Central Neuromodulators for Treating Functional GI Disorders: A Primer

Transcription

1 CLINICAL AND SYSTEMATIC S 693 CME Central Neuromodulators for Treating Functional GI Disorders: A Primer W. Harle y S obin, M D 1, Thomas W. Heinrich, MD, FAPM2 and Douglas A. Drossman, MD, MACG3 Patients with functional GI disorders (FGIDs) are commonplace in the gastroenterologist's practice. A number of these patients may be refractory to peripherally acting agents, yet respond to central neuromodulators. There are benefits and potential adverse effects to using TCAs, SSRIs, SNRIs, atypical antipsychotics, and miscellaneous central neuromodulators in these patients. These agents can benefit mood, pain, diarrhea, constipation, nausea, sleep, and depression. The mechanisms by which they work, the differences between classes and individual agents, and the various adverse effects are outlined. Dosing, augmentation strategies, and treatment scenarios specifically for painful FGIDs, FD with PDS, and chronic nausea and vomiting syndrome are outlined. Am J Gastroenterol 2017; 112: ; doi: /ajg ; published online 28 March 2017 Central neuromodulators can benefit the more challenging and refractory functional gastrointestinal disorders (FGIDs) ( 1 5 ). Rome IV considers FGIDs to be disorders of gut brain interaction. The enteric nervous system (ENS) is hardwired to the CNS in a way that neuroreceptors share similar neurotransmitters and psychiatric drugs can be used to treat disorders of both the gut and brain. Yet gastroenterologists are reluctant to use them because of the stigma attached to them or because they feel ill prepared to use them. Indeed a patient asked to take an antidepressant or atypical antipsychotic may develop false perceptions of their intended use: that they are depressed, crazy, or that the medication will alter their thinking and behavior. The growing field of neurogastroenterology now requires that we consider changing these names to that of neuromodulators or centrally targeted agents to be more consistent with their actions on brain gut pathways. This article is a primer to help gastroenterologists understand how best to use central neuromodulators to optimize patient care. We have made efforts to clarify how these agents can be used specifically for various symptom clusters or FGIDs. RATIONALE FOR THE USE OF CENTRAL NEUROMODULATORS IN GASTROENTEROLOGY There are a number of ways in which central neuromodulators can help patients with functional gastrointestinal disorders. First, many patients with FGIDs experience co-morbid anxiety or other types of psychological distress and these neuromodulators help reduce psychological distress, anxiety, hyper vigilance, selective attention, and catastrophizing associated with the GI symptoms ( 6 8 ). Second, they treat associated psychiatric diagnoses, like major depression ( 1 ). Third, they can reduce pain by down regulation of incoming visceral signals via gating mechanisms ( 9,10 ). Fourth, clinicians can take advantage of their effects on GI motor function i.e., selective serotonin reuptake inhibitors (SSRIs) improve constipation by accelerating intestinal transit and tricyclic antidepressants (TCAs) improve diarrhea by slowing transit. Fifth, providers can benefit from the action of several of these neuromodulators to help address symptoms like nausea ( ). Sixth, over time, depression, anxiety, and other forms of chronic emotional distress are believed to lead to a loss of cortical neuron density and central neuromodulators may reverse this process via neurogenesis ( 14 ). Longer treatment with central neuromodulators leads to an increase in BDNF (brain-derived neurotropic factor) and presumably increased neurogenesis ( 15 ). QUALIFICATIONS RELATING TO THE USE OF CENTRAL NEUROMODULATORS IN GASTROENTEROLOGY Gastroenterologists, while not trained in the use of psychopharmacological treatments, may want to consider their use when treating patients with FGIDs, and this article provides some guidelines. Nevertheless, none of the psychopharmacological treatments have undergone sufficient trials by FDA to be approved for painful FGIDs by FDA or other regulatory agencies. Regulatory approval for these treatments has now lagged behind the rationale for their use based on our growing knowledge of neurogastroenterology and the results, including meta-analyses of a limited number of available clinical studies targeted to these disorders. However, many if not most other non-psychopharmacologic medications used to treat FGIDs are also utilized in an off label manner, and are based on compelling clinical wisdom. Thus 1 United Hospital System, Kenosha, Wisconsin, USA ; 2 Department of Psychiatry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA ; 3 Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology, Chapel Hill, North Carolina, USA. Correspondence: W. Harley Sobin, MD, United Hospital System, th Avenue, Suite 202, Kenosha, Wisconsin , USA. harleysobin@gmail.com 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 694 Sobin et al. the recommendations made are derived from the available studies using these central neuromodulating agents for FGIDs (clinical trials and case series), as well as a larger number of studies