes mediated by sodium channel-active toxins. Given the significant compositional and functional heterogeneity of scorpion venoms worldwide, direct extrapolation to non-buthid or cytotoxic envenomation patterns should be undertaken cautiously. Given the marked interspecific variability in venom composition among scorpion taxa, therapeutic responses may not be universally generalizable, and clinical interpretation should consider regional and species-related differences.

Although this review adopts a global perspective, particular attention is given to Mexico, where Centruroides envenomation represents a major public health burden and specific antivenom therapy is widely implemented. This article is presented in accordance with the Narrative Review reporting checklist (available at https://jphe.amegroups.com/article/view/10.21037/jphe-2025-1-69/rc).

Methods

A critical narrative review was conducted to identify, analyze, and synthesize the available evidence on pharmacologic options alternative to F(ab')₂ antivenom for the management of scorpion envenomation, with particular emphasis on low-resource settings or scenarios where antivenom is unavailable. This narrative review was conducted in accordance with established reporting recommendations for narrative reviews to ensure transparency and methodological clarity.

A structured narrative search was conducted in PubMed/MEDLINE, SciELO, LILACS, and Google Scholar. Google Scholar was used as a supplementary search tool to identify additional relevant publications not indexed in the primary databases, with screening focused on the first 200 results sorted by relevance. Reference lists of selected key articles were manually screened to identify further eligible studies. Studies published between January 1990 and November 2025 were considered. The final literature search was conducted in November 2025. Only articles published in English or Spanish were included. Eligible publications included clinical trials, observational studies, experimental studies with therapeutic implications, and relevant clinical guidelines addressing pharmacologic management of scorpion envenomation. Articles focused exclusively on venom characterization, toxin biochemistry without therapeutic implications, epidemiologic reports lacking treatment discussion, or non-peer-reviewed sources were excluded. Case reports were included only when they provided clinically relevant therapeutic insight.

Search terms included combinations of MeSH and free-text keywords adapted to each database. In PubMed/MEDLINE, an example search strategy was: (“scorpion envenomation” OR “scorpion sting” OR “scorpionism”) AND (“antivenom” OR “antivenin” OR “F(ab')₂”) AND (“drug therapy” OR “symptomatic treatment” OR “adjunctive therapy” OR “alternative therapy”) AND (“Centruroides” OR “Tityus”).

Equivalent keyword combinations and Boolean operators were adapted for SciELO, LILACS, and Google Scholar, including Spanish-language equivalents where appropriate.

The literature search strategy, including databases, search terms, and selection criteria, is summarized in Table 1.

Given the heterogeneity of scorpion species, venom composition, and clinical presentations worldwide, a narrative approach was selected to allow integrative analysis of diverse pharmacologic strategies rather than quantitative synthesis.

Although this was a narrative review and no formal risk-of-bias assessment tool was applied, articles were critically appraised according to methodological rigor, clarity of outcome reporting, study design, and consistency with existing evidence. Greater interpretative weight was given to controlled clinical studies, systematic reviews, and well-documented observational cohorts, while isolated case reports and older studies were interpreted cautiously within their historical context. No restriction was applied based on study design, provided that the publication addressed pharmacologic management beyond antivenom therapy. Study selection and data interpretation were performed by the author based on predefined thematic relevance criteria. Given the narrative design of this review and the single-author structure, duplicate independent screening was not performed.

As a structured narrative review, formal systematic selection procedures such as duplicate screening or predefined risk-of-bias tools were not applied. However, studies were selected based on predefined thematic relevance to pharmacologic management beyond antivenom therapy. Publications focusing solely on epidemiology without therapeutic relevance, non-scientific sources, opinion pieces, editorials, or articles without accessible full text were excluded.

Symptom-directed supportive therapy as adjunctive management

Symptom-directed supportive therapy is primarily indicated for patients with mild to moderate envenomation or in settings where antivenom is unavailable or delayed. These interventions are not alternatives to antivenom but constitute essential adjunctive measures aimed at symptomatic stabilization. In cases of severe systemic envenomation, supportive measures serve only as adjuncts and should not delay prompt antivenom administration when it is accessible.

This strategy aims to stabilize vital functions, control pain, and reduce neuromuscular hyperexcitability while autonomic balance is restored. Although the evidence is heterogeneous, multiple studies and guidelines concur that these measures represent the initial therapeutic cornerstone in most cases (26-28).

