Sage Journals: Discover world-class research

Abstract

The increasing off-label use of medications needs a robust pharmacovigilance system. This is particularly crucial given the abundance of scientific data that can be harnessed to ensure a product’s safety. Our review focuses on the off-label use of local anesthetics, a common practice in topical and intracameral applications. However, the occurrence of mydriasis, as indicated in the monographs/summaries of product characteristics, is an unexpected adverse event. Our aim is to provide a comprehensive understanding of mydriasis caused by local anesthetics, both as an unexpected adverse event and as an off-label use, to reinforce the importance of pharmacovigilance practices. We conducted a comprehensive search in Medline/PubMed and Google Scholar from two distinct perspectives: examining the occurrence of mydriasis with the use of local anesthetic as an adverse event and as an off-label use. Our search yielded 14 articles that reported mydriasis as an unexpected adverse event with the use of anesthetics, with dental procedures being a significant contributor to this type of event. Also, we identified eight articles that explored the off-label use of local anesthetics to induce mydriasis, with the most common method of drug administration being intracameral injection. These findings underscore the importance of our research in understanding the unexpected adverse event of mydriasis and the potential for off-label use of local anesthetics. They also highlight the need for continued involvement and vigilance in this area, as our understanding of these phenomena continues to evolve and further investigation is crucial. The use of local anesthetics for mydriasis holds significant promise, particularly in ophthalmological surgeries. This approach could potentially mitigate the adverse events associated with conventional mydriatics, offering a more efficient and safer alternative. Furthermore, using a single medication for akinesia, anesthesia, and mydriasis could significantly enhance the efficiency and convenience of surgical procedures. On the other hand, it is crucial to extend the knowledge of the mydriasis-anesthesia association through risk minimization activities (e.g., the inclusion of monographs/summary of product characteristics) to communicate the risk of mydriasis with the use of local anesthetics.

Plain language summary

Is mydriasis an unexpected adverse event induced by local anesthetics, or could it indicate a new therapeutic use?

Why was the study done?

Unknown side effects of drugs can lead to undesired effects, but in some cases, they can lead to the discovery of beneficial effects that could significantly improve patient health.

What did the researchers do?

We searched the literature in Medline/PubMed and Google Scholar from two perspectives on the presence of mydriasis with the use of local anesthetic as an undesired and beneficial effect.

What did the researchers find?

This review has found several cases of undesired mydriasis caused by local anesthetics. However, it is essential to note that their beneficial use as mydriatic is also commonly observed in topical and intracameral applications, especially in ophthalmic surgeries.

What do the findings mean?

Although mydriasis could be considered an undesired event in some therapeutic interventions, this review considers the potential use of local anesthetics to induce mydriasis since it represents a promising new therapeutic indication that interests the medical community, particularly given their frequent use in ophthalmological surgeries.

Keywords

adverse event ciliary ganglion local anesthetics mydriasis off-label use

Introduction

According to the information in the monograph/summary of product characteristics (SmPC), unexpected adverse events are inconsistent in nature, severity, or consequence.^1,2 Since the monograph/SmPC is the document that provides information to health professionals, it must be updated periodically to avoid perpetuating outdated data that may result in adverse events, therapeutic failures, or unnecessary treatments.³

The update of monograph/SmPC is initiated according to risk management, which aims to detect new risks related to drugs and consequently proceed to implement minimization activities, contributing to the continuous evaluation of the benefit–risk balance of drugs^4,5; these data come from different sources, such as literature, clinical trials, spontaneous notifications, and pharmacovigilance studies.⁶

Moreover, after administering a drug, the presence of some adverse events could have an unexpected beneficial effect on the patient’s health without having an approved indication for its use^7–9; these unapproved beneficial effects result in off-label use of the drug since, for its approval as a new therapeutic indication, new information about the molecule must be submitted to demonstrate the safety and efficacy of the drug while maintaining a positive benefit–risk balance.¹⁰

Off-label use is increasing, prompting efforts to fortify pharmacovigilance practices, and due to that, significant scientific data could be gathered, potentially leading to new therapeutic indications from adverse events that are typically considered unwanted.^7,9

Despite mydriasis being an unexpected event according to their monographs/SmPCs of local anesthetics,^11–13 several cases of mydriasis caused by local anesthetics in ophthalmological procedures have been described.^14–16 Furthermore, since 1977, there have been signs of the mydriatic response of local anesthetics,¹⁷ and currently, their off-label use is commonly observed in topical and intracameral applications.^18–20 Therefore, the review aims to provide a comprehensive understanding of mydriasis caused by local anesthetics, both as an unexpected adverse event and off-label use, to reinforce the importance of pharmacovigilance practices.

Methodology

For the literature review, a search was conducted in Medline/PubMed and Google Scholar from two viewpoints of the presence of mydriasis with the use of local anesthetic (adverse event and off-label use). Adverse events inclusion criteria: (1) case reports, (2) association anesthetic event. Off-label inclusion criteria included the following: (1) clinical trials, (2) mydriasis with local anesthetics; exclusion criteria included the following: (1) use concomitantly with known mydriatic drugs (e.g., alpha-adrenergic or anticholinergics).

