Hiccups are attributable to a diverse array of etiologies, with over 100 documented in the current literature. The foremost culprits include gastrointestinal causes such as gastroesophageal reflux disease [7], while other cases point to cerebrovascular events, intracranial tumors, meningitis or encephalitis, renal dysfunction, metabolic irregularities, and psychosomatic triggers like stress or excitement [8]. Notably, surgical procedures impacting the thorax or upper abdomen, along with endoscopy, have also been implicated in the development of singultus. The estimated incidence of singultus after ESIs stands at 0.5% [9]. Singultus is categorized by duration, with most sources defining it as “persistent” if it lasts beyond 48 h and “intractable” if it persists over a month [8]. While existing literature commonly reports isolated episodes of post-injection singultus, recurring cases following multiple ESIs is limited.
It appears that persistent hiccups result from ESIs with betamethasone, methylprednisolone, triamcinolone, and dexamethasone, regardless of whether local anesthetic was used [6, 10,11,12]. Notably, hiccups have even been triggered by oral, intravenous, and intra-articular steroid administration [13]. Switching steroids during repeat ESIs has shown potential to prevent reoccurrence of singultus [6]. However, the literature even suggests that some cases of post-epidural injection hiccups may be linked to local anesthetic use without correlation to steroids [14]. Singultus has been associated with ESIs across the cervical, thoracic, and lumbar spine, suggesting no discernible correlation with the level of blockade [15]. Despite uncertainty about the injectate and approach employed during our patient’s prior lumbar ESI, the patient reported no complications from the procedure in the past.
The exact mechanism behind singultus that results from epidural injections remains unclear. One theory dictates that the volume of injectate might play a role via dural sac compression or alteration of cerebrospinal fluid volume, composition, and pressure [16]. Other theories propose corticosteroid interaction with receptors in the reflex arc or direct stimulation of nerves like the phrenic or vagus nerve [11, 17]. Steroids may also potentially lower the threshold for synaptic transmission in the midbrain, triggering hiccups [18]. Local anesthetic use could also induce sympathetic blockade and subsequent parasympathetic hyperactivity [10]. Central neurotransmitters involved in the pathophysiology of hiccups include GABA, dopamine, and serotonin, whereas epinephrine, norepinephrine, acetylcholine, and histamine play peripheral roles [19].
Refractory hiccups are typically managed progressively, starting with non-pharmacologic approaches, with escalation to pharmacologic therapy and potentially invasive methods such as vagus nerve stimulation [20], peripheral nerve stimulation, or phrenic nerve blockade [21, 22]. Intriguingly, continuous cervical epidural administration of ropivacaine (via a catheter at the C3–C5 level) demonstrated efficacy in treating hiccups resistant to pharmacologic treatment in 28 patients [23]. This paradoxical finding underscores the multifactorial nature of this rare phenomenon.
Proposed non-pharmacologic therapies and “cures” for singultus encompass various approaches involving nasopharyngeal stimulation (e.g., inhalation of smelling salts, uvular stimulation), glottic stimulation (e.g., drinking multiple sips of water, chewing lemon, inhaling pepper), vagal maneuvers (e.g., fright induction, application of cold compresses), or respiratory techniques (e.g., breath-holding, rebreathing) [8]. Other options involve hypnosis, massage, electrotherapy, and acupuncture (i.e., auricular), although limited bias-free studies exist on acupuncture due to undefined study population characteristics [24].
A lack of high-quality evidence hampers advocating a specific pharmacologic treatment for singultus [1]. Proton-pump inhibitors like omeprazole have been suggested as first-line therapy for persistent hiccups since as many as 80% of cases may be related to gastroesophageal reflux disease [25]. Baclofen, gabapentin, pregabalin, metoclopramide, and chlorpromazine are also considered effective treatments for singultus [8]. Other agents such as antipsychotics or antidopaminergics are recommended based on anecdotal cases [25], and combination therapy can also be considered [26]. Since baclofen, gabapentin, and pregabalin have a lower side effect profile they are typically recommended after proton-pump inhibitors, with metoclopramide, then chlorpromazine following. However, chlorpromazine is the only pharmacologic agent approved by the United States Food and Drug Administration for the treatment of hiccups. Chlorpromazine antagonizes dopamine in the hypothalamus, which may contribute to its role in treating singultus.
