Neurogastroenterology & Motility Neurogastroenterol Motil (2015)

doi: 10.1111/nmo.12509

CLINICAL REVIEW

Centrally targeted pharmacotherapy for chronic abdominal pain € H. T ORNBLOM *

& D. A. DROSSMAN †,‡

*Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden †Drossman Center for the Education and Practice of Biopsychosocial Care, Professor Emeritus of Medicine and Psychiatry, UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA ‡Drossman Gastroenterology PLLC, Chapel Hill, NC, USA

Key Messages

• Dysregulated brain-gut modulation of afferent signaling is important in chronic abdominal pain. • This clinical review uses a conceptual model to explain chronic pain development including the evidence for •

central neuron degeneration as a relevant factor in the chain of events. Centrally targeted medications are important in the treatment of chronic abdominal pain with effects that include downregulation of afferent pain signals and a potential role in neuron proliferation.

Abstract Background Chronic abdominal pain in the context of the functional gastrointestinal disorders departs from a more traditional approach to treating gastrointestinal symptoms. Chronic abdominal pain involves a dysregulation of brain-gut modulation of afferent signaling, so treatments directed toward the gut are not usually sufficient to achieve a clinical response. Rather the methods of treatment depend on re-establishing central pain regulation. Purpose A conceptual model of predisposing, precipitating, and perpetuating factors is used to explain how a situation of chronic pain develops and it provides the evidence for central neuron degeneration as relevant to this chain of

events. The rationale for centrally targeted medications, in particular antidepressants, is discussed with regard to effects independent of their role in treating psychiatric disorders: with regard to downregulation of afferent pain signals and their potential role in neuron proliferation. Finally, guiding examples of which drug to use and treatment combinations involving multiple drugs, augmentation treatment, are outlined and some brief clinical cases of centrally targeted pharmacotherapy. Keywords abdominal pain, antidepressants, brain-gut axis, functional gastrointestinal disorders, treatment.

INTRODUCTION Address for Correspondence Hans T€ ornblom, MD, PhD, Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41345, Sweden. Tel: +46 31 3429939; fax: +46 31 7412917; e-mail [email protected] Received: 6 October 2014 Accepted for publication: 14 December 2014

© 2015 John Wiley & Sons Ltd

The management of patients with chronic abdominal pain in the absence of structural diagnoses is one of the most challenging areas in medicine. These are the functional gastrointestinal disorders (FGID); common conditions that relate to altered gastrointestinal (GI) functioning involving motility disturbance, visceral and/or central hypersensitivity, altered mucosal

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it evolves to form the GI tract. There are no organ structures as closely connected as the brain and the gut. Accordingly neurotransmitters and medications with neural effects act both in brain and gut and we can take advantage of this relationship in planning treatment for chronic GI pain. Afferent nerve signals from the gut reach conscious perception in the brain by transmission through a chain of three neurons. The primary spinal afferent neuron has its cell body in the dorsal root ganglion and terminates in the dorsal column laminae of the spinal cord. In this region, descending modulatory fibers from brain stem centers such as the periaqueductal gray alter the sensitivity of the dorsal horn neurons and thus serve as a central control of pain perception during visceral stimulation. Among the neurotransmitters involved in this process, serotonin and norepinephrine are possible to affect by readily available pharmacotherapy (Fig. 1). The second order afferent neuron projects from the dorsal horn of the spinal cord to the thalamus and the mid-brain. Above this level, the

immune function, and dysregulation of brain-gut pathways.1 The pain of FGIDs relates primarily to visceral or central hypersensitivity, and when the predominant feature is pain, these FGIDs are subcategorized based on their bodily location: irritable bowel syndrome (IBS)2 in the mid to lower abdomen, the epigastric pain syndrome of functional dyspepsia (FD)3 in the epigastrium, the functional gallbladder and sphincter of Oddi disorders4 in the right upper quadrant and epigastrium, functional anorectal pain5 in the anorectal area, and functional abdominal pain syndrome (FAPS)6 which is diffusely located in the abdomen. Because these chronic painful disorders involve dysregulation of brain-gut modulation of pain,7 treatments directed toward the gut are not usually helpful for patients with moderate to severe pain; rather the methods of treatment depend primarily on re-establishing more normal pain regulation via centrally targeted medications or behavioral interventions. Centrally targeted treatments such as these are not always familiar to medical physicians because they have not traditionally been taught in medical schools and are only recently being studied in well-designed trials and meta-analyses. In fact one large survey show that patients with moderate to severe IBS are most often prescribed peripheral analgesics, antispasmodics, acid blockers and even opioids.8 The limited effect of these types of treatments for chronic GI pain, and the risk of opioids to produce hyperalgesia (narcotic bowel syndrome)9 must be recognized and avoided. For these disorders centrally targeted treatments including psychopharmacological medications and behavioral treatments are now shown to have clear value for chronic GI pain.10 In this text we will focus on psychopharmacological treatments by reviewing their rationale and providing the methods of using them to treat chronic and painful GI disorders.

