Pain management during intravitreal injection: integrative review

Katherine Olga Correia Alves Santos Emilly Mayara Feitoza Dias Moniery da Silva Santos Caíque Jordan Nunes Ribeiro Maria do Carmo de Oliveira Ribeiro About the authors

ABSTRACT

BACKGROUND AND OBJECTIVES:

Intravitreal injection is a very common surgical procedure in the treatment of diabetic retinopathy, diabetic macular edema, and retinal vein occlusion. Because it’s a treatment that causes pain and discomfort for the patient, therapies that reduce procedural pain are necessary. The aim of the study was to conduct an integrative review on pain management during administration of intravitreal injection.

CONTENTS:

The study was carried out in January 2021 in three databases (Pubmed, Bireme and Scielo) using the descriptors “intravitreal injections”, “pain management” and “analgesia”. After reading and analysis, 15 articles were selected. The results show several factors associated with pain management during intravitreal injection, such as the use of different anesthetics, needle gauge, injected medication, different surgical instruments and use of music.

CONCLUSION:

Studies have shown that proparacaine, especially when associated with subconjunctival lidocaine, ranibizumab and alternative techniques for intravitreal injection are preferable approaches to pain management during the procedure.

Keywords:
Analgesia; Intravitreal injections; Pain; Pain management

RESUMO

JUSTIFICATIVA E OBJETIVOS:

A injeção intravítrea é um procedimento cirúrgico muito comum no tratamento de doenças como a retinopatia diabética, o edema macular diabético e a oclusão da veia da retina. Por ser um tratamento que gera dor e desconforto ao paciente, terapias que diminuam a dor procedimental são necessárias. O objetivo deste estudo foi realizar uma revisão integrativa sobre o manejo da dor durante a administração de injeção intravítrea.

CONTEÚDO:

Estudo realizado no mês de janeiro de 2021 em três bases de dados (Pubmed, Bireme e Scielo) com o uso dos descritores “injeções intravítreas”, “manejo da dor” e “analgesia”. Após a leitura e análise, 15 artigos foram selecionados. Os resultados evidenciaram diversos fatores associados ao manejo da dor durante a injeção intravítrea, como o uso de diferentes anestésicos, calibre da agulha, fármaco administrado, diferentes instrumentos cirúrgicos e uso da música.

CONCLUSÃO:

Os estudos demonstraram que a proparacaína, principalmente quando associada à lidocaína subconjuntival, o ranibizumabe e as técnicas alternativas de aplicação da injeção intravítrea são abordagens preferíveis no manejo da dor durante o procedimento.

Descritores:
Analgesia; Dor; Injeções intravítreas; Manejo da dor

INTRODUCTION

Intravitreal injection (IVI) is considered one of the greatest advances in techniques for the treatment of retinal diseases. This procedure involves the application of antiangiogenic drugs or steroids in the vitreous, the internal and posterior extension of the eye11 Rodrigues EB, Maia M, Penha FM, Dib E, Bordon AF, Magalhães Júnior O, et al. Técnica para injeção intravítrea de drogas no tratamento de doenças vítreorretinianas. Arq Bras Oftalmol. 2008;71(6):902-7..

IVI are effective in diseases such as diabetic retinopathy, diabetic macular edema and retinal vein occlusion22 Shiroma HF, Takaschima AKK, Farah ME, Höfling-Lima AL, de Luca Canto G, Benedetti RH. Patient pain during intravitreal injections under topical anesthesia: a systematic review. Int J Retina Vitreous. 2017;3:23.. Despite being effective, the treatment also provides an uncomfortable and painful experience, which may result in non-adherence of patients in cases of diseases that require continuous treatment, negatively impacting the intended outcome.

Although it’s a minimally invasive procedure, performed with topical anesthetics, pain and discomfort are frequent in the patient’s experience22 Shiroma HF, Takaschima AKK, Farah ME, Höfling-Lima AL, de Luca Canto G, Benedetti RH. Patient pain during intravitreal injections under topical anesthesia: a systematic review. Int J Retina Vitreous. 2017;3:23.. Thus, professionals have sought scientific evidence to support their practice and promote an adequate pain management for their patients.