In our case, the decision to initiate baclofen followed by chlorpromazine for pharmacologic treatment was based on the available literature. Baclofen monotherapy has been shown to alleviate intractable hiccups [27], even those developed after ESI [28]. Additionally, in one case report chlorpromazine 10 mg every six hours resolved singultus after a cervical ESI by the following day [11]. In the case series by Abbasi et al. one patient experienced complete resolution of hiccups after one dose of chlorpromazine 10 mg, whereas another failed metoclopramide therapy and experienced resolution after starting chlorpromazine. However, in another case, a patient received haloperidol 5 mg, metoclopramide 10 mg, and gabapentin 300 mg every eight hours for singultus following a cervical ESI. Despite treatment by three agents, the patient experienced no relief, and the hiccups gradually resolved thirteen days after the procedure [15]. The literature suggests that this adverse outcome is typically resolved with pharmacologic treatment or self-limited to two weeks. Reassuringly, singultus that develops after an ESI does not appear to necessitate invasive treatments such as vagus nerve stimulation or phrenic nerve blockade.
An intriguing consideration is whether singultus is more commonly associated with cervical, thoracic, or lumbar ESIs and whether the approach matters (i.e., interlaminar versus transforaminal). In our case, the patient had an uncomplicated lumbar ESI, but developed persistent singultus after a cervical interlaminar ESI. The case series by Abbasi et al. reported persistent hiccups after two cervical and five lumbar ESIs, with the cervical ESIs using an interlaminar approach and four of the five lumbar ESIs using a transforaminal approach. Abubaker et al. reported a case after a cervical ESI and purported that there is no association between the level of injection and the development of singultus. Given that singultus can even occur after a sacral transforaminal ESI [28], sacroiliac joint injection [6], and caudal ESI [29] this statement likely holds true. It is interesting to note, however, that of the reported cases there is a slightly higher predominance of singultus following ESIs in individuals 65 years or younger [6, 10,11,12]. Recently, singultus has been reported after ESIs in patients greater than 65 years of age [28, 30]. While there could be many reasons to explain this finding, there is no conclusive evidence as to why this association exists. Furthermore, persistent hiccups occur more frequently in men than women [31]. This gender predisposition may be due to easier excitability of afferent or efferent nerves in the hiccup reflex arc, but further epidemiologic studies are warranted.
Given that hiccups can emerge after diverse interventional pain procedures and can be distressing to patients, a modified management algorithm was devised for patients experiencing singultus (Fig. 3).
Modified management algorithm for singultus after interventional pain procedures
Although there is limited supporting data to advocate for a specific pharmacologic treatment [1], historically baclofen, gabapentin, pregabalin, metoclopramide, and chlorpromazine have been recommended for singultus. However, given that many pain management patients are already on gabapentin and pregabalin, baclofen may be a better first-line agent unless there is concern over its potential side effects. Baclofen has been shown to lead to full cessation of persistent hiccups within the first six days of treatment in 34 of 35 cases, whereas Gabapentin led to cessation in 81 of 83 cases with a duration of therapy ranging up to six months [32]. Furthermore, if patients fail treatment with any first-line agent chlorpromazine should be elected since it is the only medication approved for this indication and has shown efficacy in previous reported cases [6, 11]. Patients treated with chlorpromazine should be monitored due to a higher risk for side effects such as sedation, palpitations, syncope, extrapyramidal symptoms, and dermatologic reactions [33]. If a patient complains of reflux there should be a strong consideration for a proton-pump inhibitor such as omeprazole [1, 25].
Providers should counsel patients that singultus is a rare adverse effect of ESIs and should be ready to treat the outcome should it occur. Given that singultus typically resolves with pharmacologic therapy or within a couple weeks after the ESI, providers should refer patients to other specialists, including a Neurologist, if symptoms continue beyond this timeframe. Advanced imaging should be considered in any patient with refractory singultus after an image-guided pain procedure.
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