This search was conducted independently by two investigators; then, the principal investigator collected and compared the information to ensure proper compliance with the inclusion and exclusion criteria mentioned before; in case of discrepancies between the two researchers, the principal investigator made the final decision. The keywords used for searching are as follows: adverse events (local anesthetic adverse event, local anesthetic mydriasis, local anesthetic anisocoria, local anesthetic eye, local anesthetic pupil size, local anesthetic iris); and off-label use (lidocaine + pupil, lignocaine + pupil, mydriasis local anesthetics, local anesthetics off-label, surgery local anesthetics). In total, 22 articles were retrieved (14 for adverse events and 8 for off-label use)

Local ophthalmic anesthetics

Most local anesthetics used clinically have a three-part chemical structure:

An aromatic ring (benzoic or para-aminobenzoic acid) corresponds to the lipophilic portion and is responsible for diffusion through the nerve membrane.

An intermediate connecting functional group that binds to the amino group via an ester or amide.

A hydrophilic amino group is essential in the water solubility of the molecule and, consequently, its biodistribution.

The molecules come in two forms: non-ionized (responsible for diffusion) and ionized (responsible for binding to the intracellular receptor of the neuron).^21–24

According to the connecting functional group, anesthetics are classified into two types: ester type (cocaine, procaine, tetracaine, benzocaine) and amide type (lidocaine, mepivacaine, bupivacaine, ropivacaine).²²

Pharmacokinetic

Specific physiological and anatomical mechanisms prevent the absorption of ophthalmic drugs: (I) Physiological, such as tear turnover, nasolacrimal drainage, and blinking; (II) Anatomical, which are divided into static ones, such as the corneal epithelium, stroma, and blood–aqueous barriers, and dynamic ones, such as blood flow, lymphatic flow, and tear drainage.²⁵

The pharmacological effect of ophthalmic local anesthetics depends on three essential factors: pKa, lipid solubility, and melanin binding.²⁶

Ionized local anesthetics cannot cross the nerve membrane; therefore, the speed of their diffusion depends on the ionized/non-ionized ratio. Consequently, local anesthetics with high pKa (tetracaine pKa = 8.5) have a slower onset of anesthesia than those with low pKa (lidocaine pKa = 7.8).^25–27 Factors that modify the physiological pH, such as inflammation or the use of other drugs, alter the action of local anesthetics.²⁶

Lipid solubility is a factor that also affects the biodistribution of local anesthetics because the corneal epithelium is lipophilic; therefore, drugs with high lipid solubility have a greater capacity to pass into the ocular structures.^18,25,26

Finally, melanin in dark eyes is essential for its bioavailability due to local anesthetics binding to melanin, causing a minor but sustained effect compared to light eyes.²⁵

Pharmacodynamic

Local anesthetics interrupt the electrical impulse propagation of nerve axons by reversible binding of voltage-gated sodium channels across the neural membrane at the nodes of Ranvier (myelinated axons) and along the entire axon (unmyelinated axons).^21–23,28 Therefore, the concentration to blockade the nerve impulse is lower in unmyelinated nerve fibers (type C), being able to cause complete analgesia without affecting motor and tactile function, named “differential block” (sequential blocking of sensory information).^21,22,28

Many authors mention that channels other than sodium channels, such as potassium and calcium channels,^21,29–31 are inhibited by local anesthetics. Even studies carried out by Hollmann et al. demonstrated the blockade of muscarinic M1 and M3 receptors by local anesthetics.^32,33

Topical ophthalmic anesthetics primarily impact the corneal epithelium and stroma, and the drug that crosses the anterior chamber also anesthetizes the iris and ciliary body. However, the pharmacological effect is influenced by the amount of melanin since the duration of the effect may be different in pigmented and non-pigmented irises.^27,34

The pupil

The pupil, whose diameter ranges between 2 and 9 mm, is conditioned by two opposite contractile elements, the iris sphincter muscle (constrictor) and the radial muscle (dilator), which are controlled by the autonomic nervous system through the parasympathetic (short ciliary nerves) and sympathetic (long ciliary nerves) derived from the ciliary ganglion located between the lateral rectus muscle and the orbital apex.^35–38 This structure protects the retina against overexposure to light and provides a correct focus through accommodation jointly with changes in crystalline lens position.^35,37,39 The retina can adjust to light exposure, but such adaptation is slower than that mediated through pupil contraction.³⁷

Mydriasis

The noradrenergic sympathetic system innervation acts through the excitatory 1α pupillary receptors.³⁶ The 1α adrenergic receptors are a G protein-coupled receptor associated with the Gq subunit, which activates phospholipase C (PLC) and hydrolyzes PIP2 to diacylglycerol (DAG) and inositol triphosphates (IP3), causing calcium release with subsequent contact of the radial muscle.^36,40

This system is regulated by posterior hypothalamic nuclei spread through the cervical/thoracic spinal cord to the superior cervical sympathetic ganglion, moving through the ciliary ganglion without synapsing and innervating the eye through the long ciliary nerves.^35,37,38 The regulation of the sympathetic system is complex and less understood than the parasympathetic since factors that modify the sympathoadrenal neurotransmission in the hypothalamus, that is, cognition, emotions, and pain, could cause mydriasis.³⁶

Myosis

The pupillary contraction at the molecular level is mediated by the muscarinic receptors, especially the M3 and M2. The M3 receptors are coupled to PLC, which generates IP3 and DAG, which cause calcium release, promoting the contraction of the sphincter iris muscle; on the other hand, the M2 receptor is negatively coupled to adenylate cyclase, causing the dilating effect of the sphincter iris muscles is not carried out.^36,41