Since pain is “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage’’33 DeSantana JM, Perissinotti DMN, Oliveira Junior JO, Correia LMF, Oliveira CM, Fonseca RB. Tradução para a língua portuguesa da definição revisada de dor pela Sociedade Brasileira para o Estudo da Dor. BrJP. 2020;3(3):187-8., unpleasant sensations such as fear, insecurity and anxiety are often associated with the painful phenomenon, especially in nociceptive diagnostic and therapeutic procedures33 DeSantana JM, Perissinotti DMN, Oliveira Junior JO, Correia LMF, Oliveira CM, Fonseca RB. Tradução para a língua portuguesa da definição revisada de dor pela Sociedade Brasileira para o Estudo da Dor. BrJP. 2020;3(3):187-8.,44 Segal O, Segal-Trivitz Y, Nemet AY, Cohen P, Geffen N, Mimouni M. Anxiety levels and perceived pain intensity during intravitreal injections. Acta Ophthalmol. 2016;94(2):203-4., such as IVI.

Although there are studies on the intensity of pain caused by IVI and its related factors, the available literature on its management is still scarce.

Therefore, the objective of this study was to perform an integrative review on the management of pain related to IVI.

CONTENTS

An integrative review that sought to answer the following guiding questions: what are the factors associate to pain related to IVI? What are the pharmacological and non-pharmacological methods used in its management?

The Whittemore methodological reference steps were adopted: problem identification, search, data base assessment, analysis, and presentation of results55 Whittemore R, Knafl K. The integrative review: Updated methodology. J Adv Nurs. 2005;52(5):546-53..

During January 2021, two independent reviewers performed systematic searches on the Pubmed, Virtual Health Library, and Scielo databases using the following DeCS/MeSH controlled descriptors in English, Portuguese, and Spanish: intravitreal injections (injeções intravítreas, inyección intravítrea), pain management (manejo da dor, manejo del dolor) and analgesia, united by the Boolean operators AND and OR.

Studies included were original primary; published between 2011 and 2021; with full text available in English, Portuguese and Spanish languages; investigating the evaluation and management of pain related to IVI in adult patients. Studies using animal models, systematic, integrative, narrative and scoping reviews, editorials, letters to the editor, commentaries, experience reports and research involving pediatric populations were excluded.

Duplicate manuscripts were counted only once, and then studies were screened based on their titles and abstracts. Studies considered relevant were read in full and selected according to the eligibility criteria. Disagreements were resolved by consensus or by a third reviewer (Figure 1).

Figure 1
Flowchart of identification and selection of articles

After the selection stage, the reviewers extracted the data from the articles in a standardized spreadsheet and evaluated the level of evidence using the Oxford Center for Evidence-Based Medicine 2011 (OCEBM) tool, which classifies the articles into five levels of evidence (1 to 5) according to the type of research question and study design. The level of evidence can be lowered according to study quality, imprecision, incompatibility between type of question and design, inconsistency between studies, or because the absolute effect size is too small. On the other hand, the level can be raised if a large or very large effect size is observed66 CEBM. The Centre for Evidence-Based Medicine develops. OCEBM Levels of Evidence. 2011;287-95..

The characteristics of the studies included in the final analysis are shown in table 1. During the synthesis of qualitative data, three thematic categories emerged: associated factors, pharmacological management and non-pharmacological management of pain related to IVI. All studies were published between 2014 and 2020, but most were published in the last five years (73.3%) and from research conducted in the Asian continent (66.7%).

Table 1
Description of studies included in the review

Of the articles selected for review, eight (53.3%) were classified as 1B (randomized clinical trial - RCT), four (26.7%) as 3B (case-control study), and three (20%) in the 2B category (cohort study or clinical trial of lower quality), according to the evidence levels of the OCEBM tool.

Although most studies are RCT, only two recruited more than 1.000 patients. This demonstrates the need for conducting RCT with larger sample sizes and sufficient statistical power to recommend different approaches of pain relief during IVI. This concern is even more evident in investigations on non-pharmacological management, as only one RCT with a small sample size was found.

The main results of the studies included in this review are presented in table 2.

