The Use of Contrast Agents in Interventional Pain Procedures

A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions

Honorio T. Benzon, MD; Timothy P. Maus, MD; Hye-Ryun Kang, MD; David A. Provenzano, MD; Anuj Bhatia, MD; Felix Diehn, MD; Ariana Nelson, MD; Zachary L. McCormick, MD; Benjamin P. Liu, MD; Javier de Andres Ares, MD; Magdalena Anitescu, MD; Kristine Blackham, MD; Arun Bhaskar, MD; Silviu Brill, MD; Jeremy Collins, MD; Ashish Gulve, MD; Robert W. Hurley, MD; Young Hoon Jeon, MD; Jee Youn Moon, MD; Richard L. Rauck, MD; Meghan Rodes, MD; Ryan K. Lee, MD; Vinil Shah, MD; Harsha Shanthanna, MD; Jan van Zundert, MD, PhD; Marc Huntoon, MD; James P. Rathmell, MD; Mario Sanchez Borges, MD; Steven P. Cohen, MD; Paul A. Greenberger, MD

Disclosures

Anesth Analg. 2021;133(2):535-552.

Abstract and Introduction

Abstract

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Introduction

Contrast agents are obligatory in interventional pain procedures to ensure delivery of the diagnostic and/or therapeutic agent to the target tissue or anatomic space, and to exclude off-target delivery (intravascular, subarachnoid), which may incur patient risk or diminish the efficacy or specificity of the procedure. The primary contrast agents used for this purpose have historically been iodinated contrast medium (ICM) due to their long history in medicine and ability to delineate vascular and tissue structures under fluoroscopic observation. Patients may describe a hypersensitivity reaction (HR) during prior administration of ICM, ranging from hives to laryngeal edema or even cardiovascular collapse. In these circumstances, the physician must choose either to not perform the procedure, proceed without injecting a contrast agent, premedicate the patient to lessen the likelihood of a serious adverse event, or use an alternative contrast agent, most commonly a gadolinium-based contrast agent (GBCA). Although these latter agents were developed for intravascular enhancement during magnetic resonance imaging (MRI) studies, they also exhibit radiopacity (although to a lesser degree than ICM) and can be used to document on-target delivery and exclude off-target delivery. They do not appear to exhibit hypersensitivity cross-reactivity with ICM.

GBCAs represent a significant advancement in clinical medicine. Their use allows the detection of lesions in the brain on MRI, led to contrast-enhanced MR angiography, and enables the assessment of tissue perfusion.^[1] Early clinical reports of the use of GBCAs appeared in 1984, and their clinical use was approved by the Food and Drug Administration (FDA) in 1988. The GBCAs differ in their structure and ionicity (Table 1). GBCAs have since been used in >300 million patients worldwide.^[2]

Three recent developments impact the continued use of GBCAs as an alternative to ICM during interventional pain procedures. These include nephrogenic systemic fibrosis (NSF) in patients with preexisting renal disease,^[3,4] gadolinium deposition/retention in the brain from repeated administration of GBCAs,^[5–7] and encephalopathy from unintentional intrathecal (IT) injection of GBCA.^[8–10] Appearance of these new reports of previously unrecognized adverse events resulted in calls for caution in the continued use of GBCA,^[9–11] an informed discussion with the patient,^[12] and the creation of a guideline.^[13] These developments, together with the recent finding of rare breakthrough HRs (HR after exposure to the culprit contrast medium) in interventional pain procedures,^[14] prompted a group of concerned investigators and organizations to develop a Practice Advisory (PA) on contrast agents.

1 2 3 4 5

Next Section

Abstract and Introduction
Nature of Interventional Pain Procedures
Results
Discussion
Statements and Recommendations
References
Appendix
Sidebar