A

B

A RATIONALE FOR THE USE OF CENTRALLY TARGETED TREATMENTS— THE BRAIN-GUT AXIS An understanding of the neural transmission of gut sensory input that forms the basis for the concept of the brain-gut axis is of help when explaining and motivating patients why a psychotropic drug in some instances is useful in those with treatment refractory abdominal pain. To begin, it should be realized that the brain and gut are ‘hardwired’: there are direct connections that originate when the neural crest in the embryo differentiates into the brain and spinal cord, and the latter sends out branches into the endoderm as

Figure 1 Simplified overview of ascending (A) and descending (B) neural pathways involved in visceral perception. The descending modulatory fibers from brain stem centers can alter the sensitivity of the dorsal horn neurons and serve as a central control of pain perception during visceral stimulation.

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IBS).19 In this setting, an inflammation-induced altered mucosal immune response sensitizes visceral afferent nerves. In addition, when emotional distress or some kind of significant life event co-exists, the risk for PI-IBS to develop into a situation of chronicity is markedly increased.20 The central nervous system (CNS) amplification of the visceral signals that occur in psychologically distressed persons probably raises the afferent signals to conscious awareness, thereby leading to enhanced perception of symptoms. Although peripheral sensitization may influence the onset and short-term continuation of pain, the CNS appears involved in the predisposition and perpetuation of pain, thereby leading to a more severe chronic pain condition. An altered balance of afferent signal input and a defect in central pain inhibition has a potential to result in a maladaptive central pain response, especially when exaggerated by a strong emotional responses to painful stimuli or psychosocial factors of significance. In a study by Ringel et al.21 combining pain ratings and functional magnetic resonance imaging (fMRI) examination in conjunction with rectal barostat distensions comparing patients with IBS and abuse with healthy controls, IBS without abuse history or abuse history without IBS, it was shown that pain ratings correlated with activation of dorsal cingulate regions. Moreover, the existence of an abuse history with IBS resulted in greater activation in these brain areas than in the control groups, this was further intensified and combined with a reduced activity in the ACC region involved in pain inhibition. From a clinical point of view, examples like this can be translated into a model where the more severe and constant pain situation more likely is predominantly centrally mediated and not only depending upon disease specific factors, but also psychosocial factors.

third-order neuron is located along one of three main routes of sensory transmission: The spinothalamic tract project to the primary somatosensory cortex and is of importance for sensory discrimination and localization of visceral and somatic stimuli. The spinoreticular tract conducts sensory information to the reticular formation of the brainstem, which is of importance for the emotional component of pain. Finally, the reticulothalamic tract projects from the reticular formation to the medial thalamus on the left, and further to the cingulate cortex and insula. The cingulate cortex is divided into components that include the perigenual anterior cingulate cortex, involved in affect and the midcingulate cortex involved in behavioral response modification. This multicomponent integration of nociceptive information, dispersed to the somatotypic-intensity area (lateral sensory cortex), or the insula for visceral input and to the emotional or motivational-affective area of the medial cortex, explains variability in the experience and reporting of pain (see Ref. [11,12] for review). When stimulating the peripheral input from the gut to the brain in order to measure sensory thresholds, e.g., by use of a barostat device, a proportion of patients with FGIDs qualify for the label visceral hypersensitivity (reporting an increased sensation of stimuli) or as having allodynia (reporting a stimuli as painful that previously was not). During a period of time, a lowered threshold for rectal pain was suggested as a reliable biologic marker of IBS,13 but the phenomenon cannot be the sole reason for the abdominal pain experienced in FGID as a proportion of the patients with IBS does not meet this criteria14–16 and the situation is similar in patients with FD when assessing gastric sensory function.3 On the contrary, there are studies showing that patients with the most severe symptoms of IBS have a trend for a higher sensory threshold for peripheral stimulation17 and visceral hypersensitivity does not seem to be a central pathophysiologic factor in FAPS either,18 one of the more difficult to treat FGIDs. Mechanisms other than upregulated visceral afferent signaling must be involved in the net effect of pain perception, particularly for more severe and long-standing abdominal pain. This suggests that the determinants for more severe or constant pain are more cephalad than the dorsal horn (central sensitization). Beginning at the gut level, sensitization of primary afferent pathways can occur in response to inflammation. An excellent clinical model for this and also for the importance of varying degrees of brain-gut axis disruption that may follow is postinfectious IBS(PI-