relating to the treatment of chronic somatic pain, or of psychiatric disorders, and personal experience over several decades with their use. EVIDENCE FOR THE BENEFIT OF CENTRAL NEUROMODULATORS The purpose of this article is to provide expert recommendations for the choice of central neuromodulators for FGIDs rather than provide detailed systematic reviews. However, general evidence is provided via the largest clinical analysis of the use of central neuromodulators in functional gastrointestinal disorders. This meta-analysis by Ford et al. ( 16 ) analyzed almost 1,100 IBS patients treated with antidepressants. Looking at TCAs there was improvement in 57% receiving medication while placebo treated patients improved 36% of the time. With SSRIs there was improvement in 55% but only 33% receiving placebo. The number needed to see improvement in one patient with both classes of drugs was 4. But the benefit was associated with increased side effects. There were adverse side effects in 31% of those treated with antidepressants but only 16% of those treated with placebo. What follows is information where selected medications are recommended for selected conditions, and systematic reviews at that level of discussion are not available. CENTRAL NEUROMODULATORS-MECHANISM OF ACTION Central neuromodulators involve a number of neuroreceptors, and neurotransmitter transporters ( 17 ). The key monoamine neurotransmitters released by neurons include serotonin, norepinephrine, and dopamine. Transporters function to allow for reuptake of the monoamines back into the neurons after neurotransmission occurs thereby terminating their action and allowing the neurotransmitters to be reutilized. If the action of the transporters is inhibited there is a subsequent rise in the level of these monoamines outside of neurons. A key element of many neuromodulators is to inhibit transporter reuptake of monoamines, thus maintaining neurotransmitter action in the synaptic cleft. For example, the resulting increase of serotonin levels in the central nervous system by serotonin reuptake inhibitors is thought to play a role in the treatment of major depression and a variety of anxiety disorders, although the exact mechanism of this response has not yet been fully elucidated. Medications that increase both serotonin and norepinephrine levels have also been shown to help promote analgesia and treat painful conditions such as fibromyalgia and neuropathic pain. Those agents that increase dopamine levels have a tendency to have a more stimulating effect on the patient thereby decreasing sedation. Several of the key transporters and neuroreceptors are noted below. A more detailed listing is in Table 1A. SERT SERT (serotonin transporter) removes serotonin from the synaptic cleft. SERT inhibition leads to increased levels of serotonin. Increasing the levels of serotonin has been associated with the beneficial effect of treating depression, but is also associated with the adverse effects of nausea, and diarrhea. SERT inhibition is potent in all SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and, to a lesser extent, all TCAs. NET NET (norepinephrine transporter) removes norepinephrine from the synaptic cleft. NET inhibition has been linked to the promotion of analgesia and the treatment of depression. Increased norepinephrine may also contribute to a sense of activation and other sympathomimetic effects. It is mildly constipating. It is present in all SNRIs and TCAs, but, of note, is absent in SSRIs. Table 1A. Action of central neuromodulators on different transporters and receptors Transporter or receptor Stimulate or inhibit Action Clinical Adverse effects Drug class SERT (t) NET (t) DAT (t) Inhibit serotonin reuptake Inhibit norepinephrine reuptake Inhibit dopamine reuptake Increase serotonin AD Antianxiety Nausea diarrhea SSRI SNRI TCA Increase norepinephrine AD and analgesic Dry mouth sweats Constipation SNRI TCA Increase dopamine Increase activation Nausea Buproprion, sertraline D2 Receptor antagonist Decrease dopamine Antipsychotic Antiemetic EPS galactorrhea All antipsychotics 5HT1 Receptor agonist Stimulate 5HT1 AD and improves gastric compliance 5HT2A Receptor antagonist Increase dopamine in striatum +pituitary Antipsychotic without EPS or galactorhea 5HT3 Receptor antagonist Inhibit 5HT3 Less nausea, diarrhea, pain Buspirone Atypical antipsychotics Mirtazapine, olanzapine, AD, Antidepressant, DAT, dopamine transporter; NET, norepinephrine transporter; SERT, serotonin transporter; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. The American Journal of GASTROENTEROLOGY VOLUME 112 MAY