The intricate process of pupillary contraction is regulated by a subcortical reflex mechanism triggered by light and accommodation when viewing close objects. This reflex is mediated through the parasympathetic nervous system.³⁶

Light-mediated pupillary contraction involves the capture of photoreceptive impulses by the rods, cones, and ganglion cells; these impulses are then transmitted via the optic nerve to the pretectum of the midbrain and subsequently to the Edinger-Westphal (EW) nuclei, where the information is processed, afterward, the efferent neurons of the EW nuclei synapse with the neurons of the ciliary ganglion, which innervate the iris sphincter muscle through short ciliary nerves, leading to pupillary constriction.^{35–37,42,43}

Pupillary contraction is also mediated by accommodation when observing nearby objects regulated by the retinal ganglion axons that excite the lateral geniculate body and subsequently distributed for the visual cortex; once analyzed by the latter, the efferent neurons provide excitatory to the EW nucleus, and from then on it produces the same excitatory effects as those mediated by light until reaching pupillary contrition.³⁶

Cases analysis

As an adverse event

During the review, 14 articles (26 patients) were found with mydriasis after the use of anesthetics in patients within an age range of 20–77 years (average 47.34 ± 19.24); dental procedures (6 patients) were most prevalent for this type of event, followed by blepharoplasty (4 patients) and photocoagulation (4 patients; Table 1)^{14–16,44–54}; however, until now, this event has a status of “unexpected” according to the monograph/SmPC of different local anesthetics,^11–13 despite its use as an off-label topical mydriatic.^55,56

Table 1.

Mydriasis is an unexpected adverse event by the use of local anesthetics.

Subject characteristics	Intervention	Related medications	Events	Proposed mechanism	Sequel	References
Patient with skin tumor	Skin tumor removal	Retrobulbar injection with lidocaine 1.5%, epinephrine 1:200,000 and hyaluronidase 1 U/ml	Mydriasis, corneal edema, hemorrhage	Not mentioned	Scotoma	Lincoff et al.⁴⁸
Patient with retinal detachment.		Retrobulbar injection with 0.3 ml of lidocaine 2% with epinephrine 1:100,000	Mydriasis, perforation of the retina		Partially recovered vision
Patient with skin tumor		Injection of the lower eyelid with 0.5 ml of lidocaine 2% with epinephrine 1:100,000	Mydriasis, sclera perforation, corneal edema, increase in intraocular pressure		None
75-year-old man	Blepharoplasty	50/50 of 2% lidocaine with 1:200,000 epinephrine; and 0.75% bupivacaine with 1:200,000 epinephrine transconjunctival	Mydriasis, loss of light sensitivity, and cycloplegia	Diffusion of the local anesthetic into the orbit and temporarily anesthetizing the short ciliary nerves and/or the ciliary ganglion	None	Perlman and Conn¹⁴
48-year-old woman					None
77-year-old man					None
72-year-old woman	Cervical spine surgery	The right eye was prolonged exposed to 0.5% phenylephrine/4% lidocaine solution due to improper use of a facial mask	Mydriasis	Retrograde migration of solution through the nasolacrimal duct into the conjunctiva	None	Prielipp⁵⁰
24-year-old woman	Septoplasty	Soft tissue infiltration of the nose, the mucosa of the inferior turbinate, and the mucosa of the septal cartilage with 20 ml of 1% lidocaine and 1:200,000 epinephrine	Mydriasis	Ciliary ganglion anesthesia	None	D’Souza et al.⁵²
45-year-old man	Tooth extraction	Mandibular block injection with 2.2 ml of lidocaine 20 mg/ml with epinephrine 1.2 μg/ml	Blindness, mydriasis, ophthalmoplegia, and ptosis	Anesthesia of the optic (II), oculomotor (III), trochlear (IV), and abducens (VI) cranial nerves.	None	Wilkie⁴⁴
A 21-year-old woman with insulin-dependent diabetes of 16 years of evolution	Panretinal photocoagulation	Sub-tenon local anesthetic (no specific mention of drugs)	Anisocoria and mydriasis	Postganglionic lesion, either in the short ciliary nerves or in the ciliary ganglion	None	Patel et al.¹⁶
A 49-year-old woman with insulin-dependent diabetes of 21 years of evolution					None
A 63-year-old man with insulin-dependent diabetes of 27 years of evolution					Partially recovered pupil
A 20-year-old man with insulin-dependent diabetes of 18 years of evolution		Sub-tenon local anesthetic with lidocaine and bupivacaine	Decreased vision, loss of light sensitivity, blurred vision, mydriasis, and loss of accommodation		Partially recovered pupil
A 26-year-old patient with nasal obstruction	Septoplasty	Sub-mucoperichondrial infiltration with 1% lidocaine and 1:100,000 epinephrine	Mydriasis and blurred vision	Vascular diffusion of the drug to the ophthalmic artery, affecting the branches of the third cranial nerve	None	Cankaya et al.⁵¹
25-year-old woman	Tooth extraction	2.2 ml of lidocaine 2% with 1:80,000 epinephrine mediate the inferior alveolar nerve anesthesia	Ptosis, mydriasis, with loss of the pupillary light reflex, anisocoria, and ophthalmoplegia	Intra-arterial deposition of anesthetic subsequently infiltrates the orbital apex and the superior orbital fissure or the cavernous sinus to produce regional effects	None	Williams et al.⁴⁷
29-year-old man hit on the left side of the face	Left blowout fracture	Infiltration around the eye with 2% lidocaine and 1:100,000 epinephrine	Mydriasis and loss of light sensitivity	Diffusion of adrenaline into lidocaine and retraction of periorbital contents	None	Lee et al.⁴⁶
54-year-old woman	Medial blowout fracture	Application to the orbital wall with 1% lidocaine and 1:200,000 epinephrine	Unilateral mydriasis	Local anesthetic infiltration into the eyelids and paranasal sinuses, manipulation of the lower branch of the oculomotor nerve, manipulation of the ciliary ganglion, and direct injury to the optic nerve and eyeball	None	Lee et al.⁵³
64-year-old woman	Blepharoplasty	Periocular infiltration with 1% lidocaine, 1:200,000 epinephrine, and sodium bicarbonate, and 0.04% oxybuprocaine eye drops	Blurred vision, unilateral headache, conjunctival irritation, conjunctival hyperemia, corneal edema, and mydriasis	Factors related to surgery include stress, postoperative ocular coverage, and pharmacologically induced mydriasis	Reduced vision	Kappen et al.¹⁵
A 54-year-old man with refractory glaucoma	Laser cyclophotocoagulation	Subconjunctival injection of 3–4 ml mepivacaine 2%	Vision impairment, loss of light perception, and mydriasis	Ganglionic anesthesia or neurotoxic reaction due to the anesthetic	None	Knoll et al.⁴⁹
A 69-year-old man with open-angle glaucoma			Vision loss, loss of light perception, and mydriasis
A 64-year-old man with open-angle glaucoma			Decreased pupil mobility, loss of light perception, and mydriasis
49-year-old woman	Dental treatment	Posterior superior alveolar anesthesia injection with 2% articaine and 1:100,000 epinephrine	Mydriasis and ptosis	Ciliary ganglion involvement due to local anesthetic	None	Peñarrocha-Diago and Sanchis-Bielsa⁵⁴
60-year-old woman			Mydriasis and ptosis
25-year-old woman			Mydriasis and ptosis
22-year-old woman			Mydriasis
A 45-year-old man with a previous history of surgery for cerebellar tumor	Scalp nerve block	A total of 20 ml of 0.25% ropivacaine was used to block the scalp nerve (greater occipital nerve 3 ml, lesser occipital nerve 3 ml, auriculotemporal nerve 2 ml, and supraorbital nerve 2 ml)	Anisocoria and mydriasis	Not mentioned	None	Xiao et al.⁴⁵