Table 1. Gadolinium-Based Contrast Agents
Gadolinium-based contrast agent	Type, stability	Concentration mmol/mL^a	Usual MRI dose mmol/kg (mL dose in 70-kg person)
Gododiamide	Nonionic linear, low	0.5	0.1 (14)
(Omniscan)	Nonionic linear, low	0.5	0.1 (14)
Gadoversetamide	Nonionic linear, low	0.5	0.1 (14)
(Optimark)	Nonionic linear, low	0.5	0.1 (14)
Gadobenate dimeglumine	Ionic linear	0.5	0.1 (14)
(MultiHance)	Intermediate	0.5	0.1 (14)
Gadopentetate dimeglumine	Ionic linear	0.5	0.1 (14)
(Magnevist)	Intermediate	0.5	0.1 (14)
Gadofesveset trisodium	Ionic linear	0.25	0.03 (8.4)
(Ablavar, Vasovist)	Intermediate	0.25	0.03 (8.4)
Gadoxetate disodium	Ionic linear	0.25	0.025 (7)
(Eovist, Primovist)^b	Intermediate	0.25	0.025 (7)
Gadoteridol	Nonionic macrocyclic	0.5	0.1 (14)
(ProHance)	High	0.5	0.1 (14)
Gadobutrol	Nonionic macrocyclic	1	0.1 (7)
(Gadavist)	High	1	0.1 (7)
Gadoterate meglumine	Ionic macrocyclic	0.5	0.1 (14)
(Dotarem)	High	0.5	0.1 (14)

^aUsual radiology dose for MRI of the brain or body parts.
^bUsed for liver MRI imaging.
Abbreviation: MRI, magnetic resonance imaging.

Table 2. Statements and Recommendations in Relation to Nephrogenic Systemic Fibrosis
Statements
1. The risk factors for compromised renal function include age >60 y, hypertension, diabetes, single kidney, kidney surgery, history of kidney malignancy, and kidney transplant.
Level of certainty: High
2. The development of NSF after GBCA-enhanced intravenous MRI is higher with the least stable linear nonionic GBCAs gadodiamide and gadoversetamide and the linear/ionic GBCA gadopentetate dimeglumine.
Level of certainty: High
3. Patients with mild renal impairment (CKD stage 2; eGFR between 60 and 89 mL/min/1.73 m²) are NOT at an increased risk of NSF after a GBCA-enhanced interventional pain procedure.
Level of certainty: Moderate
4. The risk of developing NSF after a GBCA-enhanced interventional pain procedure in patients with moderate renal impairment (CKD stage 3; eGFR between 30 and 59 mL/min/1.73 m²) is very low.
Level of certainty: Moderate
5. In CKD stages 4 (eGFR between 15 and 29 mL/min/1.73 m²) and 5 (eGFR <15 mL/min/1.73 m² ), AKI or dialysis, intravenous use of linear nonionic GBCAs gadodiamide and gadoversetamide and the linear ionic GBCA gadopentetate carry risk for development of NSF; the risk with GBCA-enhanced interventional pain procedures is not known.
Level of certainty: Moderate
Recommendations
1. Patients at risk of developing NSF should be identified before administering a GBCA. Patients with CKD stage 4 or kidney failure (CKD stage 5), AKI and patients on dialysis should be noted.
Strength of recommendation: A
2. In interventional pain procedures, whenever GBCA is necessary, it's indication should be stated and the gadolinium formulation and total dose adequately registered.
Strength of recommendation: A
3. In interventional pain procedures, screening for renal function may not be necessary with the stable macrocyclic GBCAs (gadobutrol, gadoteridol, and gadoterate) and the linear ionic GBCA gadobenate dimeglumine.
Strength of recommendation: A
4. The lowest possible dose of GBCA to obtain necessary clinical information should be administered.
Strength of recommendation: A
5. In interventional pain procedures, the low-risk macrocyclic (gadoteridol, gadobutrol, and gadoterate) and medium-risk linear/ionic (gadoxetate and gadobenate dimeglumine) GBCAs can be administered in patients with moderately reduced kidney function (CKD 3, eGFR between 30 and 59 mL/min/1.73 m²)
Strength of recommendation: B
6. In interventional pain procedures, when GBCA is necessary, the low-risk macrocyclic (gadoteridol, gadobutrol, and gadoterate) and medium-risk linear/ionic (gadoxetate and gadobenate dimeglumine) GBCAs may be used with caution in patients with severely reduced kidney function (CKD 4, eGFR 15–29 mL/min/1.73 m²; CKD 5, eGFR <15 mL/min/1.73 m²) and those on dialysis.
Strength of recommendation: A
7. In interventional pain procedures, GBCAs in the high-risk category (gadodiamide, gadoversetamide, and gadopentetate dimeglumine) are contraindicated in patients with CKD 4 or 5, patients with end-stage renal disease on chronic hemodialysis, and in patients with AKI.
Strength of recommendation: A
8. In an anuric patient with no renal function, GBCA should be avoided. Instead, iodinated contrast media should be considered if the use of contrast is essential. In this instance, the smallest amount should be used.
Strength of recommendation: A

Interventional pain procedures involve the extravascular injection of small doses (< 3 mL) of contrast medium.
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GBCA, gadolinium-based contrast agent; MRI, magnetic resonance imaging; NSF, nephrogenic systemic fibrosis.