3 Treating Functional GI Disorders: A Primer 695 Table 1B. Central neuromodulators-receptor actions with undesirable side effects Receptor Action Adverse effect Drug class M1 Antagonist Anticholinergic Dry mouth, constipation All TCAs, paroxetine H1 Antagonist Antihistaminic Lethargy, weight gain All TCAs, many antipsychotics Alpha 1 adrenergic Antagonist Decrease adrenergic tone Postural hypotension All TCAs some antipsychotics Cardiac fast sodium channels Antagonist Slow cardiac conduction Cardiac arrhythmia All TCAs TCA, tricyclic antidepressant. DAT DAT (dopamine transporter) removes dopamine from the synaptic cleft. DAT inhibition increases dopamine levels. This increase can be associated with activation and treatment of depression, but has also been linked to the adverse effect of nausea. Of note, excess dopamine might lead to psychosis. D2 receptor Inhibition of this receptor is thought to be responsible for the antipsychotic efficacy of most of the antipsychotic medications. In addition, inhibition of the D2 receptor may also improve nausea and is part of the mechanism of action of metoclopramide and domperidone. D2 receptor antagonism is also responsible for the extrapyramidal side effects experienced by some patients treated with this class of medications. 5HT1 receptor Stimulation of this receptor is thought to play a role in the treatment of anxiety and depression. It has also been shown to improve gastric compliance and accommodation. Buspirone is an example ( 18 ). Sumatriptan is a well-known 5HT1 agonist that is not a central neuromodulator, but helps to relax the gastric fundus. 5HT3 receptor Stimulation of this receptor has been linked to increased levels of pain, nausea and diarrhea. A number of central neuromodulators inhibit 5HT3. Several antiemetic drugs: ondansetron, dolasetron, and granisetron relieve nausea by inhibiting 5HT3. Alosetron blocks pain and reduces diarrhea by inhibiting 5HT3. The neuromodulators mirtazapine ( 19,20 ) and olanzapine, which both inhibit 5HT3, have been used to treat chronic nausea. A number of central neuromodulators act on receptors leading to undesirable side effects (more detailed in Table 1B ): M1 receptor Antagonism of the muscarinic receptor is responsible for anticholinergic side effects, such as dry mouth and constipation. There is M1 inhibition with all TCAs and also paroxetine, an SSRI. While most SSRIs cause diarrhea, paroxetine is the SSRI most likely to cause constipation, due to its M1 inhibition. All TCAs are associated with constipation. H1 receptor H1 inhibition is associated with sedation and weight gain. H1 inhibition occurs with all TCAs and a number of atypical antipsychotics. CENTRAL NEUROMODULATORS USED IN GASTROENTEROLOGY What follows is general information about the use of the various classes of neuromodulators followed by clinical recommendations for the gastroenterologist. This includes tables of the different neuromodulators used in GI with dosages ( Table 2 ) and a listing of which neuromodulators to choose for different symptom complexes in patients with FGIDs ( Table 3 ). In addition, for each medication type we summarize the information by offering our clinical recommendations. Finally, we provide in the Appendix hierarchical treatment algorithms to address predominant symptoms of pain, dyspepsia, and nausea/vomiting. However, when using unfamiliar medications or treatments in combination (i.e., augmentation), psychiatric consultation should be considered. TRICYCLIC ANTIDEPRESSANTS TCAs are central neuromodulators that have been used for many decades in psychiatry to treat depression, but newer agents have largely supplanted their use. Currently the TCAs are prescribed in low dosages (e.g., mg/day in the medical setting vs mg/day in the psychiatric setting) to treat various painful conditions or to act as a sleep aid. With regard to GI practice, TCAs are used most frequently to treat IBS-D. However, they can be used for many other painful FGIDs including centrally mediated abdominal pain syndrome (CAPS-formerly FAPS), functional chest pain, anorectal pain, and functional dyspepsia. The beneficial effects of TCAs have been linked to their inhibition of SERT and NET. There may be adverse effects due to inhibition of M1, H1, alpha 1 adrenergic (leading to postural hypotension), and cardiac fast sodium channel receptors (in high doses may cause arrhythmias). TCAs are more effective than SSRIs in reducing pain ( 10,21,22 ). The anticholinergic properties of this class of medications may be a benefit in patients experiencing diarrhea. The H1 inhibition may benefit those patients suffering from insomnia by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 696 Sobin et al. Table 2. Central neuromodulators-dosage Generic Rx name Brand Rx name Dosage TCAs Amitriptyline Elavil mg qd Desipramine Norpramin mg qd Imipramine Tofranil mg qd Nortriptyline Pamelor mg qd SSRIs Citalopram Celexa mg qd Escitalopram Lexapro 5 20 mg qd Fluoxetine Prozac mg qd Paroxetine Paxil mg qd Sertraline Zoloft mg qd SNRIs Duloxetine Cymbalta mg qd Minacipran Savella mg bid Venlafaxine Effexor mg qd MISC AGENTS Buproprion Wellbutrin mg bid Buspirone Buspar mg bid Mirtazapine Remeron mg qd Trazodone Desyrel mg qd ATYPICAL ANTIPSYCHOTICS Aripiprazole Abilify mg qd Brexipiprazole Rexulti mg qd Lurasidone Latuda NS* Olanzapine Zyprexa mg qd Quetiapine Seroquel mg qd Ziprasidone Geodon NS* SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. *NS drugs not prescribed by gastroenterologists. As a result of TCA s propensity to cause sedation and orthostasis they should be administered at night. The initial dose and titration schedule of the various TCAs is similar, however, tertiary amines (amitriptyline and imipramine) have more side effects because of their greater antagonism of cholinergic, adrenergic, and histamine receptors. Dosing