The mechanism proposed in most articles with mydriasis is focused on the ciliary ganglion; these support various author hypotheses since anesthetics provoke blockage in the nerve cells or have a neurotoxic effect in neurons that innervate the ciliary ganglion or since the lesion produced is very similar to a tonic Adie’s pupil with pupillary dilation, poor reaction to light, loss of accommodation, and positive denervation.^{14–16,44,46,47,49–52,54}

However, some authors are not very sure that local anesthetics could be the cause of mydriasis, for example, D’Souza et al. mention that although they propose the mechanism of mydriasis mediated by anesthetics, they believe that the effect is caused by epinephrine entering the eyeball through the nasolacrimal duct⁵²; or the case of Kappen and Cols, where it is hypothesized that it could be related to other factors, such as surgery or postoperative ocular coverage.¹⁵

Off-label use

During the literature review, 8 articles (168 patients) in which local anesthetics were used to induce mydriasis were identified. The most frequent drug administration was by intracameral injection (5 articles), topical drops (2 articles), and one sub-tenon administration (Table 2).^56–62 Two of them presented adverse events; (1) Claesson et al. mention the presence of corneal epithelial damage and corneal edema, but this occurred at high doses of lidocaine (16% used six times), and they concluded no adverse events occurred at the dose in which lidocaine presents the maximum mydriasis⁵⁶; and (2) Behndig mentioned the presence of adverse effects on the corneal epithelium; however, they concluded that is entirely reversible and are not clinically significant even at large doses.⁵⁵

Table 2.

Mydriasis as an off-label use of local anesthetics.