Among pharmacologic options, BZDs, particularly diazepam and midazolam, are the most commonly used agents to control neuromuscular hyperactivity induced by venom neurotoxins. Their mechanism is based on potentiation of gamma-aminobutyric acid type A (GABA_A) receptor activity, which decreases central and peripheral excitability (29). In clinical practice, BZDs are typically administered intravenously in moderate to severe cases or intramuscularly when intravenous (IV) access is not immediately available, with dosing adjusted for weight in pediatric patients. Continuous monitoring of respiratory status and level of consciousness is recommended, particularly in children, due to the risk of excessive sedation. Although multiple clinical reports and case series describe reduction of fasciculations, tremors, nystagmus, and agitation—especially in pediatric patients—the overall strength of evidence remains limited, as most data derive from observational studies rather than randomized controlled trials (12,30). Adverse effects are generally minimal at therapeutic doses, though sedation may complicate respiratory assessment (4,27,31).

For pain control, local pain, hyperalgesia, and paresthesia are common following the sting. In mild cases, non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen are recommended as first-line analgesics (32). In patients with moderate to severe pain, opioids such as morphine or tramadol may be considered; however, their use should be reserved for selected cases, with close respiratory monitoring due to the risk of sedation and respiratory depression, particularly in the setting of autonomic instability (33). Current evidence supports their role as symptomatic analgesics only, without disease-modifying effect (4,10,34).

Gastrointestinal manifestations are frequent and result from autonomic imbalance, with nausea and vomiting among the most common symptoms. Antiemetic agents such as ondansetron or metoclopramide may be prioritized in cases of persistent vomiting, dehydration, or increased risk of aspiration, particularly in pediatric or severely affected patients. While these agents improve comfort and help prevent secondary complications related to fluid loss or aspiration, they do not modify the underlying pathophysiology of envenomation. Descriptive clinical series consistently report gastrointestinal symptoms as common components of systemic envenomation syndromes; however, such reports support the clinical rationale for symptomatic management rather than demonstrating specific antiemetic efficacy (28,35).

Antihistamines are frequently used in emergency settings to manage cutaneous symptoms such as pruritus; however, their established therapeutic role in scorpion envenomation is limited to symptomatic control of allergic or local inflammatory manifestations. Experimental data from species such as Mesobuthus and Hottentotta suggest that histamine release may contribute to certain inflammatory or cardiopulmonary effects; nevertheless, these findings derive from preclinical models and involve venom compositions distinct from Centruroides species commonly implicated in the Americas. Therefore, such results cannot be directly extrapolated to the neurotoxic and autonomic manifestations characteristic of Centruroides envenomation. To date, no robust clinical evidence demonstrates that conventional antihistamines meaningfully modify systemic toxicity or disease progression in humans (36,37). When used, they should be considered adjunctive therapies for local or allergic symptoms and should not delay definitive management, including antivenom when indicated.

Finally, local anesthetics such as lidocaine, as well as regional anesthetic techniques, have been described in isolated reports and randomized controlled trials with the aim of reducing pain at the sting site. However, these approaches primarily target local nociceptive symptoms and do not impact systemic manifestations of scorpion envenomation. As such, local anesthetics are not considered an essential component of management but may serve as adjunctive options in selected scenarios for transient relief of localized pain and should not delay systemic evaluation or antivenom administration when indicated (33,38).

Pathophysiology-targeted pharmacologic therapies

In addition to symptomatic support, several pharmacologic interventions have been proposed to modulate the pathophysiologic effects of Centruroides venom, which primarily acts on voltage-gated sodium channels, causing prolonged neuronal depolarization and excessive sympathetic and parasympathetic neurotransmitter release. These pathophysiologic effects are responsible for the characteristic autonomic storm observed in severe envenomation, including cardiovascular instability and systemic complications. Pharmacologic therapies targeting these mechanisms—such as alpha-adrenergic blockers, vasoactive agents, and selected cardiovascular support therapies—aim to stabilize hemodynamics and mitigate autonomic dysfunction (Table 2). However, the clinical evidence supporting these interventions remains heterogeneous and highly dependent on context, with most robust outcomes associated with antivenom administration and supportive care (6,10,39).