can start at 25 mg, going up to 50 mg after a week if well tolerated by the patient and if needed increased to 75 mg. If there is insufficient benefit after a month at this low dose, the TCA dose can be further increased. Doses up to 150 mg have been studied in functional GI disorders ( 23 ). In patients with FGIDs, most early side effects reported by patients, other than the expected anticholinergic side effects, correlate more with the patient s underlying level of anxiety than the TCA blood levels or the number of pills taken ( 24 ). Patients should be informed that anticholinergic side effects occur early in the treatment course. However, the patient should be encouraged to adhere to the treatment course because it might take a month to experience the full benefit of the medication and side effects tend to become more tolerable over time. It should be noted that TCAs, due to their inhibition of cardiac fast sodium channels leading to a prolongation of the refractory period of the cardiac action potential, are classified as class 1A antiarrhythmic agents. They may, therefore, pose a proarrhythmic risk in certain patients. They should be avoided in patients at risk for a cardiac arrhythmia, including those with a history of myocardial infarction, left bundle branch block, bifascicular block, or patients with a prolonged QT interval. Therefore a baseline ECG should be checked prior to initiation of a TCA in patients at risk for cardiac conduction abnormalities and in all pediatric patients. TCAs should be considered first line for treating pain in patients with IBS, CAPS, or other painful FGIDs. They should be prescribed in moderate dosages (25 mg building up to 75 or 100 mg). Because secondary amine TCAs (e.g., desipramine, nor triptyline) have less anticholinergic and antihistaminic side effects when compared with tertiary amine TCAs (amitriptyline, imipramine), they are favored to allow for higher dosages to manage the pain. All TCAs can also be helpful in reducing diarrhea such as with IBS-D though this effect is greater with the tertiary amines. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) SSRIs are not primary agents for treating pain but may be used in patients with painful FGIDs already receiving a TCA but who are poorly controlled due to associated anxiety symptoms ( 3 ). They may also benefit patients with FGIDs and comorbid panic disorder, generalized anxiety disorder, depression, social anxiety, specific phobias, or a somatic symptom disorder. Patients who exhibit selective attention to their symptoms or who are hyper vigilant to worsening symptoms may also benefit from an SSRI. SSRIs may be used, in lieu of a TCA, to manage a patient who has IBS-C when pain is not a dominant feature. SSRIs are more likely to cause diarrhea while TCAs tend to be constipating. When pain is dominant, one would choose a TCA or SNRI over an SSRI. Nevertheless, unlike studies on chronic abdominal pain or dyspepsia, SSRIs were found effective in small controlled studies of patients with functional chest pain using sertraline 50 mg ( 25 ), paroxetine mg ( 26 ), and citalopram 20 mg ( 27 ). When choosing between SSRIs, the medications sertraline, citalopram, and escitalopram tend to have the fewest pharmacokinetic drug drug interactions as they exhibit minimal effects on the cytochrome P450 enzyme system. Fluoxetine and paroxetine, however, have an increased risk of pharmacokinetic drug interactions through their strong inhibition of the P450 isoenzymes 1A2 and 2D6 ( 28 ). In addition, fluoxetine, and its active metabolite The American Journal of GASTROENTEROLOGY VOLUME 112 MAY

5 Treating Functional GI Disorders: A Primer 697 Table 3. Choosing and avoiding central neuromodulators for FGIDs based on associated symptoms Symptom/syndrome Choose Avoid CAPS a TCA, SNRI, quetiapine Narcotics Chronic nausea and vomiting syndrome Mirtazapine, olanzapine, TCA SSRI, SNRI, buproprion, topirimate Functional bloating Functional chest pain TCA, buspirone, SSRI Trazodone, venlafaxine, SSRI, TCA Functional constipation SSRI (not paroxetine), SNRI TCA, paroxetine Functional diarrhea Functional Dyspepsia (PDS) Globus TCA, SNRI, paroxetine Buspirone, mirtazapine, TCA SSRI Hyper vigilance SSRI, SNRI, short-term clonazepam Long term use of benzodiazepines IBS-C SSRI (not paroxetine), SNRI TCA, paroxetine IBS-D TCA, SNRI, paroxetine Other SSRIs Insomnia Quetiapine, mirtazapine, trazodone Buproprion, sertraline, fl uoxetine Lethargy Buproprion, sertraline, fl uoxetine TCA, mirtazapine, olanzapine, paroxetine, quetiapine, trazodone CAPS, centrally mediated abdominal pain; FAPS, functional abdominal pain; FGID, functional gastrointestinal disorder; PDS, postprandial distress syndrome; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. a Centrally mediated abdominal pain syndrome, previously FAPS. norfluoxetine, have an additive half-life of days, making SSRI discontinuation syndrome (discussed later) a rarity in patients taking this medication. Thus, fluoxetine can be a useful medication for patients who may miss doses of this central neuromodulator. In contrast, paroxetine has a short half-life of less than a day and is commonly implicated in cases of discontinuation syndrome when stopped