Objective	Intervention	Patients	Technique	Drug and dose	Result	Proposed mechanism	Adverse event	References
Induce pupil dilation without using preoperative mydriatic eye drops	Phacoemulsification	12	Intracameral injection	0.3–0.5 ml of lidocaine 1%	Akinesia of the iris, mydriasis 5.2–7.2 mm	Anesthesia of all the nerve fibers of the anterior chamber	None	Cionni et al.⁵⁹
Evaluate pupil dilation from intracameral injection of lidocaine	Trabeculectomy surgery	25	Intracameral injection	0.2–0.3 ml of lidocaine 1%	Mydriasis (7.21 mm male and 5.96 mm female)	Not mentioned	None	Lee et al.⁶¹
Evaluate pupil dilation by lidocaine	Phacoemulsification	27	Intracameral injection	0.2–0.3 ml of lidocaine 1%	Mydriasis 4.52 ± 0.08 mm	Not mentioned	None	Nikeghbali et al.⁶⁰
Quantify the mydriatic and cycloplegic effects from topically applied lidocaine and tetracaine	Double-masked, randomized, intra-individually comparing study	52 eyes	Topical drops	3 drops of lidocaine 4% in one eye and contralateral tetracaine 1% every 90 s	Mydriasis (lidocaine: 3.52 ± 0.76 mm; tetracaine: 3.44 ± 0.59 mm)	Blocking constriction of the pupil to the light and paralyze the motor nerves	Changes in corneal epithelium	Behndig⁵⁵
Quantify the mydriatic effect and side effects of topical lidocaine with different pH values and concentrations	Intra-individual comparison double-masked randomized study	10	Topical drops	Lidocaine (4%, 8% and 16%)	Lidocaine 8%: mydriasis (4.16 ± 0.13 mm)	Not mentioned	Corneal epithelial damage, corneal edema, and reduced vision	Claesson et al.⁵⁶
Investigate the effects of sub-Tenon’s capsule ropivacaine injection on pupillary diameter	Strabismus surgery	16	Sub-Tenon’s	2.5–3 ml of a ropivacaine 1%	Mydriasis of 6 mm	Ciliary ganglion block	None	Savino et al.⁵⁷
Evaluate pupil dilation with intracameral injection of 1% vs topical eye mydriatic	Phacoemulsification	20	Intracameral injection	0.2 ml of lidocaine 1%	Mydriasis (lidocaine 1%: 6.54; cyclopentolate 1% + tropicamide 1%: 6.67)	Not mentioned	None	Samarai et al.⁶²
Study the effect of lidocaine to induce mydriasis in patients with type 2 diabetes mellitus	Phacoemulsification	32	Intracameral injection	0.3 ml of lidocaine 1%	Mydriasis 5.2 ± 0.5 mm	Not mentioned	None	Joshi⁵⁸

AC, anterior chamber; PC, posterior chamber.

In addition to its high-security profile, the literature review emphasizes the benefits of local anesthetics for use as a mydriatic, such as:

I. Rapid recovery of visual acuity.^58–60

II. Few systemic adverse events.⁵⁹

III. Its use causes akinesia (retrobulbar and peribulbar administration), anesthesia, and mydriasis without the need for other medications and consequently reduces intraoperative discomfort.^57,58,60

IV. It avoids severe cardiovascular effects, particularly in people with hypertension, cardiovascular diseases, and children.^56,59,60

V. Unlike topical mydriatics, they do not cause additional inflammation and prevent endothelial cell loss, so their use is recommended in patients with chronic pathologies such as “Guttata.”⁵⁹

VI. Greater light tolerance, especially when using a microscope light during surgery.⁵⁹

VII. A decrease in the presence of superficial punctate keratopathy.⁵⁹

Hypothesis

Based on the literature search, three hypotheses about mydriasis caused by local anesthetics can be summarized: efferent nerve anesthesia, afferent nerve anesthesia, and ciliary ganglion anesthesia.

Efferent nerves anesthesia

Akinesia has been observed in peribulbar and retrobulbar anesthesia, suggesting blockage of efferent nerves,^63–68 analogically it could provoke the iris muscle blockage. However, there needs to be more information to confirm this hypothesis because most of this type of anesthesia does not present mydriasis.^16,63–70 Therefore, the blockage of efferent neurons could be caused intraocularly, according to studies carried out by May et al. and Shelton et al., which mention the existence of a large number of non-myelinated neurons within the eyeball,^71,72 making them more prone to local anesthetics,^21,28,73 triggering the blockade of the efferent neurons from both the adrenergic (sympathetic) pathway derived from the cervical ganglion as well as the acetylcholine (parasympathetic) pathway mediated by the EW nucleus (Figure 1).

Figure 1.

Mydriasis as an off-label use of local anesthetics.

Afferent nerves anesthesia

While no information currently supports the optic nerve anesthesia hypothesis, several investigations have shown that optic nerve anesthesia indicates neuronal damage.^63,64,68,74 The loss of myelination inside the eye could block nerve impulses,^{21,28,71–73} thereby preventing the afferent transmission of information and preventing light-mediated and accommodation contraction. However, the low bioavailability in the posterior chamber and in the ganglion cells may be a limitation in this hypothesis⁷⁵ (Figure 1).

Ciliary ganglion anesthesia

There is support in the literature for the anesthesia of the preganglionic sympathetic neuron since, as can be seen in Figure 1, it is the only one that contains a preganglionic neuron type B,^36,41,76 and has poorly myelinated fibers,⁷⁶ which would be susceptible to blockage by the administration of local anesthetics, obstructing the transmission of the acetylcholine (parasympathetic) impulse that is responsible for the contraction of the circular muscle, causing mydriasis (Figure 1). Furthermore, Peñarrosa et al. mention that intraoral anesthetics and, therefore, those used in maxillary surgery produce mydriasis due to the proximity of the ciliary ganglion with the sphenomaxillary space⁵⁴; and this could explain the many adverse events in this type of surgery, such as those mentioned in Table 1.