Table 3. Statements and Recommendations in Relation to Gadolinium Deposition/Retention in the Brain
Statements
1. After intravenous injection, gadolinium deposition occurs essentially in all tissues, including but not limited to the brain, and may remain in the body months to years.
Level of certainty: Moderate
2. Gadolinium deposition in the brain can occur after intrathecal injection of gadolinium.
Level of certainty: Low
3. A single GBCA-enhanced MRI can cause gadolinium retention visible on subsequent MRI.
Level of certainty: Moderate
4. Gadolinium deposition in the brain may be dose dependent and can occur in patients with no clinical evidence of kidney or liver disease.
Level of certainty: Moderate
5. Brain deposition is higher with the linear GBCAs than with the macrocyclic GBCAs and washout occurs to a greater/faster degree with macrocyclic GBCAs than linear GBCAs, but brain deposition occurs with agents in both classes.
Level of certainty: Moderate
6. The available evidence suggests that the clinical relevance of gadolinium deposition in the brain is low; no adverse sequela has been reported.
Level of certainty: Moderate
Recommendations
1. The interventional pain physician should be aware of patients who have incurred a gadolinium administration burden from multiple gadolinium-enhanced MRI examinations.
Strength of recommendation: B
2. Gadolinium is a drug that should be used with caution in interventional pain procedures. It should be administered only when necessary.
Strength of recommendation: A
3. It is prudent to consider the clinical benefit of the interventional pain treatment against the unknown potential risk of gadolinium deposition in the brain for each individual patient.
Strength of recommendation: B
4. Several factors need to be considered when selecting a GBCA, including diagnostic efficacy, rate of adverse reactions, dosing/concentration, radiopacity, and propensity to deposit in organs such as the brain.
Strength of recommendation: B
5. Ongoing research and emerging evidence need to be monitored and relevant information incorporated into clinical practice as this field of inquiry evolves.
Strength of recommendation: A

Abbreviations: GBCA, gadolinium-based contrast agent; MRI, magnetic resonance imaging.

Table 4. Statements and Recomendations in Relation to Gadolinium Encephalopathy From Intrathecal Injection
Statements
1. In interventional pain procedures, gadolinium-induced encephalopathy can occur after unintentional and intentional subarachnoid (intrathecal) GBCA administration.
Level of certainty: High
2. The pharmacological properties of gadolinium, including its molar concentration and structural classification influence the risk of acute neurotoxicity and encephalopathy.
Level of certainty: Moderate
3. Case reports have shown that volumes as low as 1.5 mL of intrathecal GBCA resulted in signs and symptoms of encephalopathy.
Level of certainty: Low
Recommendations
1. The use of GBCAs is contraindicated in intrathecal interventional pain injections.
Strength of recommendation: A
2. Patients in whom there is increased risk of intrathecal injection should be identified including those with spinal stenosis, previous spine surgery, or kyphoscoliosis.
Strength of recommendation: B
3. In view of the likelihood of unintentional intrathecal spread of the gadolinium, a GBCA is not recommended in epidural injections via an interlaminar approach, including epidurograms.
Strength of recommendation: A
4. In view of the likelihood of unintentional intrathecal spread of the gadolinium, a GBCA is not recommended in transforaminal epidural injections. In circumstances of previously well-documented severe HR to current generation ICM, a shared decision-making process is reasonable to balance the relative risks of using ICM, gadolinium, or alternative interventional procedures not requiring a contrast agent.
Strength of recommendation: B
5. If it is deemed that gadolinium is necessary for an interventional pain procedure where there is a low risk of possible unintentional intrathecal administration (eg, lumbar sympathetic blocks, facet joint injections, and medial branch blocks), then the low risk of intrathecal gadolinium administration should be adequately explained to the patient.
Strength of recommendation: A
6. If gadolinium is considered essential to the pain procedure and is to be injected near the epidural/subarachnoid space, measures should be observed to avoid advancement of the needle tip into the subarachnoid space. These measures include multiple radiographic images, stabilizing the needle and repeated aspirations to detect the undesired presence of CSF. The lowest possible volume of the GBCA should be utilized and if possible, a GBCA with low molar concentration of gadolinium.
Strength of recommendation: A
7. If gadolinium is used, digital subtraction imaging guidance may be considered as this increases the detection of intrathecal spread and allow the safer use of a lower molar concentration of GBCA.
Strength of recommendation: B
8. If there is a concern for unintentional intrathecal or subdural administration of a GBCA, appropriate radiographic imaging, such as MRI and CT, should be considered to investigate the occurrence of intrathecal or subdural administration.
Strength of recommendation: A
9. If gadolinium-induced encephalopathy occurs or is considered, immediate supportive measures should be instituted.
Strength of recommendation: A