Table 2
Results of analyzed studies

Factors associated with pain related to the intravitreal injection

Despite its clinical relevance, pain is still neglected and undervalued, especially procedural pain. Several diagnostic and therapeutic procedures are potentially painful, but few services have analgesia protocols. Ophthalmologic procedures, such as IVI, are usually performed only with the use of local anesthetic eye drops.

In the present review, it was possible to identify some factors associated with procedural pain related to IVI such as needle size, for example. There is a tendency to use smaller needles, because it’s considered that they require less force to be used. Three clinical trials have compared pain intensity with the use of 27-G and 30-G needles. However, no significant differences in pain scores were observed88 Güler M, Bilgin B, Çapkin M, Ali Simsek, Bilak S. Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. Korean J Ophthalmol. 2015;29(3):190-4.,99 Haas P, Falkner-Radler C, Wimpissinger B, Malina M, Binder S. Needle size in intravitreal injections - Pain evaluation of a randomized clinical trial. Acta Ophthalmol. 2016;94(2):198-202.,1111 Loureiro M, Matos R, Sepulveda P, Meira D. Intravitreal injections of bevacizumab: the impact of needle size in intraocular pressure and pain. J Curr Glaucoma Pract. 2017;11(2):38-41..

The site of IVI application was also investigated, revealing lower pain scores when the procedure was performed in the superior nasal quadrant and higher in the superior temporal quadrant1414 Karimi S, Mosavi SA, Jadidi K, Nikkhah H, Kheiri B. Which quadrant is less painful for intravitreal injection? A prospective study. Eye (Lond). 2019;33(2):304-12.. Additionally, this clinical trial demonstrated an inverse relationship between anesthetic concentration and pain score. Therefore, IVI administered at sites of higher concentration resulted in lower pain intensity.

Some devices used in the conventional technique of IVI caused discomfort the patient, among those, the meta speculum is considered the most painful1010 Alattas K. Patients' tolerance of bimanual lid retraction versus a metal speculum for intravitreal injections. Clin Ophthalmol. 2016;10:1719-21.,1515 Khaqan HA, Imtiaz U, Malik IQ, Qureshi BZ, Rehman A. Customized disposable kit versus a conventional stainless steel instrument for an intravitreal injection: a comparison. J Pak Med Assoc. 2020;70(5):909-12.. To reduce pain caused by this instrument, three studies tested different techniques for palpebral retraction, such as the use of a disposable kit, unimanual method, bimanual method, and with the cotton-tipped applicator. In all cases, the experimental technique was associated with lower pain scores when compared to the conventional technique1010 Alattas K. Patients' tolerance of bimanual lid retraction versus a metal speculum for intravitreal injections. Clin Ophthalmol. 2016;10:1719-21.,1515 Khaqan HA, Imtiaz U, Malik IQ, Qureshi BZ, Rehman A. Customized disposable kit versus a conventional stainless steel instrument for an intravitreal injection: a comparison. J Pak Med Assoc. 2020;70(5):909-12.,1818 Raevis JJ, Karl MD, Parendo AM, Astafurov K, Dugue AG, Agemy AS, et al. Eyelid retraction discomfort with cotton-tipped applicator, unimanual and speculum intravitreal injection techniques: Eyelid retraction technique randomized comparison trial (Eyelid RETRACT). Indian J Ophthalmol. 2020;68(8):1593-5.

There are also devices such as the InVitria (FCI Ophtalmics, Pembroke, MA, USA), made of recyclable and disposable plastic, responsible for keeping the eye open and fixing it in place, also adding an anesthetic effect. They help in the application of IVI, promoting greater safety for the patient and precision for the surgeon, as well as shorter duration of the procedure. When compared to the conventional method, this device has generated results that benefit its use. Two studies concluded that despite the similarity in pain scores between the two methods, InVitria has a shorter application time, contributing to the comfort of the patient1616 Soh YQ, Chiam NPY, Tsai ASH, Cheung GCM, Wong TY, Yeo IYS, et al. Intravitreal injection with a conjunctival injection device: a single-center experience. Transl Vis Sci Technol. 2020;9(8):28.,1717 Blyth M, Innes W, Mohsin-Shaikh N, Talks J. A comparison of conventional intravitreal injection method vs InVitria intravitreal injection method. Clin Ophthalmol. 2020;14:2507-13..