Conclusion

The mydriatic effect of topical anesthetics is currently recognized, although their use is off-label. Clinical results have been promising, mainly because these drugs are commonly used in ophthalmological surgeries. Their application could help avoid the adverse events associated with traditional mydriatics, induce rapid pupillary dilation to minimize surgical time, facilitate the recovery of pupillary size as early as the first postoperative day, and enhance the patient experience. Importantly, using a single medication for akinesia, anesthesia, and mydriasis makes this approach an efficient option, ensuring a more comfortable experience for patients undergoing surgery. However, further research is necessary to evaluate topical anesthetics’ efficacy, safety, and appropriateness for mydriasis as a new therapeutic application. In addition, it is essential to reach a consensus among experts regarding the proposal of this drug for clinical practice.

Besides, pharmaceutical companies must enhance the medical community’s understanding of the association between mydriasis and anesthesia through risk minimization efforts. This could include disseminating information such as monographs or a SmPC to communicate the risks of mydriasis associated with local anesthetics, especially given the described mechanism of mydriasis and the consistently demonstrated relationship between the drug and this adverse drug reaction.

Footnotes

Acknowledgements

The authors thank Alejandra Sánchez Rios, MD, and Ricardo Osvaldo Jauregui Franco, MD, for their assistance writing the medical manuscript.

Declarations

ORCID iDs

Homero Contreras-Salinas

Janet Cristina Vázquez-Beltrán

María Soledad Romero-López

Oscar Olvera-Montaño

Lourdes Yolotzin Rodríguez-Herrera

References

Company core data sheets and benefit-risk evaluation. A drugmaker’s guide to postmarket safety reporting. 1st ed. FDA News, 2020.

European Medicines Agency. ICH Topic E 2 A Clinical safety data management: definitions and standards for expedited reporting, https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-topic-e-2-clinical-safety-data-management-definitions-and-standards-expedited-reporting-step_en.pdf (1995, accessed 12 March 2024).

Drelich

Religioni

Chung

, et al. The quality and reliability of information in the summaries of product characteristics. Int J Environ Res Public Health 2022; 19(4): 2185.

Contreras-Salinas

Barajas-Hernández

Baiza-Durán

, et al. Active pharmacovigilance in peruvian population: Surveillance of a timolol/brimonidine/dorzolamide ophthalmic fixed combination. Clin Ophthalmol 2021; 15: 583–590.

Lomeli-Silva

Contreras-Salinas

Barajas-Virgen

, et al. Harmonization of individual case safety reports transmission requirements among PAHO reference authorities: a review of their current regulation. Ther Adv Drug Saf 2024; 15: 20420986241228120.

European Medicines Agency. Guideline on Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems (Rev 2), https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf (2017, accessed 29 March 2024).

van Hunsel

Ekhart

. Unexpected beneficial effects of drugs: an analysis of cases in the Dutch spontaneous reporting system. Eur J Clin Pharmacol 2021; 77(10): 1543–1551.

Yang

Agarwal

Systematic drug repositioning based on clinical side-effects. PLoS One 2011; 6(12): e28025.

Rusz

C-M

Ősz

B-E

Jîtcă

, et al. Off-label medication: from a simple concept to complex practical aspects. Int J Environ Res Public Health 2021; 18(19): 10447.

10.

Food and Drug Administration. Understanding unapproved use of approved drugs “off label,” https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label (2018, accessed 14 June 2024).

11.

Bausch & Lomb Ireland. Tetracaine hydrochloride ophthalmic solution USP, 0.5%, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210821s000lbl.pdf (2019, accessed 13 June 2024).

12.

Akorn Operating Company LLC. AKTEN^® (lidocaine hydrochloride ophthalmic gel), https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022221s008lbl.pdf (2022, accessed 13 June 2024).

13.

Allergan Inc. OPHTHETIC^® (proparacaine HCl ophthalmic solution) 0.5%, https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/12583s037lbl.pdf (2022, accessed 13 June 2024).

14.

Perlman

Conn

Transient internal ophthalmoplegia during blepharoplasty. A report of three cases. Ophthal Plast Reconstr Surg 1991; 7(2): 141–143.

15.

Kappen

IFPM

Nguyen

Vos

, et al. Primary angle-closure glaucoma, a rare but severe complication after blepharoplasty: case report and review of the literature. Arch Plast Surg 2018; 45(4): 384–387.

16.

Patel

Jenkins

Benjamin

, et al. Dilated pupils and loss of accommodation following diode panretinal photocoagulation with sub-tenon local anaesthetic in four cases. Eye (Lond) 2002; 16(5): 628–632.

17.

Lyle

Bobier

WR.

Effects of topical anesthetics on phenylephrine-induced mydriasis. Am J Optom Physiol Opt 1977; 54(5): 276–281.

18.

Behndig

Lindén

Aqueous humor lidocaine concentrations in topical and intracameral anesthesia. J Cataract Refract Surg 1998; 24(12): 1598–1601.

19.

Cuan Aguilar

Díaz

Fonseca

Eficacia del uso combinado de lidocaína y fenilefrina como midriáticos intracamerales en la cirugía de catarata. Rev Cubana oftalmol 2020; 33(2): 1–13.

20.

Martín-Moro

Gallardo

JZ.

On the mydriatic effect of lidocaine. J Craniofac Surg 2013; 24(4): 1504.

21.

Scholz

Mechanisms of (local) anaesthetics on voltage-gated sodium and other ion channels. Br J Anaesth 2002; 89(1): 52–61.

22.

Alberte-González

Gallego-Pinazo

Pinazo-Durán

MD.