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CHRONIC ABDOMINAL PAIN AND NEURODEGENERATIVE PATHOLOGY In recent years, mounting evidence not only for an altered brain function but also for an altered brain structure in chronic pain has evolved. The ACC which originates the descending pain inhibitory pathway shows greater activation in IBS patients on fMRI relative to healthy controls.22 Furthermore, intriguing findings in studies analyzing regional gray-matter density in IBS indicate a reduced brain volume in brain areas of importance for pain modulation,23 also after controlling for anxiety and depression as covariates in the analysis.24 This finding is not exclusive for abdominal pain in conjunction with a FGID but has also been reported in fibromyalgia25 and various

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chronic pain situations of somatic origin.26,27 Thus, we could hypothesize that with a chronic pain condition the cingulate area of down-regulation, while initially more active may in time fatigue and lose neuronal density, thus presuming that there is neurodegeneration in this area. While this is yet to be confirmed, the hypothesis is compelling even if the data that links the observed signs of functional brain abnormalities to the local structural abnormalities visualized in the context of pain is still missing.

intensity may be initiated from certain predisposing factors (e.g., genetics, early family modeling or environmental exposures including infection and traumatic events such as abuse34) or the influence of the family on enabling pain behavior and health care seeking;35 then given the proper set of precipitating factors (e.g., acute infection, major stressors, medical illness, drug abuse, ongoing, or unresolved abuse34 and many others reviewed elsewhere36) the pain is expressed or intensifies. Finally the chronic illness state is maintained by perpetuating factors (e.g., psychological co-morbidities such as anxiety and depression, resultant cognitive responses including helplessness, vulnerability and low self esteem, maladaptive coping, and poor social support). From a conceptual point of view, and similar to a traumatic brain injury model, these stressful factors and exposures to medical illness and abuse lead to neuronal vulnerability and in areas such as the hippocampus are associated with suppression of neurogenesis, which can lead to the development of depression with an uncoupling of affect from context and impaired segregation of irrelevant stimuli from relevant ones37 (Fig. 2B). If intermittent abdominal pain is involved as a major stimulus during an uncoupling process, it may well be driving a central affective component resulting in the development of a chronic pain experience that no longer is linked to the initial trigger; rather pain persists and acquires an independent existence. It is likely that in addition to antidepressants other enriching processes such as physical exercise, psychological treatments, and even an effective patient-physician relationship might reverse this uncoupling process, leading to clinical improvement. This model not only provides an understanding of the benefit of central treatments in reducing chronic painful conditions via neurogenesis, but it legitimizes the physiological reality of these relationships rather than being considered ‘psychiatric’.

NEURON VULNERABILITY, BIOPSYCHOSOCIAL FACTORS, AND THE POTENTIAL ROLE OF ANTIDEPRESSANTS The regional reductions in gray-matter density associated with depression, severe psychological stress such as post-traumatic stress disorder and chronic pain syndromes28 would suggest that neuronal regeneration may be of benefit for initiating a clinical response.29,30 By the use of thymidine analogs injected into animals, neuron proliferation has been shown by their incorporation into neurons that also co-label with mature neuron markers indicating that they actually have the potential to regenerate, although in low rates.31 In studies from the treatment of major depressive disorders, it has been shown that neuron proliferation measured by serum levels of brain derived neurotrophic factor (BDNF) correlates with status of clinical response. BDNF levels are low in depressed patients and its levels are increased with antidepressive treatment where a better outcome is associated with higher BDNF levels.32 The lag phase lasting for some weeks before improvement occurs after starting pharmacologic treatment of depression fits well with the rise of BDNF levels in blood and the observed time that a ‘newborn’ neuron needs for maturation. From rat experiments, the effects on neurogenesis by antidepressants and its functional role can be better understood. Han et al. used a traumatic brain injury model to show a reduction in cognitive function associated with the brain cell loss. When treating a group of rats with a tricyclic antidepressant (TCA), imipramine, when compared to a group of rats not given the TCA there was greater post-traumatic neurogenesis and this was associated with greater improvement in cognitive function.33 The conceptual model for understanding the influence of biopsychosocial factors leading to the development of chronic pain and the associative role of neurodegeneration and neurogenesis are outlined in the combined Fig. 2A and B. In Fig. 2A, the development of chronic symptoms such as pain and its

APPROACH TO THE PATIENT A prerequisite for chronic pain treatment is to establish a good patient-provider relationship with the use of effective patient centered communication skills.38 This approach allows the clinician to address the expectations of the visit, the concerns of the patient, the relevant psychosocial factors contributing to the pain or its adaptation, and the key factors that precipitated the health care seeking. A simple way to organize the patient’s experience of pain is to construct it as in Fig. 2A, in terms of predisposing, precipitating, and perpetuating factors.