The association between pain and the type of anti VEGF substances acting on the endothelial growth factor administered was evaluated in two studies. It was found that the application of ranibizumab was associated with a lower pain score and report of good experience when compared to aflibercept and bevacizumab88 Güler M, Bilgin B, Çapkin M, Ali Simsek, Bilak S. Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. Korean J Ophthalmol. 2015;29(3):190-4.,1313 Bilgin B, Bilak S. Assessment of patient pain experience during intravitreal ranibizumab and aflibercept injection. Middle East Afr J Ophthalmol. 2019;26(2):55-9.. However, when compared to Ozurdex, the latter did not show a significant difference77 Moisseiev E, Regenbogen M, Rabinovitch T, Barak A, Loewenstein A, Goldstein M. Evaluation of pain during intravitreal Ozurdex injections vs intravitreal bevacizumab injections. Eye. 2014;28(8):980-5..

Although repeated IVI administrations may contribute to non-adherence of patients, one of the studies revealed that pain perception diminishes over the course of treatment1414 Karimi S, Mosavi SA, Jadidi K, Nikkhah H, Kheiri B. Which quadrant is less painful for intravitreal injection? A prospective study. Eye (Lond). 2019;33(2):304-12. Other factors such as age, sex, and diseases associated with retinopathy have been investigated. Some research suggested that elderly patients are more sensitive to pain77 Moisseiev E, Regenbogen M, Rabinovitch T, Barak A, Loewenstein A, Goldstein M. Evaluation of pain during intravitreal Ozurdex injections vs intravitreal bevacizumab injections. Eye. 2014;28(8):980-5.,99 Haas P, Falkner-Radler C, Wimpissinger B, Malina M, Binder S. Needle size in intravitreal injections - Pain evaluation of a randomized clinical trial. Acta Ophthalmol. 2016;94(2):198-202. while others found no significant relation between pain and age1212 Shin SH, Park SP, Kim YK. Factors associated with pain following intravitreal injections. Korean J Ophthalmol. 2018;32(3):196-203.. As for sex, women reported higher pain intensity than men88 Güler M, Bilgin B, Çapkin M, Ali Simsek, Bilak S. Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. Korean J Ophthalmol. 2015;29(3):190-4.,99 Haas P, Falkner-Radler C, Wimpissinger B, Malina M, Binder S. Needle size in intravitreal injections - Pain evaluation of a randomized clinical trial. Acta Ophthalmol. 2016;94(2):198-202.,1212 Shin SH, Park SP, Kim YK. Factors associated with pain following intravitreal injections. Korean J Ophthalmol. 2018;32(3):196-203.

13 Bilgin B, Bilak S. Assessment of patient pain experience during intravitreal ranibizumab and aflibercept injection. Middle East Afr J Ophthalmol. 2019;26(2):55-9.
-1414 Karimi S, Mosavi SA, Jadidi K, Nikkhah H, Kheiri B. Which quadrant is less painful for intravitreal injection? A prospective study. Eye (Lond). 2019;33(2):304-12.. The presence of comorbidities was associated with higher pain scores77 Moisseiev E, Regenbogen M, Rabinovitch T, Barak A, Loewenstein A, Goldstein M. Evaluation of pain during intravitreal Ozurdex injections vs intravitreal bevacizumab injections. Eye. 2014;28(8):980-5..

Pharmacological management of pain related to intravitreal injection

Despite being widely used in the application of IVI, there is no consensus about which local anesthetic is more effective for pain relief during the procedure. Among the selected studies, two investigated the analgesic efficacy of levobupivacaine, proparacaine, and lidocaine1919 Örnek N, Apan A, Örnek K, Günay F. Anesthetic effectiveness of topical levobupivacaine 0.75% versus topical proparacaine 0.5% for intravitreal injections. Saudi J Anaesth. 2014;8(2):198-201.,2020 Andrade GC, Carvalho AC. Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial. Arq Bras Oftalmol. 2015;78(1):27-31..