abruptly. Citalopram, escitalopram, and sertraline all exhibit half-lives of longer than a day, but still require a gradual taper to avoid the uncomfortable symptoms of SSRI discontinuation syndrome. Dosing: citalopram mg, escitalopram 5 20 mg, fluoxetine mg, paroxetine mg, sertraline mg. Even though SSRIs are first line pharmacologic agents for the treatment of anxiety disorders they have the potential, when the drug is first started, to induce restlessness and exacerbate anxiety. To minimize these potential anxiogenic adverse effects they are typically initiated at half of the usual starting dose. The dose may then be gradually increased after about 1 week to the regular starting dose. The beneficial effect of the SSRI is usually delayed 3 4 weeks, which may represent a problem for those patients with significant anxiety that is complicating treatment and causing significant functional impairment. In such cases, a useful strategy is to schedule a long-acting benzodiazepine to temporarily bridge this lag-time and provide symptomatic relief for the patient s anxiety symptoms. The benzodiazepine should then be tapered off after about 4 weeks of SSRI treatment. Clonazepam at a scheduled dose of mg bid is often utilized in this bridging period. The longer half-life of clonazepam helps prevent break-through anxiety and allows for an easier taper off the benzodiazepine. SSRI s are not first line treatments for painful FGIDs. However they can provide benefit when anxiety related symptoms (symptom related anxiety, symptom hyper vigilance, obsessive behaviors, social phobia, or agoraphobia) are dominant. If pain is also present, SSRI s in low dose can be added to a TCA. SSRI s can also help to improve constipation. Escitalopram may be the preferred SSRI based on tolerability and fewest drug interactions, with citalopram as a preferred alternative. SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS SNRIs are agents indicated for treating painful somatic syndromes including diabetic neuropathy, fibromyalgia and chronic musculoskeletal pain. Their value for visceral pain has not been adequately studied, but they are commonly used for this purpose off label with empiric benefit (29 31 ) Their value relates to a lower side effect burden than the TCA s with similar pain reduction ( 32 ). SNRIs can be prescribed as primary agents for treating painful FGIDs. They may also be utilized in patients with painful FGIDs who failed an initial trial of a TCA or experienced intolerable side effects from the TCA that precluded them from reaching a potentially therapeutic dose. SNRIs are used to treat centrally mediated abdominal pain (CAPS), formerly functional abdominal pain (FAPS) ( 33,34 ), functional chest pain, and IBS and other FGIDs with associated abdominal wall pain or fibromyalgia. SNRIs can also be used in IBS-C. They are less constipating than TCAs and bring more pain relief than SSRIs. Dosing: duloxetine mg qd, and milnacipran mg bid. Although another SNRI, 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

6 698 Sobin et al. venlafaxine, is dosed for depression at mg, it acts primarily as an SSRI at lower doses, and needs to be prescribed at higher doses (150 mg or more per day) to achieve adequate noradrenergic benefit via NET inhibition for treating pain. This is not the case with duloxetine, which acts as an SNRI throughout the dose range. Venlafaxine has also been studied in treating functional dyspepsia ( 35 ). However, the SNRIs tend, in general, to have a higher frequency of nausea, especially venlafaxine. Milnacipran is indicated for fibromyalgia and other chronic somatic pain syndromes. It is an SNRI but is not marketed for depression and is titrated up to doses of mg bid. This may encourage acceptance by some patients who are concerned about using a psychiatric drug. SNRI s are used as first line treatment for pain management with fewer side effects than TCA s and can be used in patients with constipation. Nausea may occur but can be minimized when taken with meals. Duloxetine has been favored in dosages of or up to 90 mg/day but venlafaxine can be used in higher dosages (>150 mg/day). As an alternative milnacipran can also be considered for pain, titrating the dose up to mg bid. ATYPICAL ANTIPSYCHOTICS The second-generation antipsychotics, such as quetiapine, aripiprazole, or olanzapine, are often called atypical antipsychotics, because they don t present the same risk of extrapyramidal side effects (such as dystonic reactions or parkinsonism) when compared to the older (typical) antipsychotics like haloperidol. The multiple atypical antipsychotics have varied clinical indications. All are approved for schizophrenia while some have additional indications for bipolar disorder and treatment resistant depression. Many of these agents have also been used for various offlabel psychiatric indications such as treatment refractory anxiety, personality disorders, and insomnia although the evidence for such use is limited ( 36 ). These agents are also used in gastroenterology as second line augmenting agents for various FGIDs. Quetiapine has been used as an augmenting agent in patients with painful IBS or CAPS who did not respond to treatment after 4 or more weeks with