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What to D.O.

Neuroleptic and Psychotropic Drugs for Abdominal Pain

Repanshek, Zachary MD; Pescatore, Richard DO

doi: 10.1097/01.EEM.0000604560.66982.19
What to D.O.

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Patients with persistent and debilitating abdominal pain and vomiting commonly present to the emergency department seeking answers and relief. Often after extensive and fruitless investigation, they come with various diagnoses of exclusion and medically unexplained symptoms that result in considerable psychosocial impairment, work disability, and continued increased health care utilization.

The list goes on—cyclic vomiting syndrome, abdominal migraine, chronic abdominal pain—but it is now obvious that the various diagnoses are probably not separate entities but part of the same spectrum of shared symptoms, comorbidities, triggers, and responses to treatment. There is substantial overlap among the definitions and diagnostic criteria for these disorders, and their pathogenesis is not completely understood, but all involve dysfunction of the brain-gut axis, including peripheral visceral hypersensitivity and central maladaptive processing of input.

The traditional approach to diagnosing chronic abdominal pain and recurrent vomiting syndromes has largely depended on the patient's cardinal complaint, most worrisome symptom, or even the clinician's subspecialty, but this interpretation of distinct disorders has given way to a more comprehensive understanding of a bidirectional network with multiple functional and structural alterations. (Rambam Maimonides Med J. 2015;6[2]:e0020; http://bit.ly/2kab1CW.)

An emerging consensus holds that the various clinical manifestations of chronic abdominal pain and vomiting can best be viewed as a dysregulation in the complex interplay between events in the gut and in the central nervous system; peripheral and central alterations in this brain-gut axis lead to changes in sensation, motility, mood, affect, and even immune function. The brain-gut axis consists of a hierarchy of reflex loops that ensure normal control of gastrointestinal function, bowel motility, and digestion.

Conscious perception of activity within these reflexes is minimal or absent in healthy individuals, but alterations in the central sensory threshold, a phenomenon called central sensitization, can be associated with alterations in motility and pain perception. Such changes can lead to symptoms of chronic abdominal pain and discomfort, vomiting, and alterations in bowel habits. (Annu Rev Med. 2011;62:381; http://bit.ly/2lRFl5I.)

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Perception of Pain

Central sensitization is a state in which the central nervous system amplifies sensory input across many organ systems. This enhanced response to sensation results in the perception of pain from nonpainful stimuli (allodynia) and greater-than-expected pain from painful stimuli (hyperalgesia). Prominent visceral hypersensitivity can affect every organ system and produce intolerable discomfort due to an amplified sensory response elicited by normal inputs such as innocuous stimuli and normal body sensations. (Rambam Maimonides Med J. 2015;6[2]:e0020; http://bit.ly/2kab1CW.)

Central sensitization in patients with chronic abdominal pain syndromes is accompanied by primary gut afferents reacting to various stimuli by transmitting at elevated firing frequencies, which are interpreted centrally as nociception. This abnormal or enhanced peripheral input is mediated by inflammatory neuropeptides, and may be related to food, early life experiences, stress, gut mucosal inflammation, menses, previous surgery, or acute gastrointestinal infection. (Gut. 1999;45[Suppl 2]:II43; http://bit.ly/2lMQswU.)

Certainly, this interaction between central perception, peripheral activity, and inflammatory neuropeptides is reminiscent of the underpinnings of chronic migraine, another frequent ED therapeutic challenge but one that has largely been addressed successfully by a comprehensive neuromodulatory understanding and approach suggesting that similar pathophysiologic precursors are responsible for chronic abdominal pain syndromes.

A number of similarities are found between migraine and chronic abdominal disorders. Both are typically exacerbated by physiologic or psychological stress and most commonly affect young adults with a strong maternal inheritance pattern. This connection is further supported by the high rate of coexisting migraine syndromes in patients with recurrent vomiting and abdominal pain (24-70%) and response to similar therapeutics.

