Title: Pharmacotherapy for Persistent and Intractable Hiccups<br/>Author: Matthew Poremba<br/><a href='mailto:2731'>[Click to email author]</a><hr/><p style="margin-top: 0px; margin-bottom: 0px; color: rgb(0, 0, 0); font-family: Calibri, Helvetica, sans-serif, EmojiFont, "Apple Color Emoji", "Segoe UI Emoji", NotoColorEmoji, "Segoe UI Symbol", "Android Emoji", EmojiSymbols; font-size: 16px;">
<span style="font-family: "times new roman", times, serif;"><b>Background: </b></span><span style="font-size:14px;">Initiation of pharmacotherapy for management of persistent hiccups (lasting >48 hours) is reasonable in the absence of a reversible cause or failure of non-pharmacologic management. Chlorpromazine has historically been the drug of choice as it is the only FDA-approved drug for this indication. Due to frequency of adverse effects described with chlorpromazine, there is continued interest in finding alternative agents for treatment of hiccups. Two published systematic reviews exist, both of which acknowledge that quantity and quality of existing evidence is low. A summary of the literature reported in these reviews is provided below. </span></p>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;"><b>Treatment Options:</b></span></span></p>
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<em><span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Baclofen </span></span></em></p>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Three published case series and two small randomized controlled trials evaluating baclofen or baclofen in combination with omeprazole were included. A cumulative 66/78 (84.6%) of patients who received baclofen monotherapy reported complete relief of hiccups. </span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Dose: Baclofen 5-10 mg by mouth three times daily, titrated to a max of 75 mg/day.</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Adverse Effects: Sedation, accumulation with renal impairment</span></span></li>
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<em><span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Chlorpromazine </span></span></em></p>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Two published case series included. A cumulative 81/100 (81%) of patients reported cessation of hiccups. Of note, these cases used intravenous chlorpromazine, while oral chlorpromazine is more commonly used in current practice. </span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">IV Dose: Chlorpromazine 25-50 mg via IVPB x 1 dose</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Oral Dose: Chlorpromazine 25 mg by mouth four times daily</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Adverse effects: Sedation, postural hypotension (with IV formulation), and neurologic side effects (including dystonic reactions)</span></span></li>
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<em><span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Gabapentin</span></span></em></p>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Two published case series exist. A cumulative 52/58 patients (89.6%) reported resolution of hiccups. </span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Dose: Gabapentin 300-600 mg by mouth three times daily</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Adverse Effects: Sedation, unsteadiness</span></span></li>
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<em><span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Metoclopramide</span></span></em></p>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">One randomized controlled trial and one case series evaluated metoclopramide. A cumulative 25/31 patients (80.6%) reported relief of hiccups. </span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">IV dose: Metoclopramide 5-10 mg IV every 8 hours</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Oral Dose: Metoclopramide 10 mg by mouth three times daily</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Adverse Effects: Neurologic effects (dystonia, akathisia - though less frequently seen than with chlorpromazine)</span></span></li>
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<em><span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Proton Pump Inhibitors (PPIs)</span></span></em></div>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">One large case series reported success in 146/183 (79.7%) of patients. However, PPIs were not included in either systematic review as they are thought to treat an underlying condition as opposed to being symptomatic treatment of hiccups.</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Gastrointestinal disorders, especially gastrointestinal reflux, are implicated as the most common cause of hiccups, and several sources advocate trialing PPIs first line for treatment for all patients.</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Dose: Omeprazole 20 mg daily, Pantoprazole 40 mg daily</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Adverse effects: Side effects short term use are minimal, however long-term complications include increased incidence of Clostridium difficile-associated diarrhea, vitamin B12 deficiency and hypomagnesemia.</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;"><em>Other Agents</em> - </span></span></div>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Amitriptyline, phenytoin, carbamazepine, valproate, nifedipine, haloperidol and pregabalin all have literature reporting their use for treatment of hiccups with treatment success. </span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;">Level of evidence surrounding use of these agents is very low and neither published systematic review made recommendations regarding their use.</span></span></li>
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<span style="font-size: 14px;"><span style="font-family: "times new roman", times, serif;"><b>Bottom Line: </b><b> </b>Selection of pharmacotherapy for treatment of hiccups should be driven by patient comorbidities, etiology of hiccups, and drug side effect profile. While there is not sufficient evidence to advocate for one agent over the other, use of a PPI, baclofen, gabapentin, metoclopramide or chlorpromazine is reasonable as these agents have the most data supporting their use.</span></span></p>
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<fieldset><legend>References</legend>
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Steger M, Schneemann M, Fox M. Systemic review: the pathogenesis and pharmacological treatment of hiccups. Aliment Pharmacol Ther. 2015;42(9):1037-1050. doi:10.1111/apt.13374</li>
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Polito NB, Fellows SE. Pharmacologic Interventions for Intractable and Persistent Hiccups: A Systematic Review. J Emerg Med. 2017;53(4):540-549. doi:10.1016/j.jemermed.2017.05.033</li>
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Cole JA, Plewa MC. Singultus. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: <a href="https://www.ncbi.nlm.nih.gov/books/NBK538225/">https://www.ncbi.nlm.nih.gov/books/NBK538225/</a></li>
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Cabane J, Bizec JL, Derenne JP. Adiseased esophagus is frequently the cause of chronic hiccup. A prospective study of 184 cases. Presse Med 2010;39: e141–6.</li>
</ol>
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