TCAs or SNRIs and have adjunctive benefit for reducing symptom related anxiety and normalizing sleep architecture ( 37 ). Low doses, mg are given nightly, but can be increased to 200 mg for patients with severe anxiety, sleep disturbance, or pain. It helps relieve pain by inhibiting NET. D2 inhibition helps relieve nausea ( 38 ). Quetiapine has a very low rate of associated extrapyramidal side effects and hyperprolactinemia, but it has an intermediate risk of metabolic effects (obesity, hyperlipidemia, and diabetes). For patients who develop too much weight gain or lethargy on quetiapine, from personal experience aripiprazole mg or brexpiprazole at mg can be substituted as pain augmenting agents and to help reduce the anxiety component of FGID pain. These agents have a reduced propensity to cause sedation and weight gain compared to quetiapine. Although studied extensively in psychiatry the evidence for using these drugs to treat FGIDs is still empiric. Olanzapine has been used in oncology, anesthesiology, and now gastroenterology to treat chronic nausea due to its 5HT3 and D2 inhibition. There is a full description of its use in the section on Central Neuromodulators and Nausea. Atypical agents, in particular quetiapine in low dosage (e.g., mg qhs), are used to augment the pain benefit of TCAs or SNRIs. Quetiapine has the added benefit of producing normal restorative sleep and anxiolysis. If weight gain or excessive sedation occurs and can t be managed by dose titration, a less sedating atypical agent (e.g., aripiprazole or brexpiprazole) can be substituted to augment the pain benefit and achieve anxiety reduction. When nausea is a dominant feature olanzapine can be considered. MISCELLANEOUS AGENTS: BUSPIRONE, TRAZODONE, MIRTAZAPINE Buspirone is a 5HT1A agonist. It is a non-benzodiazepine anti-anxiety neuromodulator that also acts to improve gastric compliance ( 18 ). By enhancing gastric fundic relaxation it is useful in patients with functional dyspepsia with post-prandial distress syndrome ( 18 ). The usual dose in treating functional dyspepsia is mg bid. Trazodone blocks 5HT2 receptors and serotonin reuptake. It has been found useful in gastroenterology treating functional chest pain (39 ). The usual dose is mg HS. It is most often utilized in psychiatry to treat insomnia. Mirtazapine is a selective alpha-2 adrenergic agonist that also blocks 5HT2, 5HT3, and H1 receptors. Due to its receptor profile it is a powerful agent in gastroenterology for managing chronic nausea, dyspepsia, and weight loss ( 19 ). In addition, its antihistaminergic properties make it a useful medication for addressing insomnia. The usual effective dose is mg qhs. Buspirone may be used for post-prandial distress syndrome variant of functional dyspepsia in doses up to mg bid, and to also help with mild anxiety reduction. Mirtazapine mg can be used for functional dyspepsia (alone or in combination with buspirone) or to treat nausea and reduced appetite associated with weight loss or sleep disturbance. Trazodone mg qhs can be considered for functional chest pain or to treat sleep disturbance. CENTRAL NEUROMODULATORS TO TREAT CHRONIC NAUSEA Among their other effects on various receptors mirtazapine and olanzapine are both potent 5HT3 inhibitors with long half-lives that allow for once daily dosing to manage nausea. These drugs The American Journal of GASTROENTEROLOGY VOLUME 112 MAY

7 Treating Functional GI Disorders: A Primer 699 can be very effective in patients who have functional dyspepsia ( 19,20 ) and chronic nausea vomiting syndrome. Generic mirtazapine also has the benefit of being inexpensive, helps with sleep, anxiety, and depression. A typical starting dose can be 7.5 mg with a usual therapeutic dose of mg (rarely 60 mg) given at nighttime. The major side effect is daytime sedation and weight gain. Mirtazapine has been used extensively in oncology for managing nausea associated with chemotherapy ( 11,12 ) and also in anesthesiology. Some patients, however, are intolerant of even low doses. Olanzapine has also been used in managing challenging nausea in anesthesiology and oncology ( 13 ). It is generally used as a second line drug for chronic nausea vomiting syndrome. Olanzapine, due its dopamine antagonism, may be used in patients who initially respond to mirtazapine and then have break-through nausea, or in patients who fail to respond to mirtazapine. Olanzapine may also be less sedating for those patients who find mirtazapine overly sedating. Typical starting dose of 2.5 mg with a therapeutic dose of 5 10 mg. Olanzapine may lead to adverse metabolic consequences, including weight gain, hyperlipidemia, and diabetes, along with a potential for neurological adverse effects including akathisia and dystonic reactions. These effects are unusual at the lower doses recommended in the treatment of FGIDs. For patients who have only occasional, or intermittent nausea we recommend ondansetron mg or promethazine 12.5 to 25 mg up to q6h. For patients requiring long term control of nausea or vomiting mirtazapine 15 to 45 mg qhs should be considered, with olanzapine 2.5 to 10 mg qd as a second line drug, If mirtazapine is not tolerated due to lethargy, or proves ineffective, consider substituting