• interventional pain management
• chronic pain: imaging
• pain medicine

Hypersensitivity reactions (HRs) to iodinated contrast are estimated to occur in 3%–13% of individuals, though serious reactions occur in less than 0.5%.1–3 For interventional pain medicine specialists, the use of contrast is essential for diagnostic precision, therapeutic effectiveness and safety. Contrast is recommended for medial branch blocks and intra-articular facet injections given the high rate of intravascular uptake and technical failures, respectively.4 5 It is also necessary to ensure proper needle placement for sacroiliac joint injections, discography, sympathetic blocks, interlaminar epidural steroid injections (ESIs) and many other procedures.6 7 For lumbar transforaminal ESIs, recent guidelines cautioned against their deployment when the injection of contrast is not viable.8 In individuals with a history of HRs to iodinated contrast, the non-iodinated-based contrast medium gadolinium is frequently substituted.

The article by Benzon et al 9 in this issue of Regional Anesthesia & Pain Medicine describes six cases of patients with documented HR to iodinated contrast medium (ICM) who were inadvertently administered iodine-based contrast dyes without premedication. None experienced any serious reactions, which raises questions regarding the accuracy of documented hypersensitivity, the clinical and legal implications and how best to manage these patients.

An allergy, as defined by Clemens von Pirquet in 1906, involves the formation of an antibody (IgG or IgE) to a specific substance on exposure, which changes the physiological reaction on subsequent exposures.10 HRs include both anaphylactoid (non-immune mediated physical sequelae which are sometimes termed “anaphylactic-like”) and non-anaphylactoid (chemotoxic) reactions.11 Anaphylactic reactions, being immune mediated and non-dose dependent, fall into the chemotoxic category. Therefore, all HRs are not the same and are not necessarily immunologic-based.

A documented HR may not fall crisply into the well-delineated categories described above. Multiple chemical sensitivity (MCS) is a syndrome in which a person attributes various systemic symptoms (commonly neurological, respiratory, or gastrointestinal) to low-level chemical exposures.12 These sensitivities may be incorrectly documented under the “allergy umbrella” despite the fact that there is no confirmed immunologic basis and their pathophysiology remains nebulous.12 Certain pain populations may be more prone to non-immune-related HRs. For example, nociplastic pain conditions, which include conditions such as fibromyalgia, irritable bowel syndrome, and possibly even non-specific chronic low back pain, have been associated with increased reports of MCS,13–16 making this particularly relevant to the chronic pain provider.

When the pain practitioner encounters a patient with an iodinated contrast HR, further analysis is warranted. Most HRs to ICM are idiosyncratic, with true allergies being rare.11 Some providers choose gadolinium as a “safe” alternative when performing interventions requiring contrast injection. The rates of acute adverse (0.07%–2.4%) and anaphylactic reactions (0.001%–0.01%) associated with gadolinium in CT scans and angiography are considerably less than with ICM use.17

Yet, gadolinium has several limitations that warrant consideration. It is notably more expensive than ICM, which may result in cost-conscious practices foregoing contrast in individuals who may benefit. Gadolinium is less visible than ICM with radiography, which can theoretically result in inadvertent administration of small amounts of insoluble (ie, depomedrol) steroid into unwanted places, such as the intrathecal space or small radiculomedullary arteries innervating the spinal cord, which have been implicated in catastrophic neurological complications with ESI.18 Administration of gadolinium (particularly the linear forms gadodiamide, gadopentetate dimeglumine, and gadoversetamide) to patients with severe renal impairment is associated with nephrogenic systemic fibrosis (NSF).3 This results from gadolinium ion dechelation and subsequent stimulation of fibroblasts.3 19 Although the number of NSF cases has declined since the addition of a “black-box” warning in 2007,3 20 much of the educational outreach of the U.S. Food and Drug Administration (FDA) has targeted radiologists and patients. How many pain physicians have this cognizance remains unknown, despite the “Dear Healthcare Provider” letter coauthored in May 2018 by four gadolinium companies at the request of the FDA.17

Only 73%–99% of gadolinium is excreted within 24 hours, promoting retention in tissues.17 Some fraction of retained gadolinium dissociates from the organic ligand and assumes a labile form;21 the actual percentage varies based on the agent and various clinical factors, making it difficult to predict who is at risk for sequelae. Whereas it is established that dechelated gadolinium is acutely toxic to various tissues, the clinical significance of chronically deposited gadolinium is unclear. The identification of gadolinium deposits in neuronal cell nuclei highlights the risk of possible DNA damage.3 22 However, the few postmortem studies to date have failed to find an association between gadolinium deposition and cytotoxic changes.3 22