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A

B

Figure 2 (A and B) Conceptual model outlining the consecutive events of biopsychosocial factors interacting with the potential to trigger a situation of chronic abdominal pain. Along the time-line to chronicity, central factors involving neurodegeneration develops and peripheral factors become less important. Successful treatment involves a mechanism of neurogenesis that can be catalyzed by a number of treatment modalities, including the use of antidepressants.

methods to help develop an effective patient-provider relationship can be reviewed elsewhere.38

Often, stressors are not initially verbalized by the patient but should always be considered as they may be reported later as a sense of trust is established with the provider. Most important, perpetuating factors address why a condition persists when it might not in others. With chronic pain, changes and adaptations occur in the patient that can lead to feelings of helplessness, vulnerability, low self esteem, and psychological concomitants such as anxiety and depression. This keeps the patient in a vicious cycle where the symptom is seen as a threat to oneself and the ensuing emotional distress and sense of inability not to control the symptoms lowers symptom threshold even more leading to greater pain, and so it continues. These factors highlight the importance of involving the patient in the clinical management with continual reassurance of benefits to ensue, a partnership in the care that is presented as an ongoing one. It has been shown that such an approach where simple efforts to educate on diagnosis and management, and provide reassurance and continuity of care39 will diminish the need for excessive health care consumption.40 Further

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ANTIDEPRESSANTS General considerations Antidepressants are extensively used for the treatment of FGIDs with abdominal pain as the predominant symptom,8 and this is particularly well studied in IBS and FD. Based on observations presented herein, it seems reasonable that treatment is targeting central mechanisms of chronic abdominal pain especially when the pain is long-standing and of moderate to severe intensity. The rationale can be supported by a number of factors: (1) the frequent comorbidity with psychiatric disorders in FGIDs, especially anxiety41 which may require treatment, (2) the independent (from psychosocial disturbance) effects of antidepressants on improving pain regulation, driven by a descending inhibitory effect, (3) the combined effects of also treating psychological distress (which can

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37% of those who received placebo (number needed to treat = 5). Subgroup analyses showed a statistically significant benefit for selective serotonin reuptake inhibitors (SSRI) for improvement of global assessment and for TCAs for improvement of abdominal pain and symptom scores. The combined clinical and scientific experience together with our understanding of the complex mode of action with regard to pain regulation supports the use of antidepressants for chronic abdominal pain associated with the FGIDs. With this background, we will provide a brief overview of each class of drugs followed by some practical approaches to their use in certain clinical situations. A summary of important properties comparing TCAs, SSRIs, and serotoninnorepinephrine reuptake inhibitors (SNRIs) can be seen in Table 2.

amplify pain experience) in the situation of a severe FGID, unrelated to a co-morbid psychiatric disorder and (4) the effects of these agents in improving general well being, coping and adherence to psychological treatments if needed. Many of these indications are offlabel use, i.e., when the patient does not have an approved psychiatric indication justifying treatment. Even so, the wealth of scientific data now showing benefit for moderate to severe abdominal pain and the failure of treatments aimed at peripheral mechanisms of GI pain more than justify their use.10,42 With regard to mechanisms of action, preclinical data in acute pain models have shown decreased afferent nerve discharge in response to colorectal distension in a dose-dependent way without any differences among antidepressants with predominant serotonergic, noradrenergic, or non-specific monoaminergic effects.43 In human studies with more chronic pain, data suggest that the effects mainly stem from central modulatory mechanisms rather than effects on visceral hypersensitivity. The resulting decrease in sensory thresholds seems to relate more to an antidepressive effect44 or other central pain modulatory effects resulting in a decreased tendency to experience and report pain.45 The effect of antidepressants on GI physiology depends on the pharmacological class of drug, rather than the indication for antidepressant treatment. The anticholinergic properties of TCAs increases the gut transit time which makes them more useful in a diarrhea-predominant or at least a nonconstipated situation if an aberrant bowel habit coexists with the abdominal pain. By the same rationale, drugs with predominant effects on serotonergic activity decrease gut transit time and are to be preferred in the constipated patient.46 In the same manner, the pharmacologic side effects also need to be addressed for an optimized adherence to therapy before finally deciding upon which drug to choose. The receptor selectivity for the major classes of antidepressants drives both their positive and negative effects and is summarized in Table 1.