Given reported differences in venom composition and clinical expression between Old World species such as Mesobuthus tamulus and New World species including Centruroides, extrapolation should be undertaken cautiously (10).

Alpha-1 blockers (prazosin)

Prazosin, a selective alpha-1 adrenergic antagonist, has been proposed as a therapy to counteract catecholamine-mediated vasoconstriction and improve tissue perfusion in scorpion envenomation. Prospective and historical clinical studies suggest that prazosin may hasten resolution of autonomic manifestations such as transient hypertension and tachycardia. A randomized trial demonstrated that the combination of prazosin and antivenom improved recovery compared with prazosin alone (40), while earlier clinical reports in severe Mesobuthus tamulus envenomation showed reductions in cardiovascular morbidity and faster recovery with prazosin therapy compared to conventional management. However, most studies are small or uncontrolled, and prazosin’s efficacy as monotherapy is inferior to antivenom. Its relatively slow onset of action also limits its utility. Therefore, prazosin may be considered a temporizing adjunctive option only when antivenom is unavailable, typically in adults presenting with marked adrenergic storm (severe hypertension, tachycardia, peripheral vasoconstriction), and requires close hemodynamic monitoring due to the risk of hypotension. It should not be regarded as a substitute for specific antivenom therapy (4,40,41).

Angiotensin-converting enzyme (ACE) inhibitors (captopril)

ACE inhibitors, such as captopril, have been proposed as an option for managing venom-induced reactive hypertension in scorpion envenomation, particularly in adults. Retrospective clinical studies have reported that captopril can reduce afterload and improve cardiovascular manifestations in some adult patients following Mesobuthus tamulus concanesis envenomation (42). However, subsequent clinical observations showed no consistent benefit in broader patient populations and highlighted a significant risk of hypotension, particularly in pediatric patients (43). Therefore, available evidence does not support routine use of captopril in scorpion envenomation. Its use should be considered only in exceptional circumstances, under strict hemodynamic monitoring, and never as a replacement for antivenom or established supportive care.

Calcium channel blockers (nifedipine)

Calcium channel blockers, such as nifedipine, were historically used in cases of scorpion envenomation presenting with tachycardia and moderate hypertension. Observational clinical series demonstrated that while nifedipine may transiently reduce blood pressure (BP), it does not improve neuromuscular or systemic manifestations, and in some patients—particularly children—it has been associated with acute pulmonary edema, hypotension, and worsening peripheral perfusion (43). More recent reviews emphasize that, despite its vasodilatory effect, nifedipine offers no meaningful clinical benefit and may exacerbate venom-induced cardiovascular instability, supporting current guideline recommendations against its routine use (44,45). Given the risk of hypotension and potential worsening of pulmonary edema—especially in pediatric patients—the use of nifedipine has been associated with unfavorable hemodynamic effects, which may limit its role in scorpion envenomation management.

Atropine

Parasympathetic overstimulation induced by acetylcholine release may cause profuse sialorrhea, bronchorrhea, bradycardia, and hypotension in scorpion envenomation. Atropine has been used to control severe sialorrhea or bronchorrhea associated with this parasympathetic hyperactivity. However, clinical experience suggests that while atropine can effectively reduce excessive secretions, its administration may worsen tachycardia, exacerbate sympathetic hypertension, or lead to adverse cardiopulmonary effects when used indiscriminately, and therefore should not be employed routinely. Although autonomic hyperstimulation with adrenergic features predominates in many cases of Centruroides envenomation, clinically significant parasympathetic manifestations such as hypersalivation and airway-compromising secretions may occur in selected patients. In such scenarios, atropine may be considered to control excessive secretions and reduce airway risk, while ensuring close monitoring (46).

Beta-blockers

Beta-adrenergic blockers, which might be theoretically considered for controlling tachycardia in envenomed patients, are not recommended in scorpion envenomation. When administered alone, β-blockers inhibit β-adrenergic receptors while leaving α-adrenergic effects unopposed, thereby potentially increasing peripheral vasoconstriction and exacerbating hypertension and hemodynamic instability. Clinical management guidelines and observational evidence consistently advise against their use in this context, and episodes of severe hypertension and clinical deterioration have been reported following administration (47). In patients who develop acute myocardial depression following the initial hyperadrenergic phase, beta-blockers may further exacerbate hemodynamic instability. During the post-catecholaminergic vasoconstrictive phase, myocardial dysfunction may predominate, and additional reduction of inotropic support may precipitate cardiogenic shock (47). Therefore, beta-blockers should be avoided in the management of scorpion envenomation, particularly in the presence of evolving cardiovascular instability or myocardial dysfunction.