olanzapine. Side effects of central neuromodulators The more common side effects of central neuromodulators are described below and have been extensively outlined previously ( 17,40,41 ). diarrhea is not an expected side effect and can be considered for patients with IBS-D. All TCAs are constipating although the tertiary amine agents (e.g., amitriptyline, imipramine) are more constipating than the secondary amine agents (e.g., amitriptyline, imipramine). Some atypical antipsychotics (e.g., olanzapine) can be constipating due to greater anticholinergic properties. Alteration of energy levels. A number of neuromodulators can cause excess sedation. These include all TCAs, paroxetine, mirtazapine, olanzapine, and quetiapine. Other neuromodulators tend to be more activating. These include fluoxetine, sertraline, and bupropion. Sexual dysfunction. Sexual dysfunction is a common adverse effect associated with medications that inhibit SERT. Paroxetine has been found to have a higher incidence than comparable central neuromodulators. TCAs are unlikely to cause sexual dysfunction, in the low doses usually used to treat FGIDs. Of the various central neuromodulators, bupropion and mirtazapine are least likely to cause sexual dysfunction. Trazodone has been linked to rare cases of priapism. Unmasking a bipolar disorder. Some patients who present with depression may actually have an occult bipolar illness, and starting a central neuromodulator may cause some patients to cycle into a hypomanic or manic episode, thereby exposing an underlying bipolar disorder. This switch from depression to mania usually occurs fairly abruptly within the first couple of weeks of central neuromodulator use. This is unlikely to occur while using lowdose TCAs for the treatment of a FGID, but may become more common with higher dose SSRIs or SNRIs. If, after the initiation of a central neuromodulator, a patient were to start developing signs of mania or hypomania (excess energy, rapid speech, euphoria, impulsivity, and insomnia) the central neuromodulator should be discontinued and the patient referred to a psychiatrist for an evaluation for an underlying bipolar disorder. Nausea and vomiting. The newer atypical antipsychotics aripiprazole, lurasidone, and ziprasidone may be commonly associated with nausea and occasionally vomiting, while the atypical agents previously discussed, quetiapine and olanzapine, more commonly help improve nausea and vomiting but may produce weight gain and metabolic syndrome. If a patient on the newer neuromodulators has moderate to severe nausea or vomiting it is reasonable to switch to olanzapine or quetiapine. Bupropion, an antidepressant, and topirimate, an antiepi leptic medication, have both been employed to prevent weight gain but have been associated with increased rates of nausea. Finally, most SSRIs and SNRIs can be associated with nausea, particularly early in the course of treatment. This adverse effect may be mitigated by recommending that the patient take the medication with food. Alteration of bowel movements. Most all SSRIs can cause diarrhea. Paroxetine, however, has more anticholinergic effects, so GI bleeding. SSRIs may predispose to GI bleeding. They block serotonin reuptake by platelets, thereby inhibiting serotoninmediated platelet aggregation. Two different studies addressed this issue. The earlier one, by Loke ( 42 ), found an increased odds ratio of GI bleeding of 2.36 in patients on SSRIs alone or 6.33 if they were on SSRIs and NSAIDS. A more recent review, by Anglin ( 43 ) found a smaller increased risk, 1.66 if on SSRIs or 4.25 if on SSRIs and NSAIDS. Richter found that use of SSRIs within 24 h of PEG placement was associated with a fourfold-increased risk of post procedural GI bleeding ( 44 ). NSAIDs should be avoided in patients on SSRIs. If the combination is necessary, PPIs are recommended. It is generally not practical to stop SSRIs prior to GI procedures. In many cases it would require stopping them days in advance due to the long half-lives and the potential of active metabolites. The abrupt discontinuation could also be associated with antidepressant discontinuation syndrome. For patients who are at very high risk of GI bleeding 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

8 700 Sobin et al. alternative central neuromodulators, such as mirtazapine or bupropion, may be preferable. it is best to discontinue the morning dose for a week then discontinue the evening dose. Serotonin syndrome. Serotonin syndrome (45 ) represents the constellation of symptoms associated with serotonin toxicity. Symptoms of serotonin syndrome may include fever, muscle rigidity, tremors, confusion, tachycardia, seizures, and pupillary dilation. It is most commonly implicated when two or more serotoni nergic medications are administered to a patient, although it has been reported when a high dose of a single serotonergic medication is prescribed. Notably agents high in serotonin effect (e.g., SSRI) when compared to agents low in serotonin effect (e.g., TCAs) are more likely to cause the syndrome. The onset of symptoms and signs often occurs soon after dose escalation of a serotonergic medication or the addition of another medication that increases serotonin