Tricyclic antidepressants Most doctors are familiar with the use of low-dose TCAs for the treatment of chronic pain and it is the most studied antidepressant class of drugs for this nonpsychiatric indication. Unlike the SSRIs and SNRIs, their mode of action involves mechanisms beyond serotonin and norepinephrine, like blockage of voltagegated ion channels, opioid receptor activation and also a possibility of neuroimmune anti-inflammatory effects.48 Their major drawback is the side effects related to anticholinergic and antihistaminic actions (drowsiness, xerostomia, palpitations) most pronounced when a tertiary amine (amitriptyline, imipramine) is used compared to the secondary amines (desipramine, nortritpyline). Aside from studies in FGIDs, patients with fibromyalgia also benefit from TCA treatment25 and peripheral neuropathy and other somatic pain states.49 Most often, low to modest dose regimens have been used which indicates that other mechanisms than the anxiolytic and antidepressive ones are in effect. The largest study so far, performed by Drossman and colleagues in 216 women with IBS, used a wider dose regimen though, escalating desipramine up to 150 mg/ day if tolerated.50 This study showed numerical but not statistically significant benefit from 12 weeks treatment in the intention-to-treat analysis for a composite symptom score and abdominal pain. This was primarily related to a 25% dropout rate mostly due to side effects. However, in the per protocol analysis of patients who stayed on treatment until the end of the study, there was significant benefit against placebo. Furthermore, in a subanalysis when benefit was assessed specifically for those patients with detectable

Evidence for the use of antidepressants in FGIDs Treatment trials of antidepressants where chronic abdominal pain is involved mainly emanate from studies of IBS, but some data also come from trials involving patients with FD. In a recent Cochrane analysis,47 a beneficial effect for antidepressants over placebo regarding improvement of IBS associated abdominal pain was seen. After combining data from 8 studies including 517 patients, 54% of patients treated with antidepressants improved compared to

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Table 1 Antidepressant receptor site effects

TCAs Amitriptyline Doxepine Desipramine Nortriptyline SSRIs Citalopram Escitalopram Fluoxetine Paroxetine Sertraline SNRIs Venlafaxine Duloxetine Milnacipran

Norepinephrine

Serotonin

Histamine

Acetylcholine

+++ ++ +++ +++

+++ +++ +++ +

++++ ++++ + ++

++++ ++ + ++

0 0 0 0 0

++++ ++++ ++++ ++++ ++++

0 0 0 0 0

0 0 0 0 0

++ +++ +++

++ +++ ++

0 0 0

0 0 0

TCA, Tricyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; SNRI, Serotonin-norepinephrine reuptake inhibitors. 0 -> ++++ = None -> Strong.

Table 2 Comparison between the major antidepressant drug classes in relation to their use in the treatment of abdominal pain TCA

SSRI

SNRI

Potential benefit

Pain reduction Depression

Pain reduction Depression

Side effects

Sedation, constipation, hypotension, xerostoma, arrhythmias, weight gain, sexual dysfunction Moderate

Depression, panic, anxiety (Pain reduction) Agitation, diarrhea, insomnia, night sweats, headache, weight loss, sexual dysfunction Minimal

Minimal

Not usual

Varies

Risk for overdose Dose adjustment

Yes

nent of FGID, but their use can be encouraged when anxiety, depression and phobic features are present. Treating these symptoms also comes with a good chance of an increased pain threshold as a secondary effect. Their side effect profile is also attractive with low frequency of symptoms like diarrhea, sexual dysfunction, tremor, insomnia, and nightmares, which can be beneficial in a situation of a patient experiencing a low threshold for negative effects particularly in the start-up phase of treatment. From a GI physiologic point of view, SSRIs in the form of citalopram has been shown to increase colonic contractility and reduce colonic tone during fasting conditions and reduce the colonic tone increase after meal ingestion.53 In IBS the same drug did decrease scores for abdominal pain and bloating independent of anxiety, depression and colonic sensorimotor function in a small crossover study involving 23 patients at a tertiary referral center.54 Improvements in overall well-being regardless of coexisting depression with paroxetine treatment in IBS patients55 and decreased abdominal discomfort in IBS-C patients treated with