Glucose-insulin infusion

Some experimental and clinical studies suggest that a glucose-insulin combination infusion may reduce neuromuscular activity and modulate potassium bioavailability and membrane excitability in severe scorpion envenomation. In a series of 25 victims of scorpion stings with cardiovascular and pulmonary involvement, continuous infusion of regular insulin combined with glucose (with supplemental potassium and close monitoring of fluid, electrolytes, and acid-base balance) was associated with reversal of cardiovascular and hemodynamic changes, as well as pulmonary edema, in the majority of patients. However, available evidence remains largely observational, and glucose-insulin infusion requires intensive metabolic and hemodynamic monitoring due to the risk of hypoglycemia and electrolyte disturbances. At present, its use should be limited to intensive care settings or research contexts and cannot be considered a practical therapeutic option in low-resource environments (47,48).

Calcium salts (calcium gluconate)

Calcium gluconate has historically been used by analogy with other envenomations where calcium disturbances are prominent; however, Centruroides species scorpion venom does not induce hypocalcemia, and clinical evidence has not demonstrated a clear benefit from calcium administration in the management of scorpion envenomation. Although such agents may occasionally be used anecdotally to address muscle spasm, there is no consensus or proof of efficacy in altering systemic or neuromuscular manifestations attributable to the venom. Consequently, routine use of calcium gluconate is considered inappropriate and may distract from more effective interventions such as specific antivenom and supportive care (45,49).

A structured summary of evidence-based therapeutic recommendations according to clinical severity is presented in Table 3.

Immune-mediated mechanisms in scorpion envenomation

Beyond their direct neurotoxic effects on voltage-gated sodium channels, scorpion venom components may also activate the host innate immune system. Experimental data suggest that venom-associated molecular patterns are recognized by pattern recognition receptors (PRRs), triggering downstream signaling pathways that promote the release of pro-inflammatory cytokines and chemokines (3). Clinically, this response is reflected by leukocytosis, elevated acute-phase reactants, and, in severe cases, a systemic inflammatory response resembling sepsis (50).

This immune-mediated hyperactivation may contribute to endothelial dysfunction, increased vascular permeability, myocardial depression, and multiorgan impairment observed in severe envenomation. The recognition of this inflammatory dimension is particularly relevant in resource-limited settings, where delayed access to antivenom may allow both neurotoxic and immunopathological mechanisms to evolve.

Experimental studies have explored modulation of inflammatory pathways, including cyclooxygenase (COX-1/COX-2) inhibition, as potential adjunctive strategies in buthid envenomation models (51). However, current clinical evidence remains insufficient to support routine use of anti-inflammatory therapies specifically targeting immune activation in scorpion envenomation. Further translational research is required to clarify their potential role.

Miscellaneous or non-recommended therapies

Several miscellaneous therapies have been described in scorpion envenomation despite the lack of evidence supporting meaningful clinical efficacy. Local application of ice at the sting site may provide mild and temporary pain relief; however, randomized controlled evidence demonstrates that ice application is inferior to topical lidocaine and does not alter the overall course of envenomation beyond short-term analgesia (4,5,38,52). Current clinical evidence does not support clear physiopathological or clinical benefit of vitamin supplementation in human scorpion envenomation, although experimental antioxidant effects have been observed in preclinical models (53).

Corticosteroids

Highdose hydrocortisone have been evaluated in large clinical trials and have not demonstrated reductions in toxicity, mortality, or complications compared with placebo (54). Despite their frequent use in clinical practice, particularly in moderate cases with prominent inflammatory manifestations, there is no robust clinical evidence supporting the efficacy of corticosteroids in altering the course of scorpion envenomation. The pathophysiology of scorpion venom toxicity is primarily neurotoxic and autonomic rather than immune-mediated, which limits the theoretical benefit of anti-inflammatory strategies. Available data do not demonstrate improvement in cardiovascular outcomes, symptom duration, or progression to severe envenomation. Consequently, routine corticosteroid administration cannot be recommended and should be reconsidered in the absence of clear clinical indications unrelated to envenomation (31).