levels. It is important to recognize that central neuromodulators are not the only medications that increase serotonin levels. The triptans, tramadol, ondansetron, and the antibiotic linezolid have also been implicated in cases of serotonin syndrome. If signs or symptoms of serotonin syndrome develop, all medications with serotoninergic properties should be discontinued and restarted later in lower dose or with another medication, or if symptoms are mild, can be reduced and observed for resolution of side effects. Hepatotoxicity. Central neuromodulators are generally well tolerated in patients with liver disease unless there is advanced cirrhosis. However, most patients with stable NAFLD or hepatitis C should have little risk of liver toxicity. In patients with decompensated cirrhosis all sedating drugs need be avoided, and dosing frequently has to be decreased. Idiosyncratic drug reactions have occasionally been reported with many different central neuromodulators. Duloxetine is one of the more common, with 7/899 of the cases of severe hepatotoxic drug reactions reported in the latest DILI network publication ( 46 ). However, central neuromodulators are more likely to cause liver injury due to the propensity of certain agents to cause weight gain and metabolic syndrome, thereby worsening NAFLD. DISCONTINUING CENTRAL NEUROMODULATORS The abrupt discontinuation of serotonergic central neuromodulators (principally SSRIs and SNRIs) may be associated with an antidepressant discontinuation syndrome. The syndrome consists of a variety of somatic complaints including nausea, headache, and paresthesias. It is more common in agents with a shorter halflife (such as paroxetine) and gradual taper of serotonergic central neuromodulators is often warranted to avoid this unpleasant syndrome. If discontinuing the central neuromodulator is planned, it is advisable that the neuromodulator be tapered off slowly over 4-weeks (25% per week). However, if the patient has been on the central neuromodulator for less than 4 weeks it is usually not necessary to taper the neuromodulator. Short-term use of clonazepam at a dose of mg bid may enhance tolerance of SSRIs and SNRIs. In tapering the medicine FINAL THOUGHTS This article reviews the use of central neuromodulators in patients with refractory FGIDs having symptoms of pain, nausea and vomiting and comorbid anxiety and depression. They are to be considered when patients have been treated with peripherally acting drugs but still remain symptomatic. Central neuromodulators can be considered as second line therapy or can be used to augment the effect of peripheral agents. Furthermore, these agents are also used to treat anxiety and depression and thus may achieve dual purpose for patients with co-morbid psychological distress. Thus augmentation may include combining peripheral and central agents, combining two central agents or combining medications with psychological intervention such as CBT. Since these recommendations are directed toward treatment of medical symptoms, we suggest that when there are major psychiatric co-morbidities present, that the clinician also consult with a psychiatrist for optimal choice of medications and dosing, Because many gastroenterologists feel ill prepared to prescribe and manage central neuromodulators, our goal was to elucidate their rational use in treating various FGIDs based on their dominant symptom complex (pain, nausea/vomiting). Although not the topic of this article, their use can also apply when treating patients with other structural disorders such as painful IBD, or cancer because of their central effect. There are limited well-designed studies on the use of many of these drugs in treating functional GI disorders. While there are many well-designed studies and meta-analyses addressing antidepressants for FGIDs, they do not always address the dominant symptoms relative to global response measures. Furthermore, few studies address the use of SNRI s, non-tca or SSRI antidepressants, or the newer antipsychotics. The large meta-analysis by Ford ( 16 ) is supportive of the use of antidepressants in IBS. However, the greatest database of knowledge on the value of central neuromodulators is based on studies done in patients with other painful conditions like migraines, fibromyalgia, and chronic pain in general. In some cases, the benefit with mirtazapine and olanzapine is based on studies in oncology patients. With these caveats, we have provided information to aid the clinician on the use of these agents by combining review of literature and personal experience. Clearly further studies are much needed. For the time being we hope we have made use of these medications more logical and accessible to clinicians ultimately to benefit our patients. CONFLICT OF INTEREST Guarantor of the article: W. Harley Sobin, MD. Specific author contributions: W. Harley Sobin: conceived the publication, performed literature review, and wrote the manuscript. Thomas W. Heinrich: consulted the manuscript. Douglas A. Drossman: consulted and wrote the manuscript. Financial support: None. Potential competing interests: None. The American Journal of GASTROENTEROLOGY VOLUME 112 MAY

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