desipramine plasma levels, there was an even greater and highly significant composite score response to desipramine with a NNT of 4.3 for satisfaction with the treatment. The more favorable response in patients without concomitant depression suggests that the beneficial effect observed in that study was not due to improvement of psychiatric comorbidity. In FD, a small study including 38 patients showed benefit with amitriptyline over placebo in improving total symptom score and nausea, and upper abdominal pain51 and a more recent multicenter study still only presented as an abstract also indicates a positive effect of treatment with amitriptyline in patients with ulcer-like dyspepsia (odds ratio 3.1 [95% CI 1.1–9.0] for adequate relief compared to SSRI or placebo) but not in dysmotility like dyspepsia.52 This supports the possible superiority of TCAs over SSRI’s for painful FGID disorders.

Selective serotonin reuptake inhibitors There are relatively few data supporting a role for SSRI treatment specifically for the abdominal pain compo-

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Nausea, agitation, dizziness, sleep disturbance, fatigue, liver dysfunction

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fluoxetine56 also lends support that subgroups of patients benefit from mechanisms other than the antidepressive and anxiolytic ones. Fluoxetine reduced abdominal pain scores in non-depressed IBS patients with rectal hypersensitivity57 in a small placebo controlled study. The SSRI’s, unlike the TCAs and SNRI’s (to be discussed below) do not have much noradrenergic effect and thus may theoretically be less beneficial for pain. However, concurrent treatment of anxiety or psychological distress may still lead to improvement particularly for global scores in patients with FGIDs.

Tetracyclic antidepressants Mirtazapine has complex effects resulting in an increased noradrenergic and serotonergic activity where the latter is dominated by a 5-HT1A, 5-HT2, and 5-HT3 activity.62 This helps explain multiple effects including for treatment of anorexia and nausea associated with weight loss. In animal studies it dosedependently reduce colonic hypersensitivity and improve gastric emptying at higher dosage.63 From aspects like these, pain-predominant FGIDs would be a putative indication. However, data from FGIDs are limited and only case-reports are present in IBS.64,65 More recently, a study in FD patients with weight loss without coexisting anxiety or depression, showed that mirtazapine 15 mg in the evening for 8 weeks was superior to placebo in improving overall symptom score, early satiation, nutrient tolerance, and weight recovery.66

Serotonin-norepinephrine reuptake inhibitors From a general point of view, considering the central roles of serotonin and norepinephrine in the descending modulatory nerve pathways, SNRIs seems like an ideal class of drugs to modulate pain sensation, particularly because of a favorable side effect profile. In the clinical setting, this is further underlined by duloxetine and milnacipran having formal approvals for treatment of chronic pain conditions and the latter is exclusively marketed as a pain medication in the United States. In a recent Cochrane review, duloxetine was found to have adequate evidence for the treatment of peripheral diabetic neuropathic pain, but also moderate quality evidence for its use in fibromyalgia,58 which is a common extraintestinal manifestation in the generalized pain situation seen in severe FGIDs. There are also some data to support their role as having dual treatment effects in patients suffering from both depression and at least moderate pain of unknown etiology.59 When it comes to GI function, SNRIs exemplified by venlafaxine has been shown to increase compliance, relax tone and reduce the postprandial colonic contraction and having a tendency for increasing the sensory thresholds in response to balloon distensions.53 In pain-predominant FGIDs, SNRIs have the advantage compared to TCAs of lacking anticholinergic and antihistaminic side effects, which most often mean that they are better tolerated. Even so, there might be an issue when it comes to the adherence to treatment in the studies involving FGID patients because of side effects like nausea, palpitations, sweating, sleeping disorders, dizziness and visual impairment.60,61 Comparing the different SNRIs, venlafaxine could be more prone to a side effect problem when treating pain. In the lower dose range, the serotonergic effects dominate and its dosage needs to be escalated to 150– 225 mg/day in order to reach a norepinephrine effect sufficient for pain modulation.