These measures may be used solely for patient comfort but should never replace targeted pharmacological management or the use of antivenom.

Synthesis of evidence

Overall, synthesis of the available evidence indicates that antivenom remains the only specific, evidence-based therapy capable of neutralizing circulating toxins and shortening or preventing severe systemic disease; early administration is associated with reductions in intensive care unit admissions and mortality and should therefore be prioritized when available (14-19). Supportive, symptom-directed treatments—including airway management and oxygen supplementation, fluid therapy, analgesia, antiemetics, and BZDs for neuromuscular hyperexcitability—constitute the backbone of care when antivenom is unavailable or delayed and have the strongest practical support in the literature (9-16). Some pathophysiology-targeted drugs have limited or conditional evidence; for example, alpha-1 adrenergic blockade with prazosin has supportive reports as a coadjuvant in settings without antivenom, although the evidence remains inconsistent and weaker than that supporting antivenom therapy (20,21). In contrast, other pharmacologic interventions are either unsupported or potentially harmful. Beta-blockers are contraindicated, routine administration of calcium salts has not demonstrated proven benefit, and routine use of nifedipine or sublingual calcium channel blockade carries a risk of hypotension. Corticosteroids have not demonstrated mortality benefit in controlled evaluations (5,26-31). Finally, non-pharmacologic first-aid measures such as ice application, tourniquets, or suction do not influence the systemic course of envenomation; while ice may provide minor local analgesia, it should never delay transport or definitive medical care (30).

What can be used in low-resource settings

• Immediate assessment and basic resuscitation: Airway, Breathing, Circulation (ABCs), oxygen, continuous monitoring [heart rate (HR), BP, peripheral oxygen saturation (SpO₂)], establish IV access. (standard of care).
• Analgesia: acetaminophen ± NSAID for mild pain; judicious opioid for severe pain with close respiratory monitoring (12,13,15).
• BZDs: diazepam or midazolam for fasciculations, agitation, tremor, or overt neuromuscular hyperexcitability; monitor sedation and respiration (9-11).
• Antiemetics/anti-secretory care: ondansetron or metoclopramide for nausea/vomiting; atropine only for dominant parasympathetic crisis (excessive bronchial secretions, severe bradycardia) and with caution (16,26).
• Cardiovascular support: cautious IV fluids for hypotension; vasopressors if available for refractory shock (prefer agents with alpha activity); avoid beta-blockers (21,27).
• Prazosin (select cases): may be considered as a temporizing measure in adults with prominent sympathetic overactivity (severe hypertension, marked tachycardia) only when antivenom is unavailable and with close monitoring for hypotension; not a replacement for antivenom (20,21).
• Avoid routine calcium, nifedipine, corticosteroids as primary therapy: they have not shown consistent benefit and may cause harm (hypotension, no mortality effect) (5,29,31).
• Supportive measures: monitor electrolytes, urine output, treat pulmonary edema and arrhythmias per local critical-care protocols.
• In addition to clinical assessment, several paraclinical parameters have been associated with severe envenomation and poor prognosis. These include marked leukocytosis, hyperglycemia, metabolic acidosis, elevated cardiac biomarkers (e.g., troponin), and evidence of myocardial dysfunction. Increased inflammatory markers and hemoconcentration have also been reported in severe cases. In resource-limited settings, recognition of these laboratory abnormalities—when available—may assist in early risk stratification, identification of patients at higher risk of cardiopulmonary complications, and prioritization for transfer to higher levels of care or urgent antivenom administration (22,50).

What definitely does not work/contraindicated

Certain interventions are either ineffective or potentially harmful in scorpion envenomation and should be avoided. These include beta-blockers, which may precipitate unopposed alpha-adrenergic vasoconstriction (27); routine calcium administration without proven benefit (29); high-dose corticosteroids lacking demonstrated improvement in outcomes (31); and delays in referral due to reliance on home remedies or obsolete therapies. A structured summary of these non-recommended or contraindicated interventions is provided in Table 4.