Levobupivacaine, a bupivacaine isomer, is one of the most used substances in IVI clinical practice due to its lower neurotoxicity. Despite it’s effectiveness, patients in the experimental group reported higher pain scores, and proparacaine 0.5% was the anesthetic that presented the best analgesic efficacy1919 Örnek N, Apan A, Örnek K, Günay F. Anesthetic effectiveness of topical levobupivacaine 0.75% versus topical proparacaine 0.5% for intravitreal injections. Saudi J Anaesth. 2014;8(2):198-201.. This efficacy increases when proparacaine is associated with subconjunctival lidocaine 1%2020 Andrade GC, Carvalho AC. Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial. Arq Bras Oftalmol. 2015;78(1):27-31..

Non-pharmacological management of pain relate to intravitreal injection

Non-pharmacological therapies have been gaining more space in health care processes, especially in the Sistema Único de Saúde (SUS, Brazil’s public health system)2121 Brasil. Ministério da Saúde. Política Nacional de Práticas Integrativas e Complementares no SUS - PNPIC-SUS. Diário da República, 2ª série - n. 102 (27-05-2015). 2015. 13550-13553 p., due to their low cost, easy use, and low frequency of side effects. Moreover, multimodal pain treatment is a practice that allows the integration of different approaches.

However, studies on this subject are still scarce in ophthalmology. Only one study was included in this category, in which 76 patients were randomized into two groups: control group and music. During the entire procedure, the same music was played for the experimental group, while the control group received conventional treatment2222 Chan JC, Chan LP, Yeung CP, Tang W, O YM, Lam WC. Effect of music on patient experience during intravitreal injection. J Ophthalmol. 2020;2020:9120235.. Although there was no significant difference between groups, the patients in the experimental group reported that the experience with music was more pleasant and preferable.

CONCLUSION

Results revealed that the management of pain related to IVI is still underestimated. As for associated factors, alternative techniques of IVI application generated less pain than the conventional one. Furthermore, inconclusive results were found when analyzing the association between pain, sex, age, and needle gauge. Regarding pharmacological methods, it was evidenced that ranibizumab injection resulted in lower pain scores when compared to other anti-VEGFs.

The association between 0.5% proparacaine and 1% subconjunctival lidocaine was more effective than other anesthetic eye drops. Studies investigating multimodal treatment, especially non-pharmacological pain management during IVI, are still scarce. Only one study tested the analgesic efficacy of music during IVI, but there were no significant results. Thus, it’s important to emphasize the need for additional studies of greater methodological rigor, with samples that provide higher statistical power, in order to know the main factors associated with procedural pain in IVI and test new strategies for its relief.