Migraine disorders are frequently treated in a two-step approach: prophylactic medication taken daily to prevent episodes and abortive therapy for exacerbations. A similar method may be used for patients with recurrent vomiting and abdominal pain disorders. Medications used for migraine prophylaxis, including antiepileptic drugs and antidepressants such as tricyclic antidepressants, have been shown to decrease ED visits and hospitalizations for people with cyclic vomiting syndrome.

Antiemetics, especially dopamine antagonists, are effective abortifacients in migraine and recurrent gastrointestinal syndromes. Triptan therapies may offer relief for some as well. Novel migraine medications, such as calcitonin gene-related peptide inhibitors, may also show promise in helping to control the symptoms of cyclic vomiting and abdominal pain. Like in migraines, opioids should generally be avoided in patients with recurrent abdominal pain because the risk of harm is likely to outweigh any potential benefit.

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No Surprise

The complex interplay of central pain interpretation and peripheral neuroendocrine activity should come as no surprise to emergency physicians because multimodal treatment aimed at disrupting such maladaptive nociception has found firm traction at the bedside. Beginning with the widespread use of droperidol for treating chronic abdominal pain syndromes, the rapid anecdotal uptake of haloperidol to combat cannabinoid hyperemesis syndrome, and the literature and experience of haloperidol's efficacy for treating gastroparesis (Am J Emerg Med. 2017;35[8]:1118), the benefit of neuroleptic therapy for disordered brain-gut axis presentations is well documented.

Much of these medications' efficacy has been attributed to their dopaminergic blockade within the central chemoreceptor trigger zone, but it is likely that antipsychotics also affect alterations in reflex responses involving GI motor and secretory functions as well as abnormal perception of visceral stimuli. This would explain why haloperidol may succeed where metoclopramide fails.

These insights into the mechanism of chronic pain syndromes—migrainous, abdominal, or otherwise—provide an exciting and evidence-based scaffolding for a new paradigm of the use of neuroleptic and psychotropic drugs for durable and effective symptom relief. (Expert Opin Investig Drugs. 2013;22[3]:329.) First-generation and older antipsychotics have nearly become the norm in the emergency department, and there is a growing literature baseand potentially an enduring role for using atypical antipsychotics. Olanzapine, for example, an increasingly utilized neuroleptic, has been demonstrated in several studies to decrease pain and improve quality of life in patients with chronic pain syndromes. (Pain Practice. 2006;6[2]:112.)

One small randomized trial examining patients with chemotherapy-induced nausea and vomiting found olanzapine had 39 percent improved efficacy over metoclopramide. (Support Care Cancer. 2013;21[6]:1655.) A systematic review of atypical antipsychotics in chronic pain management concluded that olanzapine showed consistent efficacy in chronic pain syndromes (principally fibromyalgia and chronic migraine), adding further credence to the role of modulation of the complex central sensitization and peripheral hyperexcitability common to chronic pain complaints. (Clin J Pain. 2018;34[6]:585.)

One significant operational benefit to olanzapine comes in its Zydis formulation, an orally disintegrating tablet that can be administered without the need for IV access and will be absorbed even in refractory vomiting with the inability to tolerate oral medications. If effective, there is little reason the patient can't then be provided with a short prescription to be used as needed to prevent another ED visit.

Our practice is to order 5-10 mg olanzapine in the ED, and discharge the patient home with a short course of 5 mg tablets if successful. Legions of gastroenterologists may question why their patients have been started on antipsychotics, but anecdotal experience has been good and concordant with the emerging literature, with some patients reporting sustained benefit in follow-up.

Dr. Repanshekis an associate professor of emergency medicine and an assistant emergency medicine residency program director at Temple University in Philadelphia. Follow him on Twitter @ZackRepEM. Dr. Pescatoreis the director of emergency medicine research for the Crozer-Keystone Health System in Chester, PA. He is also the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine:http://bit.ly/EMNLive. Follow him on Twitter @Rick_Pescatore, and read his past columns athttp://bit.ly/EMN-Pescatore.

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