When to refer

Refer the patient to a higher-level facility [with intensive care unit (ICU)/antivenom capability] when any of the following are present:

• Signs of systemic envenoming: persistent vomiting, profuse hypersalivation, severe agitation, seizures, neuromuscular weakness, progressive respiratory distress (10-12).
• Hemodynamic instability: persistent hypotension, shock unresponsive to initial fluids or requiring vasopressors (21).
• Pulmonary edema/respiratory failure or need for ventilatory support (15-17).
• Cardiac arrhythmia or signs consistent with scorpion-related myocarditis (16,18).
• High-risk patient groups: infants and young children, elderly, significant comorbidities (11).

Pediatric considerations

Children represent a particularly vulnerable population in scorpion envenomation due to their lower body mass and higher venom-to-weight ratio, which predisposes them to more rapid progression toward systemic toxicity (1,11,12,44). Pediatric series have documented increased risk of severe autonomic and cardiovascular complications compared with adults, particularly in endemic regions (44). Despite this increased vulnerability, pediatric-specific evidence regarding alternative pharmacologic therapies remains limited, with most available data extrapolated from adult cohorts or small observational series. Hemodynamic responses to agents such as prazosin, beta-blockers, or calcium channel blockers may differ in children, and safety margins may be narrower. Therefore, supportive pharmacologic measures in pediatric patients should be applied cautiously, and timely administration of specific antivenom should remain the priority whenever available.

Limitations of the available evidence

The evidence supporting alternative or adjunctive pharmacologic therapies for scorpion envenomation remains limited and methodologically heterogeneous. First, a substantial portion of the available literature originates from studies conducted several decades ago, prior to the widespread availability of modern F(ab')₂ antivenoms and before current standards for clinical research quality were established, resulting in evidence that is often outdated or lacks rigorous methodology (4,55). Many findings derive from observational reports, small case series, or single‑center experiences lacking adequate control groups or generalizability, and the overall body of research is constrained by inconsistent reporting, regional variability, and gaps in high-quality evidence, particularly in vulnerable and underrepresented populations (56).

Second, significant heterogeneity exists across studies in terms of the scorpion species involved. Venom composition varies markedly between Centruroides species in Mexico and other regions, Parabuthus in Africa, and Mesobuthus in India, each with distinct toxin profiles and resulting clinical manifestations. This interspecific variability limits the external validity of therapeutic conclusions, as interventions that appear beneficial in one region cannot be reliably extrapolated to others when neurotoxicity profiles differ. Scorpion venoms exhibit substantial compositional and functional heterogeneity across medically relevant species worldwide. While buthid scorpions typically produce neurotoxic syndromes mediated by sodium channel-active α- and β-toxins that trigger autonomic hyperstimulation, non-buthid genera may produce cytotoxic, hemolytic, or dermonecrotic manifestations with distinct pathophysiological mechanisms. Consequently, therapeutic strategies derived from predominantly neurotoxic envenomation models cannot be universally extrapolated to all scorpion species (57,58).

Third, clinical variability across patient populations—including age, comorbidities, time to presentation, and severity grading—further complicates interpretation. Children, who often exhibit more severe autonomic manifestations and systemic complications, are underrepresented in many studies, resulting in uncertainty regarding the safety and efficacy of certain therapies (e.g., nifedipine or captopril) in pediatric cohorts (59).

Fourth, very few studies have been conducted that directly compare alternative therapies with modern F(ab')₂ antivenom in a head-to-head manner. Most early trials evaluated drugs such as nifedipine, prazosin, or captopril against placebo or supportive care rather than against antivenom, making it difficult to determine their true clinical relevance in current antivenom-based practice (60).

Fifth, publication bias and selective reporting pose significant concerns in the available literature. Meta-analyses of controlled trials in severe scorpion envenomation highlight heterogeneity across studies and emphasize limitations stemming from small sample sizes, variable study designs, and an unclear representation of negative or neutral findings, raising the possibility that positive results are more likely to be published and thus inflate the perceived therapeutic benefit. The narrative design of this review precludes quantitative synthesis and formal grading of evidence certainty, limiting direct comparison between interventions. Substantial heterogeneity exists across studies in terms of scorpion species, venom composition, patient demographics, clinical severity, and treatment protocols, reducing generalizability across geographic and clinical contexts. Pediatric populations and other high-risk groups remain underrepresented in the literature, creating uncertainty regarding safety and efficacy in these subgroups. Additionally, several cited studies are observational, involve small sample sizes, or reflect older clinical practices. Efforts were made to minimize redundancy; however, certain reiterations regarding antivenom primacy were maintained intentionally to reinforce its central therapeutic role (4,61).