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; GBCA, gadolinium-based contrast agent; HR, hypersensitivity reaction; ICM, iodinated contrast medium; MRI, magnetic resonance imaging.

Table 5. Statements and Recommendations in Relation to Hypersensitivity Reactions From Iodinated Contrast Medium
Statements
1. Nonimmunologic anaphylaxis, also previously termed anayphylactoid reaction or idiosyncratic/nonallergic hypersensitivity reaction, comprise at least 80% of HRs to ICM.
Level of certainty: Moderate
2. HRs to GBCA are less common than HRs to ICM.
Level of certainty: High
3. The greatest risk factor for HR to CM is history of HR. Other risk factors include multiple allergies, atopic tendencies including asthma, female sex, severe cardiovascular disease, repeated exposure to contrast media, and intravascular compared to extravascular (oral, gastrointestinal, genitourinary, abdominal cavity, and subarachnoid) exposure to radiocontrast media. Seafood intolerance is not a risk factor.
Level of certainty: High
4. Reexposure to ICM in a patient with a history of HR may result in recurrent HR, especially with intravascular administration of large volumes.
Level of certainty: High
5. Most HRs occur within 1 h, usually within 20 min, of intravenous ICM administration. Immediate HR is more common with ionic than nonionic ICM. The reaction intensity may be mild, moderate, severe, or life-threatening.
Level of certainty: High
6. Late HRs may occur 1 h to 1 wk after CM administration. Most of the delayed HRs are usually mild and cutaneous in nature. However, some HRs which occur 1–6 h after CM administration can be severe or life-threatening as immediate HRs.
Level of certainty: High
7. The incidence of HR after an interventional pain procedure that involves the extravascular injection of less than 10 mL of CM in patients with a history of prior HR after an intravenous ICM-enhanced radiologic examination is low.
Level of certainty: Low
8. Premedication with corticosteroids and antihistamines is highly, but not completely effective in preventing HR in all patients.
Level of certainty: High
9. Beta-blocker use does not increase the risk of HR to CM after an interventional pain procedure, even in patients with a history of HR.
Level of certainty: Moderate
10. HRs to nonionic linear GBCAs are less common than HRs to ionic linear GBCAs.
Level of certainty: Moderate
Recommendations
1. When a HR occurs, the interventional physician should document the incident. In the report, the physician should note the name and volume of the CM that was injected.
Strength of recommendation: A
2. The physician should be notified immediately if a patient scheduled for procedure with contrast injection has a history of HR to CM. The specific type, dose, route of CM used and severity of reaction, symptom management, sequelae and results of laboratory investigations should be documented contemporaneously in the medical record.
Strength of recommendation: A
3. Patients with a history of mild HR to CM may receive appropriate pretreatment and receive a different low-osmolar nonionic CM if culprit ICM is known. Patients with relative contraindications to steroid administration should receive pretreatment only if benefits outweigh the risks and should be counseled as to expected adverse effects.
Strength of recommendation: B
4. Patients with history of moderate or severe HR to ICM should be pretreated and injected with a different low-osmolar nonionic ICM, if culprit ICM is known, and if alternative contrast choices such as GBCM or air are contraindicated. These patients may be considered for referral to an allergist for evaluation, explanation of HRs, and optimization before elective procedures using CM.
Strength of recommendation: B
5. Prophylaxis for late reactions, in the absence of an immediate reaction, is not recommended and treatment should be exclusively symptomatic.
Strength of recommendation: A
6. Patients with a history of true IgE-mediated allergic HR, and a positive skin test (done within 6 mo of HR) should receive a premedication of steroid and H1 antihistamine medication.
Strength of recommendation: A
7. Patients with a history of true IgE-mediated allergic HR should be injected with a different ICM that is skin-test negative.
Strength of recommendation: B
8. If CM must be administered within 4–12 h to a patient qualifying for premedication, the patient should receive 40 mg methylprednisolone or 200 mg hydrocortisone intravenously every 4 h and 50 mg diphenhydramine intravenously 1 h before receiving CM.
Strength of recommendation: A
9. In patients who report allergy to methylprednisolone or hydrocortisone, intravenous dexamethasone 7.5 mg or betamethasone 6 mg may be substituted.
Strength of recommendation: A
10. Recommendations for duration of monitoring in patients with history of HR to CM
Clinical setting	Duration of monitoring for HR^a following CM administration
Premedicated patients with history of mild HR and no symptoms following exposure to CM	30 min
Nonpremedicated patients with history of mild HR and no symptoms following exposure to the same CM	30 min
Patients with a history of moderate/severe HR but no reaction in the first 15 min (irrespective of premedication status)	30 min–1 h^b
Strength of recommendation: B
11. Acute HR should be managed symptomatically
Strength of recommendation: A
12. For the staff associated with interventional pain procedures, there should be an annual review of the following: (a) grading system of the severity of hypersensitivity reactions (mild, moderate, severe, or life-threatening); (b) components of documentation for witnessed or historical HRs; (c) emergency preparedness of the staff (who calls for rapid response); and (d) steps involved in cardiopulmonary resuscitation.
Strength of recommendation: A
13. Emergency equipment, including airway supplies, defibrillator, and cardiovascular support medications should be immediately available during interventional procedures involving administration of CM, especially in patients with history of HR to CM. Manufacturer and/or institutional protocols should be followed regarding maintenance and care of emergency resuscitation equipment and medications.
Strength of recommendation: A