AUGMENTATION TREATMENT In patients where monotherapy with TCAs, SNRIs, or SSRIs targeting pain is not effective or cannot be tolerated due to side effects, augmentation therapy can be considered. This concept refers to the use of treatment combinations involving multiple drugs, or a combination of psychological treatment like psychotherapy or relaxation techniques with one or more drugs. For this article, only drug combinations will be considered. The dose of individual pharmacological agents when combined can be lower compared to when used individually, and the goal is to achieve synergistic treatment effects and improved tolerance associated with fewer side effects. In the ideal situation, different receptors should be addressed by the drug combination, but even so the awareness of negative synergistic effects should be emphasized where the serotonin syndrome (hyperreflexia, spontaneous clonus, muscle rigidity and fever) is of concern. Only physicians with training in the use of augmentation treatment should prescribe these combinations. Most often, rational decisions based on clinical features can motivate which combinations to address. Buspirone can be considered in the common situation of patients having abdominal pain associated with anxiety and not responding to antidepressant therapy alone. Busprieone has 5-HT1 agonistic effects in the GI tract and can be used as a non-benzodiazepine anxiolytic on its own. Buspirone can also be considered in patients with FD (e.g., Postprandial distress syndrome) because this treatment has been shown to reduce the impaired

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number of patients with severe FGIDs should be considered. When given in this relatively low dose (25–100 mg) at bedtime to patients who did not respond after 4 weeks to a TCA or SNRI, the treatment was found to be beneficial in terms of global relief of FGID symptoms in a majority of those who tolerated it in a retrospective open-label study.77

gastric compliance and accommodation seen with this disorder.67 For patients with moderate to severe abdominal pain and/or dyspeptic symptoms treatment with 15–30 mg of buspirone bid can be considered. Adding pregabalin or gabapentin to other paindirected central-acting agents is supported by basic and clinical data showing reduced visceral hypersensitivity.68–70 Originally intended as an anticonvulsant, most clinical use of these agents have been for the treatment of neuropathic pain but also for pain associated with fibromyalgia. By binding to the a2d site, a subunit of the voltage-gated calcium channels, pregabalin modulates the release of excitatory neurotransmitters involved in nociception such as norepinephrine, substance P, glutamate, and calcitonin gene-related peptide. In a recent study by Harris et al. combining data from three different brain-imaging techniques in chronic pain patients diagnosed with fibromyalgia, the central effects of pregabalin was studied. The result suggests that the analgesic effects of pregabalin have a central component involving reductions in brain insula glutamate levels.71 Studies in FGIDs are largely lacking, but its clinical use in certain situations like when a general anxiety disorder or fibromyalgia/abdominal wall pain coexist is reasonable in a dosage between 150 and 600 mg/day where treatment effects should be expected within a month in order to continue therapy. There is also some experience from the use of the atypical antipsychotic quetiapine outside of its primary indications to treat schizophrenia, major depression, and bipolar disorder. This compound has a complex mechanism of action including weak D2 receptor antagonism and 5-HT2A receptor antagonism, partial 5-HT1A receptor antagonism, H1 receptor antagonism, and moderate to high affinity for a1- and a2- adrenoceptors.72 Its main metabolite also has effects as a noradrenaline transporter inhibitor.73 Potential clinical benefits include an analgesic effect, anxiety reduction, and establishment of normal sleep patterns,74 all of which are associated with and worsen FGID symptoms including pain. Most data stems from the treatment of fibromyalgia where recently a controlled study reported effects superior to placebo on the paindomains,75 but with effects inferior to duloxetine in yet another recent study.76 A major drawback is poor tolerability with a high proportion of patients experiencing sedation, dizziness and weight gain leading to discontinuation of treatment when used in the higher dose ranges of 100–300 mg/day. However, the use of quetiapine in lower doses (25–100 mg/day) as an augmentation therapy when antidepressants have failed or are only partially effective in a selected

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SOME EXAMPLES OF PSYCHOTROPIC MEDICATION USE IN CHRONIC ABDOMINAL PAIN IBS-D with co-morbid anxiety This 24-year-old female patient was seen by her GP 1 year ago because of significant anxiety and agoraphobia. SSRI treatment was initiated and she had a good response in reducing psychological symptoms. More recently, she developed IBS-D and is most troubled by the abdominal pain. She is not interested in stopping her SSRI treatment because of its psychological benefit. Treatment suggestion Add low dose (10–50 mg/day) TCA. This may reduce the abdominal pain and the dosage is low enough not to lead to adverse serotonergic consequences such as a serotonin syndrome. Furthermore, the diarrhea might respond due to the anticholinergic effects of TCA treatment.

Severe abdominal pain with nausea A 50-year-old male with a long history of intermittent ‘gastritis’ gradually developed chronic abdominal pain. Extensive diagnostic studies were negative. He was seen by a gastroenterologist who diagnosed FAPS and he started the patient on duloxetine 60 mg q.d. with an acceptable response. Now 1 year later, he reports lowgrade nausea without any relation to food intake. Treatment suggestion Duloxetine may be contributing to the nausea, and a dosage reduction could be considered. Alternatively, one could augment the current treatment by adding 15–30 mg mirtazepine q.d. to reduce the nausea.