Finally, many studies were conducted before the implementation of contemporary clinical trial standards such as CONSORT, PRISMA, or STROBE, resulting in incomplete reporting of methodology, follow‑up, and adverse events. These limitations collectively constrain the strength of recommendations regarding alternative therapies and underscore the need for updated, high-quality clinical research.

Strengths and limitations

Strengths

This review provides an updated narrative synthesis of the available evidence on pharmacological alternatives and adjuvant therapies to antivenom in the management of scorpion envenomation, with particular attention to low-resource settings. A key strength is the inclusion of literature from both English- and Spanish-language databases, which allowed incorporation of regional clinical series and observational studies from Mexico and other Latin American countries where Centruroides species are endemic, thereby improving representation of geographically relevant evidence often underrepresented in English-only reviews. The structured search strategy, use of multiple databases, and adherence to the Narrative Review reporting checklist enhance the transparency and methodological rigor of the review. Additionally, the integration of human, animal, and experimental studies provides a broader contextual understanding of potential therapeutic mechanisms and their clinical applicability, while acknowledging that robust contemporary clinical data remain limited.

Limitations

As a narrative review, this work is inherently subject to several methodological constraints. The absence of a quantitative synthesis (e.g., meta-analysis) limits the ability to compare effect sizes or draw firm conclusions regarding efficacy across interventions. Heterogeneity in study designs, patient populations, venom species, outcome definitions, and dosing strategies restricts the generalizability of the findings. Additionally, the available evidence varies considerably in quality, with many studies characterized by small sample sizes, lack of randomization, limited external validity, and scarce pediatric-specific data. The risk of publication bias cannot be excluded, particularly given the predominance of small observational series. Some relevant studies may not have been captured despite the structured search, especially unpublished or gray literature.

A central limitation of this review is its predominant reliance on evidence derived from neurotoxic buthid envenomation, particularly Centruroides species. Marked regional and interspecific variability in venom composition and clinical expression represents a major barrier to generalizability, limiting the applicability of these therapeutic considerations to non-buthid or cytotoxic envenomation syndromes. Furthermore, findings derived from animal or experimental models may not fully translate to human clinical practice, and extrapolation across different scorpion genera or venom profiles should be undertaken with caution.

Conclusions

Scorpion envenomation remains a significant clinical and public health concern in regions endemic for Centruroides species, particularly where access to appropriate antivenom [including F(ab')₂ formulations in some regions] is delayed or limited. Current evidence supports a pragmatic, symptom-directed approach while definitive antivenom therapy is awaited, prioritizing: (I) supportive symptomatic therapies with established clinical utility—such as BZDs for neuromuscular agitation, analgesics, and antiemetics; (II) selected autonomic modulators with uncertain or context-dependent benefit—such as prazosin or captopril—which may be considered as adjuncts but must not delay antivenom administration; and (III) avoidance of interventions lacking clear benefit or associated with potential harm, including beta-blockers, calcium channel blockers, corticosteroids, and calcium salts.

In resource-limited settings, early recognition of systemic autonomic dysfunction, structured monitoring—including pulse oximetry (SpO₂) and cardiac monitoring when available—and timely referral are essential, particularly in the presence of signs suggestive of pulmonary edema (e.g., worsening respiratory distress, hypoxemia, or crackles on examination). The lack of robust contemporary studies, particularly in pediatric populations, limits the development of definitive guidelines. Future research should prioritize pediatric populations, validated severity scoring systems, standardized outcome definitions with consistent adverse-event reporting, and prospective comparisons of adjunctive therapies against contemporary antivenom formulations [including F(ab')₂ products where applicable]. Until such evidence is available, evidence-based symptomatic management and prompt antivenom administration remain the cornerstone of care.

Acknowledgments

The author expresses sincere gratitude to the healthcare professionals and toxicology researchers whose work has contributed to the current understanding of scorpion envenomation and its pharmacologic management.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://jphe.amegroups.com/article/view/10.21037/jphe-2025-1-69/rc

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