^aThe recommended durations pertain to monitoring for possibility of a HR, in patients who had no sedation. Note that at least 15 min usually elapse from the time the CM is injected to the time the patient is in the recovery room. For patients who have sedation, additional time is usually observed as per institution's protocol.
^bPatients should be cautioned of the possibility of late HR. Immediate life-threatening CM HRs usually occurs within 1 h but severe life-threatening HRs can occur even after 6 hours. The duration of monitoring should be individually determined by the previous nature of CM HRs.
Abbreviations: CM, contrast medium; GBCA, gadolinium-based contrast agent; HR, hypersensitivity reaction; ICM, iodinated contrast medium; IgE, immunoglobulin E.

Authors and Disclosures

Honorio T. Benzon, MD*, Timothy P. Maus, MD†, Hye-Ryun Kang, MD‡, David A. Provenzano, MD§, Anuj Bhatia, MD||, Felix Diehn, MD†, Ariana Nelson, MD¶, Zachary L. McCormick, MD#, Benjamin P. Liu, MD**, Javier de Andres Ares, MD††, Magdalena Anitescu, MD‡‡, Kristine Blackham, MD§§, Arun Bhaskar, MD||||, Silviu Brill, MD¶¶, Jeremy Collins, MD†, Ashish Gulve, MD##, Robert W. Hurley, MD***, Young Hoon Jeon, MD†††, Jee Youn Moon, MD‡‡‡, Richard L. Rauck, MD§§§, Meghan Rodes, MD*, Ryan K. Lee, MD||||||, Vinil Shah, MD¶¶¶, Harsha Shanthanna, MD###, Jan van Zundert, MD, PhD****, Marc Huntoon, MD††††, James P. Rathmell, MD‡‡‡‡, Mario Sanchez Borges, MD§§§§, Steven P. Cohen, MD|||||||| and Paul A. Greenberger, MD¶¶¶¶

*Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; †Department of Radiology, Mayo Clinic, Rochester, Minnesota; ‡Department of Medicine (Allergy and Immunology), Seoul National University, Seoul, South Korea; §Pain Diagnostics and Interventional Care, Pittsburgh, Pennsylvania; || Department of Anesthesiology, University of Toronto, Toronto, Ontario, Canada; ¶Department of Anesthesiology, University of California at Irvine, Irvine, California; #Department of Physical Medicine and Rehabilitation, University of Utah, Salt Lake City, Utah; **Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; ††Department of Anesthesiology-Pain Unit, Hospital Universitario La Paz, Madrid; ‡‡Department of Anesthesiology, University of Chicago, Chicago, Illinois; §§Department of Radiology, University Hospital, Basel, Basel, Switzerland; ||||Imperial College Healthcare NHS Trust, London, United Kingdom; ¶¶Institute of Pain Medicine, Tel Aviv Medical Centre, Tel Aviv, Israel; ##Department of Pain Management, James Cook University Hospital, Middlesbrough, United Kingdom; ***Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina; †††Anesthesiology and Pain Medicine, School of Dentistry, Kyungpook National University, Daegu, South Korea; ‡‡‡Department of Anesthesiology, Seoul National University, Seoul, South Korea; §§§Carolina Pain Institute, Winston-Salem, North Carolina; ||||||Department of Radiology, Sydney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania; ¶¶¶Department of Radiology, University of California at San Francisco, San Francisco, California; ###Department of Anesthesiology, McMaster University, Hamilton, Ontario, Canada; ****Anesthesiology and Pain Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; ††††Department of Anesthesiology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia; ‡‡‡‡Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; §§§§Department of Allergy and Clinical Immunology, Centro Medico Docente La Trinidad, Caracas, Venezuela; ||||||||Department of Anesthesiology and Critical Care Medicine, Pain Medicine Division, Department of Physical Medicine and Rehabilitation, and Department of Neurology, and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland; and ¶¶¶¶Department of Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Address correspondence to
Honorio T. Benzon, MD, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. Address e-mail to h-benzon@northwestern.edu.

Conflicts of Interest
See Disclosures at the end of the article.

Disclosures
Name: Honorio T. Benzon, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: H. T. Benzon is a member of Advisory Board, Sandoz International.
Name: Timothy P. Maus, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: T. P. Maus received travel support from Spine Intervention Society, American Academy of Pain Medicine, American Academy of Neurology, International Musculoskeletal Society; and research support from National Institutes of Health and Mayo/University of Minnesota.
Name: Hye-Ryun Kang, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: David A. Provenzano, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: D. A. Provenzano received consulting fees from Avanos, Boston Scientific, Medtronic, Nevro, and Esteve and also research support from Avanos, Medtronic, Nevro, Stimgenics, and Abbott.
Name: Anuj Bhatia, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Felix Diehn, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Ariana Nelson, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Zachary L. McCormick, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Benjamin P. Liu, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: B. P. Liu is a member of Advisory Board, Guerbet and received research support from Guerbet, Bayer AG.
Name: Javier de Andres Ares, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Magdalena Anitescu, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: M. Anitescu received consulting fee from Medtronic, Boston Scientific and fellowship grant from Medtronic, Abbott.
Name: Kristine Blackham, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Arun Bhaskar, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Silviu Brill, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Jeremy Collins, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: J. Collins received research support from Siemens Healthtineers; Advisory Board, Guerbet; Stock ownership, CETA, Inc.
Name: Ashish Gulve, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Robert W. Hurley, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: R. W. Hurley received research support from Avanos and Robert Wood Johnson Foundation, National Institutes of Health.
Name: Young Hoon Jeon, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Jee Youn Moon, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Richard L. Rauck, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: R. L. Rauck received research support from Mainstay, Saluda, Stimgenics, Biogen, Medtronic, Boston Scientific, Tekada. R. L. Rauck is a consultant for BioDelivery Sciences International (BDSI), Boston Scientific, Mainstay, Salix.
Name: Meghan Rodes, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Ryan K. Lee, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: R. K. Lee is a member of Advisory Board, Bracco COVID-19; and a consultant for Philips, Bayer.
Name: Vinil Shah, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Harsha Shanthanna, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Jan van Zundert, MD, PhD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Marc Huntoon, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: M. Huntoon is a consultant for SPR (Sprint PNS System) Therapeutics, Saluda, Mainstay Medical.
Name: James P. Rathmell, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: J. P. Rathmell is the Chair, Clinical Events Committee for ReActiv8 B Clinical Trial, Mainstay Medical LLC.
Name: Mario Sanchez Borges, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: None.
Name: Steven P. Cohen, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: S. P. Cohen is a consultant for Scilex, Avanos, Medtronic, SPR Therapeutics, Persica.
Name: Paul A. Greenberger, MD.
Contribution: This author helped with the conception, design, and writing of the manuscript.
Conflicts of Interest: P. A. Greenberger is a member of FDA Allergenic Products Advisory Committee and member of FDA Pulmonary Allergy Drugs Advisory Committee.
This manuscript was handled by: Jianren Mao, MD, PhD.