Gadolinium has been correlated with dose-dependent increased T1 signal intensity on non-contrast MRI in the dentate nucleus and globus pallidus.3 17 21 This has predominantly been reported with linear gadolinium, but is also observed to a lesser degree with macrocyclic forms.21 Human and animal studies using inductively coupled plasma mass spectrometry at autopsy confirm the correlation between increased T1 signal intensity and gadolinium retention in these regions.17 21

Skin, bone, and liver retention continues for a considerable time period postexposure, with autopsy studies revealing retention for at least 2 years.21 Skin deposition has been extensively studied due to the predominance of skin manifestations in NSF, but bone appears to be a more ominous reservoir, with considerably higher levels compared with other organ systems. Osteoclasts integrate gadolinium actively into the bone matrix, where it serves as a “substitute” for calcium in hydroxyapatite formation.21

For the pain interventionalist, distinct concerns exist. ESI confer a documented 0.5% risk of inadvertent dural puncture despite the use of fluoroscopy,23 with the true risk of intrathecal deposition likely being higher when one considers that small amounts of intrathecal contrast may be undetectable by the human eye, and tiny arachnoid villi form portals connecting the epidural and intrathecal spaces. Intrathecal gadolinium can result in significant neurological consequences, including encephalitis, chemical meningitis, and seizures with optic nerve involvement (after 6–20 mL intrathecal injections).23 The current literature is devoid of documentation of gadolinium brain deposition following interventional pain procedures, though this may be attributable to a lack of surveillance, which is similar to the reason for low (<5%) reported prevalence rates for phantom limb pain right after World War II.24 To illustrate, a recent case report described a patient who received 1.5 mL of intrathecal gadolinium during an ESI and experienced mental status deterioration 2 hours later necessitating intubation.3 23 An MRI of the brain confirmed subarachnoid contrast. The woman was extubated 24 hours later with total neurological recovery, highlighting the need for more information on the relationship.

Deposition of gadolinium is dose-dependent and cumulative. In the brain, retention is associated with two or more administrations,2 3 with one study finding that MRI T1-weighted signal changes are more significant after a total dose of 76 mL.3 25 In individuals with renal failure, the threshold can be as low as 38 mL.26 This is notable because a single pain patient often undergoes multiple contrast-requiring interventions. The choice of gadolinium for the patient with HR may mean repeated exposures and increased retention in end-organs. Compounding the predicament, because gadolinium is more difficult than ICM to visualize, practitioners may be prompted to inject higher volumes.

These issues raise questions as to what the correct course of action is when a questionable history of ICM allergy is provided. One might argue based on the six cases presented by Benzon et al 9 that an unsubstantiated history of a HR is irrelevant in pain procedures given the low volume of ICM injected, the low probability of a true allergy, and the lack of negative consequences demonstrated in the article. However, this would be a simplistic interpretation of a complex issue.

Numerous class action lawsuits have been filed against gadolinium manufacturers on behalf of patients who received gadolinium. Several of these resulted in multimillion dollar verdicts for the plaintiffs. In 2017, the FDA issued an additional warning regarding brain deposition while the European Medicines Agency Committee suspended the use of gadolinium. The controversy shading gadolinium may decrease the likelihood of a practitioner using it, even when it is appropriate. Pain physicians may forego contrast when the risk of a significant HR exists, thereby reducing safety and efficacy. An example of this would be not using contrast for medial branch blocks, whereby studies have shown that intravascular uptake is common and reduces diagnostic validity.27 Alternatively, they may not offer procedures to patients with HR to ICM out of fear of litigation. For instance, whereas studies suggest that transforaminal ESIs are more efficacious than interlaminar injections, the multispecialty working group guidelines recommend against their use without real-time contrast injection.8 28 Does this mean some patients with ICM allergies will end up not receiving potentially beneficial transforaminal epidural steroids? These points raise the age-old ethical dilemma about whether to do the right thing for the patient, or for oneself (ie, risk mitigation). Unfortunately, the two goals do not always align.

Ultimately, a physician’s decision-making strategy should involve a thorough assessment of the patient’s prior reaction to ICM including the context of occurrence, the dye amount injected, the severity/timing of the reaction, and the treatment required for symptom resolution.3 If the practitioner decides to use ICM, premedication with steroid and antihistamine are advised and proper resuscitation medications/equipment must be available. If gadolinium is used, macrocyclic agents are preferred and patients should be clearly informed of gadolinium’s risks.3 Finally, procedures should be performed discriminately, with careful examination of risk: benefit ratio before each additional intervention. Although this strategy should ideally be employed for all interventions, our specialty is under increased scrutiny because all too often it is not.