REFERENCES

  • 1
    Rodrigues EB, Maia M, Penha FM, Dib E, Bordon AF, Magalhães Júnior O, et al. Técnica para injeção intravítrea de drogas no tratamento de doenças vítreorretinianas. Arq Bras Oftalmol. 2008;71(6):902-7.
  • 2
    Shiroma HF, Takaschima AKK, Farah ME, Höfling-Lima AL, de Luca Canto G, Benedetti RH. Patient pain during intravitreal injections under topical anesthesia: a systematic review. Int J Retina Vitreous. 2017;3:23.
  • 3
    DeSantana JM, Perissinotti DMN, Oliveira Junior JO, Correia LMF, Oliveira CM, Fonseca RB. Tradução para a língua portuguesa da definição revisada de dor pela Sociedade Brasileira para o Estudo da Dor. BrJP. 2020;3(3):187-8.
  • 4
    Segal O, Segal-Trivitz Y, Nemet AY, Cohen P, Geffen N, Mimouni M. Anxiety levels and perceived pain intensity during intravitreal injections. Acta Ophthalmol. 2016;94(2):203-4.
  • 5
    Whittemore R, Knafl K. The integrative review: Updated methodology. J Adv Nurs. 2005;52(5):546-53.
  • 6
    CEBM. The Centre for Evidence-Based Medicine develops. OCEBM Levels of Evidence. 2011;287-95.
  • 7
    Moisseiev E, Regenbogen M, Rabinovitch T, Barak A, Loewenstein A, Goldstein M. Evaluation of pain during intravitreal Ozurdex injections vs intravitreal bevacizumab injections. Eye. 2014;28(8):980-5.
  • 8
    Güler M, Bilgin B, Çapkin M, Ali Simsek, Bilak S. Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. Korean J Ophthalmol. 2015;29(3):190-4.
  • 9
    Haas P, Falkner-Radler C, Wimpissinger B, Malina M, Binder S. Needle size in intravitreal injections - Pain evaluation of a randomized clinical trial. Acta Ophthalmol. 2016;94(2):198-202.
  • 10
    Alattas K. Patients' tolerance of bimanual lid retraction versus a metal speculum for intravitreal injections. Clin Ophthalmol. 2016;10:1719-21.
  • 11
    Loureiro M, Matos R, Sepulveda P, Meira D. Intravitreal injections of bevacizumab: the impact of needle size in intraocular pressure and pain. J Curr Glaucoma Pract. 2017;11(2):38-41.
  • 12
    Shin SH, Park SP, Kim YK. Factors associated with pain following intravitreal injections. Korean J Ophthalmol. 2018;32(3):196-203.
  • 13
    Bilgin B, Bilak S. Assessment of patient pain experience during intravitreal ranibizumab and aflibercept injection. Middle East Afr J Ophthalmol. 2019;26(2):55-9.
  • 14
    Karimi S, Mosavi SA, Jadidi K, Nikkhah H, Kheiri B. Which quadrant is less painful for intravitreal injection? A prospective study. Eye (Lond). 2019;33(2):304-12.
  • 15
    Khaqan HA, Imtiaz U, Malik IQ, Qureshi BZ, Rehman A. Customized disposable kit versus a conventional stainless steel instrument for an intravitreal injection: a comparison. J Pak Med Assoc. 2020;70(5):909-12.
  • 16
    Soh YQ, Chiam NPY, Tsai ASH, Cheung GCM, Wong TY, Yeo IYS, et al. Intravitreal injection with a conjunctival injection device: a single-center experience. Transl Vis Sci Technol. 2020;9(8):28.
  • 17
    Blyth M, Innes W, Mohsin-Shaikh N, Talks J. A comparison of conventional intravitreal injection method vs InVitria intravitreal injection method. Clin Ophthalmol. 2020;14:2507-13.
  • 18
    Raevis JJ, Karl MD, Parendo AM, Astafurov K, Dugue AG, Agemy AS, et al. Eyelid retraction discomfort with cotton-tipped applicator, unimanual and speculum intravitreal injection techniques: Eyelid retraction technique randomized comparison trial (Eyelid RETRACT). Indian J Ophthalmol. 2020;68(8):1593-5
  • 19
    Örnek N, Apan A, Örnek K, Günay F. Anesthetic effectiveness of topical levobupivacaine 0.75% versus topical proparacaine 0.5% for intravitreal injections. Saudi J Anaesth. 2014;8(2):198-201.
  • 20
    Andrade GC, Carvalho AC. Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial. Arq Bras Oftalmol. 2015;78(1):27-31.
  • 21
    Brasil. Ministério da Saúde. Política Nacional de Práticas Integrativas e Complementares no SUS - PNPIC-SUS. Diário da República, 2ª série - n. 102 (27-05-2015). 2015. 13550-13553 p.
  • 22
    Chan JC, Chan LP, Yeung CP, Tang W, O YM, Lam WC. Effect of music on patient experience during intravitreal injection. J Ophthalmol. 2020;2020:9120235.

Publication Dates

  • Publication in this collection
    08 Oct 2021
  • Date of issue
    Jul-Sep 2021

History

  • Received
    15 Mar 2021
  • Accepted
    06 July 2021
Sociedade Brasileira para o Estudo da Dor Av. Conselheiro Rodrigues Alves, 937 Cj2 - Vila Mariana, CEP: 04014-012, São Paulo, SP - Brasil, Telefones: , (55) 11 5904-2881/3959 - São Paulo - SP - Brazil
E-mail: dor@dor.org.br