Anestésicos locales en oftalmología. Arch la Soc Española Oftalmol 2009; 84: 227-228.

23.

Zhou

Huang

Chen

Synthesis and biological activities of local anesthetics. RSC Adv 2019; 9(70): 41173–41191.

24.

Kumar

Chawla

Goyal

Topical anesthesia. J Anaesthesiol Clin Pharmacol 2015; 31(4): 450–456.

25.

Agrahari

Mandal

Agrahari

, et al. A comprehensive insight on ocular pharmacokinetics. Drug Deliv Transl Res 2016; 6(6): 735–754.

26.

Taylor

McLeod

Basic pharmacology of local anaesthetics. BJA Educ 2020; 20(2): 34–41.

27.

Bausch & Lomb. New Zealand Data Sheet MIMIS, https://www.medsafe.govt.nz/profs/datasheet/m/Minimsphenylephrineeyedrop.pdf (1995, accessed 16 April 2024).

28.

Sikka

Beaman

Street

Basic clinical anesthesia. New York: Springer, 2015.

29.

Olschewski

Hempelmann

Vogel

, et al. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology 1998; 88(1): 172–179.

30.

Komai

McDowell

TS.

Local anesthetic inhibition of voltage-activated potassium currents in rat dorsal root ganglion neurons. Anesthesiology 2001; 94(6): 1089–1095.

31.

Sugiyama

Muteki

Local anesthetics depress the calcium current of rat sensory neurons in culture. Anesthesiology 1994; 80(6): 1369–1378.

32.

Hollmann

Ritter

Henle

, et al. Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics. Br J Pharmacol 2001; 133(1): 207–216.

33.

Hollmann

Wieczorek

Berger

, et al. Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function. Mol Pharmacol 2001; 59(2): 294-301.

34.

Bellucci

Comparative efficacy of topical tetracaine solution versus lidocaine gel in cataract surgery. Open Access Surg 2012; 5: 1–8.

35.

Ferencová

Višňovcová

Bona Olexová

, et al. Eye pupil—a window into central autonomic regulation via emotional/cognitive processing. Physiol Res 2021; 70(Suppl. 4): S669–S682.

36.

Smith

. Neural regulation of the pupil BT. In: Binder

Hirokawa

Windhorst

(eds) Encyclopedia of neuroscience. Springer Berlin, 2009, pp. 2597–2601.

37.

Wilhelm

Disorders of the pupil. Handb Clin Neurol 2011; 102: 427–466.

38.

Bhardwaj

Joshi

Neuroanatomy, ciliary ganglion. In: StatPearls. Treasure Island, FL: StatPearls Publishing, 2023.

39.

Kaluzny

BJ.

Anterior movement of the crystalline lens in the process of accommodation in children. Eur J Ophthalmol 2007; 17(4): 515–520.

40.

Akinaga

García-Sáinz

Pupo

AS.

Updates in the function and regulation of α(1)-adrenoceptors. Br J Pharmacol 2019; 176(14): 2343–2357.

41.

Pintor

Autonomic nervous system: ophthalmic control. In: Squire

(ed.) Encyclopedia of neuroscience. Oxford: Academic Press, 2009, pp. 967–974.

42.

Wilhelm

Chapter 16: Disorders of the pupil. In: Kennard

Leigh

(eds) Neuro-ophthalmology. Amsterdam: Elsevier, 2011, pp. 427–466.

43.

Bouffard

MA.

The pupil. Continuum (Minneap Minn) 2019; 25(5): 1194–1214.

44.

Wilkie

GJ.

Temporary uniocular blindness and ophthalmoplegia associated with a mandibular block injection: a case report. Aust Dent J 2000; 45(2): 131–133.

45.

Xiao

Chen

Tan

, et al. Anisocoria and mydriasis after scalp nerve block: a case report. J Int Med Res 2022; 50(5): 3000605221099262.

46.

Lee

J-M

Kim

C-H

Kim

U-K

, et al. Transient ipsilateral mydriasis during correction of left blowout fracture. J Craniofac Surg 2014; 25(2): 527–528.

47.

Williams

Colbert

, et al. Amaurosis, ophthalmoplegia, ptosis, mydriasis and periorbital blanching following inferior alveolar nerve anaesthesia. Oral Maxillofac Surg 2011; 15(1): 67–70.

48.

Lincoff

Zweifach

Brodie

, et al. Intraocular injection of lidocaine. Ophthalmology 1985; 92(11): 1587–1591.

49.

Knoll

Chobanyan-Jürgens

Stichtenoth

, et al. Ipsilateral transient amaurosis, mydriasis and light reflex absence after subconjunctival local anesthesia with mepivacaine in three patients with refractory glaucoma: a case report. BMC Ophthalmol 2019; 19(1): 195.

50.

Prielipp

RC.

Unilateral mydriasis after induction of anaesthesia. Can J Anaesth 1994; 41(2): 140–143.

51.

Cankaya

Avcu

Budak

, et al. A case of unilateral mydriasis secondary to septoplasty under local anaesthesia. B-ENT 2010; 6(1): 55–58.

52.

D’Souza

Hadzic

Wider

Unilateral mydriasis after nasal reconstruction surgery. Can J Anaesth. 2000;47(11): 1119–1121.

53.