Abdominal pain non-responsive to TCA or SNRI treatment A 35-year-old female is diagnosed with FAPS. She was initially treated with low-dose amitriptyline without a good response and with troublesome side effects. duloxetine was prescribed but the benefit was not optimal. She reported that her abdomen felt sore, like a muscle

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H. T€ ornblom and D. A. Drossman

Neurogastroenterology and Motility

cal comorbidity, and environmental triggers in combination with perpetuating factors play a major role in understanding why patients develop chronic pain and why it continues. The pain can be present even without peripheral input due to central dysregulation of pain modulatory pathways, more so than visceral hypersensitivity and this concept is shared with many other chronic pain syndromes. Chronic pain associated with psychosocial co-morbidities is associated and likely contributes to structural neurodegenerative changes visualized by advanced brain-imaging techniques, and becomes the central mechanisms in the experience of constant abdominal pain. Thus, peripheral analgesics no longer can reverse the vicious cycle of increasing pain, decreasing quality of life and impaired social function. Furthermore, the wrongful use of opioid analgesics might exacerbate the pain experienced aside from inhibiting normal GI function. Psychotropic medications can reduce the pain experience both by effects on afferent signaling, improved central pain inhibition, central neuroproliferative effects, and by treating concomitant anxiety or depression. Antidepressants, particularly TCAs and SNRIs, have pain-modulating effects beyond their psychiatric indications. The majority of antidepressants also have the potential to reverse a neurodegenerative component of chronic pain by inducing neuroproliferation, ‘rebuilding’ an inappropriately remodeled brain. Their careful use in combination with supportive non-pharmacologic treatment efforts definitely should have a central role in those patients having chronic abdominal pain of moderate or severe intensity. Side effects might be a limiting factor in some instances, but combinations of medications as suggested by us can reduce the doses needed, while at the same time augmenting the therapeutic result comparing each drug individually. There is a need for high-quality research to strengthen the evidence for central-acting agents in GI therapy. Even so, by educating doctors to use these drugs in FGIDs with pain as a predominant complaint, we already now have the knowledge to form the basis for an improved outcome in a large group of patients that do not receive pharmacologic treatment according to best practice.

ache and on examination had a positive Carnett’s test suggesting an abdominal wall component to her pain. Treatment suggestion Pregabalin was added and titrated to 300 mg/day after 2 months. The muscular component decreased to an acceptable level.

Abdominal pain responsive to duloxetine 90 mg but in combination with poor sleep Fifty-five-year-old woman diagnosed with IBS-C. Her constipation is treated with a bulking agent and after adding duloxetin, the abdominal pain was partially relieved. In addition, she reports sleep disturbance and she is reluctant to use benzodiazepine or other sedative hypnotics because of a dependency to these types of medications earlier in her life. Treatment suggestion In this situation quetiapine can be used to augment the pain benefit and improve sleep. An initial dose of 25 mg at night was increased to 50 mg after 4 weeks and this restored her sleeping pattern while also reducing the abdominal pain as well.

IBS-C with insufficient benefit from peripheral agents Forty-eight–year-old woman reports a lifelong history of constipation and associated abdominal pain. Bulking agents and laxatives have helped her bowel habits to become tolerable, but have not helped the abdominal pain. Six months, ago she was started on linaclotide 290 lg q.d. that initially helped the constipation and pain. However, in the last 2 months the abdominal pain has gradually returned. Treatment suggestion The peripheral analgesic effect initially experienced by the use of linaclotide was not sufficient in this patient with long-standing pain. After discussing the rationale, duloxetine 30 mg was started to add a central-acting agent. An initial period of nausea was experienced, but with reassurance of its possibility of being a temporary side effect, treatment was continued and has resulted in a good pain control 3 months later after a dose increase to 60 mg.

FUNDING CONCLUSIONS

No funding declared.

Our understanding of chronic abdominal pain results from a complex relationship between peripheral and central neurologic communication and as such will effect pharmacologic therapeutic decisions. Individual factors like genetics, previous life events, psychologi-

DISCLOSURE Hans T€ ornblom none of relevance. Douglas Drossman none of relevance.

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© 2015 John Wiley & Sons Ltd

Centrally targeted pharmacotherapy

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Centrally targeted pharmacotherapy for chronic abdominal pain.

Chronic abdominal pain in the context of the functional gastrointestinal disorders departs from a more traditional approach to treating gastrointestin...
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