Lee

Il Kang

Jeon

, et al. Transient anisocoria during medial blowout fracture surgery. Arch Craniofac Surg 2016; 17(3): 154–157.

54.

Peñarrocha-Diago

Sanchis-Bielsa

JM.

Ophthalmologic complications after intraoral local anesthesia with articaine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90(1): 21–24.

55.

Behndig

Effects on pupil size and accommodation from topical lidocaine hydrochloride and tetracaine hydrochloride. J Ocul Pharmacol Ther 2007; 23(6): 591–598.

56.

Claesson

Johansson

Behndig

Mydriasis with different preparations of topically administered lidocaine hydrochloride. J Cataract Refract Surg 2009; 35(2): 277–281.

57.

Savino

Perrotta

Colucci

, et al. Mydriasis induced by sub-Tenon’s ropivacaine injection in patients undergoing strabismus surgery. J AAPOS 2010; 14(2): 124–126.

58.

Joshi

RS.

Phacoemulsification without preoperative mydriasis in patients with age-related cataract associated with type 2 diabetes. Clin Ophthalmol 2016; 10: 2427–2432.

59.

Cionni

Barros

Kaufman

, et al. Cataract surgery without preoperative eyedrops. J Cataract Refract Surg 2003; 29(12): 2281–2283.

60.

Nikeghbali

Falavarjani

Kheirkhah

Pupil dilation with intracameral lidocaine during phacoemulsification: benefits for the patient and surgeon. Indian J Ophthalmol 2008; 56(1): 63–64.

61.

Lee

Moster

Henderer

, et al. Pupil dilation with intracameral 1% lidocaine during glaucoma filtering surgery. Am J Ophthalmol 2003; 136(1): 201–203.

62.

Samarai

Haghighi

Sharifi

Pupil dilation with intra-cameral lidocaine versus topical midriatics during phacoemulsification. Glob J Health Sci 2014; 6(7 Spec No): 8–12.

63.

Nouvellon

Cuvillon

Ripart

, et al. Regional anesthesia and eye surgery. Anesthesiology 2010; 113(5): 1236–1242.

64.

Ripart

Lefrant

Vivien

, et al. Ophthalmic regional anesthesia: medial canthus episcleral (sub-tenon) anesthesia is more efficient than peribulbar anesthesia: a double-blind randomized study. Anesthesiology 2000; 92(5): 1278–1285.

65.

Wang

Casson

Systematic review of peribulbar anesthesia versus sub-Tenon anesthesia for cataract surgery. Asia Pac J Ophthalmol (Phila) 2012; 1(3): 170–174.

66.

Kumar

Dodds

Sub-Tenon’s anesthesia. Ophthalmol Clin North Am 2006; 19(2): 209–219.

67.

Luyet

Eng

Kertes

, et al. Real-time evaluation of diffusion of the local anesthetic solution during peribulbar block using ultrasound imaging and clinical correlates of diffusion. Reg Anesth Pain Med 2012; 37(4): 455–459.

68.

Jaichandran

Ophthalmic regional anaesthesia: a review and update. Indian J Anaesth 2013; 57(1): 7–13.

69.

Ahn

Jeong

Lee

, et al. Effects of peribulbar anesthesia (sub-Tenon injection of a local anesthetic) on akinesia of extraocular muscles, mydriasis, and intraoperative and postoperative analgesia in dogs undergoing phacoemulsification. Am J Vet Res 2013; 74(8): 1126–1132.

70.

Ahn

Jeong

Park

, et al. A sub-Tenon’s capsule injection of lidocaine induces extraocular muscle akinesia and mydriasis in dogs. Vet J 2013; 196(1): 103–108.

71.

Shelton

Digre

Gilman

, et al. Characteristics of myelinated retinal nerve fiber layer in ophthalmic imaging: findings on autofluorescence, fluorescein angiographic, infrared, optical coherence tomographic, and red-free images. JAMA Ophthalmol 2013; 131(1): 107–109.

72.

May

Morphology of the long and short uveal nerves in the human eye. J Anat 2004; 205(2): 113–120.

73.

Varga

Mravec

Chapter 8: Nerve fiber types. In: Tubbs

Rizk

Shoja

, et al. (eds) Nerves and nerve injuries. San Diego: Academic Press, 2015, pp. 107–113.

74.

Polania Gutierrez

Riveros Perez

. Retrobulbar block. In: StatPearls. Treasure Island, FL: StatPearls Publishing, 2024.

75.

Dave

Bhansali

. Pharmacokinetics and pharmacodynamics of ocular drugs BT. In: Pathak

Sutariya

Hirani

(eds) Nano-biomaterials for ophthalmic drug delivery. Cham: Springer, 2016, pp. 111–129.

76.

Hamel

Corre

Ploteau

, et al. Ciliary ganglion afferents and efferents variations: a possible explanation of postganglionic mydriasis. Surg Radiol Anat 2012; 34(10): 897–902.

Mydriasis mediated by local anesthetics: an unexpected adverse event or new therapeutic indication?

Abstract

Plain language summary

Keywords

Introduction

Methodology

Local ophthalmic anesthetics

Pharmacokinetic

Pharmacodynamic

The pupil

Mydriasis

Myosis

Cases analysis

As an adverse event

Off-label use

Hypothesis

Efferent nerves anesthesia

Afferent nerves anesthesia

Ciliary ganglion anesthesia

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References